BeOne Medicines Aktie

All right. Thank you, everyone, for joining this session. My name is Linhai Zhao, I'm the China biotech analyst.

Today, with great privilege, we have the opportunity to host the management from BeOne Medicines. On the farther right of the stage, we have Aaron Rosenberg, the CFO; and Mark Lanasa, the CMO, joining this fireside chat. So welcome.

And I think BeOne Medicines has shown very exciting data at ASCO this year and investors have been highly anticipating some exciting news from our solid tumor pipeline. Besides that, we have done extremely well for our hematology pipeline. BRUKINSA is by far the #1 BTK inhibitor globally, and we are continuing to see exciting clinical progress from our BCL-2 inhibitors and the BTK degraders.

So I think the first question, I think would be about our clinical strategy. You've taken a very disciplined, data-driven approach to prioritizing the pipeline with the 5 highlighted cornerstone programs for solid tumor, as well as a few deprioritized programs that you shared at the quarterly results. What is the go versus no-go bar for the clinical data? What is your vision on the solid tumor franchise over the next 5 years?

Thank you, Linhai, and thank you very much for having us present this morning.

So yes, we have brought a lot of molecules into the clinic, and it is our aspiration to bring additional internally discovered as well as some partnered molecules into the clinic. Through this, we have been very disciplined in our early phase approach. We think that this is critically important in allowing us to progress a large portfolio as a midsized organization.

So put simply, when a molecule is coming to the clinic, the teams are asked, what would a differentiated medicine look like for the target patient population in development? And that is something that is expected of the teams at the time of the first-in-human study. And by understanding what a differentiated medicine would look like, we're able to establish clear go/no-go criteria.

If the programs are meeting those criteria, then, great, we'll look to expand those programs. And we've highlighted 5 programs that have met those criteria and are on track to a Phase III study start. We highlighted 3 of them at the recent ASCO.

But we also announced that there were other programs that we have stopped because they weren't meeting those criteria. And these include some programs that we had previously highlighted based upon previously -- based on very strong preclinical data. So we think that that disciplined approach is really critically important to be able to progress and prioritize a broad pipeline of innovative molecules.

Yes. Can you be a little bit more particular? Preferred would be with examples. I know that differentiation or differentiated medicine can look very differently, or we have very different requirements when we are talking about different indications or different molecules.

So ultimately, it comes down to what is the target population for development. Since we recently disclosed some data, I can make a few examples.

So for example, for CDK4, what we were excited about with that molecule is really strong efficacy data with a response rate of approximately 70% across 2 different cohorts. We feel that that's clearly differentiated from what the CDK4/6 molecules deliver at a range of, say, 50% to 55% in a frontline patient population. So that hits our go criteria in combination with favorable PK and safety and whatnot. And then for GPC3, where our target patient population was hepatocellular carcinoma, there the molecule exceeded our go criteria with a response rate of 30% and a very clean safety profile.

So for both of those molecules, we have confidence that they not only deserve to go to Phase III, but can eventually be impactful medicines. We'll have a similar conversation about PRMT5 in the second half of the year. And again, we're applying that same lens to all of the molecules that we bring into the clinic, our KAT6A/B that we started in last December, again, what does a differentiated molecule look like in later-line breast cancer?

Yes. I think we're all very excited about the ASCO readout, but we can definitely discuss deeper about that later. I want to briefly touch about our pipeline or the clinical pipeline targets. We mentioned of the target to deliver 8 to 10 NMEs per year. How do you maintain the speed without sacrificing quality in clinical decision-making? And more particularly, with China being increasingly recognized as an innovation source, how would you describe BeOne's strategy to leverage China innovation given that we are targeting to deliver this amount of NMEs per year?

I can start. So what's really important to understand is that our internally delivered development work is global by its nature, that we are the leading sponsor of early-phase research in Australia, we're the leading sponsor of early-phase research in South Korea. And therefore, we're not only moving quickly, but we're moving quickly globally.

And this enables us to generate data that again enables us to have those go/no-go criteria. But also by having global patient data, we can have confidence that the data does not have significant determinations based upon ethnicity or region, and that it will meet the needs of global regulatory agencies.

We recognize that there are a lot of exciting molecules that are emerging from China as well as other global regions. Our BD approach is fundamentally global. But what we look at, again, our development model by being global in its nature, we think that that has substantial advantages over other, shall we say, regional models.

Yes. I think that's really well said. And given our global footprint, we're able to identify and seek opportunities for business development in all the geographies in which we operate. We've done excellent investments in business development with innovation that's been sourced from China. Our B7-H4 is an example of that. We recently announced a very interesting deal in the IO space for a trispecific with a company called HH Bio that emanated out of China. But we've done deals globally as well in all the geographies.

So ultimately, our clinical development organization is global first. And that puts us in a really strong position relative to competition to really deliver quality with speed to ensure that these innovations get to patients as fast as possible.

Yes. One quick follow-up on that I think is worth saying, part of BeOne's highlight on the clinical execution, and I think in more recent presentations, BeOne has been highlighting what they call the global development superhighway, right? How should we understand this competitive edge compared to other global pharmaceutical companies, especially that we are seeing more global MNCs, they are getting deals with China biopharmas that include early-stage integrations, which the biopharma -- the China biopharma companies could also be very quick in terms of getting the clinical proof-of-concept data?

Yes. So I recognize the importance and the intent of the question. Again, what I would highlight really is the global nature of our development organization. So it's important to understand that we have fully internal development capabilities across clinical development and clinical operations, statistics, regulatory and so on. But we also have in-house manufacturing, and we run our studies globally.

So yes, there may be some molecules that are able to generate limited data sets within a specific region. But when those molecules are partnered, there's always a certain amount of work that goes into the transition to the partner. And then often there will have to be a duplication of earlier data sets to ensure the generalizability of those data sets. So any speed that might have been captured through a single-region approach is then lost through the process of re-globalization.

For our CDK4 molecule, we went from the global-first patient dosed to our global-first Phase III patient dosed in only 30 months. We believe we're going to replicate that for B7-H4. Our GPC3x4-1BB will be shorter than that. So we really believe that we're industry-leading in speed, not only from Phase I to Phase III, but then also from readout to submission and so on.

Sure. And I want to briefly touch on our most recent earnings performance. I think it's another beat, strong quarter, and we also raised our full year '26 guidance. If we're looking a little bit more in detail, we can see that for the full year '26 guidance, for the EBIT level, was upgraded from $750 million to $850 million for the full year. And if we consider that in 1Q, the EBIT level was $250 million, that is more than 1/4 of the full year guidance. How should we understand the numbers here? And particularly, does the guidance leave room for higher R&D spending for the rest of the 3 quarters? And how do you balance that spending in both selling, R&D while maintaining the continuous operating leverage?

That's great, and thanks for the question. I think we've talked for a long time about our intent to run the business both as a growth organization, but also as one that does it so in a sustainable way. And sustainability is ultimately translating that growth to margin expansion, and ultimately and most importantly, free cash generation.

And I think you see those kinetics in action in our Q1 results. We feel very comfortable with the current year, that enabled us to raise, as you said, our guidance on revenue by $100 million the range, to $6.3 billion to $6.5 billion on the top line. And that translated to a bottom line improvement of $50 million across the range, to $800 million to $850 million on a GAAP operating income basis.

As you said, Q1 was quite strong in terms of its income generation. We did affirm our OpEx guide for the year. And I think that reflects our continued investment in our core capital allocation priorities. That's continuing to drive and invest in our commercial businesses that are driving profitable growth and as well as our clinical opportunities. And you saw the great data at ASCO. I'm sure we'll spend some time talking about that, as Mark alluded to earlier. And obviously, that was investment that we've contemplated in our full year guide in terms of OpEx, and that's what translates to the guidance that we updated with our Q1 results.

Sure. And I think if we talk about the earnings, we -- one thing that we have to talk about is BRUKINSA. And especially, we're talking about BRUKINSA is entering -- is already becoming the global #1, right? It's capturing more than 35% shares globally. And a natural question is, what is the room for growth further? And specifically, we've seen that for the EU part, it currently accounts for roughly 1/4 of U.S. sales. How do you see the potential in the EU market versus the U.S. market?

We're very pleased with the performance for BRUKINSA. Globally, as you said, BRUKINSA became the #1 BTKI. That eclipsed the curve toward the second half of 2025 globally; we had done so earlier in the United States. And that's really behind strong performance in all the geographies in which we operate.

We've talked historically, you were touching a bit on geographic mix, we've talked historically that our European business as an example was a little later in its launch trajectory than the United States. And important, rest of world markets are even earlier than that in terms of their launch trajectory. And you see that in the results where the United States grew in the mid-30% range, high 20s on a volume basis. Our European BRUKINSA was more like 60%. There's some FX in there, but still very strong demand-generated growth. And our rest of world markets doubled in Q1. So I think that reflects the launch life cycle of the brand.

So we do see continued opportunity in all of our geographies to continue to drive demand through new patient share. And of course, the geographies that are a little earlier in their life cycle have higher growth rates.

As we get bigger, obviously, growth rates in their percentage terms, those will naturally come down. But we continue to drive new patient starts driven behind the differentiated clinical data for BRUKINSA. At ASCO, we shared another update to our SEQUOIA data, going to [ 6.5 ] -- that unprecedented PFS at 72% over that time period. And really that's noncomparable as you look at the other medicines in the class in terms of its absolute PFS over that long of a time period. And ultimately, that's what's translating to utilization in the marketplace.

Sure. I do want to have one question specifically for sonrotoclax because we are seeing recently the good news from this drug, approved in China followed by approved in U.S. We have seen very strong conviction on this drug with -- in terms of both better tolerability and extremely encouraging high and durable and deep responses. How do you see like the early product launch? Especially, how do we see the -- how do we expect to get this drug in terms of the near-term launch? And based on the China performances or the China observations, what has been the early physician feedback on this drug?

So maybe I'll start. So my understanding from Amit, our CMO for Hematology, is that the prescriber feedback in China has been very positive, both in terms of efficacy as measured by MRD rates as well as the safety profile and the tolerability by patients, compared to what prescribers have experienced with other molecules in the class.

That said, I would say that this is similar to the feedback we've received on the development side, the CELESTIAL-301 study, our fixed-duration therapy in frontline CLL, the investigators who have been using sonrotoclax in the investigational studies are also providing positive feedback on their experience. So we're very excited about the potential for our novel BCL-2 inhibitor.

And then with BEQALZI, our brand name, obviously, the first indication that's been approved in the United States within the relapsed/refractory MCL setting. And that's a pretty narrow indication. We're very excited to get this differentiated medicine in the hands of prescribers and patients. There's significant unmet need in this relapsed/refractory MCL setting, and it's a great opportunity to gain experience.

Obviously, the larger opportunity that you referenced is with our zanubrutinib plus sonrotoclax fixed-dose combination in the frontline in CLL. That CELESTIAL-301 study is fully enrolled. Obviously, the data will have to play out.

So in the short term, we've talked about the opportunity being fairly immaterial in the very short run. Obviously, as we continue to get this in the marketplace, we'll serve those patients in the relapsed/refractory MCL setting, and look forward to the larger market opportunity. And as you said, we're really encouraged by the data as you think about a fixed-dose combination, the potential to have the kind of deep, durable responses that this combination could bring, with what we hope is efficacy and a safety profile that's comparable to continuous-use BRUKINSA. Time will tell, right, across all -- as BRUKINSA has generated such a robust data set in the short, medium and long term.

And ultimately, as you think about BRUKINSA, the differentiation in terms of efficacy in that SEQUOIA data that I mentioned, we had a really nice chart on this in our Q1 results, is really from that year 3 to year 6 time period, where you really see BRUKINSA standing with significant and durable PFS across that time period. And when you look at the other in-class competition as well as existing then base fixed-dose treatments, that's typically where you see the drop-off.

So we're really encouraged about our fixed-dose combination. Look forward to bringing the initial data set, and we hope it will be an important solution for patients. In the meantime, BRUKINSA has demonstrated significant durability, and really unprecedented durability and it's serving patients today.

Cool. And switching gears to our ASCO data. The CDK4 inhibitors, I think there are a lot of excitement about the early ORR. And we've also seen a very dose-dependent way of safety, tolerability. Can you talk a little bit more about dose selection? You chose 400 mg over 240 mg for the dosage. And how would you expect the ORR with mature follow-up? I'm aware that for the CDK4 inhibitors, the longer the maturity, you're actually going to see an increase in ORR. How do you want to comment on maturity data?

For CDK4, the maturity of the data that we presented at ASCO, the median time of follow-up or the median time on treatment was approximately 9 months. Interestingly, we do observe late emerging responses. We had 2 patients that were relatively recently detected unconfirmed responses. So these were late emerging responses.

Now that said, I wouldn't want to create a notion that we think our response rate is going to continue to climb and climb and climb from there. We're really pleased with what we have seen in terms of the response rate. And as I mentioned before, we think that it is differentiated from what one would expect from the CDK4/6 inhibitors. And that gives us confidence to move into our Phase III study.

Yes. I do want to make sure that we talk about the tolerability profile. And we're talking about the CDK4/6 versus CDK4. I think naturally, there is a trade-off between the heme toxicity versus the GI toxicity. Based on our communication with physicians, how should we think about this potential trade-off with the CDK4/6 selectivity? And particularly, what is the bar for GI toxicity to be considered as accessible based on physicians' feedback? And can you share a bit more on the mitigation tactics that we have explored for the GI tox?

Great. Again, thank you for the question. There's really 2 components there. The first relates to the heme tox safety profile. So with CDK4/6 inhibitors, it turns out that the majority of the hematologic toxicity is driven by CDK6 inhibition. And indeed, that was the core hypothesis of the molecule. By having greater 4 versus 6 selectivity, that we could drive deeper and more sustained inhibition of CDK4, which drives antitumor efficacy. That is now reflected in the high response rate, while mitigating the associated hematologic toxicity.

At the investor event that we had at ASCO, I shared our selectivity data. And indeed, we have the most selective 4-versus-6 inhibitor, with approximately 35-fold 4-versus-6 selectivity in a preclinical cellular assay. That has pulled through, in our view, based on mechanism to an unprecedented heme tolerability profile, that across 240 and 400 milligrams we only had a single Grade 3 event and no Grade 3 heme tox events at 400 milligrams.

We have had the feedback sometimes that patients don't experience hematologic toxicity. But the reality is that heme tox is the leading cause of dose reductions for the 4/6 inhibitors, and therefore, they are important. I also tried to make the point that heme tox also prohibits some combinations, and we think that there are a whole group of combinations that are available to us through having this more favorable safety profile.

Now in terms of the patient experience, the GI tolerability is also very important. What we shared in our poster was that in the fasted state, our rate of any-grade diarrhea approached 90%, and we had perhaps a 10% rate of Grade 2/Grade 3 events. However, in a small cohort of patients who had co-administration of food, that that event rate dropped substantially to 50%. And importantly, all of those events were Grade 1.

The feedback we had from investigators is that Grade 1 diarrhea is essentially very manageable. There are many successful medicines that have a moderate rate of Grade 1 diarrhea. And that's straightforward for most oncologists to manage in their daily practice. So we're very pleased to mitigate those Grade 2/Grade 3 events, which are the events that tend to lead to discontinuation -- I apologize, so your last question [Technical Difficulty] dose selection. But suffice to say, when we look at the cohorts of 240 mg and 400 mg, the response rates were quite similar. But when we do our more detailed exposure response analysis where we look at not just the dose level but actually drug exposure, we found that the 400 mg optimized our characteristics, both in terms of efficacy and safety.

We have confidence given the favorable efficacy and safety profile, that for those patients who do require a dose reduction, that they will be reducing to a very efficacious dose, if they do require dose reduction in the Phase III study.

And importantly, the study is now active. We have taken that 400 mg dose selection to global regulatory authorities who have essentially endorsed that choice, and agree that 400 mg is an appropriate dose to take into a registrational study.

Yes. That's very important to know, especially with, frankly, a lot of feedback saying that currently the regulators, they prefer like lower dosage versus higher dosage if the higher dosage doesn't show meaningful improvement.

We're absolutely aligned with the feedback of FDA's Project Optimus to move towards the lowest efficacious dose, right? We think that it's really important in terms of the overall patient experience. We and others absolutely focus, and we focus our discussion primarily on efficacy. But when you look at what constitutes a successful medicine, the patient experience vis-a-vis tolerability is also extremely important.

Yes. So a little brief follow-up on the mitigations. You mentioned the co-administration with food can effectively mitigate the GI toxicity. How are we integrating that into our Phase III protocols?

So the Phase III will require that patients take the drug with food. There's a couple-of-hour window and there's many medicines [Technical Difficulty] -- not, shall we say, problematic or burdensome to the patient [Technical Difficulty] -- a significant improvement in tolerability, medical management of low-grade diarrhea is quite straightforward, using antidiarrheals.

And that said, we continue to look to mitigate this further with, for example, in the Phase I study, we're now enrolling a cohort that's going to take primary prophylaxis with antidiarrheals and understand that impact. That's something that we can look to integrate into the protocol if need be. Again, we're very comfortable with where we are, understanding that it's a small cohort and we'll be enrolling more patients to give us greater confidence in that initial observation.

Yes. Great. And for the GPC3, you mentioned that it's kind of reached beyond your -- way beyond the go versus no-go bar. And we've seen that this molecule was not highlighted as much as the other programs previously, but it was brought up more recently highlighting the very encouraging clinical profile where we see that the Phase I data at ASCO showed very nicely controlled safety profile overall, with only single-digit percentage of Grade 3 TRAEs. And more particularly, for 4-1BB related liver toxicities, we've also seen very nice control. So what is the plan for the registrational trials in both the first line and second line plus?

Yes. And we're extremely excited about our GPC3x4-1BB, is where we have increasing confidence -- I have increasing confidence that this will be a clinically breakthrough molecule for patients with hepatocellular carcinoma. For context, at ASCO, the EMBRAVE-251 study was presented. In that study, the current standard of care, the control arm, delivered a response rate of 5%. And what we just demonstrated was that our molecule has a response rate of 30%. And importantly, it delivers a response rate of 30% actually with a better safety profile than the currently available TKIs. So we think that this is really potentially a big step forward.

There are other GPC3-targeting mechanisms such as CAR T cells or ADCs, but this is a patient population that tends to have substantial comorbidities related to liver cirrhosis. And frankly, those modalities are not well tolerated. So we really think that we are uniquely positioned in this later-line setting with a very safe and efficacious molecule. We intend to have development as monotherapy in a later-line setting.

We received a question at the ASCO investor event, "Well, what about a combination with TKI?"" We're considering that, but then we would be giving up this favorable safety profile that we have. But we also have already initiated a combination with tislelizumab, our PD-1, along with bevacizumab, to give us line of sight to a frontline opportunity as well as ultimately also early-stage, for intermediate-stage patients as well. Those cohorts are just now starting to enroll, but we're off to a good start. And we're very optimistic about not only the late-line registration opportunity, but the earlier lines as well.

Curious about the drug design for this bispecific. We've seen other 4-1BB-based bispecifics. I think a common tactic is to have differentiated binding affinity between the 4-1BB versus the other target, usually having a lower affinity for 4-1BB just to achieve conditional binding. So what is our strategy for this molecule?

Yes. The idea is similar overall, that we wanted to have conditional T cell activation really in the tumor microenvironment, not to have broad T cell activation. So indeed, the idea is that, first, what happens is through the high-affinity GPC3 anchor, that it gets anchored in the molecule and then you get local T cell activation.

It's important to highlight there are other features. We have a unique 4-1BB binder. We have made modifications to the constant chain to improve the half-life of the molecule. And we're very excited about the data. We're very excited about the platform. So you all can expect to see other tumor-associated antigen by 4-1BB targeting bispecifics coming forward for us, because we think that this might be an important platform technology where we can again improve responses with a favorable safety profile.

Sure. And you mentioned about the trispecific antibody. And I think there's no doubt that Lai seems to be very excited about that. And we've noticed that BeOne Medicines, we are a kind of a pioneer in the PD-1, obviously, has been an extremely commercially successful product. But if we came to the PD-1/VEGF field, this recent collaboration is really like the first milestone event for BeOne Medicines to enter PD-L1xVEGF. And we have the option to license this trispecific.

We know that the Phase I trial has recently been initiated. Can you share what are you looking at in this Phase I trial in order to [ create the option ]? And what is your view on the overall survival benefit that we've seen from the ivonescimab, and to share your perspective on what is our general plan for this trispecific?

Yes. I think to start at the end of your question, we recognize the data that was recently presented at ASCO for ivonescimab. HARMONi-6 study is a positive study with overall survival benefit.

Our view was twofold. So one is that it is now a highly competitive space, the PD-1 or PD-L1xVEGF. We didn't want to enter late and end up with an undifferentiated molecule. We view CTLA-4 as a mechanism that has tended to have a positive effect on overall survival. So we saw the trispecific as an opportunity to provide additional benefit with, hopefully, greater weight towards overall survival.

The preclinical data, again, was very strong. This was an IND-ready molecule. The clinical trial applications are now submitted and we anticipate to have the first patient dosed this month. Again, it's a Phase I molecule where we will have clear go/no-go criteria, and we'll be excited to see how those data unfold.

And I think just to add, I think this shows 3 elements of strategy in one deal. I think first, as Mark said, BeOne is not going to chase the seventh, eighth, ninth asset in a crowded space that doesn't support our mission, it doesn't support patients, just to have a me-too medicine. I think it highlights our business development efforts to identify interesting science and to deploy our capital in a smart and efficient way to test the hypothesis embedded in that science.

And finally, I think it showcases our global development superhighway capability where we will be able to take that potential medicine, explore, test the scientific hypothesis. And to the extent it hits, we'll move super fast. To the extent it doesn't, that's why we have a prioritization criteria.

Great. One last question. I do want to touch on our lung cancer strategy. I believe that our last significant trial in lung cancer was dated back to the trigine portfolio. And with discontinuation of EGFR CDAC program, what is the current strategy for lung cancer? We talk about the trispecifics and we have plenty of other great candidates. We have the bispecific ADCs or even trispecific ADCs that could be potentially targeting lung cancer. So just can you share a little bit more about the thoughts in lung cancer?

Yes. So we are strongly committed to lung cancer. You will see more innovative molecules from us entering the lung cancer space.

When you look at our portfolio to date, what you see are a group of molecules that capture the biologic heterogeneity of lung cancer. So we're not focused on any one target, but rather bringing benefit to multiple patient segments. We have high conviction in our PRMT5 inhibitor. We'll have our first disclosure for that molecule in the second half of the year. We're excited about our EGFR-MET-MET trispecific biologic, which is progressing well. And again, multiple other therapies, multiple ADCs in testing in lung cancer as well.

Cool. I think with that, we've reached the time. And again, thank you all for the time, especially, Mark, for the very insightful conversation. We're really looking forward to hear more updates about BeOne, particularly from the solid tumor pipeline. Thank you so much.

Thank you.

Hello, everyone. Welcome to our 2026 investor event at ASCO. My name is Liza Heapes, and I'm the Senior Director of Investor Relations at BeOne Medicines. We are very excited to host this event, both in person in Chicago and online for our global attendees. Thank you all very much for joining us. This is truly an exciting time at BeOne, and we are thrilled to walk you through our program.

Before we begin, a bit of housekeeping. I would like to remind all participants that during this presentation, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements. You can find more details in our filings with the SEC, Hong Kong Stock Exchange and Shanghai Stock Exchange.

I'm delighted that joining us to present today are John Oyler, our Co-Founder, Chairman and CEO; Dr. Lai Wang, President and Global Head of R&D; Dr. Mark Lanasa, Chief Medical Officer for Solid Tumors, who will emcee the section with our esteemed KOL guests, give program overviews and development opportunities; Dr. Shom Goel, who came in from Peter Mac in Australia to share the latest on our CDK4i clinical development data that were presented earlier today. Mark will then run us through highlights from tomorrow's Mini-Oral on our B7-H4 program; and Dr. Hong Jae Chon, joining us from CHA University in South Korea, will share data from tomorrow's Mini-Oral on our GPC3 x 4-1BB before turning it back to Mark. At the conclusion of the slide presentation, our speakers will come up for Q&A.

Now please let's welcome John Oyler, Co-Founder, Chairman and CEO.

Thanks so much, Liza. It's great to be here. I get to turn the page. So welcome. I really want to thank everyone for coming to Chicago and those of you that are joining us online. We certainly know how busy ASCO is in this time of year. And we appreciate you spending time with us and the continued partnership that you have in helping us work as one together to fight against cancer. I think that ASCO is always a defining moment of the year in oncology. And for this year, it's really an opportunity for us to step back and to show you something important about our company. It's the next phase of BeOne Medicines growth.

Today is deliberately focused on work beyond hematology. If you haven't noticed, I'm very passionate and excited about the incredible hematology franchise that we've built. And sometimes, people think I'm so excited about it that I don't understand and appreciate everything that's happening in our solid tumor portfolio. And it's true, it's hard because there's so much going on there. And really, we now have multiple programs that are accelerating this year towards late-stage development, and we have a pipeline that's increasingly positioned to drive meaningful growth. And I do want to say to the BeOne Medicines' team and all of the investigators that are working with us that we are very committed to this space and really excited and proud, so proud of everything that's been accomplished in that area.

With that said, I think we're a company that is very focused on trying to do great science. You'll see that in the pipeline today. We're a very science-oriented organization. We believe in scientific integrity and getting the best medicines to patients. I mean you have to develop the best medicines and we're committed to doing that. And I think also, as a company that's 16 years old, we've always believed that we need to find the best ways to do things. And we believe that's by working closely with the community, being one with the community to fight cancer.

As part of that process, we've built this BeOne Superhighway that you hear about, and it's taken time for us to build that, it's not easy. It's like raising a child. But at 16, BeOne Medicines is now old enough to go drive full speed on the BeOne Superhighway. And you'll hear and see evidence of how Lai and his R&D team are doing that all the time today.

So with that, I'll turn you over to my good friend and our wonderful head of R&D and business development, Lai Wang. Thank you.

Thank you, John. Thanks, everyone, for joining us tonight. BeOne is turning 16, as John pointed out. When I look back, we have gone through distinct chapters. The first chapter was our early years, about a decade of building from the ground up, that's when we designed and developed BRUKINSA and TEVIMBRA and laid the foundation for everything that follows. Then we enter the next chapter with a simple question in mind. Was that success repeatable? Or was that success a onetime achievement? Over the past 6 years, we have been working to answer that. On one hand, we built a highly productive discovery engine focused on oncology, powered by more than 1,200 research scientists and supported by a range of technology platforms.

In parallel, we built something very unique on the development side, a clinical development superhighway, a global engine designed to move programs forward with speed, scale and efficiency. These are very -- 2 very distinct capabilities. By putting them together, they change what we can do. For the first time, it feels like we are not just relying on individual assets. We are building a system that can consistently generate and deliver innovation. This is why I see 2026 as the beginning of a new chapter, one where this model comes together and starts to deliver repeatedly for patients around the globe.

I think everyone -- John said he's not going to touch on the heme, but I'm going to have one slide on heme. I think everyone is very familiar with our CLL franchise. The key point I would like to really highlight it takes 3 foundational assets to build on. It started with an anchor BRUKINSA, which set the standard care for the frontline CLL patients and comes with a combination product, BEQALZI remember the name, BEQALZI, also known as sonrotoclax, strengthening that backbone. Then finally, you need something in the relapsed/refractory setting, that's why when we designed the BTK degrader, now called tacabrutideg. Putting together, this gives us a complete framework across lines of therapy. And this is the key point. We now believe this is a model we can take beyond CLL into other tumor types.

With that strategy in mind, we have been very deliberate in how we build our disease franchise. Our strategy starts with a focus selecting a small number of disease areas where we believe we can lead and then building the depth, not just the single assets. What enabled this approach is our in-house technology stack, spanning CDAC, novel payload ADCs, you're going to see tons of that from BeOne as well as cell-therapy and emerging platforms like T cell engagers. We're not bound to a specific target or a specific platform alone. We systematically match the right biology with the right modality to build a pipeline that is deep, durable and sustainable.

The engine has clearly accelerated. From 2011 to 2020, the initial 10 years, we delivered 11 new molecular entities. Between 2021 and 2023, that's 3 years, we added another 10 NMEs, demonstrating consistent productivity and execution. The momentum stepped up again in the last 2 years with 18 NMEs across small molecules, CDAC, ADCs and bi and tri-specific antibodies, reflecting the maturation of our in-house platforms. Looking ahead, we expect to sustain this cadence of roughly 8 to 10 NMEs a year from 2026 and beyond. Innovation at BeOne is accelerating, systematic and built to scale.

Historically, BeOne solid tumor pipeline was heavily weighted towards immuno-oncology. The CDK4i chapter marks the start of the new wave with more diversified mechanisms and a clear tumor type focus. This molecule entered the clinic just 2.5 years ago, 2.5 years ago. And the Phase III now is already on the way. CDK4 is not an exception. We initiated a potential pivotal Phase II study for our GPC3 x 4-1BB, you're also going to hear about today within 2 years entering the clinic. In addition, 3 more molecules have achieved clinical proof of concept and are now moving towards registration. All are on track to start their first pivotal trial within 2.5 years of entering the clinic, some of the less than 2 years. This is a clear inflection -- reflection of the quality of our science as well as our unmatched clinical execution capability.

Today, we will share the clinical update for the first 3 assets shown on this slide with data on the remaining 2 to be shared with everyone in the second half of this year. I hope you will find the data as exciting as much as I do. With that, I will turn it over to Mark.

Thank you, Lai. Thank you all very much for joining us here tonight. Your time at ASCO is precious. We're very grateful. I had mentioned to a couple of you in conversations before starting that I'm authentically really happy, really excited to share the data. I feel like with many of you, I've been saying for a year or 2 years, we're really excited about what we're seeing with these programs. So it's great to finally be able to share the data, so you can understand why we've been and why I've been so excited.

As you just heard from Lai, our strategy in solid tumors is straightforward and ambitious to create the next CLL-like franchises from 3 solid tumor areas, breast and gynecologic cancers, GI malignancies and lung cancers. Importantly, this is not just pipeline expansion, it's a deliberate transformation with each great -- with greater breadth across targets and modalities and meaningful depth within each disease area.

This slide highlights the scale we've built with our industry-leading research and discovery organization. We now have more than 20 solid tumor assets targeting over 20 different oncogenic drivers and spanning multiple modalities. Importantly, this is not a narrow opportunity set. The diseases we're targeting represent roughly 2/3 of newly diagnosed solid tumor cases, both here in the U.S. and around the world. And by intent, each of our 3 priority areas now has multiple shots on goal across these mechanisms and disease areas of focus. We are not dependent on any single asset or outcome.

As you move across this pipeline slide, what I would like to highlight is how we're matching biology with the right modality. The depth within each disease area is by design to enable in-portfolio combinations, which we believe are the key to maximizing patient benefit. Today, I'll focus on the programs where we have the most meaningful data here at ASCO and the clearest path toward registration. These include our selective CDK4 inhibitor, a B7-H4-targeting ADC, and a first-in-class GPC3 x 4-1BB targeting bispecific. In addition to the molecules we are highlighting today, in gastrointestinal cancers, we're advancing assets like CEA ADC and our PRMT5 inhibitor. In breast and gynecologic cancers, we have several next-generation combination opportunities to build upon CDK4 data that you will see today. And in lung, we're building a portfolio that reflects the complexity of that disease with multiple approaches targeted across small molecules, biologics and ADCs.

Let's start with BGB-43395, our selective CDK4 inhibitor. We view this as a foundational asset within our breast cancer franchise with potential to redefine the standard of care in hormone receptor-positive disease. Even though CDK4/6 inhibitors are widely used in impactful medicines and are standard of care in first-line metastatic breast cancer, the class has well-recognized limitations. As you can see on this slide, neutropenia remains a major issue. It often forces dose reductions and can ultimately impact how much drug patients actually receive over time. There's also a meaningful management burden, frequent monitoring, clinic visits, which is not trivial for patients. And beyond tolerability, both primary and acquired resistance remain a significant challenge. So while the class has clearly transformed the treatment landscape, there is still a real opportunity to improve, particularly around safety, durability and overall treatment experience.

Against that backdrop, this is a very large opportunity with global sales exceeding $15 billion. What we're aiming to do is improve on all 3 of those dimensions, efficacy, tolerability and combinability. The data with BGB-43395 is very encouraging and is consistent with our therapeutic hypothesis. We're observing response rates above 70% at our Phase III doses, which is consistent with the best reported outcomes within the CDK4 selective class. At the same time, we're seeing a differentiated safety profile, particularly with respect to hematologic toxicity. Importantly, our initial registration trial in first-line metastatic breast cancer is already underway. So taken together, we believe this positions the program very well, both as a potential next-generation CDK4 and as a backbone for combination approaches.

The differentiation with 43395 is due to both potency and selectivity. As this slide illustrates, the goal is to potently inhibit CDK4 while minimizing CDK6 inhibition, which is what drives much of the hematologic toxicity with current agents. In a preclinical cellular assay, our molecule shows the highest potency against CDK4 coupled with the greatest selectivity relative to CDK6. And that's what underpins both the safety profile we're seeing and the flexibility for unique combinations. Today, we are honored to have Dr. Shom Goel, a key opinion leader in breast cancer presenting the CDK4 data update. Dr. Goel is an associate professor and clinician scientist at the University of Melbourne and the Peter MacCallum Cancer Centre. He serves as the global PI and translational PI for 4 randomized clinical trials in breast cancer and has over 60 publications, including recent works in high-impact journals such as Nature, Cancer Cell and Nature Cancer. He is the first author for the data you are about to hear, and we are excited to have Dr. Goel's insights on our selective CDK4 inhibitor and the potential impact on breast cancer treatment.

Good evening, everyone. Thank you so much, Mark, for the kind introduction. It's my pleasure to be here with you. And to share with you the data that we presented earlier today in a poster at the ASCO Annual Meeting. But let me start by orienting you to the clinical program in its full and where today's data set comes from within that program.

As you can see on this slide, the study, BGB-43395-101 is the global first-in-human Phase I study that has progressed in this stepwise fashion. On the left is when the study began back in December 2023, as you heard, with global dose escalation, and that evaluated BGB-43395 both as a monotherapy and in combination. From there, the program has moved into dose optimization shown in the middle. And the data set being presented today is highlighted in red. First, the safety expansion cohort in first-line HR-positive HER2-negative CDK4/6 inhibitor-naive breast cancer using BGB-43395 with letrozole. And as shown here, this cohort includes roughly 20 patients per dose level across 3 dose levels.

And then on the right, the program is continuing to generate data in this Phase Ib dose expansion phase. There are 40 patients enrolled in the first-line combination expansion which is the same first-line HR-positive HER2-negative CDK4/6 inhibitor-naive population with BGB-43395 plus letrozole. And importantly, we'll provide our first clinical evaluation of co-administration of this agent with food. The key point really from this slide is that this is a substantial global data set now.

And so with that context, let me move to safety first, particularly heme tox, because hematologic tolerability is a key point and differentiator for the CDK4 selective approach. So as you can see on this slide, we're looking at adverse events across 3 dose arms. We've got 240 milligrams, 400 milligrams and 600 milligrams, all given twice daily with letrozole, and what stands out immediately is the overall low frequency of hematologic toxicity. If you focus first on neutropenia, the top row in the table which is usually often a dose-limiting toxicity for CDK4/6 inhibitors, you can see that grade 3 or higher events are quite rare, just one event at the 240-milligram and none at 400 milligrams. And interestingly and importantly, even the low-grade hematologic toxicity events are uncommon. You see a similar pattern with thrombocytopenia and with anemia where all grade events are infrequent and no grade 3 events are reported at the Phase III dose, which is the 400 milligrams twice daily dose.

So I think what this table really demonstrates is a remarkably clean hematologic toxicity profile, which is consistent with what Mark showed you, being the high selectivity of this agent for CDK4 over CDK6. And clinically, that is highly meaningful because it suggests the potential to maintain dose intensity over time and to avoid the frequent heme tox, which led to dose -- leads to dose modifications that we often see with CDK4/6 inhibitors.

So let me now turn to gastrointestinal tolerability, which is the other key aspect of the safety profile here. As you can see on this slide, we are comparing outcomes in patients treated with food versus those treated without food, focusing on diarrhea, nausea and vomiting. Starting with diarrhea, without food, the overall rate is relatively high at 94% though the majority of events are low-grade and manageable. Now while the number of patients evaluated with food co-administration is currently limited at 8, that rate of diarrhea drops meaningfully to about 50%. And importantly, what we're seeing there is now limited to Grade 1 events.

And a similar pattern has been seen with nausea and with vomiting. For nausea, the rate decreases from about 61% without food to 38% with food, again, with a shift towards these lower-grade events. And for vomiting, you see a reduction from about 42% down to 13% with food. So I think the key takeaway from this slide is that the emerging data suggests that gastrointestinal toxicity from this agent is substantially mitigated through co-administration with food, reduces both the frequency of these events and also the severity of these events. Also, as noted on the left side here, there are additional mitigation strategies, which are currently being investigated, including the use of low-dose prophylactic antidiarrheals and also step-up dosing. And from a clinical perspective, the ability to actively manage these events is critical, particularly in a first-line setting where long-term tolerability is essential.

So let me now turn to efficacy. On this slide, you'll see the waterfall plots of best tumor response for 2 different dose levels, 240 milligrams and 400 milligrams, again, both in combination with letrozole. And what stands out visually is the consistent tumor shrinkage across patients at both dose levels. In the 240-milligram cohort, you can see that the majority of patients are achieving meaningful reductions in tumor burden, many beyond the threshold for partial response. And in the 400-milligram cohort, that pattern is also quite consistent with most patients achieving deep responses. And if you look at the numbers on the right, in the 240-milligram group, the confirmed overall response rate is 68.4% with an unconfirmed response rate of 73.7%. The patient with an unconfirmed response is still on treatment.

And in the 400-milligram cohort, the confirmed objective response rate is 63.2% with a similar unconfirmed response rate of 73.7%, again, with one patient with an unconfirmed response remaining on treatment. So I think if we put all that together, my impression is that this is a strong efficacy signal in the first-line for HR-positive HER2-negative disease, particularly when we consider it alongside the safety profile, which I've just reviewed with you.

So with that information in hand, let me now walk you briefly through the pivotal study design. And I'm pleased to announce that the first patient for this study was randomized at Peter MacCallum Cancer Centre in Melbourne earlier today. So as you can see on this slide, this is a randomized Phase III study in first-line HR-positive/HER2-negative advanced or metastatic breast cancer and patients are being randomized 1:1 between BGB-43395 at 400 milligrams twice a day with letrozole or a standard CDK4/6 inhibitor with letrozole.

The key eligibility criteria includes patients who received no prior systemic therapy for advanced or metastatic disease, ECOG performance status 0 or 1. And the study is powered to enroll approximately 1,056 patients. The primary endpoint is progression-free survival assessed by blinded independent central review and the secondary endpoints will include overall survival, objective response rate, duration of response, safety and patient-reported outcomes. So this design really is set to directly compare this selective CDK4 inhibitor against the current standard of care. And it's well positioned to test whether both the efficacy and the tolerability advantages that I've shown you will translate into a clinically meaningful benefit.

So to summarize, first of all, as a selective CDK4 inhibitor, what stands out to me here is the promising antitumor activity that we're observing in first-line metastatic breast cancer. As I said, we are seeing an objective response rate of around 70%, which I believe provides a strong clinical rationale to continue advancing this program, particularly in the frontline setting.

Second, on safety. I think what's encouraging is the overall favorable profile. We're seeing very infrequent low-grade hematologic toxicities and GI events that are generally manageable, especially when the drug is co-administered with food, which might help to mitigate those effects. And then third, looking ahead, we're actively planning to generate evidence in early-stage breast cancer. So that's an important next step as we think about expanding the impact of this molecule beyond the metastatic setting. And overall, taken together, we think this profile supports both continued development and a potentially meaningful role for this drug in breast cancer treatment.

Thank you for your attention. With that, I'd now like to turn it back to Mark.

Thank you, Dr. Goel. We're so excited that the first patient has now been randomized at your site in our global Phase III clinical trial. I'd like to circle back and say one of the most important implications of the safety profile is what you see on this slide, which ultimately leads to combinability. Because we're not seeing the same level of hematologic toxicity, not only high-grade events, but also low events, low-grade events, we have the unique ability to combine CDK4 with other complementary mechanisms. That includes assets within our own pipeline, such as our KAT6A/B inhibitor, our CDK2 degrader and our BCL-2 inhibitor. So this is not just about a single opportunity. It becomes a platform for in-portfolio combinations and further growth of our breast cancer portfolio.

With that, let's now turn to our B7-H4-targeting ADC. Our goal is to establish a new benchmark in ovarian cancer and other B7-H4-expressing tumors. This program has advanced very quickly, moving from first-in-human to Phase III readiness in about 2 years. We have observed a potentially best-in-class safety profile which is a critical attribute for patients with advanced cancers, but particularly in an early-line or maintenance setting. We're seeing very encouraging activity across ovarian, endometrial and triple-negative breast cancer and our emerging efficacy data enables development regardless of B7-H4 expression in ovarian cancer. Importantly, we are planning to initiate a Phase III trial in ovarian cancer before the end of the year. And we believe this combination of product attributes and timing positions us as the leading B7-H4-targeting ADC.

Let me take a minute to walk you through the slide because this is where you can see how the differentiation of our B7-H4-targeting ADC comes together. As you can see here, there are a few components that drive the overall profile of the molecule, and each of these has been very intentionally designed. First, starting with the target itself, B7-H4 is highly expressed in a number of tumors, particularly ovarian, endometrial and breast cancers, but has very limited expression in normal tissue. That gives us a strong starting point from a targeting perspective that provides a safety profile that has no apparent target-mediated toxicities.

Next is the linker, which is engineered to be stable in circulation, which helps reduce off-target toxicity but then cleavable once inside the tumor cell, allowing for payload release and bystander effect. The payload is a potent topoisomerase inhibitor with a DAR of 6. Finally, while I will not present our PK data this evening, we have observed a half-life of approximately 7 days, which supports every-3-week dosing. We presented a poster at this congress sharing detailed PK data and also explaining how adjusted ideal body weight dosing rather than total body weight dosing provides consistent exposure profile. So when you put all of these pieces together, the target selection, the antibody design, the linker stability, payload potency and consistent PK, what you get is a molecule that is designed to maximize tumor delivery while minimizing systemic exposure.

Now I'll put the Phase I trial into context. As you can see on this slide, this is a first-in-human multi-arm study evaluating the B7-H4 ADC across a range of solid tumors with a particular focus on ovarian, breast and endometrial cancers. At this point, we've completed dose escalation and have moved into dose expansion, which will also serve as our dose optimization phase. What you'll see tonight and at the Mini-Oral presentation tomorrow are the data from patients treated at dose levels under consideration for future development with sufficient follow-up to begin assessing both response rates and durability. As you'll see, the data set is still maturing, but it's already providing a clear signal, both in terms of the level of activity and the overall tolerability profile. And importantly, this is the data set that's supporting our confidence to move in the Phase III with initiation plan before the end of this year.

Let me spend a moment on safety because this is a key part of the story. Here, we are presenting data from 2 dose levels under consideration as our Phase III dose. The overall safety profile is very manageable and importantly, differentiated relative to what's been reported with other topo I conjugated ADCs with ongoing or plan development in early-line ovarian cancer. If you look across the adverse events, what stands out is that most events are low-grade, and the rates of Grade 3 and higher toxicity remain relatively limited during the period of follow-up. You can see the dose reductions in treatment interruptions are infrequent, which is important. It suggests that patients are generally able to stay on therapy and receive consistent exposure. And from a tolerability standpoint, we're not seeing a single dominant toxicity that is difficult to manage. Instead, it's a profile that appears predictable and clinically manageable. So when taken together, what this slide shows is a safety profile that we believe supports earlier-line use where tolerability becomes even more important.

Turning to efficacy. This is where you can see the real strength of the signal. As you can see on this slide, in advanced or heavily pretreated ovarian cancer, we're observing an unconfirmed response rate above 50%, with the majority of patients experiencing a reduction in tumor size. Although I am not sharing the data regarding response rate by expression, and I encourage everyone to attend our Mini-Oral presentation tomorrow morning where those data will be shared, we are observing responses across the range of B7-H4 expression, which supports a broad development approach in ovarian cancer without the need for patient selection.

Finally, let me detail how this data helps us to arrive at our planned Phase III development. As you can see, we're focusing on the first-line maintenance setting in ovarian cancer. This design is relatively straightforward, evaluating the B7-H4 ADC in combination with bevacizumab compared to bevacizumab maintenance alone in patients who have completed standard platinum chemotherapy-based first-line treatment. The maintenance paradigm is well established in ovarian cancer. There is an unmet need among patients who are not candidates for PARP inhibitor. The study primary endpoint will assess progression-free survival, along with key secondary endpoints that will help to characterize the overall benefit. And importantly, this setting allows us to introduce the drug earlier in the treatment course where we believe both the efficacy and tolerability profile can have the greatest impact. So as this slide outlines, the strategy is very focused, setting a clear, registrationally relevant setting and positioning the program for potential near-term path to approval.

To conclude, I'll turn to our exciting GPC3 x 4-1BB-targeting bispecific. This is one of the programs that best reflects how we do science, not by following the crowd, but by being deliberate about what should be possible. The field has learned the hard way that by broadly activating 4-1BB, this can create unacceptable systemic effects. So the question for us was, can we bring 4-1BB's potency forward and control where and when it is engaged? This wasn't something that we just stumbled upon. It started with a clear hypothesis. If we could focus the immune activation only where the tumor is, we could aim for real efficacy without the price of systemic toxicity.

Think of it less like turning up the volume on the entire immune system and more like designing a key that only turns the right lock. The goal is precision immune activation exactly where it's needed. And the reason we advance this program is simple. Patients with HCC run out of options very quickly. When you see how outcomes fall off after immunotherapy and tyrosine kinase inhibitors, it's not an academic problem, it's a human one, something we take profoundly personally on behalf of the people who need us. So what you'll see in the next few slides is the result of being willing to be bold to believe we could design something better and then letting the data tell the story and that brings me to where we are tonight.

Let me step back and give you a quick overview of our GPC3 x 4-1BB program and how we're thinking about the overall strategy. At a high level, BGB-B2033 is a first-in-class bispecific and our goal is to establish a new standard of care for patients with HCC and other GPC3-expressing tumors. Starting with the clinical profile, what's really notable is the monotherapy activity. As you can see, we're observing response rates over 30%, which is roughly 3x what you'd expect with current standard of care in the second-line setting.

Second, safety is a key and central part of the story here. We're seeing a highly favorable and differentiated safety profile, which opens the door to combination approaches and importantly allows us to move into earlier lines of therapy. This combination of favorable efficacy and safety is strongly differentiated from GPC3-targeting CAR Ts or ADCs and in turn enables a broader development plan with applicability to more patients.

And then third, in terms of development strategy, there are really 3 parallel paths. First is the potential pivotal expansion in late-line HCC that is already initiated. The second is that we're planning a global randomized study in the post-IO setting. And third, we're continuing enrollment in a front-line HCC triplet, which will be important in supporting development in earlier lines over time. So overall, between the level of activity, the safety profile and very deliberate development strategy, we see a clear path to building a potentially meaningful franchise.

Before getting into the data, let me take a minute to walk you through the slide because it frames the opportunity. Starting on the left, you can see the 5-year survival rates across a range of tumor types. What stands out is that liver cancer, hepatocellular carcinoma, or HCC, remains among the lowest. 5-year survival remains around 20% with only incremental improvement over time and is meaningfully below most other solid tumors. So despite some advances in therapy, outcomes remain quite poor. This is due to a combination of unique biology and patient comorbidities that are common in HCC.

Now if you move to the right of the slide, you can see the incidence and stage distribution at diagnosis. In the United States, this is not a rare disease with over 30,000 new diagnoses per year. A significant proportion of patients are diagnosed at intermediate or advanced stages. And as a result, most will ultimately require systemic therapy. Globally, as shown in the pie chart, this is also a very large and growing disease with the highest incidence in China but meaningful patient populations across Europe and Japan in addition to the United States.

So in summary, this slide highlights the combination of poor survival outcomes and substantial global disease burden that characterize HCC. And that's particularly important in the context of later-line disease where there is a desperate need for therapies that can drive meaningful responses.

Now, allow me to describe the mechanism because this is critical to understanding the clinical data. As illustrated on this slide, one arm of the B2033 bispecific binds to GPC3 on tumor cells and serves as a targeting mechanism. Once the molecule is anchored to the tumor, the 4-1BB arm engages T cells, providing a co-stimulatory signal that enhances activation, proliferation and cytotoxic function. So the key here is that the 4-1BB activation is conditional. It's happening in the presence of the GPC3-positive tumor tissue rather than systemically. You'll also see on this slide a number of design features including elements to extend the half-life and reduce off-target toxicity. The most critical design here is 4-1BB binding at a unique epitope. Those design choices are important because they help create a balance between potency and safety, which has been a major challenge for this class historically. So the hypothesis is very straightforward. Targeted 4-1BB within the tumor should drive antitumor activity while maintaining a manageable safety profile.

Now I'm very pleased to introduce Dr. Hong Jae Chon. Professor Chon is a leading clinician and investigator in hepatocellular carcinoma and currently serves as Professor of Medical Oncology at CHA University School of Medicine and Director of the Cancer Center at CHA Bundang Medical Center in Seoul, Korea. His work spans clinical trials and translational research, focusing on GI cancers, especially HCC. Professor Chon has been the global lead enroller in this Phase I study of B2033, and he will also present at the Mini-Oral session tomorrow morning. So we're very fortunate to have him with us here tonight.

With that, let me hand it over to Professor Chon.

Thank you for the kind introduction. I'm Hong Jae Chon from CHA Bundang Medical Center. Thank you, Mark. And I would like to start by building on a point that Mark made earlier. As you saw, hepatocellular carcinoma remains a disease with both substantial global incidence and few long-term survivors, particularly when we compare with other solid tumors. Even with some improvement over time, 5-year survival remains relatively low and the majority of patients are diagnosed at intermediate or advanced stages. The treatment landscape for advanced HCC has evolved with the introduction of combination immunotherapy in the first-line setting. Today, most patients roughly 75% to 90% of patients are treated with IO-based therapy upfront. However, once patients progress, the options become quite limited.

In second-line, we typically use TKIs such as sorafenib or lenvatinib. In selected patients, we can apply ramucirumab. But beyond that, as highlighted at the bottom, there is no clear standard of care after both IO and TKI therapy. So if you look at the right side of the slide, this is very well reflected in outcomes, response rate dropped significantly as patients move through lines of therapy from around 30% in the first-line setting and just less than 10% in second-line and very, very low level of -- in the third-line and beyond. So overall, this slide highlights a very clear gap, particularly in patients who progress after both immunotherapy and TKIs where effective treatment options remain limited.

Let me walk you through the 101 study design. As you can see, this is the first-in-human Phase I trial evaluating BGB-B2033. Part 1 focuses on monotherapy and begins with dose escalation, doses ranging from 1 milligram to 1,000 milligrams. And after that, it expanded into safety expansion cohort in patients with second-line or later HCC. Then as shown in the middle of the slide, we moved into dose optimization with around 50 patients enrolled evaluating active dose level in the same second-line plus population. And on the right, the program is progressing into dose expansion with around 40 patients enrolled today and a planned cutoff of 120 patients, especially in the post-IO and post-TKI setting.

In addition, as shown at the bottom, there is ongoing combination program in Part B evaluating BGB-B2033 with tislelizumab with and without bevacizumab. So overall, this study provides a structured and progressive approach moving from dose finding into dose expansion and towards a potential registrational pathway.

Now turn to efficacy. On this slide, you can see the response rate across the different dose levels: 300, 600 and 1,000 milligrams. At 300 milligrams, the confirmed objective response rate was 29%. At 600 milligrams, the confirmed objective response rate increased to 36%. And at 1,000 milligrams, the confirmed response rate is 20%. Although I would note that this cohort was relatively small, and with short follow-up. So at that time, the unconfirmed response rate was around 30% already. So if you look across all of these dose levels, what you can see is the consistent signal of activity with response rate around or above 30% at the active dose levels. The 6-month duration of response is almost 37%, again, higher than both available therapies and other GPC3-targeting investigational molecules.

Importantly, as highlighted on the right side, the patients are heavily pretreated with a median of 2 prior lines of therapy and the majority having received both immunotherapy and TKI. So we are seeing responses across a range of patient subgroups including both viral and nonviral etiology and both intrahepatic and extrahepatic disease. So overall, this slide demonstrates a meaningful and consistent efficacy signal in a population where historically, response rate has been quite low.

Let me turn to safety. As you can see on the left side of the slide, overall safety profile appears very, very favorable. Treatment-related adverse events occurred in 48% of patients with only 8% being Grade 3. No Grade 4 or 5 were reported. Serious adverse events are also limited at under 5%, and treatment discontinuation due to adverse event low at just over 3%. There have been only one dose-limiting toxicity. If you look at the right side of the slide, which shows adverse events by type, what stands out is that most events are very low grade. Most common events include AST, ALT increase, but importantly, this did not require high-dose steroids. Other events were generally manageable and occurred at a relatively lower rate. So overall, this safety profile is favorable, particularly in the context of 4-1BB-based mechanism, where historically, toxicity has been a concern.

I'd like to show 1 of my 2 -- 2 of my patient cases because I think this can help illustrate what we are seeing clinically. Let me start with first patient, and he is a 53-year-old male and diagnosed with HCC involving liver and lung and also positive for hepatitis B virus, and he had treated multiple prior treatments, including TACE and 3 prior lines of therapy, including immunotherapy and TKI. At baseline CT scan, you can see intrahepatic lesions and multiple lung metastases. But after 16 cycles of treatment, there was a substantial reduction in tumor burden and multiple lung metastases almost disappeared. In parallel with this, there was a dramatic tumor marker decrease from AFP level from over 2,500 down to the normal range. So this patient is heavily pretreated patient but achieved radiologic response and meaningful biomarker response.

A second patient is 52-year-old male and had HCC and lung metastasis, so also had hepatitis B virus and he had underwent liver resection and had received 3 prior lines of systemic therapy, including immunotherapy and TKIs. At baseline CT scan, you can clearly see the lung metastasis. However, after 2 cycles of treatment, there was substantial tumor shrinkage and almost disappeared. And again, this was accompanied by the tumor marker decrease from over 8,000 down to the normal range. This patient also was heavily pretreated patient but showed a very rapid and deep response. So -- and both of them are still ongoing and around 1 year. And I also have around 10 patients who achieved a PR and all of them are still ongoing. So I expect this compound can have very, very good duration of response.

So BGB-B2033-induced response rates are commonly observed in this treatment setting further supporting the activity signal seen in the broad data set. So what's most important is that in second-line or later HCC, we observed a response rate of above 30% with BGB-B2033 as a monotherapy. And when you look at that in context, the level of activity is comparable to what's typically seen in first-line combination immunotherapy and substantially higher than what we can see in later-line setting today. So you can see the comparison here in third-line the response rate is around just 2%, but in second-line, they are generally below 10%. Today, actually, in [indiscernible] trial in second-line, lenvatinib data showed just 5% of response rate.

So this is important. So this is a setting where historically, activity has been quite limited. And what we are seeing here is a clear step-up in efficacy and this is important because this is a monotherapy. So the ability to achieve that level of response without combination provides flexibility we can think about development going forward.

So now if you move to the right side of the slide, you can see the safety profile compared to traditional TKIs. Across key adverse events, hepatotoxicity, hand-foot syndrome, hypertension and diarrhea, what stands out is the low rate of high-grade toxicity with BGB-B2033. You will notice that Grade 3 and higher events are consistently lower than what's typically seen with lenvatinib or sorafenib. And even at the overall level, the rate of this toxicity appears more manageable. And it's important because TKIs, while active, sometimes can be difficult to tolerate and often require dose modifications. So when you look at this holistically, what this slide is showing is a combination of meaningful efficacy in a difficult setting along with a favorable and manageable safety profile and that combination is what gives us confidence, not just in the late-line opportunity, but also in the potential to move earlier and in combination setting over time. So -- and now, I will turn it back to Mark for company perspective.

Thank you so much, Professor Chon. From a development perspective, we're extremely excited by the data you presented here tonight and for tomorrow's oral presentation. This is a priority program, and we'll have the full power of our development superhighway behind it. And we recognize the patient need, the differentiation of our asset and the opportunity ahead as a first-in-class bispecific demonstrating an unprecedented combination of efficacy and safety.

Now let me walk you through how we're thinking about development. Starting on the left, 2025 to '26, this is all about establishing the foundation. We're focused on late-line HCC where we can most efficiently demonstrate proof of concept and generate registrational data. As you can see here, we've already received U.S. Fast Track and Orphan designation, which we think underscores the potential of the program. At the same time, we've expanded our 101 study to support a potential post-IO post-TKI approval pathway. And importantly, planning is already underway to initiate a global randomized study in the second-line post-IO setting. This phase is about building the core clinical and regulatory footing.

Then, as we move into '27 and '28, we will advance into earlier lines, deepening the opportunity. Here, we're starting to layer in combinations, including the tislelizumab plus bevacizumab cohort, which we expect will inform a frontline pivotal study planned for the second half of 2027. In parallel, we're broadening the scope even further looking into intermediate-stage HCC in even perioperative settings. This is where the asset begins to move earlier and into larger patient populations.

And then looking further out into 2029 and beyond, this is where we expand. At this point, we're really thinking about portfolio-level combinations and how B2033 integrates across our broader pipeline. That includes next-generation IO approaches, additional in-portfolio combinations and also novel second-line strategies aimed at patients who progress on the frontline emerging standard of care.

So taken together, this is not just a single development path. It's a long-term plan to systematically create patient impact and to build value in HCC, starting in late-line, moving earlier and ultimately expanding this foundational medicine into a multi-combination franchise built to address the needs of this substantial population of people around the world with HCC.

So to conclude, allow me to put into context what you've seen today. We see this ASCO as an inflection point for our solid tumor pipeline. Across these 3 programs, we now have clear proof-of-concept data. And importantly, each of these programs supports the potential to initiate registrational studies by the end of this year in 3 different but common tumor types. Starting with CDK4, this is in the first-line HR-positive breast cancer, where we're seeing compelling response rates along with an improved safety profile, particularly when administered with food.

Second, our B7-H4-targeting ADC in frontline ovarian cancer maintenance, here, we're seeing strong efficacy coupled with what we believe is a best-in-class safety profile. And third, the GPC3 x 4-1BB program in HCC, where we're seeing unprecedented single-agent activity with a safety profile that enables development in both later and earlier lines of therapy. Beyond those 3, we expect proof-of-concept data for 2 additional internally discovered molecules in the second half of this year, CEA ADC and PRMT5. So overall, what you're seeing is not just progress in a few isolated programs, but a broader portfolio that is systematically moving from early promise into proof of concept. And importantly, this is just the beginning with a number of additional early-stage assets advancing quickly toward that same inflection point.

This wraps up our presentation for today. I'd again like to thank Professor Goel and Professor Chon for their time and their insights. And I'll hand it back to Liza.

Thanks, Mark. As our panelists come up to the stage, please, to participate in the Q&A, let me go through some general housekeeping items. [Operator Instructions] Now let's open up.

Thank you, Liza. We have multiple questions.

Kalpit Patel, Wolfe Research. I had a question for Dr. Chon for the GPC3 x 4-1BB. Very good data there. How are you thinking about the combinability with other TKIs given the LFT increases that we've seen across various different drugs there? So thoughts there. And then there were some other data with ADC and then the CAR T for the same target at ASCO this year. So I'm just curious as to what your thoughts are there.

Thank you for -- it's a good question. And First one is the GPC3 compound has a highly favorable safety profile. So I think there are a lot of chances to have combination strategy like atezolizumab and first-line setting combination and add-on or second-line TKI and add-on. Everything is possible, I think.

And second one -- second question is also very important. There are so many GPC-targeting ADCs currently. But hepatocellular carcinoma patient is a little bit different from other solid tumors. Most of them have underlying liver disease. They are very vulnerable to liver toxicity. So the safety profile is very, very import. In this sense, I think CAR T can be a very easy way to access some targets. But if we have better alternative option, I don't think we have to insist on CAR T. Actually CAR T, even though in early-stage clinical trial, they showed very good response. But they also have high toxicity and have to go through some complicated processes like lymphodepletion and have to wait for a long time, which is not available for HCC patients, especially later line. So I think CAR-T treatment cannot be generally applied to general HCC patients. But in that sense, this bispecific antibody shows a highly favorable safety. So it is the best -- it is the most easily applicable approach for HCC patients. And ADC, actually, they also have some signal but still have high toxicity. As I mentioned, toxicity is very important in HCC patients.

And just quickly add on the sponsor's perspective about the later-line combination as you heard from Professor Chon, what we think is so exciting about this molecule is magnitude of efficacy with an extremely clean safety profile. While we believe we likely could combine TKI, we would also be giving up that really clean safety profile with that combination. So for now, we're prioritizing monotherapy development in later line, but I wouldn't want to [indiscernible] closing the door to that later-line combination.

Yaron Werber, TD Cowen. I have 2 questions and a really nice presentation. The first one on GPC3 is you're aiming to combine with the checkpoint inhibitor. Do you have any sense do you need to lower the dose potentially? Or is it safe enough you're going to get too much immune stimulation? It sounds like you're already doing that combo. And then second question on the CDK4. What's the powering of the KANDELA study for PFS? It sounds like you're starting with about 15%, 20% higher response rate. How are you thinking about durability of the PFS superiority?

Dr. Goel, maybe so Yaron, we generally -- thank you very much for the question. We generally would not disclose directly the overall powering of the study, but maybe you could talk about what would be viewed as clinically meaningful in the frontline setting in a comparative study with the existing...

Yes. Sure. Thanks for the question. So as you know, we sort of have to have a benchmark in mind for what our standard first-line therapies can currently achieve and based on first-line trials that led to approval of the existing drugs, we have figures in our head that sit around about 2 years, right? That's -- and we also look towards more contemporary data sets to help refine and inform those estimates. As you heard, the primary outcome for this study is progression-free survival. So the question is what is a meaningful improvement in progression-free survival. Yaron, my honest opinion, and this is not the way the things play out, and I understand this, but even if theoretically, one had a drug that was equivalently active, but better experience for patients, that alone, I think, would be a good thing. But here, of course, we're looking for that improved tolerability and improve potency to actually translate also into an improvement in PFS.

I would say, in my personal opinion, an improvement in PFS in the order of months would be clinically very meaningful for patients. I can't really specify this many months or that many months, but I would say something in the 4 to 6-month range would be really meaningful in my professional opinion.

To your first question about combinability with PD-1, it's a very fair question, one that we thought about in terms of there is a risk of mechanistic [indiscernible] toxicity. We mentioned at earnings that, that frontline cohort is well underway. It is early days. Professor Chon, I don't know if you have any clinical reflections on how that's going [indiscernible] in that cohort.

Actually, we have already 10 patients, but there is no toxicity issue. But I think the first-line combination of nowadays first-line setting most wisely used first-rate regimens, atezolizumab and bevacizumab combination. But nowadays, we are evaluating tislelizumab, bevacizumab and GPC3 as first line. But I think that is a very smart strategy because we have data, patient who doesn't respond to atezolizumab, they usually show the high GPC3 expression. But maybe this triple combo can compensate this kind of weakness of Atezolizumab with triple combo, I think.

Maybe I will provide qualitative statements [indiscernible] last 2 years and so we're off to a good start [indiscernible]

Maybe I'll just add a comment [indiscernible] mechanistically. This molecule was really specifically designed to be target immunotherapy with the GP end of it, but as well as on the 4-1BB side of it. We're not disclosing exactly how we design molecule in 4-1BB binding, but I can tell you it's very unique. And in a way, we're leading to tumor-local activation. So with that, also now we're having more than 50 patients with the triplet, we feel very comfortable with the combinations.

Ren Benjamin from Citizens. Congrats on all the data. Can you talk -- just sticking with the CDK4 inhibitor, can you talk a little bit about the impact of food on efficacy? Have you seen any sort of betterment in efficacy given the tolerability profile. Why you chose 400 milligrams as the dose versus 240? I guess, for Lai, given the superhighway and the speed at which you do clinical trials, can you just extrapolate based on the enrollment rates for the Phase I portion, how long a Phase III must take to read out?

So we are targeting, shall we say, aggressive enrollment time lines, given the overall positioning within the space and the fact that [indiscernible] has largely completed, if not fully completed their enrollment. That said, this is a global enrollment. We have had a team that's had a large investigator meetings here at ASCO. There's high enthusiasm for the study. So if you're looking to enroll these 1,000 patients on a globally allocated way that will meet global health authorities as quickly as possible. A qualitative statement. Shom, I don't know if you have any comments?

Yes. So in respect to your question about whether concomitant administration with food affects efficacy, I think it's fair to say that with the numbers being what they are, one can't really make a meaningful comment there. What we can say is that in the limited number of patients that we've looked at, there's no significant difference in PK as to whether the drug is co-administered with food or not. And I think that's a very important point to note.

We completed the food effect study, and there's no impact on the PK. So with no impact on PK, we do anticipate this should not have impact on the efficacy side of it.

Strong efficacy, we see not only at the selected dose of 400 milligrams, but also at the lower dose of 240 milligrams that gives us confidence there's not going to be any impact to efficacy.

Maybe just one more comment on the superhighway. Thanks for highlighting that. Certainly, we are very proud of what we have achieved with the superhighway. And hopefully, today, showing you is not just one case. Actually the all 3 programs we are delivering with the same type of discipline and the speed and the efficiency. The CDK4 program is only in the clinic in 2.5 years. The Phase III, the first patient has been randomized today. Actually, we -- not just for these events, we were really pushing and trying to get going. And in terms of how long, we need to do better than Pfizer. So in terms of the GPC3 x 4-1BB programs, that's a program now already enrolled over 200 patients, and that's only in the clinic less than 2 years. It's remarkable for HCC patients. And then in terms of B7-H4 ADC programs, similarly, in 2 years' time period, we're already ready for Phase III. We probably are starting the Phase III within 2.5 years of the molecule entering clinic.

Yigal Nochomovitz from Citi. On the B7-H4 program, I noticed that it seemed like on the waterfall plot, everyone was an ovarian cancer patient, but I believe the study also enrolled breast and endometrial. I was just curious if you didn't show that data or those weren't -- those subtypes weren't enrolled. And then just going back to the question Ren was asking on the dose for CDK4, I think you had a slightly higher confirmed ORR in the 240, and I believe I thought I saw 1 CR, but nonetheless, you're going with the 400. So if you could just expand on your thinking as to why the 400...

Yes. So for B7-H4, tonight's presentation really focused on ovarian cancer because that's where we're going to have our initial Phase III study start. But at tomorrow's Mini-Oral, we will disclose data in the additional tumor types. The overall design of that study, dose escalation and expansion and now these tumor type expansions, what we're sharing is the dose escalation and safety expansion or backfill cohorts, there's some, shall we say, enrichment of ovarian from the investigators. It was looking good in ovarian, so they enrolled a lot of patients with ovarian. There are fewer patients with triple-negative breast cancer and endometrial cancer, but we'll share those data at the Mini-Oral tomorrow. We're excited about those data, and we leave that there's a development path in those additional indications that's open to us.

Maybe if I can start for the CDK4 dose rationale, I appreciate the point that you're making that with roughly 20 patients enrolled across those 2 cohorts, the response rates are essentially the same. We, of course, on the back end, do detailed population PK analyses, exposure response analyses. And we felt confident that 400 milligrams provided the best balance of efficacy and safety the highest probability of success most likely for patient benefit. We shared all that data with the FDA, and that data selection was endorsed by FDA during our Phase III start-up.

Jess Fye, JPMorgan. For the GPC3 x 4-1BB bispecific how many patients of single-arm data do you think you would need to file for accelerated approval post-IO, post-TKI and how many of those would need to be Western patients? And then for B7-H4, what's the proportion of ovarian patients who meet that criteria for the maintenance trial you described like there's still disease or PR after frontline bevacizumab plus chemo and PARP ineligible?

Thank you, Jess. So thankfully, for ovarian cancer, the majority of patients will achieve PR, CR stable disease after the frontline therapy, roughly 90%. So thankfully, there are a few patients who are refractory from the beginning. The distribution of patients who are eligible for PARP inhibitor versus not the proportion of patients who are HRD versus HRP is roughly 40-60, something like that. So we do think that it's a substantial proportion of the frontline ovarian cancer population who would be eligible for the study. How many patients? Oh, yes. So this is speculative. As we talked about at our most recent earnings call, we have expanded our 101 study. We've added a cohort to increase the sample size of late-line monotherapy and that double pretreated patient population to 120 patients. However, the global regulatory consultations related to that patient number are ongoing. That said, in the context of having a response rate of greater than 30% with a highly favorable safety profile, standard of care of only 5%. We're optimistic going into those conversations, but that's our rationale. But we haven't had those conversations yet or we're having them right now.

Etzer Darout, Barclays. A couple of maybe strategy questions. One on B7-H4 ADC that conversation with physicians that have talked about the need or importance for a biomarker strategy in various cancers. And you've noted a couple of times around sort of maybe an all-comers approach. So I wanted to have your thinking around there as you sort of progress these different tumor types into pivotal studies?

And then secondly, on the 4-1BB program, and we've seen other bispecific pairings where there's just been failures. But given sort of the level of activity you're seeing with your GPC3 program, I'm curious about what is it about GPC3 where you're seeing this level of activity? And are there other bispecific [indiscernible] that you view as more compelling given what you're seeing with the GPC3 x 4-1BB?

Yes. So Lai, would you like to talk about additional iterations on the 4-1BB?

Sure. In terms of the 4-1BB again, this is uniquely designed 4-1BB binder. The reason we started with GPC3 and part of people will think that's very crazy because initially, the 4-1BB monoclonal antibody certainly had a liver toxicity. We believe that GPC3 is highly expressed in the cancer cell, but not in the normal liver cell. That gave us the comfort to move forward with GPC3 X 4-1BB. We actually have a [indiscernible] program in our pipeline now to targeting various different type of tumors. We believe this MOA should not only help in HCC, with the platform we have set up, we are looking forward to bringing the other molecule into the clinic in the upcoming -- next few months to a year. And that will be -- this is actually -- I'm very excited about this platform. I think this potentially can be applicable to many different type of tumors.

And also just to add to that, a lot of people work on the CD3 T-cell engagers for solid tumor. However, unfortunately, for solid tumor, not that many clean TAA available really for CD3 MOA but I think the 4-1BB is a little bit different. The MOA there and the internal selectivity requirement is a little bit different compared to CD3 and also 4-1BB is preventing the T-cell exhaustion. So in a way, in this microsupressed environment within a cold solid tumor, 4-1BB might come up to be a better way to activating T cells. Of course, we need more data to really test the hypothesis, but it's a really interesting area. We're going to really explore and put a lot of effort behind.

Your question on B7-H4 is a really important question. I think what it comes back to ultimately is clinicians are thinking about differentiation and what they're selecting when they have a group of different molecules to select from. So perhaps the treatment algorithm for ovarian cancer can be summarized that patients receive their frontline chemotherapy with platinum and taxol and then patients are essentially dichotomized as part eligible or not, and is biomarker testing needed for PARP selection. So I do think that then having a second biomarker to triage to which EDC is an additional level of complexity and it would be attractive to not have to run that second biomarker in the circumstance where you're not giving something meaningfully for efficacy. So again, we'll share our biomarker data tomorrow. I think that we are not asking patients to give something up whether their B7-H4 is high or B7-H4 is low. And then the other critical part of differentiation, particularly maintenance is the safety. We have a very clean safety profile, unlike HER-2 targeted ADCs, which have stomatitis, which can be quite problematic, we have low rates of hematologic toxicity. HER2 is in biomarker selected subgroup. So we think that there are a number of factors that would align towards having biomarker selected approach being favorable in this patient set.

It's Leo from RBC Capital Markets. I wanted to ask on the CDK4 maybe for Dr. Goel. I just wanted to ask on your clinical perspective on safety here. I guess, to what extent is the lower heme toxicity a must have given the current real-world management rather than a nice to have? And I guess, would it make you change your use given you may have more experience with prior CDK4/6 agents? And then maybe if I can squeeze one. And related to that, if the GI toxicity doesn't improve meaningfully, but the heme profile stays favorable, I guess, how does that change your view of how the drug would fit in?

Okay. So there's a lot there. Let's start with the heme. So the low rates of heme tox, that's been seen with this drug, to me, this is very important. It's not just something that is a low number on paper. And there's a few reasons for that. One is that what that indicates to me really is the selectivity that the drug has for CDK4 over CDK6. That's what I see that as a readout of and you saw the preclinical numbers from Mark to support that. And what that in turn suggests is that the thesis -- one of the theses behind these drugs is that by sparing CDK6 and reducing neutropenia, it allows us to hit CDK4 harder, right? So in that sense, I think it's more than just a low number. It potentially has deep biologic implications for the durability of cell cycle control. That's one point.

Second point to remember, and it is not a trivial one, is that with our existing CDK4/6 inhibitors, there are a fraction of patients who actually come off therapy on account of hematologic toxicities. If you look at the first-line studies with the existing drugs, I think depending on the agent, between 5% and 10% of patients came off therapy for toxicity and a large number of those were heme tox. So I think again, by mitigating heme tox, I feel that you have less patients that go down that road.

And then I guess, thirdly, just slightly as a tangential point and one that Mark mentioned, more forward-looking, I think that the lack of significant heme tox also opens up opportunities when we're thinking about combinations in the future. As many of you know, the field is moving towards triplet regimens for ER-positive disease. And I think less heme tox you have with your foundation, with your hormone therapy and CDK4, the greater your options for triplets.

With respect to the GI tox, first of all, I would say the numbers that we've seen today in terms of concomitant administration with food are relatively small. But my sense, and I've looked after a number of patients on this agent is that the concomitant administration with food. That effect, I mean time will tell with larger numbers, but my sense, my clinical sense is that there is something real there.

Your question was what if it's not the case? So I can also talk to the experience of the patients I look after who took the drug in the fasted state and also point to some data that was on our poster today, but which wasn't in my presentation, looking at the prevalence of Grade 2-3 diarrhea over time. If you look at that data, what you'll see is that by the time you get to cycle 3, there's a real drop-off in the rate of Grade 2-3 diarrhea and that, that just continues to tail off to even lower numbers as patients continue on treatment. And that is not because patients were coming off therapy for diarrhea in the first cycle, no one came off therapy because of diarrhea.

To sort of turn that into a more simple sort of anecdotal sort of nature, my experience with the agent has generally been that people have very manageable GI toxicity. If needed, low-dose intermittent loperamide, patients and doctors learn very quickly during that first 1 to 2 cycles, how to manage it and get on top of it. And after that, our experience has been that it is a very manageable thing. So I don't think even if the concomitant administration with food, that data doesn't play out. I don't think that, that would necessarily limit my view of the long-term potential for the drug.

Thank you, Dr. Goel. I think we have time for one more question.

Yanan Zhu, Wells Fargo. I have 2 questions on CDK4 inhibitor and one on HCC. On the CDK4, I was wondering if you could frame the relative efficacy here compared with Pfizer's asset in a similar stage -- in a similar setting. And then just note there are significant dose interruption and dose reduction in the study due to the diarrhea effect. With food, that's in the data, but with patients taking it with food and being able to better tolerate the regimen, could we expect even better efficacy just given the level of dose reduction seen in the current data?

On the HCC, it's a quick question. Given the high prevalence of HCC in China, what proportion of patients in your pivotal study could come from China and be okay with the FDA?

Sure. So I can start with the CDK4 questions. So I think doing sort of meaningful comparisons across different studies with different agents, honestly, is difficult with the number of patients that we've seen the data from. And so anything to sort of say, oh, this or that is very speculative. I think what I can say is from the data that I showed you today, both at 240 and 400-milligram doses of BGB-43395, the objective response rate compares very favorably to what we have seen in the global randomized trials with the currently approved CDK4/6 inhibitors. So that's very encouraging. But showing data from a limited number of patients with either agent, I can't really speak to comparative efficacy. And I'm just trying to recall what your second question was.

[indiscernible].

Yes, yes, the food. So I think that this is again speculative my answer here, but if the GI toxicity is significantly mitigated through concomitant taking food and yes, you would expect let's see how this plays out over time that, that would lead to fewer dose reductions. But I think to then take another step, and we want to maximize relative dose intensity, right? That is a good thing and fewer dose reductions maximizes relative dose intensity. But again, it would only be speculation to say and therefore, that would translate to deltas in efficacy.

If I can address your second question regarding regulatory expectation. To be very clear for everybody, we have not had that conversation with FDA yet. So this is purely my opinion based on prior experience and speculation. My prior experience is that FDA will not view that question from the perspective of there are a lot of patients in Asia, but rather is this a common disease or a rare disease in the United States and there are patients eligible for enrollment. And as I mentioned, this is actually a common disease in the United States with an incident rate between 30,000 and 40,000 patients. So I suspect that FDA's position will be that they expect that we will have a typical proportion of U.S. representation in the Phase III study. And the overall allocation may be weighted a little bit towards Asia potentially. But as the study -- as with all of our studies, we will ensure that the regional allocation meets the need of all major regulatory agencies.

Okay. Thank you all very much for participating in our panel tonight. And now would you -- Lai, would you bring us to a close?

Yes. Thank you. I'm very happy to share a few closing remarks. First, this is an inflection point in our solid tumor program history. In just 2.5 years, our first wave of new assets has already delivered 5 POCs, including 3 we highlighted today. Second, momentum is building. The next wave is coming with our next-generation IOs beyond more than what you have seen from the public domain about our trispecific. We have other things which we will bring to the clinic very soon. Also the 4-1BB bispecifics, thanks for the question, we are very excited about this MOA. And in addition to that, we'll also have novel payload ADCs following right behind.

And finally, this is about more than just individual assets. We have talked about this many times tonight. This is about innovation, execution at scale, powered by our franchise model, world-class discovery and our global development superhighway. Thank you for spending your precious time with us today, and we truly appreciate your time and interest and engagement. We hope you enjoy the rest of ASCO and a safe trip home. Thank you.

Good day, everyone. Welcome to BeOne Medicines Q1 2026 Earnings Call Webcast. [Operator Instructions] At this time, I would like to turn the call over to the company.

Hello and welcome. Thanks for joining us today. I'm Dan Maller, Head of Investor Relations at BeOne Medicines. Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentation on the Investor Relations section of our website ir.beonemedicines.com.

I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most periodic -- recent periodic report filed with the SEC.

Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation. Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our IR website, along with our earnings release. All information in this presentation is as of the date of this presentation, and we undertake no duty to update such information unless required by law.

Now turning to today's call. As outlined on Slide 3, John Oyler, our Co-Founder, Chairman and CEO, will provide a business update. Aaron Rosenberg, our CFO, will provide an update on our first quarter financial results and 2026 guidance. And Lai Wang, President and Global Head of R&D; will discuss our R&D and pipeline progress. We will then open the call to questions. And joining the team for the Q&A portion of the call will be Xiaobin Wu, President and Chief Operating Officer; Matt Shaulis, General Manager of North America; Mark Lanasa, Chief Medical Officer for solid tumors; and Amit Agarwal, Chief Medical Officer for hematology.

I'll now pass the call over to John. John?

Thank you, Dan, and welcome, everyone, and thank you for your time today. We entered 2026 with tremendous momentum and our Q1 performance reflects strong execution across the business and a very solid start to the year. From a financial perspective, we achieved significant product revenue growth and GAAP earnings per ADS. These results underpin our confidence to raise our 2026 revenue guidance range by $100 million as Aaron will discuss later.

Our foundational hematology franchise consisting of BRUKINSA, sonro and our BTK CDAC is rapidly progressing with approvals, launches and key pivotal trial milestones expected in the near term. Both our heme franchise and our solid tumor pipeline will be on display at ASCO and EHA, where we have over 60 acceptances. At ASCO, we will present proof-of-concept data from 3 exciting solid tumor programs moving into late-stage clinical trials, which Lai will tell you more about shortly.

I'll begin today by highlighting the exceptional commercial and clinical progress of BRUKINSA, which has firmly established itself as the foundational BTK inhibitor. BRUKINSA continued its global leadership in the growing BTK market with first quarter sales of $1.1 billion, representing growth of 38%. We are seeing strong performance in all markets and all indications. BRUKINSA's large, consistent and expanding body of clinical and real-world evidence has elevated the benchmark for what is possible in CLL.

We believe that the data shows that only BRUKINSA provides the long-term outcomes that patients and physicians should expect and should demand. From its inception, BRUKINSA was designed to provide the best-in-class 24/7 BTK inhibition. Our hypothesis was that achieving complete and sustained BTK inhibition would result in a superior therapeutic profile and that has been borne out in the almost 7 years since, which I'll cover in the next few slides.

At ASH 2025 BRUKINSA set a new standard in frontline CLL with 6-year progression-free survival reported at 74% and overall survival of 84%. Adjusting for COVID, those are 77% for PFS and 87% for OS at 6 years.

CLL is an indolent disease and admittedly, much of the data across the various medicines for the first 3 years looks similar, but outcomes beyond this are what truly matter to patients. So this slide builds on the scatter plot, but focuses on the landmark reported PFS at years 3 through 6 across Phase III trials in frontline CLL.

On the left, we see the data for BRUKINSA and the 2 continuous BTK inhibitors. Recognizing the limitations of cross-trial comparisons, the early landmark PFS rates for BRUKINSA are higher and continue to diverge over time. In year 6, that reaches a delta of 12%, the equivalent of 1 in 8 patients not progressing.

On the right, we see an even more pronounced delta between BRUKINSA's landmark PFS and that of fixed duration regimens such as VO. In year 6, that's a delta of 21% or roughly 1 in 5 patients. In the unmutated population, which is the majority of CLL patients, the difference between continuous BRUKINSA and VO is 27%, which is more than 1 in 4 patients who started the study.

Now AbbVie has not reported the long-term landmark PFS data to be fully represented on this chart. But I will note that despite AMPLIFY being studied in a young fit population, which has a median age of 61 versus SEQUOIA's median age of 70. It has the lowest PFS of any regimen at 3 years. The last AMPLIFY data cut was April 30, 2024, over 2 years ago. An additional follow-up data has not been provided though. Of course, it exists.

BRUKINSA is the only BTK inhibitor that has demonstrated superiority on efficacy versus ibrutinib in a head-to-head trial. Here, we can see the Kaplan-Meier curves from BRUKINSA and the other BTK inhibitors in their respective head-to-head trials versus ibrutinib in relapsed/refractory BTK naive CLL patients.

BRUKINSA demonstrated superiority with a hazard ratio of 0.69 and a p-value of 0.001. When we presented the initial early cut of these data to the CLL community, the universal feedback was, this is great. But in an indolent disease, we need to see longer follow-up. And there was an important scientific reason for that. Ibrutinib has known tolerability issues that could potentially influence the patient's ability to stay on the therapy during early treatment.

In the ELEVATE-RR study, acalabrutinib had previously showed early PFS separation from ibrutinib, but that early separation was not sustained. As you can see in the middle panel, acalabrutinib actually crossed over and became numerically worse than ibrutinib at roughly 33 months and reported a hazard ratio of one. And again, while early separation was an encouraging signal, CLL prescribers wanted to see with BRUKINSA sustained separation with longer follow-up to be convinced.

You can see that in ALPINE, BRUKINSA showed exactly that. After these data were presented, the adoption of BRUKINSA began in earnest. Pirto with a very short follow-up period of only 18 months shows the weakest early separation versus ibrutinib with a hazard ratio of 0.845 and a p-value of 0.4102. The CLL community needs to see much longer follow-up data from pirto. But given this curve, pirto may face challenges demonstrating statistical superiority on PFS.

So what about tolerability? Pirto is self-described as a third-generation BTK inhibitor, with the hope that it would be more tolerable than the second-generation covalent BTK inhibitors. In reality, the BRUIN-314 study, Pirto demonstrated numerically more adverse events leading to discontinuation than ibrutinib. This is important because it has potential ramifications for use in specific subgroups such as older patients.

Notably, in the BRUIN-313 trial in first-line CLL, the average age of patients randomized to pirto was 65 years old, roughly 5 years younger than the respective first-line trials for both of the second-generation covalent BTKis. But taken together, pirto's limited follow-up, lack of differentiation on efficacy and tolerability over ibrutinib and its mechanistic rationale designed for covalent BTKi resistance do not support moving it from the relapsed setting, where it currently plays a much-needed role.

BRUKINSA's comprehensive body of evidence continues to expand. It consistently is supporting it as the foundational best-in-class BTK inhibitor. Last quarter, we highlighted 3 published studies that illustrate BRUKINSA's efficacy and safety benefits over the existing fixed duration regimens, VO, IV and AV. And at ASCO will present new evidence from over 58,000 real-world patient data sets, each of which demonstrate the significant real-world benefits of BRUKINSA.

While BRUKINSA's momentum as the foundational BTK continues, we're aggressively moving to redefine the fixed duration treatment landscape with our next-generation foundational BCL-2 inhibitor, sonro. We intentionally designed sonro to be 14x more potent and 6x more selective than venetoclax and with a much shorter half-life to minimize drug accumulation. This differentiated profile may enable a simpler ramp-up compared to the burdensome monitoring that is required by the first-generation agent.

The trial studying this optimized ramp-up schedule is progressing well. Sonro's first approvals are as monotherapy but its true transformative potential lies in combination with BRUKINSA. The clinical data that we're generating with the combination of BRUKINSA and sonro is truly exciting. In the 101 trial shown here, ZS demonstrated a uMRD rate of above 90%, a remarkably flat PFS curve and a favorable safety profile.

This compares very favorably with AV on the right, where in a much healthier, younger population, they saw uMRD of only 34%. We look forward to sharing updated data from this trial at ASCO. With 3 Phase studies underway, the ZS combination has the potential to change the first-line CLL treatment paradigm and enable BeOne to participate in half of the market where today we have no presence.

Finally, I want to highlight the progress of our BTK CDAC, a novel potential therapy for patients who have progressed on other treatments. Our BTK CDAC is first-in-class. It shows complete BTK degradation and it holds a clear mechanistic advantage in terms of BTK mutation coverage.

Data presented at ASH 2025 showcased its profound efficacy in heavily pretreated patients, including those with mutations conferring resistance to both covalent and non-covalent BTK inhibitors. In our Phase I/II study, the patients receiving the recommended 200-milligram dose achieved an outstanding 94.4% overall response rate with responses deepening consistently over time.

Based on the strong efficacy and favorable safety profile of the molecule, we're advancing a highly ambitious clinical development plan, including several Phase III trials that are well underway. We've guided to a potentially accelerated approval submission in the U.S. relapsed/refractory CLL in the second half of this year.

In summary, our foundational hematology franchise has never been stronger. BRUKINSA is driving continued global revenue growth. Sonro is poised to disrupt the fixed duration market, and our BTK CDAC is leading the next wave of innovation in CLL. Only BeOne is uniquely equipped to provide the best-in-class therapies for every CLL patient regardless of their stage of disease.

We're looking forward to ASCO and EHA this year, where we will have a large leadership presence highlighting our foundational medicines in heme and our 3 rising stars from the solid tumor portfolio, which Lai will tell us more about shortly.

With that, I'll pass it over to Aaron to provide our financial update.

Thanks, John. In Q1, we sustained strong business momentum across our product portfolio. Product revenue reached $1.5 billion in the quarter, representing 34% year-over-year growth. BRUKINSA global revenues totaled $1.1 billion, with strong growth and performance across all approved markets and indications.

In the U.S., BRUKINSA Q1 sales were $761 million, principally driven by volume growth of approximately 28% versus Q1 2025. The U.S. saw a mid-single-digit pricing benefit on a year-over-year basis with nonrecurring gross to net favorability of approximately $20 million in the period. Excluding these items, we continue to expect relatively stable pricing in 2026, consistent with prior commentary.

Q1 results reflect the typical seasonality patterns seen across the BTKi class, including inventory dynamics and one fewer shipping week in the first quarter. The business performed nicely relative to our range of expectations for the quarter with increasingly positive demand signals in March, which have carried through to April. We are confident around performance in the U.S. for the year, and this is reflected in our guidance update.

Meanwhile, TEVIMBRA reported a 20% increase with sustained market leadership in China despite the competitive environment. We are pleased with contributions from launch markets with approximately half of the growth for TEVIMBRA coming from markets outside of China. In-licensed and other products also showed continued strength, growing 27% year-over-year including robust performance from our Amgen in-licensed portfolio.

XGEVA continued to perform very well in the quarter with $90 million of revenue. Of note, we did see several biosimilar entrants filed for approval in April, which could lead to enhanced competition for XGEVA. We are pleased with the early market reception for sonrotoclax, our foundational next-generation BCL-2 inhibitor approved in China for post-BTKi CLL/SLL and relapsed/refractory MCL.

We continue our solid execution across all geographies. The U.S. remains our largest market, generating $766 million with year-over-year growth of 36%. China revenue totaled $465 million, a 17% increase compared to the first quarter of 2025, of which 5% was driven by foreign exchange. We continue to see good performance and sustained leadership from TEVIMBRA and BRUKINSA.

Europe contributed $191 million, representing growth of 64%. Foreign exchange contributed approximately 11% of this growth given euro strengthening on a year-over-year basis. We continue to drive demand growth for BRUKINSA in Europe in all major markets, and there remains plenty of opportunity to increase brand share, given BRUKINSA's differentiated long-term data across all patient types. While the AV combination has yet to achieve broad market reimbursement, we have observed BCL-2 BTKi fixed-dose treatments gaining traction in some early markets.

As we've discussed, Europe is a more mature market for these fixed dose treatments given the legacy availability of venetoclax plus ibrutinib. The long-term data is clear on the efficacy and durability of BRUKINSA across all patient risk factors particularly for the large unmutated population, which we expect will continue to support growth moving forward. Rest of World markets grew 104% driven by market expansions and new launches in key markets such as Japan and Brazil.

Now turning to the other components of our GAAP P&L. Gross margin improved to 89% from approximately 85% in the prior year. This improvement primarily reflects the benefits from favorable product mix, price and cost efficiencies. Operating expenses grew by 16%, totaling $1.1 billion as we are investing to support our commercial growth and rapidly advance our innovative pipeline. The weighting of growth between SG&A and R&D is expected to normalize over the course of the year, with both converging toward rates consistent with the overall OpEx growth implied by our full year guidance.

Income from operations totaled $250 million, an increase from $11 million in the prior period. Income tax expense totaled $32 million for the first quarter, primarily reflecting cash tax expenses in certain geographies. Altogether, net income totaled $227 million with GAAP diluted earnings per ADS of $1.96.

Our non-GAAP P&L includes adjustments for typical items with a full reconciliation provided in the appendix. Non-GAAP income from operations totaled $414 million in the first quarter up from $139 million in the prior period. And non-GAAP net income came in at $375 million for the first quarter, which translates to diluted non-GAAP earnings per ADS of $3.24. We generated free cash flow of $161 million in the first quarter, an increase of $173 million over the prior period. Note that operating and free cash flow is typically lower in the first quarter due to working capital seasonality.

Now turning to our 2026 financial guidance update. We like what we see so far in the U.S. with strong demand growth and with relatively stable net pricing. Growth is anticipated in all markets and will benefit from continued global expansion and we anticipate modest full year initial contributions from our launches of zanidatamab and sonro. And our guide incorporates all current and anticipated competitive market dynamics. Given our Q1 performance and assessment of recent trends, we now project 2026 revenue to be between $6.3 billion to $6.5 billion, an increase of $100 million across the range.

Our estimate of GAAP gross margin remains in the high 80% range with continued benefit from mix and a full year of productivity from improvements implemented last year. GAAP operating expense expectations are unchanged between $4.7 billion and $4.9 billion. Given our top line improvement, GAAP operating income estimates are updated to be between $750 million and $850 million with a corresponding change in non-GAAP operating income.

In summary, we are pleased with our start to the year and are confident with how 2026 is shaping up.

And with that, I'd like to pass the call over to Lai.

Thank you, Aaron. Hello, everyone. Thank you for joining us today. This slide highlights recent progress across BeOne's pipeline. In hematology, BRUKINSA's MANGROVE Phase III study in treatment-naive mantle cell lymphoma remains on track with interim PFS readout expected next month, supporting a potential first chemo-free regimen in this setting.

Sonro is approaching a key inflection with U.S. PDUFA decision expected soon alongside EU submission and ESMO guideline inclusion. Our BTK CDAC continued to advance with potentially pivotal Phase II programs in relapsed/refractory CLL and Waldenström, and the Phase III head-to-head study versus pirto is on track to complete enrollment in early 2027.

In solid tumors, TEVIMBRA received U.S. priority review in HER2-positive gastric cancer. In parallel, the CDK4 inhibitor has activated its first Phase III site under the GPC3 x 4-1BB bispecific is enrolling a potentially pivotal HCC study.

In addition, we acquired an exclusive option to license a novel PD-1 VEGF CTLA-4 trispecific, which is expected to enter the clinic in June. In immunology, we made a data-driven decision not to pursue IRAK4 in rheumatoid arthritis, while the BTK CDAC CSU Phase II study is on track to initiate by year-end. The progress you just saw reflects the very deliberate way we are building our pipeline.

Our strategy starts with focus, selecting a small number of disease areas where we believe we can lead and then building depth not just the single asset. What enables this approach is our in-house technology stack, expanding CDAC's novel payload ADCs, cell therapy and emerging platforms like T cell engagers. We're not bound to a specific target or platform alone. We systematically match the right biology with the right modality to build a pipeline that is deep and sustainable.

The engine has clearly accelerated from 2011 to 2020. We delivered 11 new molecular entities building the foundation with assets like zanu and the tisle. Between 2021 and 2023, we added another 10 NMEs, demonstrating consistent productivity and execution. The momentum stepped up again in the last 2 years with 18 NMEs across small molecules, CDAC, ADC and trispecific antibodies, reflecting the maturation of our in-house platforms.

Looking ahead, we expect to sustain a cadence of roughly 8 to 10 NMEs per year from 2026 and beyond, innovation that BeOne is accelerating systematic and built to scale. As our innovation engine accelerates, it is producing a broad but intentionally focused pipeline across our key disease areas. We have built depth with multiple mechanisms and modalities coexisting within the same indications. This is important because it creates unique opportunities for proprietary combinations developed entirely within our own portfolio, which drives higher return on investment rather than relying on external assets. 2026 marks a true inflection year for our solid tumor portfolio.

After several years of disciplined build-out, we now have a new wave of programs advancing toward registration. In breast cancer, our CDK4 inhibitor is moving to late-stage development in a large, well-established setting, while the B7-H4 ADC continues to advance with encouraging signals in gynecological and breast cancers.

In liver cancer, the GPC3 x 4-1BB bispecific represents a focused, first-in-class approach designed specifically for HCC with a potentially pivotal study actively enrolling. We're also advancing our PRMT5i inhibitor, which has already been evaluated in first-line settings, underscoring its potential relevance in earlier lines of therapy. Finally, based on the exciting early data, we are planning pivotal trials for our CEA ADC, further strengthening the solid tumor portfolio.

Taken together, our solid tumor pipeline is clearly shifting from early promise to late-stage execution with multiple programs advancing towards meaningful late-stage milestones. While several of these programs we highlighted are in large well-understood cancers, such as CDK4 in breast cancer, there remains less appreciation for the opportunity in hepatocellular carcinoma, HCC. As we said at JP, there is much work left to do in cancer and HCC is a clear example. As the sixth most common cancer worldwide, it is the third leading cause of cancer death, reflecting dismal 5-year survival rates that are well below many other major cancers.

A truly differentiated, potentially game-changing approach in this setting can meaningfully improve patient outcomes and expand what is already a multibillion-dollar market. The unmet medical need, you just saw in HCC demands not only innovation, but the ability to execute with a sense of urgency. Our first-in-class program, GPC3 x 4-1BB is a clear demonstration of our unprecedented clinical execution capability.

We moved from first-in-human dosing to enrolling the first patient in a potentially registrational study in just 19 months. This is exceptionally fast for a novel bispecific in solid tumor. Dose escalation was completed under 6 weeks per cohort. We have enrolled over 200 patients in 20 months, including over 45 first-line HCC patients treated in combination with tisle and bev, giving us early experience across clinical meaningful settings. Along the way, the program has received a fast track and orphan drug designation by FDA.

At the bottom of this slide is the simple view of the potential pivotal study design with ORR per IRC as the primary endpoint. ASCO 2026 will be an important moment for BeOne. We have 24 abstracts accepted, including 3 oral presentations, underscoring both the breadth and the momentum of our pipeline. You will see the clinical updates across key programs, including our CDK4 inhibitor, B7-H4 ADC and the GPC3 x 4-1BB. Please join us at our ASCO Investor Relations event on June 1 to learn more about our clinical data and why we are so excited about these assets.

At BeOne, we move quickly to clinical proof of concept and advance only programs with the strongest data into late-stage development. You can see how that discipline is being applied across the portfolio and the actions we are taking this year. We will have additional data disclosure this year for programs such as PRMT5i and the CEA ADC, while new assets like ADAM9 ADC and the KLRG1 have recently entered the clinic.

At the same time, we have made a data-driven deprioritization decisions in programs such as CDK2 inhibitor, EGFR CDAC, MAT2A inhibitor and the PanKRAS inhibitor, allowing us to reallocate resources towards the potentially highest impact opportunities. This is exactly how our strategy is intended to work, move faster to proof of concept, identify the most promising candidates and invest aggressively to maximize patient impact.

In addition to our focus on our internal breakthroughs, we are further strengthening our pipeline through selective external innovation. BON-110 is a good example of the approach and it represents a potential backbone for our solid tumor portfolio. What differentiates the trispecific from PD-1 VEGF bispecific is the addition of a CTLA-4, which gives the potential for deeper and more durable immune activation.

Importantly, this creates a broad opportunity for proprietary combinations across our pipeline, including ADCs and 4-1BB-based programs. This program -- this is on track to enter clinic next month. We have covered most of the milestones already, so I will just call out 3 remaining 2026 catalysts.

First, we expect to initiate the sonro Phase III study in second-line plus multiple myeloma later this year, extending our BCL-2 strategy into a new important patient population. Second, in the half -- in the second half of this year, assuming the data is supportive, we expect an accelerated approval submission for our BTK CDAC in relapsed/refractory CLL. And finally, we anticipate a U.S. approval for TEVIMBRA in first-line HER2-positive gastric cancer, marking a meaningful regulatory milestone in solid tumors.

I will now turn it back to John.

Thanks, Lai. We'll now open the call to Q&A. Can you please limit the number of questions to ensure that we have time to hear from as many attendees as possible.

Operator, can you please go ahead?

[Operator Instructions] Our first question is from Yigal Nochomovitz from Citigroup.

John, you've consistently highlighted BRUKINSA as the only BTK to demonstrate superiority versus ibrutinib in ALPINE, as you just noted on Slide 10. I'm just curious because one of your competitors, Lilly, has also been highlighting pirto's performance versus as recently as some of their materials in the recent earnings call stating 76% risk reduction versus ibrutinib in treatment naive and 27% PFS risk reduction in relapsed/refractory BTK naive. So I'm just wondering if you could help contextualize that and sort of sort out the apparent disconnect there.

Thanks for the question. I appreciate it. And I think that's probably best handled by Amit.

Yes. Happy to take that, John. Thank you for that question. So unequivocally, what we're saying is correct. BRUKINSA is the only BTKi to demonstrate superiority to ibrutinib in a head-to-head study. So before I talk about some of the specific problems with the pirto claims, let me just talk about a couple of important study conduct principles.

So in an open-label study, when you have 2 arms being compared, the standard industry practice based on regulatory guidance is to actually look at the data assessed by an independent review committee or an IRC rather than relying on investigator assessments. This is for the obvious reason that investigator assessments can favor the experimental arm over the control arm. Also, it is important to ensure that there is no discordance in the investigator and IRC results, and I'll come back to that in a minute.

A second important aspect is that there should be predefined alpha allocation for the subgroups being tested and the order of testing itself. So all of the claims have to be based on alpha-allocated predefined subgroups rather than exploratory subgroups.

So with that, to talk a little bit more specifically about the BRUIN-314 based claims. Now what you may have seen in some of the presentations is a claim on risk reduction compared to ibrutinib in the relapse setting of about 26%. But if you actually look at the IRC data and John had this in his previous -- in his presentation, what you see is that there are only 2 events that separate the 2 arms.

So the pirto has reported 48 events and the ibrutinib arm has noted 50 events. So if you compare this to the investigator curves, you can see that there is a significant discordance,and this really highlights the importance of the IRC curves. Now with the 2 event difference here, the likelihood of this comparison showing statistical significance even with longer follow-up seems to be very low and John made the important point that with ibrutinib in particular, as patients are able to tolerate it, we've seen what happened with the ELEVATE-RR study as well.

Now moving on to the treatment-naive group, the claims are even more questionable. Because this is a very small subgroup of the overall trial population. And according to the JCO paper is not even listed in the hierarchy of testing. So this is not a predefined group. And moreover, even in this group, when you look at the IRC-assessed difference, that is not statistically significant.

And finally, for the treatment-naive group, given the extremely short follow-up of the BRUIN study, questions around long-term safety, treatment sequencing as well as overall benefits over other BTK inhibitors remains quite questionable.

So I think really to conclude what I can say is based on all of this data, BRUKINSA remains the only BTK inhibitor to have shown clear superiority. Thank you.

Thanks Amit. And I don't think that's a like technical statistical answer. I think this is the governing chart, IRC, that the industry recognizes and as Amit shared, the data is what the data is. So anyway, we're very comfortable with that statement.

Okay, thank you. Operator, can we have next question please?

Our next question is from Kalpit Patel from Wolfe Research.

One on BRUKINSA's CELESTIAL-TNCLL trial. We were expecting uMRD results, but we didn't see that on the slide deck. So curious on the update there. And then second, for the degrader, the CDAC, what hurdle are you targeting? What efficacy hurdle for filing for accelerated approval?

Thanks so much. Those are great questions, but I think we're back to you, Amit.

Yes, happy to take those as well. Thank you, John. So for the CELESTIAL uMRD question, let me start by talking a little bit about how that study is set up. So just as a quick reminder, the CELESTIAL-301 study effectively has dual primary end points. One is the uMRD at the end of the treatment in the 2 arms and the other is PFS or progression-free survival.

So in our case, progression-free survival is the traditional regulatory end point and is the base case for our filing. So we expect PFS to be the endpoint that will support regulatory approval for that regimen. UMRD is not currently accepted as a regulatory end point but obviously remains scientifically very interesting as well as there's efforts ongoing from a regulatory perspective as well.

So in Q3 of this year, our IDMC will review the uMRD data across the arms and tell us whether statistical significance has been met or not. Irrespective of the outcomes for UMRD, we would disclose that externally at the next proximate opportunity and the study will continue to the PFS readout, essentially unchanged with no change in the study conduct.

Now it is worth noting that demonstrating statistical significance versus VO is an extremely high bar. And if positive, the CELESTIAL-301 study would be the first study to show uMRD superiority for a BTK and BCL-2 combination over VO. In prior large studies, VO has shown the highest benchmark uMRD rates. So just as an example, if you look at the recently reported CLL17 trial, the uMRD rates for VO are 73.3% and for VI they are 47.2%.

Even with the uMRD rate difference of 25% in the 2 arms, the PFS for VO and VI are essentially superimposable. So you can imagine that even if the ZS uMRD rates are on par with the VO rates, we will actually feel quite good about the likelihood of demonstrating PFS benefit. Based on this data and the data that we've seen to date with the SONRO-101 study, we remain very confident in achieving the PFS endpoint, even if uMRD is not statistically significant.

Also, we have a separate ongoing Phase III head-to-head versus AV, which we feel, based on the data presented so far represents a meaningfully lower bar for uMRD than VO in terms of the MRD rates. And either trial can enable global registration in that frontline setting. So we look forward to bringing ZS to patients based on these 2 trials.

Now quickly, just on the degrader. We've been enrolling patients in -- the relapsed/refractory patients in a Phase II study. And as far as benchmarks are concerned, I think this is an evolving area depending on what are considered available and approved therapies in the U.S. But certainly, based on that study and -- as well as the studies run with pirtobrutinib as monotherapy, we're sort of looking at the benchmark of somewhere between 50% to 70% depending on the population.

Thanks so much for the answer. And could we have the next question please?

Our next question is from Jessica Fye from JPMorgan.

I was just hoping if you could give us a status update of what inning you think we're in of BRUKINSA's launch in Europe? And then for the BTK CDAC, which I believe you suggested could be launching next year in relapsed/refractory CLL following potential filing later this year. Can you talk about how we should think about the initial launch ramp for that one?

Perhaps I can kind of answer the first question. I'm not very good at innings because I'm from Pittsburgh and our baseball team is not so great. But I think as we all know, Europe takes a while to launch and to work your way on to reimbursement. And I think we've always been behind there versus the U.S. We're very encouraged by what we see, but I think that it's still pretty early in those days, and we see the opportunity for substantial growth for BRUKINSA as a single agent. Of course, with the combination when sonro comes into play, we think this is game-changing, and the opportunity for that is just tremendous in every country across the world. That's the first question.

The second question on the CDAC launch ramp, I think that's a question that we could refer to Matt.

Glad to take that question around CDAC launch ramp. I think you've already heard from Amit and also from John about aspects of the CDAC clinical profile, which we anticipate will be very strong and particularly note the head-to-head trial design versus pirto on those later lines of therapy.

So in terms of overall launch ramp, we think that it should be relatively robust. Would anticipate a typical S-shaped uptake curve, but again, we think it's a well-prepared market, and we're confident about its prospects.

And I think one of the nice things about that program and sonro is both of these largely leverage the existing infrastructure that we have in place which is great for us and makes it much easier effort, but it's also economically highly favorable. So that's a great thing about having several programs that overlap on the clinicians that are using those medicines.

Thank you so much. Can we have the next question, please?

Our next question is from Leonid Timashev from RBC.

Just wanted to ask on the immunology programs. It looks like CSU is moving ahead potentially to a Phase II, I guess, is that suggesting that you're encouraged by what you're seeing out of the Phase Ib. And related to that, could you maybe provide some color on why the IRAK4 and RA was discontinued?

Sure. I think probably Lai, you are best to answer that question, please.

Yes. We are planning to initiate the Phase II for our BTK CDAC program in the CSU by the end of the year. In terms of -- based on the current data we have seen from the Phase I study. In terms for the IRAK4 in the rheumatoid arthritis, we decide to not further pursue the trial based on emerging new data. We're in the process of analyzing the data and decide the next steps for this program.

All right. Operator, could we have the next question, please?

Our next question is from Ziyi Chen from Goldman Sachs.

Congrats on a very strong first quarter. Just one question regarding the recent deal on the HH160, the PD-1 VEGF CTLA-4 trispecific. Could you share a bit more about your view on the asset and particularly amid the competition of emerging PD-1 VEGF bispecific and also different strategy for trispecific? And also talking about the Fc silent strategy, it's definitely going to be reduced toxicity of the CTLA-4 but also it's going to lose potentially T-reg depletion. So what is your view on that?

Sure. Thank you so much for the question. Again, I think we'll go right back to Lai.

Yes. This molecule we call BON-110, previously for the HH160, was engineered to simultaneously blocking the 3 well-established pathway, and there certainly has been bispecific between the PD-1 VEGF and the PD-1 CTLA-4 demonstrating clinical activity. We believe by adding the CTLA-4 arm, we will present potential differentiation from the current existing bispecifics. As for the tuning out the Fc function is to exactly to the point you raised is to try to mitigate the tox concern. We do believe from preclinical data, this kind of engineering will be able to still retain largely the efficacy by removing some of the safety liabilities.

Thank you. All right. We have another question, please?

Our next question comes from Gregory Renza from Truist Securities.

Congrats on the quarter. Maybe I'll weave in Aaron here for a bit and just ask a bit on the guidance. Aaron, you acknowledged that you like what you see with the growth in the markets, but also some assessment of recent trends. Perhaps you could just elaborate further on the pieces that enable you to feel confident about revenue performance for the rest of the year?

And if you could, if I may just ask a bit about, some of the factors to consider when it comes to the net pricing. I think we heard you mention consistency, but just wanted to give you an opportunity to elaborate further on maybe some of those headwinds, but also pressures if they are, by and large, passed into guidance at this point.

Great. Thanks for the question, Greg. So as I said in the prepared remarks, we really do like what we see and the setup for the year. Q1 came in on expectations, but particularly, we were encouraged by performance in the United States, both in March and into April.

You mentioned price. When we issued our original guidance, we talked about relatively stable net pricing. We feel very confident in that as we enter the year, given where we are with our various contracting opportunities. So we feel really good about that moving forward in the -- for the balance of 2026. I did touch on in Q1, we had $20 million or so of nonrecurring gross to net. So that obviously occurred in Q1, and we anticipate that will pass through for the year.

So overall, we really like where the business is sitting, strength in the United States, but really strong performance across all of our geographies. I think you see really strong growth with our European business. our China business continues to perform and demonstrate leadership and we're still in very -- using Jessica's analogy very early innings in Rest of World where the business doubled again in the first quarter. So we really like to set up. That's what gives us confidence for the guidance update with the $100 million improvement across the range.

All right. Thank you, Aaron. Could we move to another question, please?

Our next question is from Michael Schmidt from Guggenheim.

Congrats on the great first quarter here. Perhaps switching back to the pipeline, a question about the GPC3 x 4-1BB bispecific where sounds like there's things are starting to emerge that are quite interesting. And perhaps could you just comment a bit more about the pivotal study in second-line HCC. How should we think about the efficacy bar in this setting? It seems like there's an ORR readout planned. And then longer term, how do you think about the overall opportunity for this asset, perhaps in frontline HCC and other opportunities.

Thanks for the question. Good to hear your voice, and perhaps we can have Mark answer that. And if Mark doesn't jump in, we'll have Lai answer that. Maybe he's been disconnected.

So happy to address this question. In terms of the -- we're in the process of having the discussion with the health authorities to discuss about the bar. You will see our -- the Phase I data at this year's ASCO. The abstract should be released soon, but we will have further data updates at the ASCO oral presentation as well as at our investor relationship -- relation events. We're quite confident about the early data we have seen with this asset.

And certainly, we have already enrolled over 40 patients in the frontline HCC in combination with tislelizumab as well as bevacizumab. The early data is quite encouraging. We're looking forward to bring this effective medicine to patients around the globe with HCC.

Thanks so much, Lai. Could we jump to the next question?

Our next question is from Reni Benjamin from Citizens.

Congratulations on a great quarter. My question is regarding sonrotoclax and the launch in China. Can you talk a little bit about kind of how that's going, kind of is it tracking like BRUKINSA did? Or is it tracking according to internal expectations? And maybe related to that, what do you think might be the competitive dynamics once sonrotoclax is approved here in the U.S., even though it will be for MCL, any sort of on-label or potential off-label use that might impact BRUKINSA or the CLL market as a whole?

Thanks for the question. Xiaobin, do you want to start? Maybe I can finish.

Yes. So the launch is very encouraging. In China, we got approval in January and 8 days later, we launched the product. So far, YTD, we have over 300 hospitals across the country started to treat patients in China. And also sonrotoclax is also included in China, in the CSCO guideline for first-line CLL, second-line CLL and also second-line mantle cell and also for the AML. So second line AML is also listed in the guideline. And we are very, very happy the initial feedback from hospital is very encouraging. So this is China situation.

Thanks so much, Xiaobin. I think that with the launch in the U.S., we're very encouraged by everything we see with sonro. As we've described it's a more potent, more selective, specifically designed PK parameters to try to make this a very differentiated and more effective medicine. We believe that will be the case in the initial indication, where it's approved as a single agent. And the combination data, it's just in our minds, game-changing.

Now you have to work your way to approvals before you're an official commercial product, and we are working our way through that process. At the same time, we will take the data that we have, and we'll share it with the guideline committees all across the world and see if they are willing to have those join the guidelines, and it's great data. So hopefully, there's some chance that, that can occur. But we're very, very excited about this as game-changing medicine and many indications based on the data we see today.

Okay. Thank you so much. Could we take another question or 2, and then we probably have to wrap up.

Our next question is from Yaron Werber from TD Cowen.

Great. Maybe a couple of questions. Just the first one, you mentioned a little bit that AV, Aaron, is gaining some traction in some markets. I wasn't sure if those were sort of ex U.S., and I don't know if you can expand on that. And then secondly, on the CDK4 inhibitor at ASCO, any sense sort of what can we expect? How mature would the durability data be at that point on efficacy?

Thanks, Yaron. Nice to hear your voice, too. You stuck in 2 questions there. I think on the AV question, I think that what Aaron was referring to probably is the statements that they've made that they're having some international success in some perspective. I think from our point of view, it's not something that we've seen widely in the U.S., and it's hard for us to track exactly.

From the CDK4 perspective, at ASCO, I do believe that we have Mark back connected. So let's see if he can handle that question, and we can hear him.

Thank you, John, and I hope you could hear me okay. Thank you, Yaron, for the question. We're very excited to share our updated data at ASCO for our CDK4 program. We encourage everyone listening to the call to visit our poster, which will be on Monday morning of ASCO. We will be sharing data from approximately 60 patients who are frontline for stage IV disease treated in combination with letrozole. What we will show is a strong response rate across a range of doses tested that informed our Phase III dose selection.

We'll also be showing early but encouraging data about the beneficial effect of food and improving the GI tolerability profile. Because the anticipated progression-free survival for frontline breast cancer is over 2 years, the maturity still remains quite low at this time. But again, we're very excited to share the early efficacy and safety data.

Okay. Next question, please. Thank you, Mark.

Our final question is from Sean Laaman from Morgan Stanley.

John, in the business, you're showing some really strong operating leverage, and you've now got meaningfully positive operating income and net income. Maybe it's a question for Aaron. But looking out, how would you characterize sort of growth in OpEx versus the top line and just the efficiencies that you're really showing in your R&D engine.

Great. Thanks for the question, Sean. I happen to -- this happens to be amongst my favorite questions because that means our pipeline has so much opportunity is going to make such a difference for patients. And ultimately, as you know, that's what creates value in this industry. We don't provide long-term guidance, but I've shared a number of times. We really have 2 objectives as we think about managing the business financially. The first is that we are undoubtedly a growth company. You see that in our performance and in our guidance. And the second is to do that in a sustainable way, which means driving continuous operating leverage.

Now we've talked about moving toward margin expansion continuously but in a measured way that matches the opportunity in front of us. So we really like the setup to be able to hit on both of those objectives and look forward to running the business and making a difference relative to our purpose for the long term.

Thanks a lot, Aaron. And I do want to thank everyone for participating in the call. I think, again, in summary, we delivered a very strong first quarter and a solid start to 2026. We executed against our priorities. We drove revenue growth, and we're raising our full year outlook. At the same time, as you can see, the pipeline is entering a really critical phase of execution with foundational strength in hematology and a clear inflection point in solid tumors as our programs are advancing into later-stage development.

We have demonstrated, again, the power of the BeOne super highway and our strategic competitive advantage that we have in executing, which help make investment in R&D more attractive in our organization than other places in the industry. And again, the aspiration and vision of our company, which we feel closer to than we ever have is to be the company that is creating the most impact for cancer patients globally.

That means lots of medicines and lots of indications that are truly game changing for patients. And I feel more confident today than I ever have that we're on a path to being that company not in decades, but in years. I really want to thank the patients and the families that we serve, our physicians and our partners and our more than 12,000 colleagues and their families whose focus and urgency make our progress possible.

We're really encouraged by the momentum. We're confident where we're headed, and we're focused on developing medicines that are great for patients. So thank you all so much for joining us today, and have a wonderful week.

Good day, everyone. Welcome to BeOne Medicines Q4 and Full Year 2025 Earnings Call. [Operator Instructions]

At this time, I would like to turn the call over to the company.

Hello, and welcome. Thanks for joining us today. I'm Dan Maller, Head of Investor Relations at BeOne Medicines.

Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentation on the Investor Relations section of our website, ir.beonemedicines.com.

I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most recent periodic report filed with the SEC.

Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation. Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our Investor Relations website along with our earnings release. And all information in this presentation is as of the date of this presentation, We undertake no duty to update such information unless required by law.

Now turning to today's call as outlined on Slide 3. John Oyler, our Co-Founder, Chairman and CEO, will provide a business update, including commentary on our foundational CLL franchise; Aaron Rosenberg, our CFO, will provide an update on our fourth quarter financial results and 2026 financial guidance; and Lai Wang, President and Global Head of R&D, will discuss our R&D and pipeline progress.

We will then open the call to questions. Joining the team for the Q&A portion of the call will be Xiaobin Wu, President and Chief Operating Officer; Matt Shaulis, General Manager of North America; Mark Lanasa, CMO for Solid tumors; and Amit Agarwal, CMO for Hematology.

I'll now pass the call over to John. John?

Thanks, Dan, and thank you, everyone, for joining us today. Q4 marked another solid quarter of execution and a really strong finish to the year and what a year it was. 2025 certainly lived up to its promise as a year of inflection for BeOne. From a financial perspective, we delivered on our commitments, achieving significant product revenue growth, GAAP profitability and meaningful cash flow generation.

In 2025, our foundational BTK inhibitor, BRUKINSA, became #1, both in the U.S. and globally. And as you can see on this slide, the gap between BRUKINSA and the competition is widening. And that's not just a commercial achievement, it's a scientific one. BRUKINSA's long-term data have consistently raised the bar in CLL, setting a new standard for efficacy and safety. These results are reinforced by an expanding body of clinical and real-world evidence, all of which support the program's best-in-class hypothesis.

CLL is a $12 billion and growing market due to remarkable therapeutic innovation and improvement in patient outcomes over the past 15 years, but it wasn't always that way. As recently as the mid-2000s, patients with CLL received fixed duration chemo and outcomes were quite poor.

In fact, the median progression-free survival for patients taking chlorambucil was less than 1 year. In 2008, bendamustine was approved and used in combination with rituximab and the use became widespread, providing substantial benefit over the first chemo-based regimens. 6-year progression-free survival increased to 32%, which was better, but still not great. The FDA approval of ibrutinib in 2016 marked the first chemo-free option and a seminal innovation for patients.

Anchored by data that were superior to chemo, the field switched away from fixed duration approaches to continuous BTK inhibition. Why? Because it provided the best long-term outcomes for patients. You can see ibrutinib's 6-year progression-free survival and overall survival of approximately 61% and 77%, respectively. At the same time, the field was developing new fixed duration treatments that were enabled by the discovery of BCL-2 inhibition and the approval of venetoclax. These ven-based approaches greatly improved upon historic chemo-based regimens, and they began to approach the long-term benefits provided by the 2 continuous BTKIs, albeit with approximately 10% delta in 6-year progression-free survival.

However, the VI regimen was not approved by the FDA and the addition of obinutuzumab to ven has significant safety challenges, which I'm going to touch on later. As good as continuous use ibrutinib was, the molecule was not optimized for potency or selectivity. The second approved BTK inhibitor, acalabrutinib, was designed to be more selective than ibrutinib and to have a very short half-life of roughly 1 hour with the hypothesis that these changes would translate to a more favorable safety profile, including fewer cardiac adverse events.

And in that respect, acala achieved its goal, demonstrating statistically significant improvement in afib in the ELEVATE-RR study. However, in that same study, acala demonstrated non-inferior PFS compared to ibrutinib. As shown on this scatter plot, acala's 6-year progression-free survival and overall survival of 62% and 76% in treatment-naive CLL is nearly superimposable on ibrutinib. But innovation never stops. The bar set by the first 2 continuous treatments would be raised yet again by a differentiated foundational medicine, enter BRUKINSA.

BRUKINSA was designed from inception to be both more potent and more selective than ibrutinib with complete 24/7 target coverage. We took that preclinical hypothesis into the clinic where in head-to-head global Phase III trial, BRUKINSA demonstrated superior efficacy to ibrutinib and a more favorable safety profile. And this includes statistically significant improvement in afib. And at ASH 2025, BRUKINSA set a new bar for long-term patient outcomes. Here, we can see 6-year progression-free survival and overall survival of 74% and 84%. And adjusting these for COVID, those are 77% and 87%, respectively.

Now I really appreciate you bearing with me as I know I've spent a lot of time on this slide, but the data, as you can see here, is really important. These data clearly established BRUKINSA as a foundational standard against which all current and all future regimens must be compared and the long-term outcomes that patients and physicians should expect and demand. At BeOne, we believe that true innovation comes from improving upon the best. BRUKINSA did just that when it demonstrated superiority in terms of safety and efficacy over ibrutinib. No other BTK inhibitor can make that claim.

Here, we see the Kaplan-Meier curves from head-to-head trials of BRUKINSA and other BTK inhibitors versus ibrutinib in relapsed/refractory BTK-naive CLL patients. And this is as assessed by Independent Review Committee or IRC. In all of these studies, the IRC assessed PFS is the predefined key secondary endpoint to demonstrate superiority over ibrutinib.

In the ALPINE trial, BRUKINSA showed the greatest early separation from ibrutinib and remains separated with a hazard ratio of 0.69 and a p-value of 0.001, demonstrating statistical superiority on PFS. We presented longer-term follow-up data from that study at ASH just a few months ago. In the ELEVATE-RR study, acala showed early PFS separation from ibrutinib, albeit less than BRUKINSA, but that early separation was not sustained. As you can see in the middle chart, acala crossed over and became numerically worse than ibrutinib at roughly 33 months. ELEVATE-RR ultimately reported a hazard ratio of 1.

And this brings me to pirtobrutinib, a non-covalent BTK inhibitor, which recently reported data from its head-to-head trial against ibrutinib in CLL. On the right, we see the curves from relapsed/refractory BTKi naive cohort of BRUIN-314, which comprised 2/3 of the enrolled patients in that trial. You can see that pirto with only 18 months of follow-up shows the least early separation versus ibrutinib with a hazard ratio of 0.845 and a p-value of 0.4102. We need to see much longer follow-up from BRUIN-314 based on the minimal early separation in these short-term curves, and pirto may face an uphill battle and showing statistical superiority to ibrutinib in PFS.

Now if you've learned anything about BeOne Medicines over our 15 years of existence, it's that we're never satisfied with the status quo. And despite the incredible progress the industry has made, it's hard not to dream about the next chapter of CLL innovation. And we think it's time to start talking about a cure.

And with that, we proposed 3 aspirational goals for the next wave of innovation in CLL: The first one is an obvious one, life expectancy equal to that of the general population matched for geography and age for any patient diagnosed with CLL. Second, for patients who prefer a time-limited therapy, any regimen must deliver long-term outcomes that are at least as good as the best continuous treatment available. And finally, any treatment designed to offer long-term life expectancy must also deliver quality of life, ease of use and convenience.

Applying these aspirations to the scatter plot clearly implies the need for further improvements on what's currently available. And we do believe that BeOne is the only company with the foundational assets in our CLL portfolio and pipeline to take us there. The next chapter of CLL innovation is going to come from options that address the unmet needs and deliver the best long-term outcomes for patients.

So what about fixed duration? There's a clear desire from some patients and physicians for fixed duration options that provide a break from treatment. For fixed duration to change the treatment paradigm, it must elicit a deep response, demonstrate sustained progression-free survival, be safe with only minimal infection risk over continuous BTKi and be convenient to administer. And we would argue it must be compared to the foundational CLL medicine, BRUKINSA.

Naturally, patients want to be off treatment. But just as they want to know what they're gaining, every patient also wants to know what they're giving up. If that's overall survival, it's important that this is considered in the shared decision-making. So how do current fixed duration options compare to BRUKINSA? In our opinion, not very well.

Existing ven-based BTKi regimens have liabilities that have limited their uptake and approval. These include underwhelming efficacy as seen in the AMPLIFY trial, where the AV combination had an inferior depth of response compared to chemo, demonstrating an undetectable MRD of only 34% despite AMPLIFY enrolling a young, fit and low-risk frontline population. In fact, AV's PFS at 3 years follow-up was roughly the same as BRUKINSA's at 6 years. And it's quite noteworthy that we haven't seen an updated cut from AMPLIFY for nearly 2 years.

And similarly, with respect to safety, AV and VI have limitations due to ven, a less potent and less selective first-generation BCL-2 inhibitor. In terms of convenience, the low depth of response for AV may result in most patients having to be treated for far longer than 1 year to reach an undetectable MRD. In addition, ven requires cumbersome patient monitoring due to its long half-life and TLS risk, which calls into question the convenience benefit of this all-oral regimen.

At the highest level, the primary benefit of fixed duration therapy is the treatment-free interval, during which patients are not exposed to the potential side effects of ongoing therapy. In CLL, this means avoiding the agents that suppress rapid B-cell expansion, which allow for immune recovery and a reduced risk of infection.

So fixed duration therapies should lower infection risk over time, not raise it. The CLL17 trial studied fixed duration VO and VI versus continuous ibrutinib, and it was presented at ASH a few months ago. The chart on the left shows the CLL17 trial data, which tells a clear and quite concerning story. First, after 1 year of VO, severe infections continue to climb for 3 years while the patient was off treatment, as seen in blue. These infections are serious, often requiring hospitalization and IV antibiotics.

Second, even after 4 years, severe infections were still higher with VO than with continuous ibrutinib despite the 3-year treatment-free period. As a reminder, BRUKINSA demonstrated roughly 1/3 fewer grade 3/4 infections versus ibrutinib in the ALPINE study. The VO arm also showed a 67% nominally increased risk of death versus ibrutinib. These findings are quite consistent with data from other recent studies, such as AMPLIFY, where the AVO regimen was not FDA approved. In fact, the FDA specifically called out the higher death rate due to infections from the AVO arm.

In our view, this profile stands in direct opposition to what patients want and deserve from a fixed duration treatment. And if you now look at the table on the right, for the highest risk patients, roughly half of all CLL patients, VO shows notably lower PFS. This data shows that patients have an approximately 50% higher chance of progressing within 6 years. 50%.

Look, there's a narrative that the current fixed duration options are good. And if someone I love was diagnosed with CLL, my first inclination might also be towards fixed duration. But if I knew the disease had potentially 50% higher chance of progressing within 6 years. And if I knew that fixed duration wasn't reducing the risk of serious infection over 4 years, just accelerating it into the earlier years, I certainly would encourage them to think twice. The risk-benefit profile of current fixed duration regimens simply does not justify a shift away from established continuous BTKi therapy.

The evidence that existing time-limited therapies may not provide long-term outcomes comparable with BRUKINSA continues to build. Here, we can see 3 recently published match-adjusted indirect comparisons of BRUKINSA versus AV, VI and VO, which reached that conclusion. And these reflect the early trends we're seeing in real-world data. Our goal for patients that prefer a fixed duration treatment option is simple. We aim to develop a more efficacious time-limited regimen that does not come with caveats or accommodations. And we believe ZS is that therapy.

The clinical data being generated by combining the best-in-class BTK inhibitor with a potentially best-in-class BCL-2 inhibitor just looks different. With all the caveats of cross-trial comparison, ZS has demonstrated the highest undetectable MRD rate, the highest PFS for the respective follow-up when compared to other ven-based fixed duration therapies. ZS shows a favorable safety profile with fewer high-grade adverse events and no deaths.

And in terms of patient convenience, we've not yet observed any clinical or laboratory TLS, and we're very optimistic that for most patients, only one clinic visit during ramp-up will be required after zanu lead-in. Today, the CLL landscape is roughly split evenly into patients who receive continuous BTK inhibitors and those who receive some form of fixed duration treatment. And currently, BRUKINSA captures approximately half of the continuous BTK segment of the market. ZS will enable BeOne to participate in the other half of the market where today we have no presence.

In summary, BeOne remains the only company with fully owned potentially best-in-class assets across 3 foundational MOAs in CLL: BRUKINSA, sonro and our BTK CDAC. As I said earlier, we think it is time to start talking about a cure. All 3 of these foundational assets, whether it's monotherapy or in combination, represent the next chapter in CLL innovation, raising the bar for patients everywhere.

Now I'll pass it over to Aaron to provide the financial update.

Thanks, John. I'm pleased to share our fourth quarter and full year results as we delivered against all of the financial commitments that we established in the beginning of 2025.

Product revenue reached $1.5 billion in the fourth quarter, representing 32% year-over-year growth. BRUKINSA global revenues totaled $1.1 billion, growing 38% with strong performance across all geographies. For full year 2025, BRUKINSA global revenues were $3.9 billion, representing growth of 49%. And as John shared earlier, BRUKINSA has established itself as the leading BTKi globally by an increasing margin as we closed 2025.

In the U.S., BRUKINSA fourth quarter sales were $845 million, driven by volume growth of approximately 30% versus Q4 2024. Our leadership is directly linked to the differentiated breadth, quality and consistency of BRUKINSA's clinical data, including those shared at ASH 2025. Pricing dynamics in the United States were consistent with commentary provided last quarter with a mid-single-digit pricing benefit on a year-over-year basis.

These results include the previously mentioned typical seasonality benefits seen in the fourth quarter of the year for both current year performance and the 2024 baseline. Meanwhile, TEVIMBRA reported an 18% increase, reflecting continued market leadership in China. This growth was supplemented by contributions from launch markets. Our in-licensed products also showed continued strength, growing 9% year-over-year.

We continue to observe solid execution across geographies. The U.S. remains our largest market, generating $850 million with year-over-year growth of 38% China revenue totaled $399 million, an 11% increase compared to the fourth quarter of 2024, supported by TEVIMBRA and BRUKINSA's market leadership and growth from our in-licensed assets. Europe contributed $174 million, with 53% year-over-year growth as we continue our launch trajectory with BRUKINSA with increased share across all major markets. And Rest of World markets grew 74%, driven by market expansion and new launches.

Now turning to the other components of our GAAP P&L, and my commentary will be on a full year basis, unless otherwise noted. Gross margin improved to 87% from approximately 84% in the prior year. This year-over-year improvement primarily reflects the benefits from favorable product mix, price and product cost efficiencies. Operating expenses grew by 12%, totaling $4.2 billion as we are investing with discipline to support our commercial growth and rapidly advance our innovative pipeline. Income from operations totaled $447 million, showcasing the inflection in 2025 to a company that is at scale and profitable.

Bridging from operating to net income, other income and expense included a nonrecurring $40 million equity investment impairment in the fourth quarter. Income tax expense totaled $130 million for 2025, increasing from $112 million in 2024, including $25 million of nonrecurring tax expenses and $20 million of timing-related tax expenses in certain geographies. These effects, in part driven by our valuation allowance status, disproportionately impacted the fourth quarter. Altogether and including these onetime items, net income reached $287 million in GAAP -- with GAAP diluted earnings per ADS of $2.53.

Our non-GAAP P&L includes adjustments for typical items with a full reconciliation provided in the appendix. Non-GAAP income from operations totaled $1.1 billion in fiscal 2025, up from $45 million in 2024. And non-GAAP net income came in at $918 million for full year 2025, which translates to diluted non-GAAP earnings per ADS of $8.09. We continued our strong trend of cash flow generation with free cash flow of $380 million in Q4. Full year 2025 free cash flow was over $940 million.

Now turning to our 2026 financial guidance. We expect another strong year of revenue growth with continued global leadership for BRUKINSA. We anticipate that the U.S. will continue to see strong demand growth with relatively stable net pricing. Growth is anticipated in all markets and will benefit from continued global expansion in important rest of world markets. We anticipate modest initial contributions from our launches of sonrotoclax and zanidatamab as physicians begin to gain experience with these medicines ahead of launches in their respective larger market opportunities. We are pleased that these practice-changing medicines are becoming available to patients as they fulfill important unmet medical needs.

In total, we project 2026 revenue to be between $6.2 billion to $6.4 billion. As you model quarterly phasing for 2026, please recall that we expect similar seasonality in shipping weeks in Q1 2026 as we observed in Q1 2025. And therefore, we believe it is more useful to consider year-over-year growth rates in this upcoming period. Our GAAP gross margin percentage is expected to be in the high 80% range with continued benefit from mix and a full year of productivity from improvements implemented last year.

Operating expenses on a GAAP basis are anticipated to be between $4.7 billion and $4.9 billion. This level of investment ensures we are positioned to capture the full value of our commercial and late-stage pipeline opportunities. GAAP operating income is expected to be between $700 million and $800 million and non-GAAP operating income is expected to be between $1.4 billion and $1.5 billion. In terms of other income and expenses, we expect expenses to be between $25 million to $50 million. This includes interest expense associated with the Royalty Pharma arrangement.

Turning to income taxes, where we have historically been in a valuation allowance, whereby our accumulated deferred tax assets have a reserve against them. Given our recent history of earnings, we believe that there may be sufficient positive evidence to recognize a portion of these assets in 2026. The exact timing and magnitude are uncertain, but we believe that a potential reversal would result in a material tax benefit to the income tax provision when recognized. When this reversal occurs, we will reflect deferred taxes in our financial statements, and our effective tax rate will become a more meaningful and predictable metric. We will provide additional updates on income taxes throughout the year.

In summary, we are pleased with our performance in 2025 and like our setup for continued growth and financial strengthening as reflected in our 2026 guidance. I would be remiss if I did not take this opportunity to thank our global teams across all parts of BeOne for their incredible dedication to our company's purpose and the corresponding results that can be seen so clearly in our financial performance.

And with that, I'd like to pass the call over to Lai.

Thank you, Aaron. Hi, everyone. Thanks for joining us today. 2025 has been a standout year for BeOne R&D. Most notably, it was a breakout year for sonro. We achieved our first global approvals in China for relapsed/refractory MCL and CLL. In addition, regulatory submissions for relapsed/refractory MCL are under review in both the U.S. and the EU, with FDA approval expected in the first half of this year.

Our BTK degrader continues to advance steadily towards registration. In 2025, we initiated 3 Phase III studies, including a head-to-head trial versus pirto. In solid tumors, we also made a strong progress. TEVEMBRA delivered a positive Phase III readout in HER2 positive gastric cancer in combination with zanidatamab and chemotherapy. Importantly, the next wave of innovation is here. In 2025 alone, 5 assets achieved clinical PoC. And over the past 2 years, we have advanced 17 new molecule entities into the clinic.

BeOne has moved through two defining chapters in our history. In the first 10 years, we built from the ground up. With limited capabilities, we delivered two breakthrough medicines, BRUKINSA and TEVEMBRA and prove that BeOne could innovate at the highest level.

The second chapter over the past 5 years was about scale and readiness. We invested heavily to build a powerful discovery engine and a truly differentiated global clinical development super highway, transforming BeOne from a company with isolated wins into one capable of repeatable success. Today, we're positioned better than ever to deliver a continuous stream of innovation. 2026 marks the beginning of a new era for BeOne.

Over the next 3 years, we are focused on four priorities. First, we will deepen our leadership in CLL, building on our 3 foundational medicines. Second, we'll expand across hematological malignancies, including indolent and aggressive lymphomas as well as AML. Third, we'll establish BeOne as an oncology powerhouse in solid tumors, with leadership in 3 strategically chosen subtypes driven by both internal innovation and external partnerships. And finally, we plan to advance one to two potential cornerstone immunology assets towards registration. It took us 15 years to build our foundational CLL franchise. We believe we can move faster and do even better across other diseases. With greater scale and a sense of urgency, we can reach far more patients than ever before.

In CLL, today BRUKINSA is approved for both treatment-naive and relapsed/refractory patients, giving us a strong foundation. Looking ahead, in the frontline setting, BRUKINSA will serve as the foundational therapy either as continued use for patients who prefer finite therapy as a potentially best-in-class fixed duration regimen in combination with sonro. In the relapsed/refractory setting, BeOne will offer BTK-CDAC anchored therapies, we see a potential accelerated approval opportunity for our BTK CDAC as a continuous use monotherapy as early as next year. There are 3 Phase III studies ongoing to establish strong evidence versus current standard of care.

Beyond that, we believe the BTK CDAC and sonro combination has the potential to deliver best-in-class fixed duration therapy for relapsed/refractory patients with strong efficacy, safety and convenience. A Phase III study is being planned. Finally, we are also developing an alternative fixed duration option, combining sonro with anti-CD20 therapies, currently being tested head-to-head against venetoclax in a Phase III study.

We are also advancing our 3 foundational hematology assets across non-CLL indications. These molecules have demonstrated strong activity across multiple B-cell malignancies, including mantle cell lymphoma, Waldenström's macroglobulinemia, follicular lymphoma and marginal zone lymphoma. We're particularly excited about the Phase III interim analysis for zanu in combination with rituximab in treatment-naive mantle cell lymphoma expected in the first half of this year. If successful, this would represent the first chemotherapy-free regimen in this setting. In addition, we're expanding into multiple myeloma with plans to initiate a pivotal Phase III study in combination with CD38 antibody and dexamethasone by the end of this year.

2026 will also be the year we expand beyond BTK and BCL-2 MOAs in the hematology-oncology. A new wave of assets is entering the clinic, led by our proprietary, off-the-shelf iPSC-derived gamma delta T-cell therapy with 12 genetic engineering modifications. This program is highly differentiated and designed to overcome many of the limitations of the existing off-shelf cell therapies. I'm very excited about its potential in the clinic. In parallel, we're advancing T-cell engagers and T-cell boosters for B-cell malignancies particularly for aggressive lymphomas to address challenges such as tumor antigen loss and inadequate or unsustained T-cell activation.

For AML and MDS, we are building a focused portfolio to address the significant unmet medical need. Beyond sonro, this includes a first-in indication KAT6 inhibitor, supported by strong translational data and a next-generation Menin inhibitor designed to overcome all known resistance mutations. We also have additional undisclosed preclinical programs underway that will continue to fuel our future pipeline. In summary, we have built a hematology portfolio defined by durability, differentiation and depth, positioning BeOne for sustained impact well beyond our current leadership areas. With that, let me turn to solid tumors.

Previously, our solid tumor focus was largely on immuno-oncology. Over the last 2 years, we have fundamentally reengineered the portfolio, shifting towards critical oncogenic signaling pathways across breast, gynecological, lung and gastrointestinal cancers, using multiple therapeutic modalities. As you can see on the slide, we now have more than 20 assets across these focused disease areas. Among them, 5 programs have achieved proof of concept in 2025, and I will walk you through these key assets now.

First, based on strong emerging efficacy and the safety data from Phase I expansion cohorts, we plan to initiate a Phase III trial in frontline hormone receptor-positive breast cancer in the first half of 2026. The safety profile suggests potentially best-in-class hematological safety with manageable gastrointestinal toxicity. The Phase III study will compare BGB-43395 against the physician's choice of CDK4/6 inhibitor in combination with letrozole with progression-free survival by central radiology review as a primary endpoint.

Beyond the CDK4, we have 4 additional solid tumor programs advancing rapidly towards registration, all supported by compelling and evolving clinical data. B7H4 ADC, encouraging activity in gynecological cancers and the triple-negative breast cancer. A Phase III study is expected to start within 1 year. GPC3x41BB bispecific, the strength of the positive data from this program has been a pleasant surprise, showing very exciting monotherapy signals in PD-1 pretreated HCC patients in its first-in-human study. A pivotal trial will be initiated before year-end.

PRMT5 inhibitor, this asset stands out with a potentially best-in-class potency, selectivity and brain penetration. Based on emerging Phase I data, we accelerated this program into frontline non-small cell lung cancer. CEA ADC, we are seeing promising monotherapy activity in heavily pretreated patients and are planning for the pivotal trials.

It is important to note that all 4 assets have been in the clinic for less than 2 years and the 3 for less than 18 months. This is a level of focus, efficiency and execution we aim to deliver across the portfolio. Together, these 5 PoC assets represent a step change in BeOne solid tumor impact with multiple modalities, rapid clinical execution and a clear path to registration, we are no longer building a pipeline, we are building a solid tumor franchise, and this is only the beginning.

To complement our growing portfolio, we have also invested heavily in clinical execution capability. We now call this our global clinical development super highway, designed to deliver industry-leading speed, quality and reliability. Let me give you a few examples. Over the past 2 years, we have completed around 200 dose escalation cohorts across multiple first-in-human studies with a median of just 1.5 months per cohort. The industry norm is roughly 3 months. In late-stage development, last year, we completed enrollment of CELESTIAL TN CLL study with around 700 CL patients across 20 countries and more than 200 sites in just 14 months. And as you know, CLL is not an easy indication to enroll.

On the regulatory side, our most recent NDA filing, sonro's initial filing with the FDA in mantle cell lymphoma was completed within 1 month of top line data. Industry standards are typically 4 to 6 months. Finally, we're equipping the super highways with AI and automation. Today, we can already deliver near real-time data analysis and insights across all early stage clinical trials. Over the next 2 to 3 years, we expect AI and automation to unlock even greater gains in speed, quality and decision-making. This global clinical super highway is a core competitive advantage for BeOne. We look forward to sharing continued progress in future updates.

Very quickly, on 2026 catalysts, I have touched on most of them already, so let me highlight a few key ones I haven't mentioned yet. First, we just initiated a global Phase III study of ZS versus AV in treatment-naive CLL directly comparing two all-oral fixed-duration regimens. Second, in the first half of this year, we expect to file tislelizumab for HER2-positive gastric cancer in combination with zanidatamab and chemo. And finally, in immunology, we anticipate multiple proof-of-concept readouts this year, including BTK CDAC in CSU and IRAK4 CDAC in RA.

I will now turn it back to John.

Thank you so much, Lai, for the comments. Really appreciate it.

I think with that, we're going to jump to Q&A. And operator, please limit the number of questions to ensure we have time to hear from as many attendees as possible, but please go ahead.

[Operator Instructions] Our first question comes from Michael Schmidt at Guggenheim Partners.

I had a commercial question around the BTK inhibitor market and BRUKINSA. Specifically, could you comment some more on how you think about potential net pricing development in the BTK inhibitor market longer term, especially as we see your competitor products enter the CMS drug price negotiation program this year and next?

Yes. Thank you. Nice to hear from you. I think from the perspective in this space, as we've tried to lay out, this is a very differentiated value proposition with BRUKINSA versus any of the current therapies that are on the market, whether it's safety profile or whether it's just the long-term PFS and overall survival. This is, in our mind, a best-in-class product that has demonstrated the translation of its mechanism of action into real clinical results. And I think at this point, certainly, there are challenges for those other products, but we're just standing by the value that the products are creating for patients, and it's there. That's why we're showing it to you.

Can we jump into the next question, please?

Yes, our next question comes from Yaron Werber with Cowen.

Congrats on really a lot of progress. I have a question that I think a lot of us have been getting. In the guidance, what are you assuming in terms of competition from AV or Jaypirca probably sort of late, late in the year? And then maybe secondly, in terms of sonro for MCL, both in China and in the U.S., can you just help us think through a little bit kind of what's in the initial opportunity?

So Matt, perhaps you can answer that a little bit, and then we can jump to Xiaobin.

Sure. Yes. I can provide some perspective on AMPLIFY and then Jaypirca as well. As you know, AVO was not approved. And as we've discussed before, AV, while approved, was studied only in a very young and very fit patient population, which had a median age of around 61. So we think those are some natural limitations there.

Moreover, I think that we continue to be very confident in the clinical profile of BRUKINSA. We've outlined, as you heard from John, the importance of meeting some criteria for treatment in CLL, deep and durable remissions, PFS, safety and convenience. And we see that AV doesn't live up to that standard. Certainly, on MRD and PFS, it's very straightforward with safety and tolerability. I think that situation holds true. And then the convenience is still tied to some of the cumbersome nature of utilization.

Now as for Jaypirca, we have seen some data back at ASH. And overall, that body of evidence doesn't yield the level of compelling data that we think is going to really change the treatment paradigm in the earlier lines of therapy. Particularly, we continue to hear from clinicians that, that evidence does not rise to the level of burning a line of therapy with a continuous BTK and that they will continue to position Jaypirca after the continuous BTKs. And obviously, in our case, that bodes really well for BRUKINSA.

So China approved beginning of this year, 2026. And we launched so quickly after that approval. And since launch, this is about 6 weeks and the reaction in the market has been very positive. We medicated or doctor prescribed for over 300 patients.

And the approved indication is relapsed refractory mantle cell lymphoma and CLL. And so far, the safety profile has been also very good. So no major safety concern observed. So there's a very positive experience from all the major China hematology centers. It looks like very positive. And we are aiming definitely to be a market leader for the BCL-2 market going forward. This two approved BCL-2 in China. One is the venetoclax and another one is China local lisa.

Our next question comes from Ziyi Chen with Goldman Sachs.

Congrats on the results. I got one question on the immunology pipeline you mentioned about. I think this is probably the first time during the earnings briefing, you mentioned about immunology is going to be the next thing out of the 4 pillars you're going to be working on.

So Lai mentioned about there are going to be 1 or 2 cornerstone therapies that you could potentially pursue and move into pivotal studies for immunology. Could you elaborate a little bit more about what's going to be the strategy for the immunology beyond hematology and solid tumor that BeOne already been very strong at? And what's going to be over the next few years, what's going to be the path and a journey towards becoming some meaningful player in immunology?

Please, Lai. And thanks for the question.

Thanks for the question. In our preclinical pipeline, we have roughly about 20% of our assets are focused on immunology. We acknowledge we're still a young player in the immunology space. For us, we're going to be opportunistic, looking for potential opportunity to be the first-in-class or best-in-class. Our goal is in the next about 2 to 3 years to identify 1 or 2 molecules, which we feel like can be a cornerstone assets for us to build around.

So we're looking forward to share with you the updates in the upcoming additional earnings calls. But there are some very exciting molecules we're really developing at this moment. Some of that is already in the clinical stage.

Can we have another question, please?

Yes. The next question comes from Yigal Nochomovitz from Citi.

I just wanted to -- you made some excellent arguments regarding the fixed duration and the inferior options today versus continuous BTK. But I just wonder if you could just clarify, if ZS does become the fixed duration regimen of choice and the standard of care in treatment-naive, could you just clarify how you're not going to sacrifice the long-duration revenues with continuous BRUKINSA? I think that would be helpful to understand a bit better, please.

Sure. Aaron is going to answer to that.

Thanks for the question, Yigal. And you've seen the different forms of the pie chart that John shared in his slides. In the current dynamics, that's a view on the U.S. the dynamics aren't too dissimilar outside the U.S., although fixed-dose treatment for BTK BCL-2 combinations are a bit more mature in Europe.

About half the market is receiving fixed-dose treatment, half is receiving continuous use. And as you saw in that view, we're currently getting about 50% on a new patient basis for BRUKINSA. So what we're trying to state really clearly there is the combination of sonro plus zanubrutinib opens up 50% of the market where we don't play at all today. So from that dimension, and as we continue to mature candidly in our market share within the continuous use class alone with BRUKINSA, we view this as very market expanding.

Yes. I think the promise is there, and we're hopeful that the data translates as positively as we've seen so far. It really could fulfill the promise and the story that's being told now about fixed duration. And were that to happen, that would be a really wonderful thing, but it would place us in a truly, truly unique position.

I think regardless of that for this 50% of the population that is already on fixed duration, if we're anywhere near the data we're showing at this moment, it's just on every one of those boxes, checking what would be required to be a best-in-class medicine. So we're really, really excited about this opportunity. We just need to wait a little bit for a little more data to mature from that perspective.

Our next question comes from Reni Benjamin at Citizens JMP.

Congratulations on a great year and the guidance that's provided. I guess my question is regarding the BTK degrader. You had some pretty encouraging data that was presented at ASH. I thought that there was a potential for an accelerated approval in the first half of this year. I think it's been pushed out to the second half.

Can you just kind of confirm that I'm reading that right? And can you provide some color as to what's causing the pushout and how we should be thinking about the first approval?

Great question. Amit, will you please respond?

Yes. Thank you for the question, Reni. So I don't think there's been a change in terms of the timing and kind of how we're thinking about this. Obviously, this is a single-arm approach.

And so in terms of what we're looking at there is based on a single-arm trial. And so we're following that data and look forward to having the interactions with the FDA midyear and file based on our interactions with the FDA. So there's really no change in terms of the timing there.

Our next question comes from Sean Laaman at Morgan Stanley.

Just trying to understand a bit better the long runway of growth potential for BRUKINSA here. You did $3.9 billion, I think, for the year at around 40% growth. Calquence did -- I think they did double-digit growth to get to $3.5 billion and IMBRUVICA is growing negative mid-teens, but still did $2 billion.

So that's about $3.5 billion where BRUKINSA is not operating, if you like. And clearly winning the battle against IMBRUVICA, but given the compelling data that you have to show best-in-class, what's the tipping point? Or what's the wrestle here to really start eating into that Calquence share?

Aaron, would you like to answer that?

Thanks, Sean. And as we've been talking, we certainly feel very confident in the totality of the evidence for BRUKINSA. And ultimately, the dynamics you're describing in terms of our performance in the marketplace, it's the data that's resonating and ultimately translating to the growth that you've described.

As you look at the market share slide that we showed in the deck, on a new patient share, we're currently getting about 50% of the continuous use BTK market. We are the global market leader, but we're not quite at 50% yet because we continue to mature into that profile. So as you think about the growth for our business is the continued maturation into our growth profile. And certainly, we believe having the best-in-class medicine in the continuous use BTK space, there's more than ample opportunity to continue to grow share over time.

And I think our challenge is really just get people to look at the data. It speaks for itself. That is a portion of the data that we're sharing on this call, whether it's the long-term data, whether it's the head-to-head data, whether it's the combination data versus their combination data, every place you look, the story is the same.

And there's work being done in real-world data from that perspective, too. But I just think it's this overwhelming body of evidence. And that's the challenge. Of course, we're the only person that wants to share that information. The rest of the industry, it may not be in their best interest. But it's really, really important that we share it for patients so that they're getting the best medicine.

Our next question comes from Chen Chen with UBS.

So my question is on B7H4 ADC. And actually, I think this is not in the model or in the valuation right now, but I heard that you are going to initiate Phase III like within the next 12 months. So may I know that's been -- so the clinical trial would be initiated in the first half or the second half?

And also, it has shown some promising efficacy and safety in gynecology and some breast cancers. So may we know like in which indication are you going to initiate a Phase III trial? And also, I think the B7H4 ADC is roughly like at least like 12 months later than our peers, B7H4 ADC. So what are the differentiation of this molecule?

Thanks for the question. Mark, could you address that, please?

Thank you very much for the question. So we're really pleased with the progress that's been made with our B7H4 targeting ADC. This has progressed swiftly through Phase I dose escalation. And as you heard from Lai, we are planning to disclose efficacy and safety data for the dose escalation in the first half of the year at a major medical congress.

We recognize that the competitive landscape that there are a number of competing molecules, both within B7H4 and more broadly within the topo 1 conjugated ADC space, particularly in breast and gynecologic malignancies, which is why we're moving with urgency. I think that we will be able to speak in more detail regarding the differentiation of our compound once we disclose the data.

But suffice to say, we're very happy with the emerging efficacy data and think that we also have a nice safety profile with no target-mediated toxicities beyond what one would expect for a topo 1 conjugated ADC and a good hematologic safety profile. So it's checking all the boxes to be on a path for a Phase III study start as soon as possible. And again, we'll be able to share more details about first indication for Phase III versus subsequent indications for Phase III as we disclose data throughout the year.

Thanks, Mark. And could we take 2 more questions, please?

Yes. Our next question comes from Leonid Timashev with RBC Capital Markets.

I wanted to ask on the BTK degrader development pathway, specifically on the Phase IIIs. I guess, given you're going to have a potential accelerated approval and you're running 3 Phase III studies, I guess, what's the incremental value of each of those studies? I guess do you need ultimately all 3 to fully realize the opportunity? Or do you think you're still going to have rapid uptake as the data starts to flow in over time?

Amit, would you like to answer that question?

Yes. Thank you for that question. I think from a BTK degrader perspective, again, we're very encouraged by the data that we've seen so far. We do think that this is going to really be a foundational treatment as a BTK asset for the future. And in terms of the Phase III, I think we're answering important questions with the Phase III studies that we have right now, particularly with the 2 global Phase III studies. I think one is in a slightly later line with the investigator's choice as the control arm. And then the other study is really a head-to-head study against pirtobrutinib.

And so we do see incremental value, especially from that pirtobrutinib study to be able to show that as far as that population is concerned, the BTK degrader has a really sort of clear role in terms of the monotherapy. And then beyond that, we are obviously, as Lai showed, working on a BTK degrader plus sonro combination as well. And so you'll continue to see us generate more data there.

Thanks, Amit. And are there any more questions? Or should we wrap up now?

We have one more question from Rebecca Liang from Bernstein.

Congratulations on the great results. So you showed a very interesting chart on the patient share between fixed duration and continuous therapies.

I'm wondering how you see the future development between BRUKINSA and sonro. After sonro plus BRUKINSA becomes a viable option. Given that now the fixed duration therapy has half of the patient share, but obviously, much lower commercial sales.

So venetoclax, for example, only selling around $2 billion to $3 billion versus the whole BTK market at around $10 billion because of the limitation of fixed duration in treatment duration. So how do you see the future commercial -- the sales split between the 2 products, even if there's maybe no immediate guidance for the long-term peak sales, but qualitatively, the split between the 2 products?

First of all, I would clarify that although half the patients in CLL in that pie chart are listed as fixed duration, they're not all getting then. There's all sorts of other things, even chemo surprisingly, that is still being given to patients.

So first of all, as we move into that segment of the class, I think ven has been very limited by its usability, especially in the community setting. So I think that having a fixed duration treatment that can replace, I don't know, I'd say, some of these less evidence-based fixed duration treatments in that half that are being used broadly in the community center, I think, is a huge, huge value to patients. And we would expect with the quality of the early data from that, that this really could be a unique product combination within that 50% of the market for sure.

To be clear, there's lots of patients that have different prognosis in CLL. And if we jump back to that, you have deletion 17p in unmutated patients. You also have mutated patients. About half of them are high-risk factor patients. And those patients are hard to handle, for sure. And they're very hard for the current fixed duration therapies to address. I don't have the slide number, maybe someone will flash it to me. But when you go back to the slide that showed on the left-hand side, the infection rates associated with VO. On the right-hand side, you could look at the numbers there. When you look at unmutated patients and deletion 17p patients, really, the outcomes are not good at all. And that's because this is a harder disease to fight.

And our hope is it would be great if our SZ doublet, which is all-oral and easy to use and seems pretty safe, can treat all patients indefinitely, and that's truly, truly a cure. But we don't have long-term follow-up yet on that. I think the early data makes it appear this is going to be better than any fixed duration evidence-based therapy that you've seen to date. But we need time for that all to mature.

And although it could be possible that this therapy even in the highest risk patients is very compelling and can be as efficacious as continuous use BRUKINSA. It's a high bar. It's a really high bar. And you just go back and look on that scatter plot where VO is on the scatter plot versus continuous ibrutinib, which is the comparison that's made in CLL 17. Well, that's not the relevant comparison. The relevant comparison is continuous BRUKINSA which, of course, has much better-looking 6-year data from a patient and physician perspective.

So we need to see how the thing evolves, but it will take time. It will take more than 6 years to understand and establish for those high-risk patients. Is this really something that's as good as and competitive with long-term continuous BRUKINSA use. It'd be great if it is, but nobody can be sure of that.

And anyway, thank you so much for the question. And I'd like to thank everybody for today's discussion. It really marks the close of a strong fourth quarter, and it's a pivotal full year for BeOne. And I think as you just heard, 2025 was defined by really flawless commercial execution and accelerated R&D momentum across our whole business. And I do believe that our performance reflects what truly differentiates BeOne as a company. It's our commitment to scientific excellence, our exceptional speed, our relentless focus on developing the best long-term outcomes for all patients.

And on behalf of everyone here, I really want to thank the broader oncology community, the patients and families who inspire our work, the clinicians who partner with us every day and our almost 12,000 employees all around the world who continue to raise the bar. I truly believe that together, we're how the world stops cancer. And as we enter 2026, we're more confident than ever in the opportunity ahead of us.

So thank you again, everyone, for your time today, and have a wonderful week.

Great. Good morning, everyone. My name is Jess Fye. I'm a large cap biotech analyst at JPMorgan, and we're continuing the 44th Annual Healthcare Conference today with BeOne. First, you're going to hear a presentation from the company, and then we're going to go into a little Q&A. If you are in the room, raise your hand, we can pass you a mic. [Operator Instructions]

But with that out of the way, let me pass it over to the company's Co-Founder, Chair and CEO, John Oyler.

Great. Thank you so much, Jess, and thank you all for being here. It's interesting 44 years. I think I've been coming for about 25 and I really want to say how proud I am of the industry that it's made such an impact in our fight against cancer.

Over this time across a broad range of cancers, the impact on overall 5-year survival has been meaningful and dramatic. And you can see that here. Now we see critical new therapeutic modalities that were months met with skepticism, and they're just beginning to become very important in treating cancer and other diseases. And we're only seeing the tip of the iceberg right now. And this is what makes me really excited about the real impact we can have for patients.

But with that said, there's still a lot to do. 10 million people across the world are dying from cancer every year, 10 million. And that's the reason I'm here. It's the reason I wake up early in the morning. By the way, those of you here early in the morning, thank you for waking up early in the morning to join us in our fight against cancer and fighting for life in this industry. We're really committed as a company to doing this. It's why we changed our ticker to ONC to [indiscernible]. It's why we're relentlessly focused on innovation and on speed.

Cancer is an incredibly formidable foe, but we're not going anywhere. Together as an industry, we're here and we're how the world stops cancer because we must. I'd like you to note our customary disclosures. I'd like to start today with a brief look back at 2025. This was an incredible year of inflection for BeOne. From a financial perspective, we made an important commitment at this conference last year, significant product revenue growth, GAAP profitability and meaningful cash flow generation and we delivered on every one of them, and we're just getting started.

2025 saw our foundational BTK inhibitor, BRUKINSA become #1 both in the U.S. and globally. That's not just a commercial achievement. It's a scientific one. Our long-term data has now raised the bar and set a new standard for efficacy and safety and CLL treatment, which we'll explore further today. And our pipeline made incredible progress in 2025. In heme, Sonro, our foundational BCL2 inhibitor received breakthrough designation and priority review in the U.S. for relapsed MCL. And recently, it received its first-ever regulatory approvals.

Sonro had 4 regulatory approval submissions in total in 2025 and we also initiated 5 Phase III trials across a broader heme franchise. In solid tumors, we saw positive topline results for the Tisle Zani triplet combo in first-line HER2-positive gastric cancer, which showed a clinically meaningful improvement over the standard of care. Six assets achieved proof of concept across 4 modalities and 5 new molecules entered the clinic. These accomplishments set us up incredibly well for 2026 and beyond.

So let's talk about CLL. CLL is a $12 billion in growing market today due to the tremendous therapeutic innovation and improvements in patient outcomes over the past 15 years. But it wasn't always this way and it wasn't this way when I started coming to this meeting. As recently as the mid-2000s, patients with CLL received fixed duration chemo, and the results were poor.

In fact, the median progression-free survival for frontline patients taking chlorambucil was less than 1 year. This chart shows 6-year overall survival on the x-axis and 6-year PFS on the Y-axis. Only roughly 1 out of 5 patients with CLL survived 6 years and 1 out of 10 did not see their cancer progress.

In 2008, bendamustine was approved, and the use of benda plus rituximab became widely used in early 2010, and it provided substantial benefit over the first chemo regimens. As you can see, 6-year PFS increased to 32% and nearly half the patients survived 6 years. So this was better, but still not great.

In 2016, the FDA approval of ibrutinib for frontline CLL marked the first chemo-free option in CLL, and it was a seminal innovation for patients, anchored by data that were superior to chemo, the field switched away from fixed duration therapy to continuous treatment BTK, and this was because it provided the best long-term outcomes for patients. You can see ibrutinib 6-year progression-free survival and overall survival, approximately 61% and 77%, respectively.

At the same time, the field was beginning to explore fixed-duration treatments that were enabled by the discovery of BCL-2 inhibition and the approval of venetoclax. These ven-based approaches greatly improved upon historic chemo-based fixed duration regimens, and they began to approach, albeit with a 10% negative delta in the 6-year progression-free survival. The level that we could see in the long-term benefit of continuous BTK.

However, the VI regimen was not approved by the U.S. FDA and the addition of obinutuzumab to ven has significant safety challenges, which I'll touch on later. As impressive as continuous use ibrutinib was on efficacy, the molecule was not optimized for selectivity and it showed cardiac tox related issues. The second approved BTK inhibitor, acala was designed to address this and to be more selective than ibrutinib and to have a very short half-life, just about an hour with the hypothesis that these changes would translate to a more favorable safety profile, including fewer cardiac adverse events.

And in that respect, acala achieved its goal, it demonstrated statistically significant improvement in AFib in the ELEVATE-RR study. However, in that same study, acala demonstrated non-inferior PFS compared to ibrutinib.

Interestingly, as shown on this chart, acala's 6-year PFS and overall survival of 62% and 76% is nearly superimposable on ibrutinib in terms of efficacy and long-term patient benefit. But the field didn't remain static. The bar set by the first 2 continuous treatments was to be raised yet again, by a differentiated foundational medicine, enter BRUKINSA.

BRUKINSA was designed from inception to be both more potent and more selective than ibrutinib, with complete and sustainable 24/7 target coverage. We took that preclinical hypothesis into the clinic where BRUKINSA demonstrated both superior efficacy to ibrutinib and a more favorable safety profile in head-to-head global Phase III trial.

At ASH 2025, BRUKINSA set a new bar for long-term outcomes for patients with CLL. Here, you can see 6-year progression-free survival and overall survival of 74% and 84%. If you adjust for COVID, those are 77% and 87%, respectively. With these data, BRUKINSA has established the foundational standard against which all future regimens must be compared. And the long-term outcomes for patients and physicians should expect and demand these type of results. As I'll discuss later, we really do believe in the promise of fixed duration treatment, but not at the expense of PFS, of OS and of safety. These data are the data that every oncologist, every health care professional, policymaker and patients should see and discuss when they're facing a treatment.

At BeOne, we're relentlessly focused on developing innovative medicines that develop the best long-term outcomes for patients. Because behind each one of these data points, actually our lives. This is Lynn. I had the privilege of meeting her last year. Lynn was diagnosed with CLL 6 years ago. Her specific type is Deletion 17p, which is high risk, which traditionally had meant much poorer outcomes prior to BRUKINSA. Over half of all CLL diagnoses are considered high risk. And for these patients, fixed-duration treatments have not shown to be as efficacious as continuous therapy.

Lynn is thriving today, thanks to continuous BRUKINSA. She's a loving partner. She's a mother, she's a grandmother. And from my perspective, she's a real force to be rocking with. Her journey reminds us that behind every innovation are real people and their lives and the lives of their families are changed. Lynn's gratitude and resilience continues to inspire the team every day. And it's because of her in thousands of patients that are similar that we get up early every morning, and we fight with all we have for every improvement possible against this disease against progression and against side effects. Lynn's story is why we all do what we do.

At BeOne, we believe true innovation comes from improving upon the best. Here on the left, you can see the Kaplan-Meier curves from the ALPINE trial of BRUKINSA versus ibrutinib. It's in relapsed/refractory BTK naive CLL patients. In the ALPINE trial, BRUKINSA separates from ibrutinib and remain separated with a hazard ratio of 0.69 and a p-value of 0.001, which demonstrates statistical superiority over PFS.

When we presented this initially, the early cut of this data to the CLO community, the universal feedback was nice data, but we need longer follow-up. And there were 2 important scientific reasons for that. First, ibrutinib was known to have tolerability issues that could potentially influence patients' ability to stay on therapy during treatment.

And secondly, the ELEVATE-RR study acalabrutinib showed some early PFS separation from ibrutinib, but that separation was not sustained. As you can see on the right, acala crossed over and became numerically worse than ibrutinib at roughly 33 months. ELEVATE-RR ultimately reported a hazard ratio of 1 and its last reported data cutoff with September 15, 2020.

While early separation was an encouraging signal, the CLL prescribers wanted to see sustained separation with longer follow-up to be convinced. And you can see that in ALPINE BRUKINSA's longer follow-up, showed exactly that. After these data were presented, the adoption of BRUKINSA began in earnest. We continue to present data from this study, including the 6-year follow-up at ASH in December, a month ago. That brings me to pirto, a noncovalent BTK inhibitor, which recently reported data from its head-to-head trial against ibrutinib in CLL.

On the right, we see the curves from the relapsed/refractory BTK naive cohort of BRUIN 314. And this comprises of 2/3 of the patients enrolled in that trial. Importantly, the curve shown here for both studies were all assessed by Independent Review Committee or IRC. And this is the global regulatory standard for all oncology trials. It's the global standard because it corrects for potential bias associated with investigator-assessed outcomes in an open-label study such as these. In both studies, the IRC PFS was also the predefined key secondary endpoint to demonstrate superiority over ibrutinib.

You can see that with pirto with only 18 months of follow-up, it does not show meaningful early separation versus ibrutinib. There's a hazard ratio of 0.845 and a p-value of 0.41. Just look at the data. With the caveat of cross-trial comparisons, there was roughly a 12% separation at 24 months for zanu in Alpine, which was sustained roughly a 5% to 6% at 24 months for acalabrutinib in ELEVATE-RR, which was short-lived and roughly 3% and for pirto at 18 months in BRUIN 314. So we certainly need longer-term follow-up data for BRUIN 314, but based on the minimal early separation in these short-term curves, pirto may face quite an uphill battle in showing statistical superiority to ibrutinib on PFS.

Let me switch to safety because part of the hypothesis around this molecule was a safer molecule. From a safety standpoint, the data are similarly underwhelming. Despite their hypothesis, pirto did not show a meaningful safety difference versus ibrutinib across clinically important metrics such as infections, cytopenias and AEs leading to treatment discontinuation and ibrutinib is the least selective of all the covalent BTKs.

In contrast, as you see below, BRUKINSA has consistently shown long-term safety benefits versus ibrutinib. Taken together, the efficacy and safety data do not support moving pirto beyond the relapsed setting, where it currently does play a much-needed role for patients that have progressed on covalent BTK inhibitors. We do believe the next chapter of CLL innovation will continue and will come from options that address unmet needs and deliver on the best long-term outcomes for patients. There's a clear desire from patients and physicians for fixed duration first-line options that will provide a break from treatment.

For fixed duration therapies to change the treatment paradigm, they must elicit a deep response, demonstrate sustained progression-free survival, be safe with only minimal infection risk over continuous BTKI and be convenient to administer.

And we would argue they must now be compared to the foundational CLL medicine, BRUKINSA. These criteria are not being met by the current fixed duration options. Existing ven-based BTK regimens have liabilities that have limited their uptake in approval. These include underwhelming efficacy as demonstrated at ASH 2024 with the AMPLIFY trial where the AV combination actually had inferior depth of response, UMRD, to its comparator, chemo, and which may result in patients being treated for much longer than 1 year.

In this respect, the absence of longer-term data from AMPLIFY at ASH this year was quite noteworthy. And similarly, with respect to safety, the VI regimen contains ibrutinib, which is cardiotoxic. As a reminder, neither AV or VI regimens are approved in the U.S.

Lastly, then as a convenience challenge due to its long half-life and TLS risk, which requires cumbersome patient monitoring. At the highest level, the primary benefit of fixed duration therapy is the treatment-free interval during which patients are not exposed to the potential side effects of ongoing therapy.

In CLL, this means avoiding continuous BTK agents that suppress rapid B cell expansion, allowing for immune expansion and a reduction of risk of infection. So fixed duration therapies should lower infection risk over time, not raise it. The CLL 17 trial presented at ASH this year, studied fixturation VO and VI versus continuous ibrutinib and was presented last month. The chart on the left shows this trial data which tells a clear and quite concerning story.

First, after 1 year of VO, there was roughly a doubling of severe infections and these continued to climb for 3 years, even while the patient was off treatment. It's seen in blue. These infections are serious, often requiring hospitalization and IV antibiotics.

Second, even after 4 years, severe infections were still higher with VO than with continuous ibrutinib despite the 3-year treatment-free period. This is potentially because Obin, a CD20 directed monoclonal antibody has shown to cause prolonged depletion of both B cells as well as some populations of T and NK cells. And thus, it may severely impact the overall immune function.

In contrast, rather than destroy the B-cells, the BTK inhibitors prevent the B-cell proliferation by blocking BTK, a key signaling node in the cell activation pathway. The VO arm also showed 67% nominally increased risk of death versus ibrutinib. These findings, they're quite consistent with data from other recent studies, such as AMPLIFY.

In our view, that profile stands in direct opposition to what patients want and what patients deserve from a fixed duration treatment. In contrast, in ALPINE, BRUKINSA demonstrated 2/3 the rate of grade 3/4 infections versus ibrutinib. And if you now look at the table on the right for the highest-risk patients, IGHV unmutated, or deletion 17p, roughly over half of all CLL patients VO shows a notably lower PFS.

In summary, the risk-benefit profile of VO simply does not justify a shift away from established continuous BTK therapy. We do believe the next innovation in frontline CLL will come from combining our best-in-class foundational medicines. BRUKINSA plus a better design, more potent and selective BCL-2 inhibitor, sonrotoclox. As you can see in this slide, this combination checks all the boxes and it's poised to be the first regimen that delivers truly on the promise of fixed duration.

Our confidence in ZS is based on the totality of clinical data. But there's key aspects of the data that we find exceptionally compelling. Here, you can see the undetectable MRD rates and time to blood MRD from our Phase I trial which was presented at ASH last month. All of the data from our heme franchise is generating, these might be the most compelling when they're shown to KOLs with whom we meet.

Let me explain. First, the combination of ZS can drive very high rates of deep response. Secondly, and perhaps most impressively, it does so exceptionally quickly with kinetics previously unseen in any other trials of drugs targeting similar mechanisms. This type of deep response is what we're looking for in fix duration regimen to give physicians and patients the confidence to stop therapy and to still achieve positive long-term outcomes.

The CLL landscape is roughly split evenly into patients who received BTK inhibitors and those who receive some form of fixed duration treatment, whether ven-based CD20 chemo or other. We believe that ZS will fundamentally change the treatment paradigm for patients who want effective therapy without lifelong treatment. This will enable BeOne to access a segment of the market that we previously have had no presence in. And therefore, we view this as a market-expanding opportunity relative to continuous BTK BRUKINSA.

Innovation in frontline CLL is vital, but we must also address the growing unmet need in relapsed setting. While pirto has been successful in addressing the C481 mutation. Over time, we've learned this is just one of many potential mutations that can occur. Therefore, we've pioneered fundamentally a new modality, our first-in-class BTK-CDAC to address this important patient unmet medical need. This CDAC is both first-in-class and best-in-class, and it leads the way in the next novel foundation modality related for relapsed CLL.

Regarding its potency, as shown on the left, we observed similar DC50 and 90 values for our BTK to the nearest competitor molecule in head-to-head BTK degradation assays in both human and whole blood B cells. We also have shown complete target degradation at 1/4 of our moving forward dose.

And we believe that our BTK-CDAC holds a clear mechanistic advantage in terms of BTK mutation coverage, which is shown on the right. The robust clinical activity that we see with this molecule in heavily pre-treated patients is extremely exciting.

In our Phase I trial, the BTK-CDAC demonstrated an overall response rate of 86% with a median follow-up of 18 months, and the 12-month PFS is now mature at 79%, a very favorable profile compared with pirto in a similar patient population. These data from the -- form the base of our confidence in our ongoing phase III head-to-head trial versus pirto in relapsed setting and we believe this program can redefine what's possible for patients who relapse after BTK therapy.

In summary, BeOne is the only company offering potential best-in-class foundational medicines for every CLL patient type, and we'll continue our relentless approach to fighting CLL and other heme malignancies. 2026 promises to be a milestone rich year for our foundational heme franchise. We expect Phase III data from the BRUKINSA Mangrove trial in frontline MCL. We're really excited about that. And the first U.S. approval in relapsed MCL and initial global launches for Sonro. We expect accelerated approval submission for our potentially pivotal Phase II BTK-CDAC trial in relapsed CLL. And in addition, we're planning new Phase III trial initiations and multiple exciting new molecules will enter the clinic.

The BeOne story starts with CLL because it's an illustrative example of how our capabilities have come together to create significant patient impact. CLL is just the first case. But I'm here to tell you the next wave of BeOne innovation, it's already here.

In the last decade, we've become a scaled, proven and highly efficient R&D powerhouse. Our R&D team now comprises of about 4,800 people, making us one of the largest oncology-focused teams worldwide. We have deep expertise in designing small molecule inhibitors and biologics and our emerging leaders in protein degradation buy and tri-specific antibodies and ADCs. The sheer output of our research organization is remarkable, and it places us among the most prolific in the industry, irrespective of market cap. For example, in the last 18 months alone, we put 15 new molecular entities in the clinic. But it's not just numbers, each molecule has differentiated therapeutic hypothesis with best-in-class and first-in-class potential. And with our capabilities now at scale, we have the ability to deliver between 8 to 10 NMEs into the clinic each year.

I'm frequently asked, what's the part of the BeOne story that's not yet widely appreciated. And for years, I'd say, it's the huge competitive advantages and capabilities that we're investing in and building. But now I think that's much more understood when people see our speed, our cost, our productivity. But today, it's certainly the untapped potential value of our pipeline. This chart helps illustrate that point. We believe that BeOne is punching well above its weight from a pipeline productivity perspective.

In our third quarter earnings call, we highlighted 4 solid tumor programs achieving proof-of-concept in 2025. These include the CDK4, B7-H4 ADC, PRMT5 and GPC3 4-1BB. Today, I'm happy to add a fifth program, our CEA-ADC. Each of these programs has achieved clinical proof of concept with key potential differentiation and they're moving rapidly into late-stage development. Each represents a significant market opportunity and each will have external data catalysts this year.

At BeOne, we aspire to become the world's leading oncology company. And in our relatively short 15-year history, this lofty goal is becoming a reality before our very eyes. BeOne was purpose-built to discover, develop and deliver breakthrough medicines to more patients faster and to do so sustainably and at scale. We analyzed each step of the drug development ecosystem, optimizing for speed, cost, quality and scale. It wasn't easy. It took a tremendous amount of capital and human effort, but it certainly was worth it.

Because today, our fully integrated in-house model is a truly unique strategic advantage, both for our internal innovation and also for our external partners and collaborators. We call this capability, the BeOne Global Development Super Highway.

When you consider that clinical trials comprise the vast majority of the time and cost to develop medicines to patients, it's very surprising to me that the traditional industry model outsources clinical development to CROs. We took a different approach. From the beginning, we believe that this and manufacturing should be a core capability, not something to be outsourced.

So we built an integrated global organization of nearly 6,000 colleagues across clinical development and manufacturing. What's the secret? How do we accomplish it all? It's that we have people that are dedicated and motivated and driven to action. It's that we're delivering innovation at a pace that is comparable to the largest MNCs in the industry. It's that we're able to have fast proof of concept, which is the most important value inflection point in our industry. It's that we're able to be decisive and prioritize the most impactful and differentiated medicines that we have. And it's that being internal, we can move fast.

We can employ technology and enroll patients at a speed if you can. The results overall are unquestionably incredible. These are a few examples of how the global super highway enables industry-leading execution across development and registration. Over the past 2 years, we completed 200 dose escalation cohorts with a median time of 1.5 months per cohort.

We've spoken a lot about the exciting data being generated by ZS, while we enrolled 700 patients in the Phase III CELESTIAL trial in just 14 months across 20 countries, and we achieved the U.S. Sonro filing in record time 2 months from data cutoff and 1 month from the top line data. I'm often asked, how can we enroll patients so fast? This slide shows our global infrastructure that enables geographically diverse patient enrollment at greater speed.

The trials enrolled are with global intent and are designed to meet specific agency requirements such as the FDA's Project Optimis. This is one of the many areas we've optimized that leads to time advantages compared to traditional CRO-based model for drug development. And from a financial perspective, we're in a strong position. We generated over $350 million in free cash flow in Q3, and we have a solid balance sheet with over $4 billion in cash.

We've proven we can scale globally and that we can do it profitably. From a capital allocation standpoint, we'll continue to invest in commercial assets across geographies that drive profitable growth. We'll continue to fully invest in our prolific and innovative pipeline to maximize long-term value for patients and shareholders. And we'll continue to pursue value-creating business development, including opportunities that leverage our global development superhighway.

I started my presentation today with how proud I am to be part of an industry that's made such an impact in its fight against cancer. And yet, I think all of us can agree it's simply not enough. That's why at BeOne Medicines, 2026 isn't just another year on the calendar, it's another promise. A promise that we'll keep pushing boundaries, will keep relentlessly innovating and we'll deliver therapies that can truly transform lives. Every breakthrough, every trial, every molecule in our pipeline is a step closer to a world where cancer is not a life sentence, but it's just a challenge, which we can overcome.

For the sake of all patients like Lynn and the 10 million more who simply want to be, we must all fight together as one. Thank you.

So considering the breadth of the company's pipeline, what's the framework that you use to make decisions regarding what to resource?

I think that one of the things we're trying to do is have a very, very robust early set of opportunities that we can prioritize from. Because it's hard when you're a smaller company to prioritize and stop programs that are initiatives. From that perspective, we invest heavily in the early stage of research and development which most of the industry does not. And then we try to apply a much higher hurdle rate. That hurdle rate is the traditional things that companies think about the commercial opportunity, the patient opportunity, the competitive landscape.

But in all of those frameworks, I think having many more things to prioritize, you do stop a lot of things, but it lets you set an incredibly high bar, which has led so far to assets in the clinic that are very, very compelling.

And maybe kind of related to that kind of prioritization, right? So with the company transitioning to profitability, from here, how should investors think about the potential for margin expansion? And kind of what's the time frame over which BeOne could achieve margins on par with other global large caps?

Well, my exceptional CFO doesn't provide long-term guidance, but has communicated very clearly a dual mandate of the company. One is growth but the other is margin expansion over time. And I think, although in doing that, we do have the benefit of a time with incredible breakthroughs, all of these new technologies. We have this incredible team and this advanced and advantaged global super highway. And we want to think about the right ways to create long-term value with that.

So those are things we bear in mind, but we're committed to those 2 concepts in the framework of let's help patients and let's do the right thing for the long term.

Okay. And then you spent a lot of time in the presentation talking about kind of the data in CLL we just thinking about the kind of the volume opportunity for the BTKIs in CLL. And what does that look like from here?

Well, I think we've talked about the industry currently being $12 billion, $13 billion and growing. I think we do see, as fixed duration, options come to market, which we believe ZS will be that actually do meet the requirements that can be much larger share. We think this is a very unique combination that is likely to have data that so far, no one has any data that looks anything like it.

So from that perspective, that expansion into that setting, where there's a lot of fixed duration treatment right now that probably isn't as efficacious that probably isn't as high priced, there's a real expansion opportunity there. At the same time, I think in the fundamental continuous BTK therapy space, we still are -- we're the #1 player, but we're sharing the market with 2 other major players. We've crossed over and will continue in our mind, given the data to expand in that segment, too.

And then just thinking about kind of Sonro and how it fits into your CLL strategy and the pie chart you showed that was kind of like half fixed duration, but 1/4 is sort of other. Do you need Sonro in a fixed duration combo to crack into that half of the market? Or like is that only accessible with a fixed duration option? Or can you get there with mono BRUKINSA?

Look, I think mono BRUKINSA looks different as we showed with the long-term data than the other continuous BTKIs. I think that data alone, if you didn't have Sonro, it starts to raise some questions about some of the fixed duration treatment that you've seen in the past. There's reasons why you'd make that choice over ibrutinib if the cardiotox isn't there, if the PFS and OS long term looks better, I think it does, again, change the bar and it may change that decision-making process.

It certainly would, in my mind, if I were a patient. So yes, I think there's continued opportunity there.

Maybe switching gears a little bit. What gives you the confidence to pursue a frontline trial for BGB-43395?

The reason that we have that confidence, I think, is the data that we have collected and generated in the first-line setting. We haven't presented that data because it was too immature yet at a scientific meeting. So it's what we're seeing from that perspective and the conversations we're having with KOLs. As we've said, we're going to share that data at a scientific meeting in cancer as soon as we can. But I think we have the confidence to tell the investment community we're moving in that direction.

Something to watch out for. And it looks like we're out of time. So we're going to stop right there. And thank you, guys.

Thanks, everyone, for coming early, appreciate it.

All right. Good afternoon, everyone. Thanks for joining us here for Jefferies Global Healthcare Conference in London. My name is Clara Dong. I'm a biotech analyst here at Jefferies. So it's my absolute pleasure to have the BeOne team here joining us here on the stage.

We have CEO of BeOne, John Oyler; Aaron Rosenberg, CFO; and Mark Lanasa, the Chief Medical Officer of Solid Tumor. Welcome.

So it's been a really eventful year for BeOne, I have to say, with your name change, achieving profitability and BTK inhibitor BRUKINSA is now leading the global revenue. And I have to say BeOne is probably among the fastest-growing biotech companies today. So for those less -- might be less familiar with BeOne, can you talk about what makes BeOne's strategy and development platform or infrastructure very unique for enabling those milestones here?

Sure. Thank you for the question, and it's a pleasure to be here again this year. Very exciting times. We are a company that from the beginning, decided to do things quite differently. And we felt if we really want to transform the way medicine is made, have more attractive R&D returns, we needed to change the way we did things. And the vast majority of the money spent to make an oncology medicine, and we fight cancer is really spent in clinical trials, probably 75% to 90% of the cost of the medicine delivered to a patient.

So as a result, we from the beginning had a plan to go out and build our own infrastructure. And today, we have what we call the BeOne Global Super Highway, which is about 6,000 people all over the globe, 2,000 in manufacturing, 4,000 in clinical trials in 40 to 50 countries all around the world, running our own trials. So we're not working with third parties in the same way. And that lets us be faster. It lets us go places. They're less interested in or they aren't, and it lets us collect high-quality data quickly and cost effectively. I think this is fundamentally very different than almost any company in the industry. And it's very, very unique to us.

From that perspective, we also have a strong research team. We're very science-based. We put 16 new molecular entities in the clinic in the last 2 years, and we expect that to be increasing, not decreasing over time. And from that perspective, we have great products that are late stage in hematology, BRUKINSA, which is a wonderful commercial medicine already for patients with lymphoma, but then we're in earlier stages in solid tumor and doing a little bit in I&I. So that's a little bit about our company.

And since you mentioned the R&D capability, I mean, BeOne has built a really extended pipeline across multiple modalities, small molecules, degraders, ADCs and anything I can think of across oncology areas. And what gives you confidence that BeOne can remain highly competitive across all those areas?

Well, we're in a lot of the modalities, but not all. We haven't been a major player in CAR-T or radiopharm or cell and gene therapy, some other areas, we've been less focused on. But clearly, we've built with great scale in many of these areas. In protein degradation, I think we are probably one of the most prolific R&D companies in the world with 3 programs in the clinic and I think 20 preclinical programs at this moment.

From the other perspective in biologics, as I had mentioned, we build our own manufacturing, which gives us the ability as we're doing R&D and even are to be able to leverage that and move quickly and cost effectively. We learned that the hard way by working with third parties, and we really struggled to do that. It was slow, and it was very expensive. But as a result, we're doing a lot in biologics, a lot of bispecifics, trispecifics or ADCs. And by ADC, it doesn't have to be a toxin. Your payload could be something else. It could even be a degrader. So I think we do feel like we're able to do a lot in research in these areas, be very strong. And in addition to that, when they move forward into the clinic, because we've built this BeOne Global Super Highway that has got cost and time advantages that we really can pursue these and understand what's working and what isn't and triage and wind up with some incredibly impactful medicines for patients.

And as a global company, you're operating in many, many regions and your drugs are selling across the globe. And maybe could you break down the geographic diversity of your revenue base? And what kind of efforts are you making to kind of further expand the company's global footprint?

Great. Thank you for the question, and we're very proud of the financial performance for the company in 2025. We've talked about this being an incredible inflection point, and that's really showing itself across the financial profile. With respect to the globalization of our business, where we sit today, if you look at Q3 results, which we just announced, more than 50%, I believe it's 52% of our business is in the United States. We are growing significantly with our European business that printed a 71% year-over-year growth and now accounts for 12% of sales. And we're growing even more rapidly in rest of world countries with 133% year-over-year growth in the third quarter in many important markets like Japan just coming online earlier this year. So we continue to globalize. I'd expect over the longer horizon, we will continue to have a profile that looks very much like any major biopharmaceutical that's in a mature phase.

And maybe a relevant question is maybe talk about your manufacturing scale across the globe as well.

Sure. So we certainly have, as John mentioned, significant operations from a manufacturing perspective. We do follow a regional model that includes significant investments in the United States, where we have investments and partners for our small molecule production as well as the investment that we made in our biologics facility just outside Princeton, New Jersey, where we invested more than $800 million. It will be the future home of our production for TEVIMBRA, our PD-1 for the U.S. and other markets around the world.

Great. And let's now talk about your CLL franchise, which is really a key pillar of BeOne story here. So maybe could you provide a high-level overview of your CLL strategy? And then what's your really ambition in CLL? What's your vision?

I think in CLL, our vision is to make the best medicines and be able to provide the right treatment for any patient with any type of CLL at any stage. From that perspective, we have 3 important medicine or potential medicines in this space. Our BTK inhibitor, BRUKINSA, which is approved and which I think, as we mentioned, is the #1 revenue-generating BTK in the world. It is a molecule that was designed to be in all disease compartments 24/7 a day with superior PK, high potency, high selectivity. And the belief was if you want to fight cancer, you're better off sustainably inhibiting at every moment and preventing that cancer from growing. That data is broad and impressive.

And most recently, our ASH abstract published, which shows the 6-year data and 6-year follow-up for BRUKINSA. It's 74% milestone PFS, which is double digits better than results previously reported by any monotherapy BTK in this space. So it's really impressive data. And that's the PFS data. The OS data is quite similar. So we're very excited to share that later this year, but it's consistent with everything we've seen. We've run a head-to-head with ibrutinib. It showed superiority. One of the other BTKs ran a head-to-head, it didn't. And actually, at the time the study was last reported, it was numerically worse. So I think from that perspective, we believe this is the continuous therapy treatment of choice already. It's established from that perspective. And there's a breadth of data, including the data we'll report at ASH, including lots of real-world data. But the more you look at it, the clearer it is that, that hypothesis was a strong one.

From the other perspective with our BCL-2, we've shared some data about its kinetics. And basically, when you look at its speed and depth of MRD negativity, so your inability to measure CLL in blood, what we've seen is a much faster and deeper response than we've ever seen with a venetoclax set of combinations with a BTK. And roughly in a 6-month period, you can see a deeper response than in 15 months with, say, AV or IV, for example. From that perspective, once you have a year's worth of treatment, the 15-month full course, you're seeing a much, much deeper response. And it's not just in the mutated population, which traditionally is the population that the venetoclax-based therapies have done well in. It's also in the unmutated population, which that has not been true for.

So from that perspective, it really looks like this is a combination that can do things that other fixed duration therapy hasn't. And that's really important because right now, only half the patients are getting continuous therapy in first-line CLL. And roughly half of those patients, maybe a little less are on BRUKINSA today. So as we think about this combination, it really lets us broaden that. I think 20% of patients are on venetoclax or combinations thereof in the first-line setting. So it really is helpful to this franchise. But more importantly, with the data, the way it looks, I think it's going to be very, very helpful to patients.

The third piece of our CLL franchise is our BTK degrader. And we're really excited about this because the covalent BTKs have similar mutations. They overlap, there's some differences. But there's a noncovalent medicine, pirto that was developed to kind of try to address some of these mutations. And it doesn't address all of them, but it addresses some. And it's approved in relapsed/refractory setting. The beautiful thing about the degrader mechanistically is it looks like it has much broader applicability and so we also have a lot of early data in the second- and third-line settings from that perspective, which compares extremely favorably with the pirto data. And a year ago, almost a year ago, we announced we'd be starting a head-to-head study against pirto. And so that's in progress from that perspective. And we're very excited about that for relapsed/refractory patients. And then again, there's many other combinations from these. So really, we're incredibly excited about the prospect for CLL patients and our ability to help them no matter what their subtype is or what their line of therapy is.

I see you are talking about the fixed duration regimen here. So I want to talk about your kind of clinical strategy for running Phase III head-to-head trials versus standard of care with both BCL-2 Sonro and BTK degrader. Maybe just talk to us about why are you running those Phase III head-to-head trials? And why is this strategy so important?

I think we also ran BRUKINSA against ibrutinib. It's because the data supports it and because that's the fundamental question that matters to patients. So we're not afraid of that. And of course, we analyze the risk, and we're not wild cowboys taking stupid risks. But when you look at the data that exists and that is in hand, those are very warranted studies. And we're running our BCL-2 sonro plus BRUKINSA against VO. VO is good. Other people didn't do that. We're running against that despite the fact it's a high hurdle. We're doing it. We're running against AV. I'm sorry, against -- we're running against pirto with the degrader. We're not afraid to do these studies because the data supports them.

By the way, if you are successful in those studies, it ends all the questions. It ends all the nonsense about it. You've shown you're the best medicine. The commercial market is there, and it's clear for you. And I think that we've done that historically in the company. You'll continue to see us do that where we find it warranted, and we're excited and happy to be doing that. I think from the other perspective, in the CLL space, the only thing we ask is for people to look at the data, it's so clear when you actually look at the clinical data. There's been a lot of noise about fixed duration therapy. There was a lot of noise about the recent data, it's not that recent, -- the data that came out over a year ago, which was the combination of acala plus venetoclax. This is going to sweep the market. It's going to take the whole market.

Well, it was supposed to be approved 6 months ago, we're waiting on the data. We haven't seen the follow-up data. The approval in the United States has been delayed. In Europe, it was approved. But in that study, the milestone PFS at 3 years, which is only 21 months off therapy, the first 15 months you're on therapy, it's pretty close to our 6-year milestone data that I just mentioned. And we're fighting cancer. Patients want efficacy when they have cancer. And so I think that all we ask is people look at the data. Clinicians look at the data, patients look at the data, you all look at the data. We think it's, at this point, increasingly clear.

And maybe if we can talk about the time line for sonrotoclax and BTK degrader to enter the market globally. And then how should we think about the CLL market in the long run? Do you think the BCL-2 inhibitor and BTK degrader will actually expand the CLL market?

Thank you, Clara. Yes. So our expectation is that we'll be presenting data at this year's ASH for sonrotoclax and our expectation is that will lead to initial approvals in the United States and globally for sonrotoclax in 2026 and that we have potentially registrational cohorts that are enrolling for the BTK degrader that could enable a first market approval for the BTK degrader in 2027. So these molecules will be coming soon. And we think that, as John was saying, this will present an option for patients despite or regardless of what molecular subtype they have and regardless of where they are in their patient journey.

And then beyond CLL franchise, you also have a very, very broad pipeline in solid tumors. So I also want to talk about that. And across your solid tumor programs, I mean, we hear a lot of discussion on the CDK4 inhibitors, and you did commit to initiating a Phase III trial in the frontline HR-positive/HER2-negative breast cancer next year. So maybe just talk to us about what you've seen with your CDK4 inhibitors and to support your -- such a rapid development path.

So it's a very exciting time within the solid tumor portfolio. As John mentioned, we brought 16 new molecular entities into the clinic over the past 2 years, the majority of them in the solid tumor space. At the earnings call that we just had, we highlighted 4 programs that we believe are progressing towards a Phase III study start, not only the CDK4 but also PRMT5, B7-H4 ADC and our GPC3 x 4-1BB bispecific. For CDK4 specifically, we have enrolled cohorts of patients in the frontline setting as well as the second-line setting and frontline, it's in combination with letrozole. What we're seeing in that patient population is a high response rate higher than what one would expect for the approved CDK4/6 inhibitors. And we think that, that will pull through to ultimately have improved PFS. We are intending to start a Phase III study for our CDK4 inhibitor in the frontline in combination with a nonsteroidal aromatase inhibitor, which we believe will show superior PFS over the currently approved CDK4/6 inhibitors. That study will start by the end of the first half of '26.

And you just mentioned other preclinical and early-stage clinical products in your pipeline. So maybe talk to us about what's the differentiation of your PRMT5 inhibitor as well.

So for all of the medicines we bring into the clinic, our aspiration is to develop first-in-class and best-in-class medicines. And to do that, everything that we bring forward needs to have what we believe is substantial preclinical differentiation that is reasonably likely to yield clinical differentiation. So in the case of our PRMT5 molecule, what that means is that preclinically, we have the most potent PRMT5 inhibitor of any clinical stage asset. This greatest potency also leads to the greatest selectivity. And critically, it was designed to be CNS penetrant, which we view as a really essential characteristic, particularly in non-small cell lung cancer, where, unfortunately, CNS metastases occur in about 30% of patients.

So that molecule is off to a great start. It's only been in the clinic for 10 months. But again, using our development super highway, we've enrolled over 100 patients in approximately 10 months' time. We're seeing responses across multiple tumor types, including non-small cell lung cancer, pancreatic cancer and other less common tumor types.

And maybe we can also touch briefly on your BTK degrader platform. I mean this platform is highlighted by a very promising data in BTK degrader. So you also have a KRAS degrader and EGFR degrader. So maybe talk to us a little bit about those 2 programs as well.

So as you heard from John, we're very excited about the data that's emerging from our BTK degrader. We've initiated Phase III studies. We also have an IRAK4 degrader, which we recently disclosed has met its clinical proof of concept with high target degradation in target tissue of skin. We think that this is a potential first-in-class molecule for I&I indications and recently started a Phase II study in rheumatoid arthritis. We're very excited about degraders as an entity because of their catalytic mechanism of action that has advantages over small molecule inhibitors, which require a one-to-one stoichiometry to inhibit specific enzymes.

So as you mentioned, we have an EGFR degrader that's in the clinic that's progressing well. We've disclosed other targets. For example, we have a CDK2 degrader, which should enter the clinic by the end of this year and provides another opportunity to hit CDK2 in a differentiated way that can be combined with our CDK4. And we also have a pan-KRAS degrader coming forward, which we think mechanistically is very attractive in KRAS because amplifications could be a mechanism of resistance. So by actually removing the protein, you can prevent amplification, you can prevent conversion from the off state to the enzymatically on state.

And then with such a broad pipeline, maybe a question to you, Aaron. How does BeOne invest in R&D and kind of balance your internal invest in R&D versus maybe outside asset acquisition or BD activities?

Sure. Thank you. So we're very pleased with how our financial profile and particularly our balance sheet has evolved over the course of the year. We continue to operate against 2 mandates. One is we are a high-growth oncology company. On the other hand, we will do so in a sustainable way. And you see that in our financial performance. In the beginning of the year, we committed to GAAP operating income and cash flow generation for the year. If you look at our Q3 results with $125 million in net income and $354 million of free cash flow, I think we're well underway to achieve those goals.

As we think about the longer term, and I didn't provide perspective on '26 specifically, but in my prepared remarks in the third quarter, we did talk about how the pace of our margin expansion will be measured given all of the incredible opportunities that you just heard from Mark in terms of investment in more than 20 Phase III trials next year. So we continue to operate with discipline.

I think to your first order question, the key focus is making sure you're investing in the right programs, you're testing your hypotheses and you have a very high bar that you don't sacrifice. And with the depth and breadth of our pipeline and so many opportunities, we're able to maintain that high bar without question.

In terms of capital allocation, I think our priorities around capital allocation are unchanged. It's about investing to grow the business. It's about investing in the pipeline. And we'll continue to be active on the business development side. And certainly, with our balance sheet position, we have additional strategic flexibility in that regard. But we're really disciplined on prosecuting the wealth of opportunities we have coming out of our internal engine and looking for complementary assets related to those pipeline assets.

Got it. And maybe for the last minute or so, I also want to touch on AI. So in the world of AI, maybe tell us how is BeOne leveraging AI in drug discovery and development? And how do you expect this to have -- what kind of impact would you expect on the efficiency and innovation across your pipeline?

Sure. I think there's lots of areas in which it's being used in an ad hoc fashion as a tool in research with structure folding and other things. We're certainly doing a lot of that in manufacturing, same thing for process optimization and other areas. Those, I think, are very straightforward. I think we see a huge opportunity in the clinical trial side of things from that perspective. And overall, I think there's great promise, but it's hard. AI is very good when there's huge data sets in predicting what new ideas, new things could be.

In the area of overall drug discovery, a lot of the data is very fragmented and not public. A lot of the data is not high quality and in legacy systems. And so it's a harder problem that just is going to take some time and energy. But the system is only as good as the data that it's built upon. And for overall drug discovery, predicting what's going to work in a disease state. That data needs some time and energy, and we needed to involve a bit and probably have a system where we have more access. The real key to unlocking that would be tapping into real-world data, which right now is not high quality, unfortunately.

Great. Thank you, everybody, for tuning in person and online. That concludes our session here. Thank you.

Let's chat with BeOne Medicines. My name is Michael Schmidt, senior biotech analyst with Guggenheim. And it's my great pleasure to welcome Aaron Rosenberg, CFO of BeOne as well as John Scotti, Head of Strategy. Welcome. Thanks for joining us.

Thank you for having us.

So there are a lot of exciting things happening at BeOne Medicines. BeOne is one of the fastest-growing large biotech companies in my view. And this is the first year in its history really that the company has reached profitability. At the same time, BeOne has one of the deepest product pipelines in the industry. And so if you maybe step back for one second, Aaron, what are the key competitive advantages of the platform as you see it?

Great. And thank you again for having us. So we could probably spend the entire time, I think, talking about the differentiating features of BeOne Medicines. So we'll focus on a few. And I think what we often point to is our fully integrated CRO-free clinical development organization. Clearly, we have incredible discovery capabilities. You see that in action in our performance, putting 10 internally developed NMEs into the clinic in 2024 and 16 since that time to date.

And clearly, we have that capability in basic science. But what we recognized upon our founding was the critical importance of clinical development in terms of realizing the value of that innovation ultimately to the patient. Core to our mission is this focus on access, global access and in fact, to many parts of the world that typically the industry doesn't serve. And we looked at how do you solve that problem. It was recognized how much expense and development and time goes into the clinical development process. I think we often talk about 70% of the cost of developing medicines is in the clinical development process.

So to solve that problem, the company invested in a vertically integrated clinical development organization that has now more than 3,600 clinical development professionals. And now that extends to our global manufacturing capability. And the value of that is our ability to take our inventions and bring them to market with incredible speed and time advantages. And just to bring it to sort of what does it mean in practicality, I think we point to a few examples. We can look at some of our really exciting solid tumor candidates, say, our CDK4, where I think when we look at this program, we started maybe 3 years behind competition, give or take.

And now we've closed that gap as we've announced our intent to go with our first-line pivotal trial in the mid part of next year, maybe cut that down to about 15 months. We look at our CELESTIAL trial in treatment-naive CLL for sonro plus zanu, and we enrolled that study in about 14 months from start to finish. So you think about what really matters in this industry, that's being able to develop your medicines with incredible time advantages, and we're seeing that in action through that capability.

Right. So obviously, so a super efficient development platform. You also have been very successful commercially though. And so BRUKINSA, your anchor product in a way, has now captured sort of the leading market share in the BTK inhibitor market. And so yes, maybe let's touch a bit about that. And what is driving BRUKINSA growth right now in this stage of its life cycle?

Sure. I think when you talk about BRUKINSA, it starts with the medicine. This medicine was designed from inception to be fundamentally different with 24/7 target inhibition. And ultimately, that design has played itself out in the incredible differentiated data profile. And we're really excited to share a lot at the upcoming ASH, one of which is the 72-month data, SEQUOIA data, which really shows how durable BRUKINSA is in terms of sustained PFS with 74% landmark PFS, 77% on a COVID-adjusted basis. This is really unprecedented.

And when you think about particularly CLL, the importance of sustained long-term PFS for patients because this is an indolent disease, and often, you look at other medicines in the class, both existing and emerging, it's really 2 to 3 years is just not enough to see that sustained durability of the mechanism. And we're seeing that with BRUKINSA in a fundamentally differentiated way. And what does that mean? That's translated to its impact on both for patients and what's happening in the real world with prescriptions.

So what's driving BRUKINSA? Clearly, we're doing incredibly well in the United States with 47% growth on a year-over-year basis in our most recent report, more than 40% volume. We are the leader within our China business from market share by far. And we're really in the earlier days of launch globally. You think about in our European business, where we grew 71% on a year-over-year basis, much earlier in the product launch cycle where we're growing share across all the major markets. And there are many markets around the world where we're much even earlier in launch, and we're seeing incredible growth.

So we're really excited about BRUKINSA, what it's doing for patients and what it means for the long-term sustainability of our franchise. Obviously, this is the foundation of our CLL franchise. I'm sure we'll talk more about our pipeline assets, but this is really where it starts, and we're really pleased with the performance and ultimately, what this medicine is doing for patients every day.

Great. And so as we think about the CLL market longer term and especially around market dynamics, how will the potential increased uptake of fixed duration regimen affect the market opportunity longer term? And maybe stepping back, how do you think about fixed duration treatments in general in the CLL space? And do you expect them to gain more uptake? And if so, how will it affect the market overall?

Sure. So why don't I start and I'll invite John to jump in as well. So first and foremost, we're big believers in finite treatments. But we do believe that they need to meet 4 specific criteria, and we've talked about this a lot in our various discussions with investors.

First is to have a deep response measured through uMRD. The second is to have deep and sustained PFS and really looking at continuous use BRUKINSA as that benchmark. And we just talked about the 72-month SEQUOIA data. The third is having a safety profile that's no worse than what you can get today with continuous use BRUKINSA, and that's obviously a very high benchmark. And then lastly, when you're talking about fixed duration therapy, it's having the convenience effect. And what we know is while ven is a very effective medicine, it's actually very difficult to administer. And that's really limited its uptake.

So when we look at existing offerings for fixed duration treatment with respect to ven-based treatments, it really doesn't meet the mark across any of those 4 variables. So we're really excited, of course, about our potential combination with sonro plus BRUKINSA, which we believe meet all 4 of those criteria, and we can talk a bit more about the data. In terms of the market opportunity, as we come with our treatment around zanu and sonro, this is really a market expanding opportunity. And this is even before we get into our BTK CDAC.

Today, continue -- if you focus on the U.S. as an example, today, continuous use BTKs are basically getting about 50% of the market, of which we're, call it, we're getting approximately half. About 20%, 25% is getting a ven-based regimen and then CD20s and chemo-based therapies are getting the balance. So there is a significant opportunity to grow the entire market to bring an offering that solves patient needs for that fixed-dose treatment as well as the subset of patients that continuous use BTK will continue to be the right offering.

So overall, we see this as a market-expanding opportunity. And what BeOne Medicines is doing is bring offerings that can fill all portions of the patient journey. So whether you're treatment-naive and you're seeking a fixed-dose treatment, continuous use BTK and certainly in the relapsed/refractory setting that between BRUKINSA, sonro and our BTK CDAC that we can really fulfil all patient need, and that's really what we're seeking to bring.

Maybe I can just add, if we talk about then sonrotoclax and adding on to what Aaron said. If you step back and you think about then, it's a great drug actually. It's nearly a $3 billion drug. It's still growing. But its use, as Aaron mentioned, is effectively capped the academic setting, primarily in CLL, and there's reasons associated with that, that have to do with the fundamental characteristics of the molecule and the convenience challenges associated with the TLS ramp-up, the lab monitoring, et cetera, as we all know.

And so when you think about a drug like sonrotoclax, which is our BCL-2 inhibitor, we essentially designed a molecule that is 14-fold more potent, it's sixfold more selective, and there's a half-life of 5 hours, which is very different from the 26-hour half-life of venetoclax. And that's important because there's no drug accumulation. So number one, we have a molecule that is hitting the target harder. It's doing so with a wider therapeutic index, and it's doing so in a way that we hope will enable much broader access outside of the academic setting. And that's why we view this as a market expanding opportunity.

Great. I'll come back to sonrotoclax in a second, but you did mention that you completed enrolment of the CELESTIAL-301 study earlier this year, which is obviously built on some very exciting Phase II data that I think you'll update again at ASH. But on the earnings call recently, you also announced another Phase III study of the same combination head-to-head versus venetoclax, acalabrutinib. So what drove the decision to add the second study?

So maybe I can answer that one. I think when you think about the way this market has evolved and if you start first with BRUKINSA, we have, as Aaron mentioned, an overwhelming body of evidence from human PK to head-to-head trials to real-world evidence that this is the best-in-class BTK inhibitor. And yet, despite all that, there are still some physicians that ask us, well, where is your head-to-head data against acalabrutinib?

And I think when you think about SZ, which, as you know, we have an ongoing study against VO, which is the CELESTIAL-301 study that's fully enrolled as of February of this year. That is the standard of care in the U.S. from a fixed duration standpoint. And this is a company that is unafraid of running head-to-head trials because we view them as critical to delivering the best drugs to patients. And fast forward to AV, our view is that ultimately, we want to dispel any doubt that could possibly exist in the market that SZ when it eventually hopefully is approved and used in CLL is the best regimen against any comparator that exists in the market. And that's really the genesis for the trial.

Ultimately, we feel very confident about the trial because if you look at the AMPLIFY data of AV, they had 34% MRD. And what we're seeing in Phase I with ZS is 92%. So it looks very different. And again, this is due primarily most likely to this characteristics of sonrotoclax, et cetera. And ultimately, to Aaron's point earlier, our goal is to deliver a fixed duration regimen that patients and physicians can feel confident enough that they have achieved a deep enough response. So when they stop therapy, they can sustain long-term outcomes that are comparable to what we're seeing with BRUKINSA, which we really do feel like is the bar. Aaron referenced the 7-year -- 6-year 74% COVID unadjusted 77% COVID-adjusted PFS. That's our goal.

All right. Super helpful. And then maybe just one more on the CLL space. So you talked about the value of the long follow-up you have on the BRUKINSA data, the multitude of trials that are ongoing, fixed duration, et cetera. And so as we think about non-covalent BTK inhibitors entering the space, how do you think that will shape the landscape?

Yes. Maybe I can take that one as well. So we're all aware of the BRUIN 314 study, which is the pirtobrutinib head-to-head against ibrutinib that was in the ASH abstracts. So just keep in mind, this was a mixed population study, about 2/3 of it were relapsed/refractory, 1/3 was frontline. And when we look at the data, particularly in the relapsed/refractory setting, we compare those to our data, which is zanubrutinib against ibrutinib in the ALPINE trial in which we demonstrated head-to-head superiority on PFS.

If you look at their data at 18 months follow-up, they have about a 9% delta in response rate versus ibrutinib. If you look at our data, again, cross-trial comparisons and all the caveats that go along with that. But if you look at our data, our delta versus ibrutinib is about 12% on response rate at roughly similar follow-up. And what's most interesting is if you look at the deletion 17p subset, which are the most aggressive clones, these are the clones which arguably require the deepest level of constitutive BCL -- our BTK target engagement, they had virtually no difference between pirtobrutinib and ibrutinib.

I think their response rate was -- pirtobrutinib response was 80.6%, ibrutinib was 80%. And again, if you go and look at our data at roughly similar follow-up, we had a delta north of 20% in that population. So we feel very good about how zanubrutinib is performing in that population. And mechanistically, if you ask, well, how does that make sense? We feel that zanubrutinib really doesn't leave that much BTK engagement on the table. This is a drug that at trough is fully engaging the target. We've presented data and published data to the effective target engagement across all disease compartments and tissues at very, very high levels.

And pirtobrutinib, as you know, is a non-covalent inhibitor, which by default requires a thermodynamic equilibrium between on and off states, which is very different than covalent. And then if you think about the frontline setting, which, of course, was part of that trial, I think it's just too early to say much about that. And Aaron made -- alluded to this earlier, but in that trial, in the BRUIN 314 trial, only 1/3 of patients were frontline. The follow-up was, I think, 22.5 months. And we're talking about 18-month landmark PFS in which just over half the patients are really reaching that point.

And CLL is an indolent disease. It takes time for patients to progress. Ultimately, those data are really just a handful of events at this point. And we're going to have to wait for a much longer follow-up to see how those pan out against the bar of 74% at 6 years that zanubrutinib has set.

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John, thanks. This is maybe a good segue to talk about your BTK CDAC actually before we come back to sonrotoclax. But as we -- you obviously are running a head-to-head study against [indiscernible]. And so yes, maybe just stepping back, high level, how do you think about your BTK franchise strategy beyond BRUKINSA using or leveraging the BTK CDAC?

So the BTK CDAC is a very exciting molecule. It's a degrader. It's a fundamentally different mechanism. So there are a few key differences between the degraders and inhibitors. Number one is it's catalytic. One degrader can degrade several thousand copies of BTK protein. It's very different, of course, from the standard 1:1 stoichiometry that are associated with small molecule inhibitors. And then it also, by virtue of degrading the entire protein as opposed to binding solely to the kinase domain, it degrades the protein such that any scaffold function associated with that protein that is independent of the kinase domain is also obliterated effectively.

And there are mutations associated with zanubrutinib and also non-covalent inhibitors like pirtobrutinib that are in the kinase domain that abrogate kinase activity yet still result in BTK signaling. These are so-called kinase dead mutations. And they have implications from a durability of response, if you think longer term. And also those drugs are not active against those mutations. Our degrader retains activity against those mutations. And as a result of that, it seems, at least where we're going initially with the program is in the relapsed/refractory setting, again, intuitively, this makes the most sense initially given the profile of the molecule.

We have a pivotal -- potentially pivotal Phase II cohort that is fully enrolled and we will have data in the first half of next year, and we hope to be able to use those data to register the product, again, we'll see. That is in the relapsed/refractory CLL post-BTKi and post-BCL-2 setting. And we also have multiple Phase IIIs ongoing, one of which is versus investigator's choice, the second of which is head-to-head against pirtobrutinib. Again, we're confident in the profile of the molecule. We had an 84% response rate thus far in very heavily pretreated fifth-line patients, of which 80% of them have seen a BTKi and a BCL-2.

And in that data set, the 12-month landmark PFS was 79%. And when you look at -- when you look at, for example, the late-line pirtobrutinib BRUIN 321 study, they had slightly less pretreated population and a median PFS of 14 months. So we'll see how those data hold up in Phase III, but there's a reason why we're confident here. And I think KOLs have been very enthusiastic about this molecule because they're seeing responses in patients where they really don't have any other options.

Right. All right. So looking forward to that first registration data next year. What else will we learn at ASH about the BTK CDAC?

So at ASH, we're going to have several abstracts for the BTK CDAC. We'll have updated data across several B-cell malignancies, CLL, Waldenstrom's, et cetera. And we're looking forward to sharing some of those data in a month's time.

Great. And then yes, maybe then a couple of questions on sonrotoclax. You already mentioned its profile and areas of differentiation versus venetoclax, which is obviously established BCL-2 inhibitor in hematology. I think -- so this product is nearing disclosure of first registration data later this year, I believe, at ASH and MCL initially. And so maybe talk about how much more we will learn about its profile in MCL and how that will translate into the overall product offering as you think about it?

So of course, so at earnings, if you look at our earnings call, we had some data in the abstract on MCL. And maybe stepping back just a second. This is a product that received breakthrough designation in relapsed/refractory MCL. We plan to file globally based on those data later this year. And those data and longer follow-up will be presented at ASH in a month. And what's interesting about those data is when you look at them, again, this is a single-arm trial, so keep that in mind. When you look at them compared to historical benchmarks of venetoclax in the literature, you see trials of venetoclax in which venetoclax was used at 3x the approved dose.

And even despite the fact that it was triple the dose that is typically used of venetoclax, you see response rates comparable to what we're seeing and our PFS and duration of response outcomes are nearly double. And so again, in our view, when we look at the data that is emerging from that program as a single agent, we see the 14-fold increased potency, the greater therapeutic window really translating. And those are the data that you're going to see in a month and longer follow-up at ASH.

Okay. Great. And then we already talked about sonrotoclax's important role in your fixed duration regimen in CLL. But you also announced on the earnings call actually a Phase III study in multiple myeloma. And so stepping back, how do you think about the longer-term opportunity for sonrotoclax and specifically in multiple myeloma? So what's the size of that opportunity?

Yes. For multiple myeloma specifically, you're correct. We did announce that we will move forward to a Phase III later next year. Specifically, this is going to be in the translocation (11;14) population, which is about, give or take, 20% of multiple myeloma. This is going to be sonrotoclax as part of a triplet regimen with dara and dexamethasone. We acknowledge the competitiveness of the space. There are many, many, many options for patients with multiple myeloma, which is fantastic.

But a lot of the bispecifics, as you know, right now, are IV, and this would be a regimen that does not require infusions given subcutaneous daratumumab. That's point one. Point two, we saw early data from -- which we actually presented at R&D Day for venetoclax -- sorry, for sonrotoclax versus venetoclax in a combination with dexamethasone. And as you know, venetoclax in the CANOVA trial was close to reaching -- to being successful, but it didn't quite make it. And again, cross-trial comparisons, but we're seeing greater evidence of activity for sonrotoclax versus venetoclax in multiple myeloma, specifically in that translocation for (11;14) setting, which is underpinning our confidence to move forward with the pivotal trial.

Okay. Great. So obviously, between the 3 molecules, so BRUKINSA, sonrotoclax and the CDAC, you have really the CLL and hematology market in a broader sense under control and strong control. And so as we think about your solid tumor pipeline, the CDK4 inhibitor has kind of stands out as one of the more advanced programs. You did commit to a Phase III trial next year in first-line breast cancer. And so maybe just stepping back, talk about differentiation perhaps relative to Pfizer's atirmociclib.

Maybe I will just for the sake of the audience here, just remind everyone of what we disclosed on our earnings, and I'll come back and answer your question. So we decided to prioritize the first-line Phase III. And subsequently, we also decided to -- decide not to pursue a Phase III in the second-line setting, and let me just walk through the logic behind that decision.

So first and foremost, we're seeing some very encouraging data in the first-line setting for our CDK4 inhibitor. And then when you think about the second-line setting, this was always intended to be a transitional opportunity. The PFS of CDK4/6 inhibitors in the post-CDK4/6 setting is unfortunately only on the order of months, 6 months or so when you compare that to a couple of years in the first-line setting. And then on top of that, the second-line competitive landscape, as you all are aware, is extremely heterogeneous, and it has gotten even more competitive just in the past few months with recent data sets from other additional regimens.

And so when we step back and we looked at our data in the frontline setting, and we thought in the second line in 3, 4 years, if and when this would have made it to market in the second line, it was not likely to be an extremely impactful medicine in that setting. And so we decided to prioritize in the frontline setting. Now with respect to Pfizer, Pfizer presented some -- what we felt to be very interesting data at ESMO for their CDK4 inhibitor. They showed a 68% response rate, which is above the response rates that you would expect for a CDK4/6 inhibitor in the frontline setting.

And importantly, given they have longer follow-up, that response rate did appear to translate to a greater degree of PFS benefit than you would expect again with the CDK4/6 inhibitors in the frontline setting. They had 67% PFS at 24 months. What I can say about our molecule is that we're seeing a similarly high response rate as Pfizer. Obviously, we do not have the duration of follow-up yet to comment on durability, but we will definitely be presenting data for our CDK4 inhibitor in the frontline setting next year, primarily to give investigators confidence ahead of starting that Phase III in the first half of '26.

And then I just want to make one more final comment. This is a molecule that entered the clinic 40 months behind Pfizer. And they started their Phase III earlier this year. And so we really -- by virtue of the infrastructure that we have, it's incredibly valuable. We've been able to catch up materially in the clinic from quite behind to within roughly a year, give or take.

Great. Well, thanks, John and Aaron. Our time is up, unfortunately, so we have to wrap up here. I did have more questions about your pipeline, which has a lot of moving parts, a lot of molecules advancing, but we'll save that for next time. So thank you. Really appreciate the time.

Great. Thank you very much.

Good day, everyone. Welcome to BeOne Medicine's Q3 2025 Earnings Call Webcast. [Operator Instructions] After the speakers' remarks, there will be a question-and-answer session.

At this time, I would like to turn the call over to the company.

Hello and welcome. Thanks for joining us today. I'm Dan Maller, Head of Investor Relations at BeOne Medicines. Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentation on the Investor Relations section of our website, ir.beonemedicines.com.

I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most recent periodic report filed with the SEC.

Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation.

Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our Investor Relations website along with the earnings release. All information in this presentation is as of the date of this presentation, and we undertake no duty to update such information unless required by law.

Now turning to today's call as outlined on Slide 3. John Oyler, our Co-Founder, Chairman and CEO, will provide a business update; Aaron Rosenberg, CFO, will provide an update on our third quarter financial results and financial guidance; and Lai Wang, our Global Head of R&D, will discuss our R&D and pipeline progress. We will then open the call to questions. And joining the team for the Q&A portion of the call will be Xiaobin Wu, President and Chief Operating Officer; Matt Shaulis, our General Manager of North America; and Mark Lanasa, our Chief Medical Officer for solid tumors.

I'll now pass the call over to John. John?

Thanks, Dan, and thank you, everyone, for joining us today. The third quarter marked another strong quarter of execution. From a financial perspective, revenue reached $1.4 billion, which represents 41% year-on-year growth. GAAP earnings per ADS were $1.09, which represents growth of more than $2 over Q3 of last year. And we generated over $350 million of free cash flow during the quarter.

As Aaron will touch on, we strengthened our balance sheet and ended the quarter with over $4 billion in cash. BRUKINSA has continued its momentum with sustained U.S. leadership, and it's now the #1 BTK inhibitor globally. Sonro, our next-generation BCL2 inhibitor recently received FDA breakthrough designation in relapsed/refractory mantle cell lymphoma. And we're really excited about the totality of data emerging from that molecule, some of which we're going to highlight today.

BRUKINSA, Sonro and our BTK CDAC are the core elements of our leadership in B-cell malignancies, and they'll be on display next month at ASH where we'll present 47 abstracts from across our heme portfolio. The quarter also yielded multiple developments across our growing solid tumor pipeline, including clinical proof-of-concept for multiple early-stage assets, which Lai's going to discuss in more detail later.

So let me start with BRUKINSA, the backbone of our heme franchise. BRUKINSA continued to perform exceptionally well in the third quarter, growing 51% and exceeding $1 billion in quarterly global revenue for the first time. As a result and also for the first time, BRUKINSA is now the global value share leader amongst the growing BTK market. This, of course, is a major milestone for BRUKINSA and for our company.

As I discussed in detail on our Q2 earnings call, the commercial success of BRUKINSA is not by chance. It's the direct result of an overwhelming body of evidence that has accumulated over more than a decade. It's evidence that spans preclinical human pharmacokinetics, head-to-head clinical trials real-world data sets and patient physician preference in the market.

The evidence is remarkable for both its strength as well as its consistency, and this evidence continues to build with each new piece of data, both reconfirming and further strengthening our initial therapeutic hypothesis that BRUKINSA is the best BTK inhibitor.

At BeOne, we're relentlessly focused on our goal of discovering and developing innovative medicines that deliver long-term outcomes for patients. At ASH, we're presenting a 74% landmark PFS at 6 years for BRUKINSA in first-line CLL. This is from our Phase III SEQUOIA trial. We believe that these data have set the bar for what monotherapy BTK can and should be, what they should achieve in CLL.

With all the caveats of cross-trial comparisons, this is double digit better than what has been reported for other single-agent BTKis at 72 months. Interestingly, this level of sustained PFS at 6 years is in the same ballpark as other recent data from BTK van fixturation regimens at only 3 years.

Long-term follow-up from years 3 through 6 when patients are not on active therapy will be critically important to inform the future relevance of these regimens within the CLL treatment paradigm. And I think along those lines, what's also relevant about this year's ASH is what you're not seeing.

Given what I've just said about the importance of our long-term BRUKINSA data in CLL the absence of other long-term follow-up data from many other relevant CLL trials, such as AMPLIFY with the last data cut off April 30, 2024, CAPTIVATE and ELEVATE where data hasn't been reported for a couple of years.

Long-term data are the gold standard in CLL for a reason because CLL is an indolent disease, and it takes time to fully and truly understand how these regimens perform. BRUKINSA delivers the level of progression-free survival that patients and physicians should expect and should demand.

We believe in the promise of fixed duration, but we also feel that the current van-based options fall far short of that promise. In our view, the current options fail to satisfy the 4 key criteria that you see on this slide, depth of response, sustained PFS, safety and convenience. Specifically, we have concerns related to the low MRD negativity rates and sustained PFS for AV combinations, the cardiac safety, uveitis and general tolerability for IV combinations.

The long-term effects on the immune system and the related additional hospitalizations due to infections of obinutuzumab use and the overall treatment burden and feasibility of use with all of the van-based regimens. Our goal in fixed duration is simple. We aim to develop a more efficacious time-limited regimen that does not come with caveats or accommodations.

And based on the data we've generated to date, we believe that the combination of zanu and sonro is well on its way to achieving just that. Our confidence in ZS is based on the totality of clinical data to date, but there are a couple of key aspects in the data that we find exceptionally compelling.

Here, you can see the uMRD rates and the time to blood MRD from our Phase I trial. This was presented at our R&D Day in June, and we'll provide a further update on these curves at ASH. Of all the data our heme franchise is generating, these might be the most compelling to the KOLs that we meet.

So let me explain. First, the combination of zanu and sonro can drive very high rates of deep response. Secondly, and perhaps more impressingly, it does so exceptionally quickly with kinetics previously unseen in other trials of drugs targeting similar mechanisms.

This slide is so important that we're going to show it to you twice today, once now and once in live section. This is the type of deep response that we're looking for in a fixed duration regimen to give physicians and patients the confidence to stop therapy and to achieve positive long-term outcomes.

BeOne stands out as the only company with fully owned potentially best-in-class assets across the 3 foundational MOAs and CLL, BRUKINSA, sonro and our BTK CDAC. All 3 are anchored in differentiated design hypotheses and bolstered by an ever-growing body of evidence. All 3 of the potential for the broadest utility in the class. And all 3, whether as monotherapy or in combination, represent significant opportunities for patients, physicians and for our shareholders.

Together, BRUKINSA, sonro and our BTK CDA are driving the future treatment paradigm and the $12 billion and growing global CLL market. Before I close, I'd like to introduce what we're calling our development global super highway. For those of you that are newer to our story, BeOne was built different. Early on, we recognized the vast majority of the time and cost to develop and deliver a medicine was in clinical trials. We felt that such a critical component of the biopharma supply chain should be a core competency rather than something that is outsourced to a CRO.

We saw the synergies that were possible by vertically integrating manufacturing with an industry-leading clinical organization. And we know from experience how hard this can be for a small company. So fast forward 15 years, and we're proud to have built a global organization of nearly 6,000 colleagues across these 2 areas: clinical development and manufacturing. And in today's hypercompetitive costly and complicated era of drug development we really believe that this global super highway is unique to BeOne, and it's critical to generating superior returns on R&D investment.

To close, we're in the midst of an exciting milestone-rich period for both our heme franchise and our solid tumor pipeline. By the end of '26 we expect the initial global approval and launch of sonro and potentially pivotal data for our BTK CDAC. Our internal clinical team will be running more than 20 Phase III trials we anticipate more than 10 proof-of-concept data readouts and our research organization will advance around 10 new molecular entities into the clinic, 3 of which will be a heme and not just in CLL, but broadening our portfolio to help patients in other areas.

Now I'll pass it over to Aaron to provide the financial update.

Thanks, John. In the third quarter, we sustained business momentum across our product portfolio with another quarter of solid execution by our global commercial teams. Product revenue reached $1.4 billion in the second quarter, representing 40% year-over-year growth. BRUKINSA global revenues eclipsed $1 billion for the first time in a quarter growing 51% driven by strong performance across all geographies.

As John mentioned, BRUKINSA is now the leading BTK globally. In the U.S., we grew BRUKINSA volume by approximately 40% versus Q3 2024, driven by the quality and differentiation of our long-term clinical data across all patient types. The pricing dynamics in the United States were consistent with commentary provided last quarter with a mid-single-digit pricing benefit on a year-over-year basis.

Meanwhile, TEVIMBRA reported a 17% increase reflecting continued market leadership in China, albeit in an increasingly competitive market environment. This growth was supplemented by early contributions from launch markets.

Our in-licensed products also showed continued strength, growing 17% year-over-year, driven by growth of 31% from the Amgen in-licensed asset portfolio. We continue to see solid execution as we look at revenue from a geographic dimension. The U.S. remains our largest market, generating $743 million with year-over-year growth of 47%.

China revenue totaled $435 million, a 17% increase supported by TEVIMBRA and BRUKINSA market leadership and growth from our in-license assets.

Europe contributed $167 million, with 71% year-over growth as we continue our launch trajectory of BRUKINSA with increased share across all major markets. And rest of world markets grew 133% and driven by market expansions and new launches.

Now turning to the other components of our GAAP P&L. Gross margin improved to 86% from approximately 83% in the prior year. This improvement reflects the benefit from favorable product mix, price and product cost efficiencies, offset by period costs related to repositioning of our manufacturing capacity. Operating expenses grew by 11% and totaling $1.1 billion as we are investing with discipline to support our commercial growth and rapidly advance our innovative pipeline.

I thought it's worth noting that the Q3 2024 base for R&D has higher expenses for both business development milestones plus approximately $25 million in accelerated depreciation charges. Together, this has the effect of depressing the year-over-year growth rates in our Q3 2025 R&D expense, which you can observe to a degree on the non-GAAP P&L slide, which excludes depreciation.

We continue to invest assertively to advance our most promising development candidates. Income tax expense totaled $22 million for the quarter. And altogether, net income reached $125 million, representing diluted earnings per ADS of $1.09. Our non-GAAP P&L includes adjustments for typical items with a full reconciliation provided in the appendix.

Non-GAAP net income reached $304 million, reflecting an increase of $252 million compared to the previous year. This performance translates to diluted non-GAAP earnings per ADS of $2.65 for the third quarter.

The third quarter saw a notable progress in our priority of balance sheet strength as a competitive advantage. In August, we entered into a transaction to monetize our global IMDELLTRA royalty rights, generating $885 million in cash in the quarter while allowing us to participate in the potential upside with the asset. The Royalty Pharma agreement is accounted for as a liability, and therefore, we will continue to recognize the full IMDELLTRA royalty in other revenue as it is earned while simultaneously amortizing the financing liability and interest expense, please see our 10-Q for a full description of the accounting for this transaction.

And with our meaningful top line growth with margin expansion, we've seen a notable increase in free cash flow generation to $354 million in this quarter. Cash generation is the key metric of business sustainability, and we are very pleased with our progress on this dimension.

All in, Q3 ending cash and cash equivalents totaled $4.1 billion, an increase of $1.3 billion versus Q2. Moving to our 2025 financial guidance. Given our continued execution, we are updating our full year revenue guidance to be between $5.1 billion and $5.3 billion. Our gross margin guidance is unchanged, remaining in the mid- to high 80% range. And we are updating our operating expense guidance to be between $4.1 billion to $4.3 billion.

We remain committed to achieving positive GAAP operating income, and we expect to generate positive free cash flow for the year. Overall, we are pleased with our execution through the first 3 quarters of 2025, and we remain focused on full year delivery across all financial performance measures.

Now while early and staying away from providing detailed guidance, I'd like to provide some perspectives on 2026. As you consider your models for the fourth quarter of 2025 and into the first quarter of 2026, I thought it would be useful to remind you of the seasonality patterns in the U.S. of the BTK class. This includes factors such as typical inventory increases at the end of the year, followed by normal drawdowns in January.

Also, just like this year, Q1 2026 will have fewer shipment gains versus a typical 13-week quarter. This is simply the nature of the calendar, but it's something that should be considered in quarterly phasing. And while we remain committed to margin expansion across our planning horizon, the pace of improvement will be measured in the near term to ensure we are investing to maximize the value of our late-stage pipeline opportunities.

We look forward to providing our detailed 2026 guidance on our Q4 earnings call in February. And with that, it seems like an excellent time to pass it over to Lai who will share more progress about our pipeline.

Thank you, Aaron. Hi, everyone. Thanks for joining us today. Let me start with hematology. We have 50 abstracts, including 6 orals from our hematology portfolio have been accepted for presentation at ASH this year. This is a tremendous validation of the strength and the depth of our signs. I will highlight some of those key data later in my presentation.

Importantly, sonro has now received FDA breakthrough therapy designation for mental cell lymphoma. We're actively working on its first filing around the globe and our BTK integrated program has just started the Phase III head-to-head trial versus pirtobrutinib in the last refractory cell patients, a major step towards transforming the space.

On the solid tumor side, our momentum continues to build. We have achieved proof-of-concept for several innovative programs, including our CDK4 inhibitor, B7-H4 ADC, PRMT5 inhibitor under GPC3x41BB bispecifics. To be noted, most of these assets have been in the clinic for less than 18 months and some less than 1 year, this is the level of efficiency and the focus we aim to deliver across the portfolio.

For CDK4 we aim to initiate a Phase III trial in first-line BC in the first half of 2026. On the non- oncology side, our IRAK4 CDAC program achieved over 95%, IRAK4 [ protein ] degradation in healthy volunteers skin tissue, a clear PD proof-of-concept. We have already initiated a Phase II trial in rheumatoid arthritis.

Over the past few years, especially in the last 24 months, we have dramatically increased our output from the discovery engine. In that time, we have advanced 16 new molecule entities into the clinic, including 13 from our internal research team. Among them, all molecules have already achieved clinical proof-of-concept, supporting pivotal study plan.

This does not count our 4 degrade program, achieving tissue PD, POC. Across the portfolio, our programs have complete R&D-enabling studies in the medium of just 10 months, well ahead of industry benchmarks.

Even more impressively, in 2024 and 2025, we have completed over 170 dose escalation cohorts with a median time of only 7 weeks. This level of speed and the precision is what defines BeOne. Our ability to move fast, execute flawlessly under turn innovation into impact.

Moving on to our solid tumor portfolio. An area we are very excited about and where we feel increasingly confident in several programs advance towards registration. This confidence is built on strong evolving clinical data.

First, our CDK4 inhibitor program is moving forward quickly. We plan to initiate a Phase III trial in first-line hormone receptor positive breast cancer in the first half of 2026 driven by emerging strong efficacy and the safety data from our expansion cohorts. In addition, we depriotized the Phase III development in the second-line post-CDK4/6 setting due to the evolving competitive landscape.

In that context, we decided for competitive reasons to delay the disclosure of our late-line data since it is also relevant to our dose selection in frontline. Second, our B7-H4 ADC program has completed dose escalation, and we are now conducting dose optimization studies with particularly encouraging responses seen Gynecological and

Endometrial breast cancers.

Third, our PRMT5i Inhibitor stands out with potentially best-in-class features, including potency, selectivity and most importantly, brain penetration. Based on the emerging Phase I data, we are now accelerating this program into frontline lung and frontline pancreatic cancer.

And finally, our GPC3 x 4-1BB bispecific has delivered a pleasant spikes, while seeing very exciting signals as monotherapy in its first in-human study in heavily pretreated HCC tumors. Altogether, this is a portfolio that is maturing quickly and backed by early clinical momentum, and we are incredibly energized by what's ahead.

For our other solid tumor assets, we'll continue to execute and prioritize programs with the strongest potential. Our CEA ADC, EGFR x MET x MET Trispecific and the FGFR2b ADC programs are all showing encouraging early signals while continuing advancing the CDK2 Inhibitor, EGFR CDAC and the Pan-KRAS Inhibitor programs through Phase I dose aspiration studies.

At the same time, based on the current data and the broad competitive landscape, we have made the strategic decision to realign the B7-H3 ADC, and Pro-IL15 programs within the portfolio. This really reflects BeOne's disciplined development strategy, focusing our resources on programs with clear differentiation and advancing them quickly to the most important value inflection point clinical POC, where we can make database decisions.

This is how we continue to build a high-quality, high-velocity portfolio in solid tumors. Moving on to our hematology portfolio. Our sonro program is shaping up to be a potential best-in-class BCL2 inhibitor, offering greater efficacy improved safety and better convenience compared with the first-generation agents venetoclax.

We're now in the process of filing for approval in relapsed/refractory mantle cell lymphoma globally. And then we look forward to sharing good news very soon in this space. The most critical indication for sonro is CLL. We have completed enrollment in our Phase III trial comparing the ZS fixed duration regimen versus VO earlier this year.

In addition, we plan to launch another global Phase III study in the first half of 2026. Comparing ZS versus AV and mean to establish ZS as the best oral fixed duration regimen in treatment-naive CLL.

And finally, in 2026, we also plan to initiate a Phase III in second-line plus multiple myeloma exploring sonro-based triplet combination. Next, a quick update on the ASH presentation for sonro. What you see on this slide are 2 selected abstracts published early this week on sonro monotherpy, starting with mantle cell lymphoma in 103 relapsed/refractory patients who had [ power ] BTK inhibitor an anti-CD20 therapy.

So achieved an overall response rate of 53% with a medium progression-free survival of 6.5 months and a median duration of response of 15.8 months. These results look favorable compared to advanced historical data in a similar population even when [ Van ] was used at 3x of its clinical proven dose.

On the CRL side, the table on the right shows the data from a single arm study of 100 patients or post BTK in factor and post-chemoimmunotherapy. Here, sonro achieved a 76% over response rate with 19% compete responses. Both the efficacy and the safety profile look quite favorable relative to advanced previous published data in a similar population. Altogether, this results reinforced sonros strong potential to be the best-in-class BCL2 inhibitor in hematological malignancies.

In addition to the sonro monotherapy update, we are also presenting new data on the sonro combinations with Zanu under or with obinutuzumab in CLL at this year's ASH. For the ZS combination, we have more mature data as additional patients have gone through treatment. The 12 months uMRD rate has reached 92% and the most impressively with a median follow-up of 27 months to date, no patients have progressed in the 320-milligram cohort, which is truly remarkable.

For the ASH presentation, we have another data cut with additional months of follow-up showing consistent results. In terms of the safety, the profile continues to show a clear advantage compared to other fixed duration regimens. And in terms of convenience, we're very optimistic that for the vast majority of patients, only 1 clinical visit during the ramp up will be required for -- after [indiscernible].

This is a meaningful improvement for both patients and the physicians. What's most exciting about this combination is the kinetics of the uMRD achievements, which John showed you earlier. As shown on the left, the medium time to uMRD with the ZS combination was only around 4 months after starting the combo and importantly, this is independent of IGHV mutation status by about 1 year of combination therapy. That's the dashed line on the graph, the vast majority of patients achieved uMRD in contrast with the IV combination on the right, the medium time to uMRD is 16 months for IGHV mutated and 10 months for unmutated patients.

And at the 1-year mark of combo treatments, many still remain MRD positive. So overall, we believe that combining 2 potentially best-in-class agents, anu and sonro may provide the only true fixed duration options that delivers optimal efficacy safety and the convenience for patients with CLL in a reasonable time frame.

Now the update on our BTK CDAC, BGB-16673,16673 is the most advanced program of its kind in the clinic with clear best-In-class potential. We have initiated a head-to-head Phase III trial against the pirtobrutinib in the potentially pivotal Phase II study in [indiscernible] is expected to have a data readout in the first half of 2026.

We're also planning a fixed duration combination Phase III study with sonro in relapsed/refractory CLL and potentially pivotal II in Waldenström's Macroglobulinemia has been initiated. We will also show new BTK CDAC data at this year's ASH meeting. The table on that showed the CLL results published in the abstract. 16673 demonstrated an over response rate of 86.4% and with medium 18 months follow-up, the 12-month progression-free survival is now mature at 79%, a very favorable profile compared with pirtobrutinib in the similar patient population.

We also reported new data in Richter's transformation on the Waldenström's Macroglobulinemia in Richter's The OR was 52% with nearly 10% complete responses. In Waldenström's, we saw 83% ORR with a 26% VGPR risk. Altogether, this data further strengthens CDAC's position as a potentially best-in-class BTK degrader across multiple B-cell malignancies.

The robust clinical activity we observed is consistent with the preclinical data package with regard to the potency as shown on the left, we observed similar DC50 and DC90 values for 16673 and the [ Nurex ] molecule in head-to-head BTK-degraded assays in both human whole block cells and B-cells. And we believe 16673 holds a clear mechanistic advantage in terms of BTK mutation coverage as shown on the right, except for the A42AD mutation, 16673 can cover all other BTK mutants, whereas we observe the [ nurex ] molecule to 2 resistant hotspot at Methionine 477 and Glycerine 480 [ resumes ]. The broad mutation coverage of 1673 further reinforces its best-in-class potential.

And its ability to deliver potentially more durable responses for patients. Together, sonro and 16673 highlighted the depths, quality and the momentum of our hematology portfolio advancing rapidly towards multiple late-stage milestones and the transformation opportunities in the years ahead.

Finally, I'd like to share a few key milestones we are tracking for the remainder of this year and into 2026, focusing on the ones I have not mentioned earlier.

First, for BRUKINSA, the Phase III in term analysis readout for the MAMRO study in treatment-naive mantle cell lymphoma has been delayed from the second half of this year to the first half of next year due to the slower-than-anticipated event rate.

In addition, we are anticipating accelerated approval for sonrotoclax in relapse/refractory mantle cell lymphoma and the CRO in China early next year. Important milestones as we continue to broaden access for patients globally.

Turning to our early stage pipeline. We're anticipating POCs for CDAC before the year-end and the other assets in 2026. We look forward to sharing more data in future updates. And with that, I will turn the call back to John.

Thanks, Lai. We'll now open the call to Q&A. [Operator Instructions] Operator, please go ahead.

[Operator Instructions] Our first question will come from Yaron Werber with Cowen and Company.

Hopefully, you can hear me.

Yes.

Congrats, really nice quarter. I'm going to violate the rule right away. Just 2 quick questions. Number one, BRUKINSA's the global leader. You're obviously a little bit behind in Europe in terms of when you launched any sense and when new territories are coming in to accelerate that?

And then secondly, Life for the CDAC data in the first half next year in CLL for the potentially support accelerated approval, can you give us a sense of what to expect there? And sort of how mature is the PFS is going to be?

Right. So Xiaobin, do you want to start?

Yes. In Europe, we grow for BRUKINSA are tremendously, so close to 70%. And we notified in Europe in some country like Germany, Austria, AMPLIFY launched. And we don't see much excitement among the [indiscernible] and the company may actively switch the mono acala to AMPLIFY. But so far, we have not -- we see some prescription, but not extremely a lot prescription.

Therefore, the total acala in Europe, if you see the number, is flattening.

So regarding to the CDAC data, and this is a single-arm study, so likely to be based on the ORR as well as the DOL. So depending on the first discussion with the agency, as usually, it will be probably about 12 months after the last patient.

Our next question comes from Reni Benjamin with Citizens Bank.

Congratulations on another amazing quarter. Would love to just focus on the earlier stage pipeline a little bit. You had mentioned proof-of-concept data. Can you maybe provide a little bit more color as to what you're seeing with some of these other assets? And should we be thinking that all these would likely progress to Phase III trials moving forward?

And if I can sneak one in, is there a teaser you could provide regarding the 10 new molecular entities that you're filing next year? Is there a novel target that you're most excited about?

We wish that science worked in a way where everything worked. But Lai, why don't you answer that question?

I'll probably refer to Mark because he is in the frontline for all this data, Mark?

Thank you, Lai. Thank you, [ Reni ] what I would say is that for all of our early programs, we established very clear criteria of what success looks like based upon the preclinical data what are we looking for in terms of PK, PD, safety and ultimately, efficacy? If you think back to the slide that Lai showed where he talked about where the different programs stand. I think you can think about that as some of those programs are meeting all of those criteria, the 4 of CDK4, PRMT5, B7-H4, GPC3, and therefore, we're actively planning acceleration to Phase III studies and program growth. Others, we continue to wait for data. And we believe that we'll have the data to make the final determination for both of the programs in the first half of '26.

Yes. Then in terms of the new [ molecular ] entities we are going to bring to clinic next year. I'm going to use the GPC3 4-1BB as an example. To be honest, among the program we took into the clinic last year, that certainly was not the most exciting one for us based on the preclinical data. But certainly, we are very pleased with what we have seen in the clinic today. So I'm not going to say which one is the most exciting one for us in the next year, but we're certainly looking forward to bring more. Just want to emphasize one more thing. What you have seen from BeOne is really just the beginning, what you can see from our really prolific discovery engine.

Next question comes from Andrew Berens with Leerink Partners.

Let me give my congratulations on the progress and execution for the quarter. I think with Aaron's question, you answered one of the ones I had because Astra in their earnings release today did highlight the fixed duration AMPLIFY regimen getting traction in Europe, but it sounds like you guys have not seen a lot of that yet.

So I just wanted to confirm that that's what you said. And then a question on the PRMT5 program. It's still expected by year-end. Just wondering, I know you mentioned the first-line PDAC and non-small cell lung cancer opportunity. Just wondering how you think of combination partners for those settings?

Yes. I confirm and the -- so Ocala market share and also the revenue in the last 3 months are pretty stable in Germany and not increasing -- of course, with AMPLIFY approval and the fixed duration of AMPLIFY will be added to the respective guideline. This may give some plus for [ Ocala ]. But overall, in Europe and also in Germany, the [ Ocala ] total data flattening.

Mark, do you want to take the second part?

So we, as you heard, are very excited about our PRMT5 molecule. That's only been in the clinic since January of this year. But given its high potency and CNS penetration, we're now seeing objective responses across multiple tumor types, including both lung and pancreatic cancer as well as additional tumor types. And critically, given its high selectivity, we're also seeing a very favorable safety profile that we think will enable combinations, which will be key to unlocking the potential of this mechanism.

And therefore, we're advancing into frontline to combine with current standards of care. We do not yet have the data, but it is our expectation that we'll be able to combine with chemotherapy and PD-1 in non-small cell lung cancer and standard of care chemotherapy in frontline pancreatic cancer, and we'll look for similar development opportunities in early lines of other tumor types with frequent MTAP deletion.

Okay. Any belief that maybe combining with some of the selective agents might work in certain mutations like RAS mutations.

So we are very interested in RAS biology. Our pan-KRAS molecule is advancing through Phase I. We discussed at R&D Day a commitment to bring multiple additional RAS targeting molecules into the clinic. So certainly, in pancreatic cancer, for example, we will ultimately look to combine PRMT5 with KRAS. So again, the aspiration given potency and selectivity is that we should be able to combine with whatever is the appropriate additional therapies for that patient given the disease state and any other concurrent mutations.

Our next question comes from Yigal Nochomovitz with Citigroup.

Okay. Great. This one is for Lai or Mark. Maybe. Could you give a little more detail on the design of the CDK4, Phase III in terms of what you can say at this point about the control arm, the size of the study, anything on the powering? And also what are the doses that are the final contenders for that study?

Please go ahead, Mark.

So at R&D Day, we talked about the 3 dose levels that are being explored in our expansion phase, 240, 400 and 600. We've completed enrollment of our frontline cohorts. And we're very excited with the data as they're coming in.

We are seeing a high response rate that we think will justify as initiation of a Phase III study the core hypothesis with the molecule is that having a more selective CDK4 inhibitor will be superior to currently available CDK4/6 inhibitors.

And therefore, we're intending a head-to-head study we're still waiting for data to make final decisions around study size and powering, but we certainly should be able to share those details in the near future as we move towards a Phase III study start by the end of the first half of next year.

Okay. And then I think Lai mentioned the new Phase III ZS versus AV. I was just wondering regarding the rationale around that. I was under the impression you kind of already knew the conclusion there that ZS was better? So I'm just curious as to the rationale for that additional investment to further prove that point.

Please go ahead.

Yes. Thank you for the question, and we agree with your comments. But we felt this is important to establish ZS as really the best oral fixed duration regimen. So we picked the one which likely will be approved soon by FDA, the AV regimen. We do have a lot of confidence in term for this particular study.

Yes. I think if I just elaborate a little bit on that, we encourage everyone to look frequently at the CLL data, especially the long-term data that we've presented but still people will say, well, there's no head-to-head study against [ Ocala ] versus [indiscernible].

And still, people will discount the body and wealth of information that's there. And I think when you look at the data and you talk to the top KOLs, I think at this point, with this long-term data, it's very clear.

But nonetheless, there's always someone who says there's not direct head-to-head. And I think this commercially is helpful, and it's helpful to bridge that information gap help educate people more quickly. I mean just when we're looking at that space, the long-term data, it's meaningfully different with all the cross trial comparison.

As we said, it's double-digit different. look at the PFS, look at the OS data. It's impressive, but we still get that comment in a small portion of the population around the globe. So we just think, it's important to do this so we can ensure that everyone is getting the best medicine and the best regimen. So we're committed to doing it.

Our next question comes from Leonid Timashev with RBC.

I just want to ask maybe on some of the commercial dynamics you're seeing outside of the early line setting in CLL and maybe more in the relapsed/refractory setting is how is BRUKINSA share holding up or growing there? And then ultimately, how do you expect the mix of a degrader BRUKINSA and covalent inhibitors to play in the future there?

Sure. Matt, please.

Sure, happy to address that. Yes, we continue to see strong new patient start share across the lines of therapy, including in that relapse setting. And then as we've discussed in the past, we're really confident in our overall CLL franchise leadership strategy.

You made reference to the multiple mechanisms that are in our portfolio. And as you've heard from John, we continue to have confidence in our BTK mono due to our head-to-head superiority with another BTK and our best-in-class profile. Including PFS, safety and tolerability in the long-term setting that John mentioned.

We also see an opportunity for therapy that will include zanu plus sonro. We've spoken before about the requirements for therapy there. And we're confident in a really strong MRD PFS safety and tolerability profile, but also in the convenience that sonro can bring to that regimen.

So of course, we see the future opportunity for fixed duration with zanu plus sonro. But right now, we're confident in monotherapy. Of course, when it comes to the degrader we see a clear opportunity there in later lines of therapy. I'm sure you're familiar with resistance mutations that can happen in those earlier lines, and we have the confidence to do a head-to-head superiority study for the degrader versus pure dose. So we see a strong opportunity across patient types in the cross lines of therapy in CLL.

Our next question comes from Sean Laaman with Morgan Stanley.

Just to go back on the CDK4 inhibitor, just to maybe throw some meat on the bones around the decision not to pursue later lines and to go for first line. And then also just to confirm, are we still going to see some data at San Antonio and what do you hope to present at that forum?

Thank you very much, Sean. Yes. So again, what we're seeing in our expansion cohorts is a very strong emerging response rate. We are waiting for data maturity. Now in the context of the strength of that data and also importantly, the context of emerging data externally, so there are a number of new agents that are leading to both fragmentation in the second-line as well as an increasing bar for success in second-line.

We always view the second-line opportunity as a transitional opportunity for this molecule and the key study as the frontline study. So given this external dynamic and our strong internal data, we made the decision to deprioritize second-line and to accelerate frontline.

And again, we're very much looking forward to that study. Currently, we then subsequently made the decision that we would not share the second-line data this year San Antonio. We think those data are relevant to our dose level selection for Phase III in frontline and we, therefore, will not have data for this molecule at the San Antonio, but look forward to sharing data at a future venue that will -- should we say substantiate our plans for the Phase III study in frontline.

Great. And one quick follow-up just on zani plus sonro versus [V plus O]. So Phase IIIs are recruited earlier this year. What's sort of the signpost pathway or the map going forward in terms of future announcements around that trial?

Lai, do you want to answer that, please?

Yes. So to me, in that particular study is a PFS events-driven studies, as you can imagine, with the control arm using the vial, it's really good therapy as well. So it would take a little bit of time to get into the PFS readout at the same time, we are also monitoring the uMRD rate, this will be something we can probably take an earlier look at.

Our next question comes from Jess Fye with JPMorgan.

I have one on the EGFR targeted assets. I guess what in particular makes you say that the EGFR cMET product goes in the promising bucket, whereas the EGFR CDAC is in the still exploring bucket. Is that based on clinical data? Or if not, can you just elaborate on kind of how you segment of those.

Sure, Mark. Please go ahead.

Sure. Thank you, Jess. So we have a number of different EGFR targeted therapies that are moving forward. And as I mentioned earlier, for each program based upon the preclinical evidence, we have expectations of what we would like to see for the molecule initially in terms of PK and safety, but ultimately in terms of efficacy. So what we're seeing from the EGFR MET-MET Trispecific, though it's very early days in dose escalation is that we are seeing clinically meaningful responses with that agent.

With the EGFR degrader, we continue through dose escalation. We've had some tumor regressions. We're happy with the PK and the safety profile. We simply need more data maturity. It's important to highlight that these are 2 totally different mechanisms of action, and therefore, our expectations for what we would expect from each molecule are somewhat different.

Our next question comes from Clara Dong with Jefferies.

Can you hear me?

Yes.

Congrats on the quarter. So you talked about the seasonality for the entire BTKi class. So just wonder how the seasonality dynamics differ across key regions in the U.S., Europe and the rest of the world as well. And then just looking at the time line for sonro and the BTK CDAC entering the market, sonro expected to file for MCL in the U.S. this year and BTK CDAC could have a pivotal readout next year in CRL.

So is this the right understanding that potentially BTK CDAC that can be approved first in CLL in the U.S.? And how do you anticipate this influencing physician sequencing strategy across B-cell malignancies special in CLL?

So Aaron, going to lock.

Great. Thanks for the questions, Clara. So as I said in my prepared remarks, I just wanted to reinforce as you think about your models, the seasonality patterns, this is really a focus in the U.S. where we typically do see inventory builds across the sector in the fourth quarter and then that unwinds to a degree in the first quarter. And then we did reference back to the same calendar issues that we experienced in '25 also in '26.

Globally, you see that to a lesser effect in our business in China, Q4 is typically a relatively lighter quarter by comparison. But given the magnitude and import in terms of percentage of revenue, for BRUKINSA in the U.S., we thought it was really important to highlight as you think about rolling over your models from '25 to '26.

So I can hand it over to Lai.

Aaron, you're correct. In terms of in the U.S. as well as probably use out of that -- CDAC is likely to get the CLL approval probably ahead of the sonro, but that's not the case in China. In China, we already filed the [ someone ] for the CLL, which we're also anticipating approval early next year.

In terms of sequence of the therapy, we view that CDAC can provide a really broad coverage in terms of patients who had BTK inhibitor. As shown actually in one of the slide in today's presentation, this really covers pretty much everything except maybe one mutation. So we do believe this is probably at this moment based the level evidence is positioned very well in the later line therapies after the COVID and BTK inhibitor.

Our next question comes from Michael Schmidt with Guggenheim Partners.

I just had another bigger picture question around the CLL market. As you noted in the slides, I mean it sounds like the AMPLIFY regimen has moderate uptake. But fixed duration treatment will clearly be part of the CLL treatment landscape longer term, including your own combination. And so I was just wondering how you think about how that might impact the overall size of the CLL market, the BTK inhibitor market longer term?

And then just a clarification on seasonality, Aaron. I know you made some comments around inventory in stocking at the end of the year. But then when I look at guidance, it seems like the top line the higher end, the top end of the range for revenue could be achieved with almost only flat Q-on-Q growth. And so was just wondering if there's anything else going on in 4Q that we should be aware of?

So maybe I'll start with a quick answer around that. As I laid out earlier in this long-term PFS really matters. You have 6 years of follow-up for data matters. These are cancer patients and you don't want progression there's no area outside of CLL I've seen where people talk about, let's take a regimen where you give up years of milestone PFS.

You just don't see that. Whether it's van-based fixturation treatments or other BTKs or [Porto], really all options beside chemo, they look pretty decent at 2 to 3 years. And there just isn't enough time to understand the durability and the outcome for patients. BRUKINSA consistently shows best long-term patient outcomes in CLL.

It's why it's the standard of care, and it's why it's the global leader. The more follow-up we show as we're doing at ASH, the more differentiated it looks. The 6-year data in CLL in first-line and second-line and in all high-risk subgroups, the story is the same, the best long-term outcomes for patients. It's 6 years follow-up, 74% PFS rate for BRUKINSA in first-line CLL.

When you COVID-adjust this at 77%, our OS is 84%, 88% COVID-adjusted. In ELEVATE TN, Acalus PFS is 62%, and their OS is 76% at the same time period. In second-line and deletion 17p, it's the same story. Unparalleled median PFS from Alpine and our SEQUOIA Deletion 17P data shows that BRUKINSA works very well in high-risk patients. It's just not the case with the other options.

And we're still reporting our follow-up data because it tells the story. Where is the other data? Where is the long-term data from ELEVATE? Where is it from CAPTIVATE. Where is it from AMPLIFY. It's very noticeable, it's not being reported. And with respect to [Porto] it's 18 months of follow-up in second-line CLL it's not even close to being long enough. And as we've mentioned, 2 to 3 years, you just can't differentiate yet.

And I think from that perspective, we're extremely confident in both the short term. And when we talk about long term, the really exciting thing is this desire to have fixed duration treatments. It's a great thing if you can get there. And so far, it does look like SC is going to be unlike anything we've seen yet. It's too early to be sure. There's not enough long-term follow-up data for that either, but the early data looks noticeably different than anything we've seen before. So we're really, really excited about that.

Now maybe I'll jump to Aaron to answer some of the other parts of that question.

Yes, thanks. Obviously, there's tremendous opportunity across the franchise as we think about where we're participating today in a $12 billion in growing market, whether you look at it from either a BTK space or an overall CLL space. To your question on the guidance, we did reinforce the seasonality really to make sure we support dialing in your modeling in that regard, given the history. We feel really confident on our execution over the course of the year.

As you referenced, we've taken up the bottom of our range from where we started we started the year at 4.9% to 5.3%, and now we're at 5.1% to 5.3%, showing increased confidence and really the great execution from our global teams. As you said, if you annualize the current quarter run rate and you think about the next quarter, we feel that the range that we provided is certainly within our expectations. The import of the seasonality common is really specific to the United States, and we want to make sure that, that perspective is really incorporate. Thank you.

There are no further questions at this time. I will turn the call over to John Oyler for closing remarks.

All right. Thank you all. I would like to point out that a few weeks ago, BeOne celebrated our 15th anniversary as a company. It's very hard to believe that in this relatively short period of time we've been able to become one of the leading oncology companies in the world.

I'd really like to think that this is because, as you heard today, were driven by scientific excellence, exceptional speed, and a relentless drive to provide the best long-term outcomes for patients. And on behalf of everyone here at BeOne, I'd really like to thank the broader oncology community including the patients, their families, the clinicians, our employees and all of you who have been with us for the journey.

We truly believe that together, we are how the world stops cancer, and we're just getting started. So thank you again for your time today and your thoughtful questions. Have a great day.

Okay. I think we're okay. Good afternoon, everyone, and welcome to Morgan Stanley Global Healthcare Conference. I'm Sean Laaman, Head of U.S. Mid-Cap Biotech Equity Research here at the firm. Before we begin, for important disclosures, please see Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you do have any questions on that, please reach out to your Morgan Stanley sales representative.

For this session, we have from BeOne Medicines with CMO of Solid Tumors, Mark Lanasa; and GM of North America, Matt Shaulis. I hope I pronounced that correct.

You got it.

I got it. Maybe -- do you want to make some introductory comments or I'll just go straight to our macro questions.

Happy to go to questions.

Yes. Great. So starting with Mark perhaps for the first 2. With China's rise in biotech innovation. How are you thinking about BeOne's competitive position here? And will this influence your R&D and business development strategy?

Thank you, Sean, and thank you for having us today. So BeOne Medicines, we're definitively a global organization. We now have 11,000 employees based on 6 continents around the world. Our R&D and commercial organizations are global by intent. We recognize that we have particular strengths in the United States and in EMEA as well as in China. We think that, that positions us well for the growth in impactful biotech that's emerging out of China.

We do have a strong presence within our research and discovery organization within China. And I think that gives us, shall we say, the opportunity for direct human-to-human contact and real human relationships that enable early insights into emerging data sets and also can lead to connections that can facilitate our business development discussions. Ultimately, though, this -- our business development strategy is largely going to be about complementing our robust and growing internal portfolio of agents.

Wonderful. And how are you currently leveraging AI or thinking about AI's future potential disruption?

So AI is a really, really important emerging technology, and it's something that we're thinking about extensively within the development organization across the entire life cycle of developments, we think that there's potential applications. So simple things in terms of could help with medical writing and the development of the protocol, but then can that pull through into the scheduled assessments, which can pull through into building the clinical database, which then pulls through the programming of the tables, figures and listings, which then pull through.

And so the reporting -- so you can see how these things can all be interconnected. At our recent R&D Day, we gave several examples of how we're using AI not only to accelerate the life cycle for development but also to enhance quality. So for example, one area where we were using a lot of resource was in review of SAEs development of narratives and the review of those narratives, 200 to 400 hours a month.

We reduced that by 90% to 20 to 40 hours per month. We recently have been able to compress our database lock times from DCO to lock from about 35 days, cut that in half to about 15 days. And my favorite statistic is that for our SMC, our safety committee meetings for Phase I studies, it used to take us 2 to 5 days, it now takes us 3 to 5 minutes to make the outputs for those.

So we think that AI has a huge impact in terms of efficiencies in the development side. Now I will also add that on the discovery side, we haven't seen the same level of impact. So AI is really good at analyzing large data sets and having unique insights and observing trends, but it hasn't been so good yet in coming up with a really innovative hypothesis. So for our scientists working in the lab, it's still largely the same of human being coming up with a creative solution to a novel problem.

Wonderful. Wonderful. Thank you. Matt, what's been the most impactful for BeOne on the regulatory side? Is it MFN? Is it tariffs? Is it the FDA?

Yes. Maybe I can just start by commenting a little bit on MFN and tariffs and then invite Mark to talk a little bit from a regulatory standpoint. And clearly, we've watched the MFN situation evolve with letters going from the Trump administration to, I think, 17 different CEOs and for our part, we didn't receive a letter, but we know that the overall objectives are to lower prices via that MFN construct in the U.S., and that can mean things like MFN for Medicaid or pricing on new drugs that follows that MFN construct and even things like direct purchasing.

So while we are looking at this carefully, we're studying it, and we're prepared from a long-range planning and an operational standpoint. We also know that there's not a binding commitment and it will be a matter of what sort of voluntary concessions have been made. So I think for our part, we welcome a dialogue about access and balancing that with continued support for innovation. And similarly, I think that some things like 340B and PBM reform could be equally good topics.

On the tariff front, this is a situation where we've been able to study impacts on manufacturing or the inputs to our R&D and believe that our strategy to have a global footprint around manufacturing, including footprint right here in the United States, holds us in good stead. And we have factored in any impact here into the guidance that we've already provided, and we don't see any additional material impact. But Mark, maybe you want to comment on the regulatory front?

Yes. As it relates to regulatory, certainly, we're aware just from reading the news, of the changes and changes in personnel that have been happening at FDA. Now that said, with a portfolio of our size, we are in contact with the FDA across these programs all the time. And if I was only assessing it based upon the feedback we're receiving from FDA, I'd say there's basically no change. There's been no change in cycle times, review times, quality of feedback. So actually, I find that reassuring because we think it's in our interest in everybody's interest to have a high functioning FDA as a partner.

Wonderful. Maybe to turn to the revenue. So BRUKINSA, I think is north of 50% new patient starts now and clearly outpacing certainly IMBRUVICA and Calquence. How do you think about the momentum in that product goes from here? It still seems, for example, like there's still quite a lot of revenue generated by IMBRUVICA and losing share to BRUKINSA. So how do you characterize that? And what's the next inflection point in the U.S.?

Sure. Look, I think we're really encouraged with the progress. that we've made so far. We're the overall #1 BTK across the utilization of the class in B-cell malignancies. We're continuing to grow. It's really on the basis of the product's differentiated profile due to that broadest label.

We also see that we're fueling the growth overall for the class. BTK classed about $1.8 billion, growing at around 11% back in the second quarter. And then our performance is driven by underlying demand growth, about 35% as compared to the same second quarter a year ago and about 10% sequentially.

So we just continue to see that it's the best-in-class profile, including the only molecule with head-to-head superiority data versus another BTK. We're supplementing that with additional data sources to further elucidate some of those advantages. And we're seeing that when we look at our outcomes in the clinical study setting, we tend to have better PFS and we're seeing also a longer DOT. So we think of that, DOT combined with the new starts is going to continue to drive some growth.

Got you. And you recently announced some positive top line results from Sonrotoclax in R/R MCL. Can you run us at the current treatment landscape? And what we're seeing in the space, what you see is the bar for that?

Why don't you jump in on that one, Mark, and then I can maybe add some comments.

Sure. So we're very excited about the data with Sonrotoclax, which should provide the first approval opportunity for our novel BCL-2 in relapsed/refractory mantle cell lymphoma. There are no approvals for BCL-2. Indeed, there are no BCL-2 formal approvals within in mantle cell lymphoma generally.

In that relapsed space, the new approved therapies are pirtobrutinib, the BTK inhibitor as well as cellular therapies. Because of the limitations of access of cellular therapies, pirto is the more commonly used option. So we think that, that sets the bar in terms of regulatory standard for an accelerated approval. Not ready to share our data yet today, but we're very comfortable with the data that we have seen that it will support a favorable regulatory review, and we look forward to having those conversations.

I guess in the refractory MCL and CLL, I think you've had the submissions accepted in China. But how should we think about the path forward for global regulatory submission.

Sure. To put pretty straightforward, right? I think it was in the second quarter that we had the relapsed/refractory mantle cell submission in China. And then it will be later this year that we'll do global submissions. And then, of course, I think that bodes well for review and then subsequent approval sometime next year right here in the U.S.

Sure. And I guess, where I become -- I'm interested in your story, but where I become really interested in is the potential in the combination of BRUKINSA and sonrotoclax. So I think that could be really underappreciated part of the story if the data pans out the way that we think it might. So maybe a bit of a reference if you could sort of map out what you see on the venetoclax in combination with obinutuzumab, is that the predominant portion of the market?

And I think what happens generally when people analyze your business and look at the opportunity for sonrotoclax. They might benchmark it against venetoclax and say, well, if gets 1 for 1, and maybe it's a $3 billion drug. But I think what might get missed, if it's in combination with BRUKINSA, I mean it could be more than double that in theory, and you're looking at many billions above what market expectations might be if that combination were to work. So maybe correcting on that thinking, well, challenge me on that thinking and say, why wouldn't I be thinking like that?

Sure. And maybe I can just provide some broader perspective about fixed duration and also where we see zanu and plus sonro fitting into that. And we do believe in the promise of fixed duration. We've also commented previously about the 3 requirements that are needed for success: deep and durable remissions, strong PFS and, of course, a strong safety and tolerability profile. And we've also commented previously that some of the other regimens including AV and even to some extent, VIO have opportunities for improvement.

Particularly when you look at MRD rates, we saw AAV in the mid-20s with our MRD rate and then Phase I data for zanu plus sonro had shown MRD rates up in the 90s. And so we think that, that is going to translate into a really strong efficacy profile. We've also seen ultimately that some of the limitation for Ven relates to its clinical profile.

I know Mark has often commented and we often have a dialogue about the overall potency for sonro, also its selectivity and the short half-life relative to then, we think all lead to a clinical profile that could have better ramp and monitoring and lower risk of TLS.

Now we think that Ven has been fairly stable with strong academic utilization and some use in the community setting but the clinical profile has limited it in that community setting. So we think that zanu plus sonro could potentially address some of that, not only because of efficacy and safety, but also potentially because of the ability to improve the convenience for both clinicians and patients.

So that's a little bit more of the long-term perspective. We believe in BTK mono now and the limitations of fixturation, but are really hopeful about ultimately a best-in-class profile for zanu plus sonro.

Sure. Sure. And then if we think about Ven plus acalabrutinib and the regulatory submission, I believe, fairly recently. How do you think about that? Firstly, as a potential risk to BRUKINSA sales, if at all? And secondly, as potentially something that could trail blaze for you when -- even when you come to market with your combo between sonro and BRUKINSA.

Sure. And happy to comment back on those sort of 3 criteria, right, for success with a deep and durable remission, strong PFS and safety and tolerability profile. Those are areas where we don't think that the AV data has really met higher benchmarks. Also, when we look at that study, we see that it's really in a young, very fit patient population and also lacked some of the risk factors for everyday utilization.

So we think those are some of the challenges, whereas on the other hand, the BTK mono data has been very impressive across that setting. Now there might be some utilization, but we think in the long term, the way that zanu and sonro will meet those criteria and potentially be a little bit easier to use is when the real game changer can happen.

Perfect. You've noted that you don't see significant near-term uptake for fixed duration therapies. So we're kind of moving on from that. But how are you thinking about sonro and zanu fixed duration combination possibly replacing zanubrutinib mono?

Yes. So I think it's more a matter of how the landscape is going to evolve in the future. We not only look at line of therapy, we also look at patient types. And we've seen really strong clinical data in del 17p and TP53 with zanu mono and then there could be some opportunities in other patient types for zanu plus sonro.

It could be the case that it's successful in that del 17p plus TP53 population, but we'll have to see how that ultimately plays out. We do know too that in the case where we do transition to more fixed duration, we'll, of course, have the opportunity for 2 molecules to be used rather than 1. And of course, we think there'll be good revenue capture there.

The other thing that we think about is how the landscape may evolve. We think that there's going to be opportunities by virtue of us having 3 molecules in CLL to have a true CLL franchise leadership strategy and that can mean BTK mono or zanu plus sonro fixed duration therapy, but then also potentially opportunity later in lines of therapy for our CDAC degrader. Go ahead, Mark.

I think that so the question in a way is there's fixed duration therapy, then there's continuous therapy. And the question is, well, will some patients move from continuous over to fixed duration? That's possible. There's also the question about the entire ecosystem of frontline therapy that you could view chemoimmunotherapy, which we view as a inferior option at this date given the data we had in SEQUOIA, there's still a substantial proportion of patients who are receiving what is a fixed dose or a fixed duration therapy.

So with a really compelling new fixed duration therapy, we could be building that market. We could be increasing the share for a BTK plus BCL2 combo in the front line. So it isn't necessarily just pulling patients away from continuous, but actually, creating a new market or initiating a larger...

Got you. I guess you've got a number of -- on the heme space, a number of pivotal trials to kind of read out. How are you thinking about preparations for commercial launches?

Yes. I think that we're in really great shape, frankly. We've built out all the right infrastructure from a sales and marketing, market access and medical affairs approach and accomplished a tremendous amount with BRUKINSA in literally just the 2 years since the CLL launch. So that gives us the reach that we need with hematologists in both the academic setting and in the community setting, and we think that we're set up for real success with these next launches. And I would say, in general, that applies to sonro as well as to the degrader then in future years.

Sure, sure. I've got a few solid questions or solid tumor questions. So on 43395 the CDK4 specific, I guess, before getting into the guts of the science. I just wanted to tease out from you. I mean the -- when you started the trial, I think you were 3 years behind Pfizer. And then you've really narrowed that gap to -- I think at the R&D Day, you said 18 months, if I'm not mistaken. But I think you're planning on a registrational study to commence this year. And I think Pfizer has started a Phase III this year. So well, first of all, how do you get so hot on their heels? And secondly, why aren't you even hotter on their heels?

So we -- we have done the math. And if we're reading all the publicly available data sources correctly, we believe that our first patient dosed with our CDK4 selective inhibitor was approximately 40 months after Pfizer's first patient dose. We have built this large operational infrastructure, where CRO free.

So when we put all of those resources behind it in terms of the global footprint and all the right teams and whatnot, we can move very, very quickly. So to date, we had the first patient enrolled in that study in, I believe it was December of '23. As of today, we've enrolled over 400 patients. As you stated, Pfizer enrolled the first patient in their global Phase III study in frontline, I believe in March.

So we believe that we can initiate a frontline Phase III study approximately 15 months after Pfizer. So we've reduced that gap from 40 months to 15 months, which is much -- which is really a tremendous reduction, which makes us, I think, much more competitive in that future treatment landscape.

Perfect. And could you remind us benefits of hitting CDK4 and sparing CDK6. And what are some of the benefits that you hope to show over drugs by brands?

Yes. So the CDK4/6 inhibitors have been transformational in the management of patients, women who have hormone receptor positive breast cancer, with a doubling of PFS in the frontline and improvement now of overall survival. That said, they're not without some disadvantages. The key disadvantage is actually hematologic toxicity. And then there's some other side effects as well that can lead to dose interruption and down dosing. It turns out that most of the therapeutic benefit, at least preclinically, comes from the innovation of CDK4, and CDK6 drives most of the hematologic toxicity.

So the core hypothesis is that by improving both potency for CDK4 and selectivity for 4 over 6 that you can improve efficacy through increased and deeper inhibition of the target, but you can also improve safety through reduced hematologic toxicity that then triggers dose interruptions.

We believe that our data to date is supportive of that hypothesis that we have been able to progress nicely through dose escalation. We're well within our target efficacious range. We've seen evidence of efficacy that we shared at R&D Day and at San Antonio last year, both as monotherapy and in combination with fulvestrant. We continue to see objective responses emerging from our ongoing Phase Ib investigations. And we're seeing efficacy and also a dramatic improvement in the hematologic safety profile compared to the currently available CDK4/6 inhibitors.

So we think the preclinical science to date is bearing out. We understand that we're going after a high bar that PFS in the frontline setting is approximately 2 years, and we're looking to have superiority over that. So it's an aspirational goal, but we think the data is trending in a way that we can get there.

Sure. And what would you say to someone that said to you that you needed to hit 6 to confer efficacy as well as 4?

That remains to be seen. We believe that hypothesis as well. So we have a CDK2 small molecule inhibitor that is progressing through early development. And one of the targets of new molecules that will enter the clinic prior to the end of the year is a CDK2 selective degrader potentially first-in-class molecule. So it is known that when patients are exposed to CDK4/6 that can lead to upregulation of cyclin E, which activates CDK2.

The question is, is that something you need from the beginning? Or is it something that you could add if that resistance pathway emerges? And then there's also the really important question about going from a doublet to a triplet and having a really good safety and tolerability profile. CDK2 has not been without its challenges in terms of safety. But again, we're very committed to CDK2 as a target, and we'll be looking to build triplets of ovarian suppression plus CDK4 plus CDK2, either as later line or an early line treatment option.

Sure. Sure. Two parts to the next question. But could you just please remind me what you showed for CDK4 drug at the R&D day. What were some of the high points that gave you some confidence that it's still worth pursuing?

Yes. So what we have been looking to achieve in terms of PK, PD, safety and efficacy. So for PK, what we have shown is nice dose proportionality, half-life of 10 to 14 hours, which well supports are selected twice daily dosing. For PD, we have a clear pharmacodynamic marker in terms of reduction of TK1. So we've achieved the target level of TK1 inhibition, which is a marker of cell cycling, which is a mechanism of action of an 80% reduction.

And then for safety, as I mentioned, we have a really nice hematologic safety profile with extremely low rates of Grade 3 neutropenia or anemia. And then for efficacy, we are seeing emerging responses, objective responses, conferred responses. The mechanism of action these drugs is largely cytostatic rather than cytotoxic. So it could take some time for responses to emerge. So we're gladdened by the data as they continue to emerge, and we look forward to sharing more data later this year and then next year as well.

And that will be at San Antonio?

Yes.

Great. Can you draw some comparisons between [ it ] and Pfizer's shot on goal?

So preclinically, our molecule is a little more than 4x more potent as a CDK4 inhibitor in a preclinical cellular assay compared to a atirmociclib that conveys greater 4 versus 6 selectivity. Their molecule is about 20-fold selective 4 versus 6, ours is about 35-fold selective 4 versus 6. Again, it's still early days. Pfizer has disclosed data. They've not disclosed a really large body of evidence nor have we. But we think that based upon the available data, we do see an emerging improvement in the hematologic toxicity profile that we believe is related to the greater 4 versus 6 selectivity.

Great. And how are you addressing concerns around toxicity and resistance?

So the main toxicity that we've observed with our CDK4 to date is GI toxicity, specifically diarrhea. The majority of patients receiving the drug do have diarrhea of some grade. That said, virtually all the cases are Grade 1 or Grade 2. In the dose optimization phase as we presented at R&D Day, there have not been any discontinuations or dose reductions related to diarrhea. It's been very manageable by the investigators, and they said that it is -- the profile that we're seeing is entirely consistent with that of a frontline drug.

In terms of resistance, it's simply early days, so this is something that we'll be looking to characterize both in this study and beyond to understand what are the treatment-emergent mechanisms for resistance to a more potent, more selective CDK4 inhibitor.

Sure, sure. And I guess sort of looking more forward on this one. How do you see the time lines unfolding. So we'll see some data at San Antonio and what are some of the proof points?

So we -- in our most recent earnings, we guided that our start date for second line and later study has shifted into '26. So that is simply to give the data a bit more maturity so we can have confidence around the dose we're selecting. So we have a single dose, both for later line and for frontline and that we would also look to start a frontline Phase III study in the middle of next year.

The later line study could actually move relatively quickly because PFS in that population is probably only about 6 months with currently available therapies. The frontline study would be, of course, much larger with an anticipated PFS in the control arm of approximately 2 years.

Sure. Got you. Back on the commercial, the most recent quarterly, the BRUKINSA numbers were really solid and sort of what stood out to me, in particular, there was a real solid performance in Europe, which I think might be generally underappreciated by investors if you do some benchmarking that BRUKINSA could be thought of as underweight Europe compared to other companies. First of all, just to verify that and then how do you realize that opportunity in Europe? Is it an expanded sales force? It's just a matter of time before that, that just continues to deliver the numbers that we just observed.

Yes. So look, I think in Europe, we've made really great progress on sort of a coverage and reimbursement front. And we also think that we're rightsized commercially and from a medical affairs standpoint, in order to continue to achieve really robust growth. And so as we look across all the regions in the world, we continue to see Europe as a good source for continuing to support overall global growth.

Awesome. I do get still a little bit of inbound on pirtobrutinib and just to get your view on why or why it might not be a competitor in first line, why you think it might remain in second or later lines of therapy? And maybe to talk a little bit about your head-to-head trial with the degrader.

Sure. Maybe I could start out, Mark, and then transition to you. And I think this morning's news had been a positive press release from Lilly, and I think it's important to contextualize that as a study compared to BR and also one that excluded the del 17 patients. And then similarly, if we look at BRUIN314, that's a study with a noninferiority design on ORR.

And the feedback that we continue to hear from clinicians is that while there is value in having that option, it's likely sequenced after patients will have seen other mechanisms. And of course, you made reference, Sean, to some of our clinical trial designs, and we've decided to do a head-to-head superiority study of our degrader versus pirto. We're confident in the benefit that the CDAC degrader can bring to patients.

And we think that, that would be another potential rationale for having pirto after other mechanisms. Now certainly, with some of the way that the market has grown through more innovative agents that offer better PFS, we think that there's the potential for there to be more patients in those later lines of therapy. So it could still be a viable place for innovation and clinical development activity.

But we continue to have a lot of confidence in our CLL franchise strategy across BTK, BCL2 and now that real confident move with the degrader in the later line of therapy.

I'm sorry, just to add a couple of things. So one is something you've seen from us is the PK. So zanubrutinib was designed to have a round-the-clock coverage of BTK and is a covalent inhibitor. We feel that there's really not anything left on the table. We'll see what the data ultimately shows from Lilly. But we think we've set very, very strong benchmarks in our SEQUOIA and ALPINE studies.

As Matt said, we have technical confidence in the likelihood that our degrader will be superior to pirtobrutinib head-to-head. We shared that data at R&D Day. And so far as we're seeing a longer progression-free survival in a more heavily pretreated patient population. And the last point -- to a point you made before is that the threshold treatment naive study of zanu plus sonrotoclax, we enrolled that study in just over a year, 600 to 700 patients in frontline CLL, really, really efficient.

We have similar enthusiasm from investigators for these 2 Phase III studies with a degrader. So again, we think we're going to be able to deploy our operational resources and quickly enroll both of these Phase III trials.

Sure, sure. And you've seen -- you reminded me, you've seen a similar pattern as what we have observed with the CDK4 and the compression of time lines between the first to market. You've seen that kind of again with the degrader. So maybe talk us through the situation or the comparison with Nurix and when we might see more data from the degrader program.

From our degrader program?

Correct.

Yes. I'm sorry. I don't know if we can answer to that question in so far as that disclosure.

Yes. I think we'll have more disclosures coming at congresses and meetings in the future, and just overall look for the degrader opportunity in the near term after sonro so in coming years.

Okay. Great. Mark, we've talked about the CDK4. But given -- we've got a couple of minutes left. If you look at your portfolio on the solid side, what's the program, you're probably going to say that you're all excited. But what's the one program that really excites you beyond the CDK4?

Yes. So we highlighted four programs at R&D Day in addition to CDK4, it was FGFR2b, the B7-H4 ADC. And the one I would highlight is our PRMT5 inhibitor. That's an NTA cooperative PRMT5 and we are excited by really favorable safety profile, great PK, strong PD and we're observing responses across multiple tumors and our molecule is designed to be CNS penetrant.

So we're again leveraging our operational capabilities to move as swiftly as we can to close the gap, the development gap with our competitors. We look forward to sharing data for that molecule in 2026, but are excited about the potential of that molecule across multiple tumor types.

Yes. Wonderful. I'm not sure if this is a question to ask now, but I'll ask it anyway. If I look at the business turning to profitability for this year, and I mean, clearly, there's a strong top line growth story. And we have trouble getting a good handle on what's going to happen with OpEx over the next few years. Particularly, we've got such sort of a robust pipeline. But I want to say that you're actually making money at the bottom line. I'm just wondering if that's the way to think about it or the cash flow that is generated will be plowed more back into the pipeline.

Yes. I think it's safe to say that we'll continue to take a balanced approach. There's extensive innovation opportunities in the pipeline. And so we'll continue to do things like out-license from a BD standpoint in order to drive capital but also make really strong investments in the pipeline.

Great. Well, we're just out of time. But I'd invite you either make a closing remark? Or is there anything that I didn't ask that I should have?

I think you covered it all. I think for us, things like a CLL franchise leadership strategy, as we've outlined with multiple molecules and then the opportunity to roll those really strong performances into future innovation are a lot of the sort of direction and trajectories for us to come.

All right. Well, thank you for your time, gentlemen. Being a pleasure to host you. Thank you.

Thank you.

Thank you very much.

Good day, everyone. Welcome to BeOne Q2 2025 Earnings Call Webcast. [Operator Instructions] At this time, I would like to turn the call over to the company.

Hello and welcome. Thanks for joining us today. I'm Dan Miller, Head of Investor Relations at BeOne Medicines. Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentation on the Investor Relations section of our website, ir.beonemedicines.com.

I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most recent periodic report filed with the SEC. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation.

Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our Investor Relations website along with our earnings release. All information in this presentation is as of the date of this presentation. We undertake no duty to update such information unless required by law.

Now turning to today's call as outlined on Slide 3. John Oyler, our Co-Founder, Chairman and CEO, will provide a business update; Aaron Rosenberg, our CFO, will provide an update on our second quarter financial results and financial guidance; and Lai Wang, our Global Head of R&D, will discuss our R&D and pipeline progress. We will then open the call to questions. I'll now pass the call over to John. John?

Thank you, Dan, and welcome, everyone, to our Q2 earnings call. We had a spectacular second quarter. Our revenue reached $1.3 billion, which represents 42% year-on-year growth. GAAP earnings per ADS grew $2 from Q2 of last year, and we generated $220 million of free cash flow in Q2. This is an absolute increase of over [indiscernible] versus last year.

From a commercial perspective, BRUKINSA has cemented itself as the #1 BTK inhibitor in the U.S. market. This quarter, we also hosted an R&D Day where we shared 3 takeaways with you. First, why we believe our internal capabilities and our sense of urgency will drive superior returns on R&D. Second, how our hematology franchise is poised for sustained leadership into the next decade. And three, why you should pay close attention to our prolific and differentiated solid tumor pipeline.

I want to come back now to BRUKINSA, the cornerstone of our CLL franchise. BRUKINSA's best-in-class profile has resulted in rapid adoption by patients and physicians across the U.S., despite launching in CLL 9 years after ibrutinib. Here, we see the U.S. revenue performance of the 3 approved covalent BTK inhibitors since BRUKINSA's CLL approval. The chart speaks for itself. The gap between us and the competition continues to widen. BRUKINSA is both the market share leader and it's the fastest-growing brand, and it's the only BTK to be approved in 5 indications.

Now the success of BRUKINSA is not an accident. It's the direct result of an overwhelming body of evidence accumulated over more than a decade. This evidence is remarkable, both for its strength as well as its consistency. When we designed BRUKINSA, our preclinical hypothesis was that sustained inhibition of BTK in the disease compartment and improved selectivity for BTK over off-target kinases would translate to a differentiated medicine for patients. Since then, BRUKINSA has treated thousands of patients in clinical trials and over 200,000 patients commercially. BRUKINSA has differentiated itself each and every step of the way, from human PK, to clinical response, to PFS and now in the market where it continues to generate compelling real-world data.

As you know, the goal in an oncology drug development is to hit the target hard and then never let up. Never give the cancer an opportunity to grow. As you can see on this slide, the prior generation BTK inhibitors only hit the target for a fraction of the day. But BRUKINSA is different. It was designed to inhibit BTK 24 hours a day, 7 days a week. We hypothesized that BRUKINSA's superior target coverage would translate to superior clinical benefits for patients. As you can see on this slide, in the ALPINE trial, BRUKINSA drove higher responses compared to ibrutinib. This result was clear at the earliest data cut and more importantly, it was maintained with longer follow-up.

Next, we follow the data to see whether the collective and consistent results across preclinical human PK and tumor shrinkage would be associated with improved and sustained PFS. Clearly, it was. BRUKINSA is the only BTK to demonstrate superior PFS and favorable safety in a head-to-head trial against ibrutinib. In the ALPINE trial, BRUKINSA exhibited a 34% reduced risk of progression or death and lower cardiac toxicity versus ibrutinib. There were 0 cardiac deaths in the BRUKINSA arm versus 6 on the ibrutinib arm. In the Deletion 17P and TP53 subpopulations, which are the toughest patients to treat, BRUKINSA's treatment effect was even more pronounced. BRUKINSA showed a remarkable 52% reduced risk of progression or death versus ibrutinib. The ALPINE data showed that BRUKINSA is the best-in-class option for all types of patients regardless of mutation or risk status.

So fast forward to today, patient and physician adoption has driven BRUKINSA to be the top BTK inhibitor in the U.S. This slide shows 2 examples of recent presentations and publications supporting BRUKINSA's differentiation versus both acalabrutinib and ibrutinib.

On the left is a real-world study that demonstrated that patients treated with BRUKINSA had longer time to discontinuation, lower discontinuation rates and less healthcare resource utilization than those treated with acalabrutinib and ibrutinib across all patients, and this was even more pronounced in the population of older patients over 65 as shown here. On the right is just one example of another recent publication by a leading CLL KOL that recognizes BRUKINSA's differentiated data and how BRUKINSA can provide the best outcome for their patients.

Looking beyond BRUKINSA, BeOne stands out as the only company with fully owned differentiated and potentially best-in-class assets across all 3 foundational MOAs in CLL. We're already combining these assets in multiple Phase III trials with the goal of improving outcomes for CLL patients even further. We believe our relentless focus on serial innovation and CLL positions us as the only company that can address the full scope of unmet patient need across all lines of therapy and subpopulations.

With that said, we're far more than a CLL company. We're a global oncology company, and we have a wealth of upcoming milestones on the horizon. By the end of 2026, we expect the initial global approval of sonro and potentially pivotal data for our BTK CDAC. Our internal clinical team will be running more than 20 Phase III trials, and we anticipate more than 10 proof-of-concept data readouts and our research organization will again advance more than 10 NMEs into the clinic. And with that, I'll pass it over to Aaron to provide the financial update.

Thanks, John. Product revenue reached $1.3 billion in the second quarter, representing 41% year-over-year growth. BRUKINSA's global revenues were $950 million, growing 49% year-over-year, driven by strong performance across all geographies. As John mentioned, BRUKINSA is now the clear value share leader in the growing U.S. BTK market, and we continue to grow volume at a robust rate across all approved indications. This was seen again in Q2 with demand growth of 35% year-over-year and 10% sequentially, driven by the quality and differentiation of our long-term clinical data across all patient types. With our strengthening market position, we have seen competition aggressively discounting. Despite this, given our broad access strategy and having protected class status, the vast majority of patients have unfettered access to BRUKINSA and an even greater number achieve access upon appeal.

We strongly believe in open access policy, which is clearly in the best interest for patients and preferred by doctors. Moving forward, we will continue to pursue contracting strategies that seek to achieve this goal while preserving the value of our clinically differentiated innovative medicines for the long term.

From a pricing perspective, Q2 performance includes a mid-single-digit benefit largely associated with the annual increase taken at the beginning of the year. And as mentioned last quarter, we also see some modest additional benefits on net pricing from Medicare Part D reform given our designation as a specified small manufacturer. We are confident in our long-term market leadership position for BRUKINSA and our revenue guidance fully factors in current market conditions.

Meanwhile, TEVIMBRA reported a 22% increase, reflecting continued market leadership in China, supplemented by early contributions from launch markets. Our in-licensed products also showed continued strength, growing 27% year-over-year. Our China team launched zanidatamab in the quarter, providing an important new treatment option for patients with HER2 high-expression biliary tract cancer, a historically underserved patient population.

Our geographically diverse product revenue mix continues to fuel strong growth across all key regions. The U.S. remains our largest market, generating $685 million with year-over-year growth of 43%. China revenue totaled $429 million, a 23% increase, supported by TEVIMBRA and BRUKINSA's market leadership and growth from our in-licensed assets. Europe contributed $152 million, with 87% year-over-year growth as we continue our launch trajectory with BRUKINSA with increased share across all major markets. And rest of world markets grew 168% driven by market expansions and new launches. BRUKINSA was launched in Japan in March and had the largest uptake in the class in the 3 months since. TEVIMBRA is also launching in key markets, including Japan, South Korea and Brazil, and we are encouraged by early market response.

Turning to our Q2 '25 GAAP P&L, which illustrates our focus on top line growth with meaningful margin expansion. Total revenue for the quarter was $1.3 billion, the drivers of which I previously highlighted. Gross margin improved to approximately 87% from 85% in the prior quarter. This improvement reflects the benefits from favorable product mix, price and production cost efficiencies. Operating expenses grew by 18%, totaling $1.1 billion as we are investing smartly to support our commercial growth and rapidly advance our innovative pipeline. Income tax expense of $5 million for the quarter includes discrete adjustments of approximately $14 million, primarily related to updated provision estimates for R&D tax credits.

Our continued focus on margin expansion has translated to net income reaching $94 million in the quarter, representing diluted earnings per ADS of $0.84, a significant improvement as compared to the same quarter last year. Our non-GAAP P&L includes adjustments for typical items with a full reconciliation provided in the appendix. Non-GAAP net income reached $253 million, reflecting an increase of $230 million compared to the previous year. This performance translated to diluted non-GAAP earnings per ADS of $2.25 for the second quarter.

Given our execution, we are updating our full year '25 guidance with total revenue expectations now ranging between $5 billion and $5.3 billion. The mid- to high 80% range for GAAP gross margin reflects favorable mix dynamics and the earlier realization of cost of goods efficiencies for TEVIMBRA. It also accounts for recent anticipated approval for BRUKINSA's tablet formulation. The tablet achieves a lower cost of goods in addition to the many patient benefits that this new formulation affords, including reduced pill burden and size with improved support of dosing flexibility.

Operating expense guidance is unchanged. We project operating expenses between $4.1 billion and $4.4 billion. We remain committed to achieving positive GAAP operating income, and we expect to generate positive free cash flow for the year. Free cash flow is a broader measure of cash generation, accounting for both operational activities as well as capital expenditures. We are pleased with our execution in the first half of 2025 and remain focused on full year delivery across all financial performance measures. And with that, I'd like to pass it over to Lai.

Thank you, Aaron. Hello, everyone. Thanks for joining us today. As John mentioned, we recently hosted an Investor R&D Day. In addition to a data and the portfolio update, we talked about how BeOne R&D is at a pivotal moment in its journey.

Over the years, we have built a strong research, internalized global clinical development and manufacturing capabilities from ground up, allowing us to discover, develop and deliver novel oncology medicines faster and more cost effectively than industry standards. Our strategically advantaged capabilities are now at a scale and fully functional across R&D. You all know we have built a strong CLL franchise, but it took us a long time.

Now with all these newly built capabilities, we believe we can reproduce our success in CLL across our disease area of focus. And more importantly, do it much faster. This is very exciting. Our goal is to build a deep pipeline in each of these disease areas to create strong in-portfolio synergy.

Next, some highlights from our R&D progress in the second quarter. We have filed sonro's initial NDAs with the first 2 in China for relapsed/refractory CLL and the refractory/refractory mantle cell. The plan is to file mantle cell lymphoma globally later this year with a longer follow-up. We presented over 60 abstracts from our heme portfolio at ASCO, EHA and ICML and initiated new Phase III studies for sonro and our BTK CDAC in relapsed/refractory CLL.

In addition, we provided updates from our solid tumor portfolio at ASCO and R&D Day. For the CDK4 program, we're actively planning Phase III trials for both first-line and second-line hormone receptor positive breast cancers.

In the next few slides, I will walk you through our progress in CLL. We have built a comprehensive registration program that spans the full spectrum of CLL from treatment naive to the relapsed/refractory settings. In the frontline setting, BRUKINSA has already established itself as a leading BTK inhibitor. With the combination of BRUKINSA plus sonrotoclax, we are advancing what we believe will be the best-in-class fixed duration regimen.

For relapsed/refractory patients, our BTK degrader should become a cornerstone of continuous therapy. We are also advancing fixed duration regimens, including sonro plus CD20 antibodies. In addition, we're evaluating sonro plus BTK CDAC, which can potentially be used for all patients in second line regardless of what frontline treatment was used. We're determined to offer CLL patients important options throughout their treatment journey. Sonro, our next-generation B-cell inhibitor has key characteristics that position this product to be potentially best-in-class. Sonro is 14x more potent than venetoclax, which may translate into superior efficacy in the clinic.

In addition, improved selectivity, shorter half-life and the lack of drug accumulation could offer a more favorable overall safety profile. And perhaps most importantly, sonro offers opportunity for a more patient-friendly ramp-up with potentially only one clinical visit. Yes, only one clinical visit during ramp-up compared to up to 8 visits for venetoclax. Sonro has a broader development program with 3 Phase IIs for accelerated approvals and the 3 ongoing Phase III studies.

Diving into the combination data. The zanidatamab plus venetoclax-ZS regimen achieved a very high rates of undetectable uMRD at 10 minus 4, 92% in the 320-milligram cohort regardless of the risk status. With a median follow-up of 25.5 months, no PFS events have occurred in the 320-milligram cohort and only one event occurred in the 160-milligram cohort. There are a total of 137 patients treated in these 2 cohorts combined, not a small data set. 35 patients have elected to stop the therapy after week 96 and all remain in remission with some beyond the 12 months without treatment.

I would like to draw your attention to the table shown on this slide. With the normal caveats of a cross-trial comparison, ZS has demonstrated the highest uMRD rate and an unmatched PFS for the respective follow-up when compared to other venetoclax-based fixed duration therapies. There are some important deficiencies with other fixed duration therapies, like the low 34% rate of uMRD and underwhelming 3-year PFS rate of 77% observed with AV despite the ultra-fit population started in the AMPLIFY trial.

For the new treatment paradigm in frontline CLL, safety and convenience are as important as efficacy. ZS showed a favorable safety profile with fewer high-grade adverse events and no deaths [Audio Gap] associated with the intravenous use of obinutuzumab and the cardiac toxicity and death associated with ibrutinib.

In terms of patient convenience, we did not observe any clinical or laboratory TRS, and we are very optimistic that for the vast majority of patients, only one clinical visit during ramp-up will be required for after [ zani really ]. In conclusion, we believe that ZS combination has the potential to be the game changer for our fixed duration option for CLL patients.

Moving to the third asset in our heme franchise, our BTK CDAC is the most advanced BTK degrader in the clinic with the best-in-class features. As a mechanism, degradation can overcome and preventing emerging resistance mutations and disrupt the scaffolding function of BTK proteins. Long half-life in the clinic has resulted in sustained BTK degradation with daily dosing. We have a broader development program ongoing, including 2 pivotal Phase IIs for accelerated approval, 2 ongoing Phase IIIs and one more in start-up. We provide an update on BTK CDAC Phase I results at EHA. In the graph on the left, you can see our BTK CDAC trending towards almost 2 years of median PFS in heavily pretreated CLL patients, which looks favorable to the recently published pirtobrutinib data from BRUIN321 study shown on the right, with the usual caveats of a cross-trial comparisons. The head-to-head trial versus pirto will start soon.

Going beyond the CLL. Here, we present an overview of the broad clinical development plan and the clinical study across our heme franchise in non-CLL indications. Designed to maximize the clinical and commercial value of BRUKINSA, sonrotoclax and the BTK CDAC as part of our strategy for our B-cell malignancy franchise and beyond.

Moving on to the solid tumor. Our solid tumor pipeline includes diverse modalities and mechanisms across 3 disease franchises, breast and gynecological cancers, lung cancers and GI cancers. We revamped our entire solid tumor pipeline over the last 2 years. Every single asset you see on this slide either entered the clinic in the past 2 years or will be in the clinic by the end of this year. This showcases our ability to quickly establish a deep and highly competitive pipeline in disease areas of focus. The portfolio synergies created by this molecule should not be underestimated.

Finally, I'd like to highlight a few key milestones within our pipeline. We have successfully achieved the critical goals we set at the beginning of the year with some completed ahead of the schedule such as the CLL and the mantle sell filings for sonro in China. In the latter half of the year, we anticipate several significant milestones. Including the global filing of sonro in relapsed/refractory mantle cell. In addition, we expect potentially pivotal data from our BTK CDAC in relapsed/refractory CLL and initiated global filings in 2026.

Turning to our early stage pipeline. As you have heard, we have a number of proof of concept catalysts expected across multiple modalities and disease franchises. We're also actively moving some of the -- some of these assets into late-stage development, including our CDK4 inhibitor and B7-H4 ADC. We look forward to sharing more data in future updates.

And with that, I will turn the call back to Dan.

Thanks, Lai. We are now ready for Q&A. Joining us for the Q&A portion of the call is Xiaobin Wu, President and Chief Operating Officer; Matt Shaulis, our General Manager of North America; and Mark Lanasa, Chief Medical Officer for solid tumors. I kindly ask participants to limit the number of questions to ensure we have time to hear from as many attendees today as possible. Operator, we are ready for the first question.

[Operator Instructions] Our first question comes from Jessica Fye with JPMorgan.

Congrats on a strong quarter. On BRUKINSA, I think in the beginning of the year, you mentioned you expect flat U.S. net price this year. Is that expectation evolved at all now that we're halfway through the year? And were there any inventory changes at the end of 2Q relative to the end of 1Q, you might be able to quantify?

Second, what was your reaction to the BRUIN-CLL-314 data for pirto versus IMBRUVICA in that mixed frontline and relapsed population? And what are you going to be watching for when those details are eventually presented?

And then lastly, for the CDK4, I think at the R&D Day, you had talked about starting a second-line Phase III trial as soon as 4Q '25, and I see that's now in the press releases 2026. I guess recognizing that the, like as early as framing doesn't definitively mean you were going to start in late '25. What's the additional information you hope to gain prior to initiating that second-line Phase III trial and can you confirm what we should expect to see updated clinical data for that asset this year?

Thanks, Jess, for the question. So we have 3 parts to that question. I think the first on BRUKINSA and net pricing. Maybe, I'll ask Matt to comment on that.

Sure. Thanks for the question, Jessica. And we anticipate stable pricing through the remainder of the year and similarly have no significant inventory levels to comment on.

The second part of that question was the BRUIN314 reaction. Lai, I think I'd point that one to you.

Yes. Thank you for that question. It is important to note that in the BRUIN314 study, [ OR superiority ] was not formally tested. Therefore, it is not statistically significant. Now I also want to point out, including the treatment-naive patients, it's likely to help the OR difference. Our ALPINE study of BRUKINSA versus ibrutinib in the relapsed/refractory CLL still remains the only head-to-head trial to demonstrate the superiority of one BTK inhibitor over another based on PFS endpoint. And the PFS endpoint is the golden standard in CLL.

We believe in this setting, a positive readout of non-inferiority OR compared to ibrutinib is highly unlikely to be practice changing for the following reasons. Number one, there's no PFS data yet. Number two, it is compared to ibrutinib. Any new -- we believe any new continuous BTKi needs to demonstrate superiority over BRUKINSA, not ibrutinib. BRUKINSA should be the true standard now in treatment-naive settings.

Number three, I think that it is still very early data. For BTK inhibitor, you really need a long follow-up to demonstrate your therapeutic benefit. We also expect pirto will primarily be sequenced after the covalent BTK inhibitor, particularly if we start thinking of the entire treatment journey for CLL patients, it is hard to imagine this data set will convince physicians that a better option is to go with pirto versus BRUKINSA given the results from BRUKINSA.

Just a final note. I think the BRUIN314 alone is not sufficient for regulatory filing. As Lilly stated in their press release, it will be combined with 313 to form the basis for regulatory submission. BRUIN313 study is a pirto versus BR in treatment-naive CLL without 17p deletion.

I think the key question here is whether BR is still a valid control and when it is filed for NDA in, let's say, 2026, if the trial reads positive. And also OS trend, I think, will be another important element to watch out. I'll probably pass this on to Mark to address the CDK4 question.

Thank you, Lai, and thank you, Jess. Good morning. We set an ambitious target for our first Phase III start by the end of 2025. As the data are now coming in, we believe it would be prudent to let the data mature just a little bit more to inform our Phase III dose level selection. The magnitude of delay will be very modest, but it happens to move in from late '25 into early '26, which is why we're providing this updated guidance. I would also highlight for the first time we're disclosing our intent to start a frontline study with our CPK 4 inhibitor in 2026. So we remain very excited about that program.

To your other question, we intend to share the data from dose optimization in combination with fulvestrant in this year's San Antonio Breast Cancer Symposium.

Our next question comes from Sean Laaman at Morgan Stanley.

On the CELESTIAL-TNCLL trial, and I think it's 303. Ultimately, if you proved successful there, how do you think that the market plays out? Do you look at the V plus O combo was the initial target market? And how do you think about pricing if you're selling BRUKINSA and sonro into that market? And then do you -- what do you see or how should we think about the time-based therapy bleeding over into the normal course of operations or the rest of the market? That's my first one.

Sure. Happy to address that one, Sean. And I would say that we're very optimistic about the prospects for zani plus sonro. And you've heard from Lai some of the clinical underpinnings of that. Certainly, when it comes to our overall approach to driving adoption in CLL, we think that, that's going to be one of the primary drivers. And from a pricing standpoint, we're going to look at various different comparators for it. When it comes to fixed duration overall, I can say that so far, we haven't really seen much uptake of initial fixed dose utilization. Ven plus BTK isn't approved in the U.S. at the current time. So usage is off label. And we think that frankly, given what we've seen in the data so far, in comparison to continuous BTK, it would be inappropriate to see fixed duration use right now.

As we've spoken many times, what we've seen of the current regimens that are available is that they're in very young and fit populations. And here I'm speaking about [ AV ] that also have limited risk factors. And we think that the benchmark really hasn't been met for deep and durable responses, strong PFS and safety and tolerability. However, to your point, with CELESTIAL, we believe that zani plus sonro is going to satisfy those benchmarks. So we don't see substantial fixed dose or fixed duration uptake in the near term, we see that BTK mono is going to continue to be strong. And then later, when we see the zani plus sonro data, we see that there will be bigger opportunities for fixed duration then.

Great. Great. And -- just on the pirto equation, many KOLs we speak to sort of reticence to see or reticent to say that they will see pirto moving to [ 1L ] even on good data because they're potentially losing that second-line option. But just to grab your latest thoughts on the resistance mechanisms associated with pirto versus BRUKINSA -- and what -- just frame the risk for us there, that would be very useful?

Yes, Lai, why don't you take that one?

Yes, I can probably take that question. In terms of the resistance mechanisms, it's still evolving. And clearly, pirto can work on covalent BTK inhibitor failed population, especially for the [ cysteine-481 ] mutations. And there are several other settlement mutations pirto can work on. So -- and unless there's a really strong data set demonstrating, I think a covalent BTK inhibitor works after pirto. I do believe a physician want to keep that option with the pirto to be treated, to be used after the covalent BTK inhibitors. And for the other things which I mentioned earlier on is about the data for 314 is still very, very early. And it's only OR non-inferiority. So we are also eagerly waiting for that data to be matured. And most importantly, I think if something want to go into the front line, it really need to compare to BRUKINSA, not ibrutinib any more.

In the interest of time. That's all I have for now.

Our next question comes from Ziyi Chen with Goldman Sachs.

Congratulations on a very strong quarter. Just 2 questions on financials and also the U.S. tariff. We actually see -- saw the gross margin has been improved notably in the second quarter compared to first quarter. So while the product revenue, we had seen 18% quarter-over-quarter growth, the absolute dollar amount for the cost of goods sold in second quarter was flattish versus the first quarter. So could you help us understand a bit more about how you have been controlling the manufacturing costs and optimizing that? And -- because this is really not being explained by product mix change. We guess definitely in terms of BRUKINSA, there has been some improvement.

And another question is really on the U.S. tariff impact on the gross margin side. Just regarding the potential U.S. tariff on the pharmaceutical imports, which I think President Trump said that they will be put up initially a small tariff then eventually, it goes up to 150% in 18 months and getting up to 250%. So that's our guidance on the gross margin, which has been raised from mid-80s to mid- to high 80s reflect that potential tariff? And how should we look at the gross margin assumptions going forward?

Great. This is Aaron. Thank you so much for the question. So I'll take it in 2 parts. You're right. We've seen some improvement in gross margin on a quarter-over-quarter basis and certainly relative to last year. As I mentioned in my prepared remarks, that's really coming from improved production efficiencies, particularly for TEVIMBRA. We have a bit of price and also for mix. But we're certainly making efforts across our manufacturer and supply chain to continue to drive efficiency improvements. Largely in this quarter, it's TEVIMBRA. And then I also did mention as we think about the full year guide, the potential improvements for BRUKINSA.

It's a great question relative to the U.S. tariffs. We've talked about in the past how our current guidance contemplates what we know today about tariffs. And that impact has largely been mitigated by how we globalize and regionalize our supply chain, and that includes our U.S. production for BRUKINSA and our investment in our Hopewell facility where I sit today, where we are qualifying this facility for TEVIMBRA production. As you mentioned, the big uncertainty remains around the current Section 232 investigation. We've all seen the headlines.

We will monitor and obviously be very agile in our response to ensure both financial efficiency as well as, most importantly, operational efficiencies as we supply our life-saving medicines for patients. As I said, our '25 guide includes what we know today. Candidly, any announcements beyond that would likely not have a significant influence in our '25 results, just the way in which inventory is positioned and how that flows through the P&L. Future impacts while we believe would be manageable within the context of our P&L, it's just really too early to say to provide a forward outlook.

Just a quick one. Looking at the filing, you mentioned about second quarter, we saw benefit in net pricing for BRUKINSA in the U.S. Could you elaborate a bit more on that? What has been the benefit? And how should we look at the net pricing going forward?

Thank you, a great question. As we talked about historically, we do see relatively stable net pricing. That is what we are -- have seen in our current results. In my prepared remarks, we talked about mid-single-digit pricing in the U.S. This is largely the pull-through of our early year price increases, which is consistent with market practice and well within what the requirements under the IRA mandates. We do see some incremental benefit on a year-over-year basis relative to Part D reform.

And I think we talked about at the last quarter, the prior year, including the manufacturing liability around the donut hole, which goes away and that's replaced this year by the manufacturer liability under the cost share. And in our case, we do benefit from the specified small manufacturer designation.

So the combination of those 2 leads you to our mid-single-digit performance on a year-over-year basis for this year. I would say that modest benefit you see in the changes from Part D reform is something that you see more significantly in the front half of the year given the lapping of the donut hole, which largely occurs in the first half just based on that prior regime.

Our next question comes from Kelly Shi with Jefferies.

Congrats on another great quarter. First one, for the revenue guidance raised to $5 billion to $5.3 billion, what drove to this low-end bump? And specifically which product underpin that outlook? And second one, you point to 20-plus expected R&D milestones over the next 18 months. Could you provide more granularity on which ones might have been the most impactful events? And lastly, what are the newest learnings from adding translational studies regarding how BeOne's BTK degrader tackle resistance mutations acquired from the first-gen BTK inhibitors differently from pirto?

Great. Maybe -- this is Aaron. Maybe I'll start. Thanks for the question. So our update to our revenue guidance to $5 billion to $5.3 billion, really just reflects our confidence in execution in the first half of the year. We don't provide product revenue guidance. But I would just say, as you see in our current quarter performance as well as Q1, across the portfolio, both from a product perspective and a geographic perspective, we're pleased with our performance, and this update just signals our confidence in our execution. On that, maybe I'll hand it over to Lai on the R&D questions.

Yes. I'll probably address the -- the third question first about BTK degrader in terms of the resistance versus, let's say, pirto. There are 2 well-known resistant to pirto, which after the covalent BTK inhibitor, one of them is L528W, another one is T474 mutations. So far, BTK degrader can really work well with those mutations. And we're still at the early stage in terms of the experience of the BTK degrader in the clinic. So there hasn't been that many patients really progressed.

We're actively following what kind of mutation were -- resistant mutation were emerging from the BTK degraders. But having said that, it doesn't look much more promising in terms of being able to overcome more broader spectrum of the BTK mutation for degrader versus the pirtobrutinib. Also, we have done some translational work using the cell line, using the animal model. It does seems like the degrader can probably have longer tumor suppression compared to, let's say, a pirtobrutinib or other covalent BTK inhibitors.

Your other question is about the exciting milestones. Maybe I will talk about what's on the heme side of it. Then I will pass this over to Mark to comment on the solid tumor side of it. On the heme side of it, I think certainly be able to file sonrotoclax globally. This will mark the really important critical step for sonrotoclax. We are truly excited about this molecule for everything we have seen in the clinic. The combination of the sonrotoclax plus zanidatamab outstanding. Its own activity right now in the mantle cell lymphoma, which is the monotherapy study we did globally, and the data looks really interesting. This really formed the basis for the initial global filing and we're also now seeing activities for this one in the multiple myeloma, et cetera. It's not listed here, but certainly, we are moving very aggressively about that one into the potential pivotal stage as well.

Then on the degrader side, we're very excited to get the pirto going, probably will be next couple of months. So we'll get pirto trials going and I think that one will potentially bring a better drug for patients in the relapsed/refractory settings. So Mark?

Thanks again, Lai. Again, for the solid tumor, the most important data disclosure that we're likely to have for the remainder of 2025 will be our CDK4 data at San Antonio Breast Cancer Symposium. Many of the new molecules that Lai highlighted in the solid tumor portfolio will have early data emerging. We're very pleased with the progress of the portfolio and we are hopeful that we'll be able to share data from multiple programs in the first half of 2026. And as Lai mentioned, at the R&D Day, we highlighted 4 programs, including CDK4, B7-H4, PRMT5 and FGFR2b that are showing very encouraging early data. And again, we look forward to disclosing more data from those programs, likely in the first half of next year.

Sorry, maybe just a I forgot to mention, which is that degrader will have the pivotal Phase II readout next year and hopefully that will lead into also a global filing for the degrader. That one is definitely very important in milestone as well.

Our next question comes from Yigal Nochomovitz from Citigroup.

Just a few questions, a couple on BRUKINSA and then one on the pipeline. Regarding BRUKINSA, you mentioned the majority of patients have unfettered access, and there's a step-up in access on appeal. I'm wondering if you could just provide a little more specifics in terms of the numbers associated with the access out of the gates and then what the access on an appeal?

And then more generally, just in terms of the overall business globally, obviously, it shifted ex China. I'm just wondering if you've reached a point where it's essentially a steady state in terms of the product mix, revenue mix, China, Europe, United States and you're going to see steady growth across the board, or if there's still an expectation of movement of revenue more ex China. And then lastly, maybe for Lai. Could you comment more specifically on some of the powering assumptions on PFS -- PFS with respect to the CDAC versus [ pirto ] Phase III.

Super. Thanks for the question. And I'll start out and then hand things over to Aaron for revenue mix. Regarding your question around access out of the gate and then appeals, I think all of the access conversations start with our continued belief in BRUKINSA as a differentiated asset that's best-in-class amongst the BTKs and has this overwhelming body of evidence that John described, including thousands of patients in clinical trials, and we continue to evolve that with real-world evidence and other data. So we're seeing a preference for BRUKINSA with HCPs and with patients. And when it comes to the access component, oncology is a protected class and BRUKINSA continues to be listed on all Medicare Part D formularies.

When it comes to that appeals process, it's important to remember that any preference or step edits don't impact existing patients at all. It's limited in new patient starts. And here, it's also important to remember that the majority of our claims are filled initially. And then if an appeals process is needed, we've been very successful in supporting accounts to work through that process. So going forward, we're really confident in continued access and growing demand and extending our value share ownership. Aaron, over to you for the next question.

Great. So I'll just really quickly and actually invite Xiaobin for his perspective. But certainly, Yigal, we're growing globally. And as we think about the mix of business, every region is growing at different paces. We're still quite early in many parts of the world in our launch trajectory. We've historically talked about Europe being earlier. Rest of World markets, including really important markets globally or even earlier in their launch cycle. So we would expect that our revenue mix to continue to diversify over time. But that's coming from a position of growth in all regions, including our China business. So Xiaobin, maybe I'll invite you for your perspectives.

Yes, sure. So as Aaron mentioned before, the biggest revenue driver today is U.S. and we achieved $685 million with growth rate of 43%. China is the second biggest contributor and grew also 23%. And we just got the publication of the IQVIA data and we moved up one position to be sixth biggest oncology company in China. And we grow very fast outside the U.S. and also China. In Europe, we grew close to 90%. In the rest of the world, means new markets and also [ JPAC ], we grew 170% and then you can say the dynamic. In China, we grew -- continues to be very strongly and far above the market. Outside China, we grew even much faster, including U.S., Europe and the rest of the world. That is a very healthy dynamic and we grow actually everywhere.

Yes. Maybe to the last question about the -- about our degrader PFS. I think on the Slide #28, if you take a look at, there was also a table under that PFS curve, was to point out the patient population we treated, our CADENCE 101 study had more [indiscernible] therapy, but more importantly, the double-exposed patient population was higher. And also, you may have some patients who are triple exposed. And with that kind of the worst prognostic patient population, we are seeing this nice PFS trend give us the confidence, but I don't have much more data than what you can see here because the data cut here was about March. So certainly, we have some -- a bit more data. But over speaking, I think that it's definitely trending towards the right direction. But again, I want to point out this is a cross-trial comparison.

Our next question comes from Reni Benjamin at Citizens JMP.

Congratulations on an amazing quarter. Maybe just to -- you're approved in 75 markets globally. Can you just remind us what's the total number of markets you'll be approved at in peak? And should this playbook be repeated for TEVIMBRA and sonrotoclax? Or are there other factors that may impact which markets you go into with either of those 2 drugs? And then just talking about the tablet formulation, which you've mentioned in the prepared remarks, is this something that could materially impact sales going forward? Or does it really just impact the cost of goods? And does this ultimately replace the current formulation?

Yes. For the first one, Dr. Wu, would you like to respond to total number of markets at peak and how it might differ from TEVIMBRA?

Sure. Our regulatory approval in so many countries, I can't remember anymore. We have a bunch of list, over 70 countries, including all the major markets for both products, TEVIMBRA and BRUKINSA, U.S., EU, U.K., Switzerland and many other major markets. In addition to those major market, we got also quite some approval -- regulatory approval in the emerging market like India and Indonesia, Thailand, so many other -- Brazil and Israel and many other countries. It's a bunch of list. If you want, we can send it to you the concrete list. In most of those countries, we launched product already, and we are also launching products in new markets.

And I'll gladly address the tablet question. This is primarily our commitment to patients. And ultimately, this tablet will be a more convenient and easier to use formulation. With regard to impacting sales in a material way, we think that this will continue to solidify our market leadership position on a commercial basis. And then I think you also asked a great question around will the formulation ultimately replace the capsule? In due course, we will move to simply having the tablet available for those patient-focused reasons.

Got it. And I'm sorry, just as a quick follow-up to Xiaobin's answer. Is the 75 markets that you're currently -- or greater than 70 markets that you're currently globally marketing in, is that -- is that it? Or does this -- is there even more to be expected, right? Or have we penetrated as many and now it's just growing in those markets, that's important?

Yes, great question. So we continue to expand our footprint. Just remember on our mission and BeiGene is set up also to -- our mission is to reach out to many more patients. So to provide innovative and affordable medicine. Therefore, our mission continues, and we definitely want to expand to more markets. In addition to that, we also get some new indications in this already registered market and expanded to new indications. We -- for the 70-plus registered countries, we do not have every indication yet in TEVIMBRA and also for -- even for BRUKINSA, we continue to register new indications. Yes, expanding continues.

Our final question comes from Michael Schmidt with Guggenheim.

Congrats on the great second quarter here. Bigger picture question on the covalent BTK inhibitor market in the U.S., which is still growing at 10% right now here in the first half of 2025. And so -- just curious if you could comment on what is driving overall market growth right now in the covalent BTK space? Is it duration of treatment versus additional patients coming on to therapy? And how should we think about the peak potential for the class, especially as we think about potential fixed duration combinations coming in into the future.

And then how big of a near-term growth driver is the first-line MCL opportunity for BRUKINSA based on the mangrove data later this year. And then lastly, we're getting questions just on how you feel about expanding the BTK degrader development into autoimmune and inflammatory conditions. I know you mentioned you have a CSU study up and running now. But how should we think about the long-term potential of the degrader in autoimmune and inflammatory?

I'm happy to start out with the questions around covalent BTKs and the market as well as frontline mantle cell and MANGROVE and then maybe then pass it over to Lai. And I fully agree with your viewpoint that we see opportunities for longer DOT among the drivers. Certainly, if you look at ALPINE or other data sources, you'll see that BRUKINSA's duration of therapy is longer and of course, that goes hand-in-hand with better PFS. So we do see that there will be some growth potential within BTK for those reasons. And -- or some of what we described earlier, we think that the current fixed duration regimens, including AV, don't offer the deep and durable responses, the high PFS and the safety and tolerability that really is the benchmark for treatment. So we'll see what we believe will continue to be continued mono BTK growth in the market moving forward.

Now for mantle cell and MANGROVE, we're certainly very encouraged. We think that will be a strong data set. Of course, mantle cell has limitations to the overall size of the patient prevalence and the opportunity for treatment. So we'll certainly see growth potential, but CLL will continue to be our main driver. With that, Lai over to you.

Thanks for the question about -- I think the question is related to how do we view about BTK degrader in non-oncology indication, especially for autoimmune. As you pointed out, we have started the study -- a Phase Ib study in the CSU. I want to point out 2 features about our BTK degrader. One of them is -- probably 3 features. Number one, it has really long half-life. This potentially can support different dosing frequency, which for certain disease, that might be very beneficial.

Number two, it has been penetration. I think that will be also applicable for certain autoimmune disease. Number three, I think this one like the degrader mechanism, it can destroy a scalpel function. And for certain disease area, that's also very important. We're actively exploring different potentials for this molecule in the autoimmune disease. So stay tuned.

At this time, we've reached the end of the question and answer. I will turn the call over to John Oyler for closing remarks.

Thank you. In closing, our second quarter results demonstrate exceptional execution across our key priorities. Our success is due to the sense of urgency and dedication of our more than 11,000 colleagues across the globe and the joint efforts of the patients, clinicians, advocacy groups, regulators and investors who have united with us in a joint effort and shared commitment to fight cancer globally. BeOne has already helped more than 1.8 million cancer patients, and I truly believe this is just the very beginning of what we will accomplish.

I'm looking forward to sharing more updates and milestones with you as we progress through the year. And I would like to thank you all for joining us today and for your thoughtful questions. Thank you.

Hello, everyone. Welcome to BeOne Medicine's 2025 Investor Research and Development Day. My name is Liza Heapes, I'm Senior Director of Investor Relations at BeOne. We are very excited to host our investor event today, both in person in New York City and online for our global attendees. Thank you all very much for joining us.

This is truly an exciting time at BeOne, and we are thrilled to walk you through recent progress to date and provide a sneak peek of what lies ahead. I would like to remind all participants that during this presentation, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy.

Actual results may differ materially from those indicated in the forward-looking statements. You can find more details in their filings with the SEC, Hong Kong Stock Exchange and Shanghai Stock Exchange. I'm delighted that joining us to present today are John Oyler, our Co-Founder, Chairman and CEO; Dr. Lai Wang, Global Head of R&D; Dr. Remus Vezan, VP of Hematology Clinical Development to take us through our BCL-2 program, Dr. Jacob Soumerai from Massachusetts General Hospital, who will share sonrotoclax data. Dr. Amit Agarwal, also our VP of hemo clinical Development, walking us through our BTK degrader programs and early research assets; Dr. Mark Lanasa, Chief Medical Officer for solid tumors; Dr. Shom Goel who came in from Peter Mac in Australia to share the latest on our CDK4 clinical development data.

At the conclusion of the slide presentations, our speakers will be joined by Aaron Rosenberg, our CFO and moderator for today's Q&A session.

Now please let's welcome John Oyler, BeOne Co-Founder, Chairman and CEO.

Thanks so much, Liza. And if you didn't notice, there was a small break in the middle, which probably will make all of you happy in about 45 minutes. So I just really want to thank everyone for joining us. We know that everyone's very busy. There's time and energy taken to try to understand our company. And we really appreciate all of the effort that you have made to date in helping us in this fight against cancer, and we really, really appreciate it.

This is our first investor meeting under the name BeOne Medicines. And I think our company BeOne, it was never simply about making one medicine to fight cancer. A lot of biotechs are, we were not. It was about trying to entirely transform the R&D process to do that to be able to make medicine more affordably and more excessively for cancer patients here in the United States and all around the world.

We also believed in doing that, we had to fight cancer, do it in a better way to improve the R&D process; and thirdly, provide superior returns to investors so that we'd be able to continue to fund the next generation of medicine for cancer patients. I think you'll see we're well on our way in all those areas.

The name BeOne, likewise, is very purposeful. B is because the singular goal of any cancer patient is simply to be. One, because we all need to work together as one and no patient, no family, no clinician, no hospital, no company, no policymaker, no country can fight the formidable cancer enemy alone. We all need to work together. We need to change the process to be better at what we do.

Of course, within One in red, you can see Onc. And this represents our commitment to oncology, which I think we wanted to reiterate to the world. Because right now, given some policy that's occurred, given success in other areas like diabetes and weight loss, some companies are pulling away from cancer. We're not. We were built to fight cancer. We will be here fighting cancer with patients, with clinicians forever. That's what we're here to do.

We were built differently from day 1. We remain mission-driven. We remain founder-led. We have a tremendous sense of urgency in everything we do. And I think that will flow through in what you see today. We're fighting cancer through scientific innovation, unquestionably, and that's what you will see today. But we're also fighting it through R&D business process innovation, and we're doing that because we really want to drive broader accessibility, again, here in the U.S. and around the globe. And we want to be able to provide superior returns in an industry that struggled to do that to any investment dollar that's coming in so we can continue to make great oncology medicines for the future.

So it's great to have a noble vision and it's great to have one that's really hard, but success isn't about a vision, it's so much more. It requires incredible people, and I think you'll see some of those from our team here today. It requires tremendous teamwork because this is one of the hardest things you can possibly do. There's so many different areas of expertise that need to work together to make a medicine.

And of course, it requires a lot of hard work some of which is not glamorous at all to get things done that need to get done. And I think you'll see we're an organization that isn't afraid to roll up our sleeves and do that work. Sustainable success also requires building strategic competitive advantages. And since day 1 of this company, we've been investing very heavily to build these. It's now been 15 years.

The simple and biggest example is clinical development. Clinical development is the vast majority of time and the vast majority of cost associated with making an oncology medicine. Yet it's largely been outsourced and is not a core competency of most oncology companies. We have built this internally over 15 years. And we now have this spectacular global team of over 3,700 people that is operating largely CRO free. They're doing the hard work and the heavy lifting that you will see the results of here today and what we're able to do as an organization, which I think will shock you at the speed and the quality of what we're doing.

We also have incredible internal manufacturing and research teams. They enable us further cost and speed advantages. Each of these capabilities, strategic advantages are incredibly hard to build. They took every penny that we ever generated in this company of revenue, reinvested or upfront licensing fee or financing that we raised to build these capabilities. It also took every penny we ever pinched, and we pinched a lot of pennies so we could spend it building capabilities and running programs.

This only exists these capabilities because of the tremendous efforts of the people that are here today and here with our company today and that have collaborated with us and also those who have previously worked at BeOne who really built these through brilliance, through dedication and through hard work, driven by their commitment to fighting cancer.

Today, BeOne has already helped 1.7 million patients, 1.7 million patients and their families fighting cancer. To me, that's something that makes me unbelievably proud, grateful and thankful that there's such a wonderful group of people within our company and around us working with us to help have that impact for patients. And what I can say unquestionably is this is just the very beginning of BeOne.

It goes without saying that if you want to build a sustainable business, it's critical to continue to be sustainable. It's critical to have the right core values and have them across your organization. And we have that. We simply live our core values. And with that, we always strive to have positive influence in every environment in which we're working, and we strive to work cooperatively with all elements of the industry.

So what are we going to share today? First, we're going to share how our unique R&D model has already proven that we can deliver quality, speed and cost sustainable advantages. And we can do that in a manner that provides superior returns to investors so we can continue to build the medicines for the future. From that perspective, this is core to everything we're doing, and I really think you'll see a wealth of information today that give you the confidence to have that true belief.

Our goal is to be the most impactful oncology company in the world. And I think when you see what we're doing, we're well on the way to that. Secondly, we're going to talk about hematology. And we have built a hematology franchise over the last decade, and we have 3 incredible medicines that can be combined to create the solutions for patients, not only today but in the future for the next 5 years and the decade beyond. And we are sure that we can continue to grow into the hematology leadership we already have in CLL and that it's highly sustainable and that we do have the right medicines for the future. And we can build more broadly in hematology outside of CLL and some of the other indications we're already approved in to become a broad hematology leader.

And third, in solid tumors. Although it took us a decade to build this franchise in hematology, we believe now we have several opportunities to build franchises that are similar in solid tumors and that we can do so in roughly half the time, and we're very excited to share this information with you. The data associated with some of these programs, which in their own right, if they weren't in BeOne, if they were in a small biotech company, I think there'd be huge excitement and a lot of value attributed to them. So we're glad to share some information about them.

So with that said, I think that you will see there's new data being presented to. And that's highlighted on the right-hand side of the slide. I know you come, you want to see new things. There's new programs that are disclosed here at a wealth of new data. So I know you want to get to that. And I think that the magnitude of what we're about to share to me is honestly a bit overwhelming. But I think as you can see, it's tremendously exciting. It has the potential to be massively impactful for patients all around the world. So we really should get to the heart of things.

So with no further ado, and I think Liza said we should see what lies ahead. And I'd like to introduce Lai Wang, who is a good friend of mine, and he's also well known for being BeOne's second biggest Dallas Cowboys fan. So here he is, Lai.

Thank you, John. Good morning. It's really nice to see the turnout. Thanks for coming. I'm really excited to share that BeOne R&D is at a pivotal moment in its journey. Over the years, we have built a strong research, global clinical development and the manufacturing capabilities from the ground up, allowing us to deliver, develop and discover novel oncology medicines much quicker and more cost efficiently than the industry standards.

The strategic advantages capabilities are now scaled and fully functional across R&D. This inflection point signifies the dawn of new era for BeOne, where our commitment to excellence and the pursuit of scientific breakthroughs will enable us to profoundly impact the field of oncology. Since 2019, we have transformed from a middle-sized setup into a scaled and highly efficient research powerhouse.

Our discovery team now comprises over 1,200 research scientist making us one of the largest oncology-focused discovery team in the world. We have made a substantial investments in a variety of the modalities, including putting the greater record, chimeric, degradation, activation compound CDAC, bispecific/trispecific antibodies, antibody drug conjugates and the cell therapies.

As illustrated on the graph on the right, our new arrow is marked by a significant increase in preclinical programs and diversified modalities. CDK and complex biologics, including bispecific/trispecific antibody drug conjugates now constitute the majority of our portfolio. Typically, it will take 2 to 5 years to progress from target identification to a new molecule entity entering clinical trial.

With our recent investment, we observed a substantial rise in the number of AMEs entering the clinic, especially starting from the second half of 2023. In 2024 alone, we had 10 new molecule entities entering clinic really function as a strong testimony about how strong and how productive is our discovery team. At BeOne, we prioritize quality over quantity. The rigorous innovation approach we have applied to BRUKINSA is now being used across multiple programs. We focus on conducting the crucial experiments and the only move high-quality molecules into the clinic, stopping any programs that does not meet our standards.

Over the last 3.5 years, we have terminated 60 programs that did not make the cuts. This disciplined approach ensures that only the best candidate move forward. For instance, sonrotoclax was designed to be more potent and more selective than venetoclax. And also address venetoclax's associated inconvenience issue by designing a short half-life molecule. This will be easier for ramp-up.

The FGFR2b ADC has the potential to spell ocular toxicity associated bemarituzumab by preserving ligand signaling. Additionally, IRAK4 CDAC can achieve complete target degradation in tissues by facilitating a very fast ternary complex formation involving IRAK4 CDAC and E3 ligase.

Next, I would like to highlight some of the technology platforms in which we have heavily invested in recent years, beginning with putting the graders. We currently have 23 degrader programs in our pipeline, including 3 in the clinic, BTK, EGFR and IRAK4, which are designed for hematologic malignancies, solid tumor and autoimmune disease, respectively.

Preclinically, we have 17 small molecule programs, including 2 we are introducing today, the CDK2 and the KRAS. In addition, there are 3 degrader antibody conjugates DACs at the discovery stage. Our dedication to protein degradation is evident in the scope and the depth of our pipeline. The biology underlying the CDAC platform is fascinating. As illustrated in this circular diagrams, CDAC provides many unique advantage across multiple dimensions, some of which we foresee -- we did not see at the beginning of exploring these modalities. Later in our discussion, we will dive into strategies such as increasing potency, enhancing selectivity, reducing on-target resistance and impairing scaffold with specific examples.

For now, I would like to briefly highlight 2 additional advantages. First, targeting undruggable protein is conceptually straightforward. As long as the CDAC molecule combined target, it has the potential to degrade the target protein. The binding does not need to neutralize the protein function. Secondly, by utilizing a tissue-specific E3 ligase, we can potentially minimize the degradation in the normal tissue, therefore, enhance the safety profile.

Now let's turn to ADCs. We currently have 25 ADC programs, including 4 already in the clinic. Today, we will provide updates on a couple of those programs. Our initial wave of ADC assets consists of mono TAA ADCs. The second wave starting from the end of this year, we're going to bring a set of the bispecific TAA ADCs interconnect, although still using the topoisomerase as the payload.

Moreover, this mono TAA as well as bispecific TAA antibodies can serve a building block for future novel payload ADCs, including DACs. Our investment in the technology platforms go way beyond just degrader and ADCs. We believe that technology is fundamentally tied into innovation in our industry.

Since cancer is such a complex disease, it requires a multi-facet approach to target the various pathways as well as many different targets within their pathway. So choosing the right modality for each target is vital to create a perfect job and then to create a deep portfolio for certain disease area, you really need to draw from a diverse range of technology platforms.

Our journey with CLL began in 2012 when we started our BTK program, followed by BCL2 in 2017 and BTK degrader in 2019. We are anticipating the first CRL approvals for sonrotoclax and BTK CDAC in at least one of the major markets within the next 2 years. For the -- so for the sale franchise, we leveraged only 2 technology platforms, our traditional small molecule inhibitor and the protein degrader platforms.

This journey spanning 15 years is a tremendous success by an industry standard, but we feel it is long. Now with our expanded discovery capabilities in both people, team and the technology platforms, we believe we are in a much better positioned to build a similar franchise across our disease area of focus which are listed here. And more importantly, we can do it much faster.

Our goal is to create a deeper pipeline by introducing 8 to 10 new mode entities for each dose area over the next 3 to 6 years. For example, I'm going to use the breast cancer and the gynecological cancer franchise as the example. Our first molecule, a CDK4 inhibitor which we're going to give you some update today enter the clinic at the end of 2023. So only 18 months ago. Take a guess, by the end of this year, how many molecules we have in the clinic for this franchise, 8. We have 8 new molecule entities in the clinic just for this franchise in just 2 years. This is what now we can do.

And certainly, you will hear a whole lot more about our breast cancer oncological cancer franchise in marked sections. The competition in oncology has heated up in the past 10 years. For almost any target you pick, there are so many competitors work on it. We firmly believe the future of oncology really relies on innovative combinations. Our deep pipeline empowers us to develop unique and proprietary combinations that address our mathematical needs in cancer treatment.

This slide presents several examples we will discuss throughout the presentation, Using BRUKINSA and sonrotoclax, as example, I strongly believe this might become the best treatment option ever for CLL patients. You will hear a lot more about this in the later sections. This strategy enables us to maximize the potential of our assets and ultimately enhancing the patient outcomes.

Our philosophy of rigorous scientific innovation, combined with our scale and the sense of urgency, sense of urgency is really important, has led to an industry-leading pipeline. This slide showcases our extensive portfolio, ranging from proven therapy like BRUKINSA, TEVIMBRA, to very promising early candidates in early stage development.

Our pipeline reflects our unwavering commitment to advancing transformative medicines and improve patients' lives worldwide. Currently, we are executing 96 trials -- ongoing trials involving 30 assets across various phases, modalities and disease areas. This slide illustrates the breadth and depth of our clinical portfolio. I will spend the next few minutes also to share with you how we are building our clinical development capability to handle this large and growing clinical portfolio.

Building our global clinical development organization has been a significant undertaking. It is hard. The time line highlights our journey from inception in 2013 to our current state and beyond. We began laying the groundwork in 2013. And from 2017 to 2024, we're concentrating on establishing our global capabilities.

Today, after streamlining and optimizing our process over the past few years, we're not only operational but thriving. In addition, we have ongoing plan to further enhance our efficiency through the integration of AI and automation. Our global chemical team consists of over 3,700 professionals, covering a wider range of functions to drive our efforts.

Each scale on the slide represents a different function within our team, recruiting specialized talent and assembling this formidable team of clinical developers is no trivial task. This visualization highlights the collaborative and the integrated nature of what we do. At BeOne, we harness our internal global clinical capabilities to drive speed, cost, quality and site access. We will showcase some speed examples in the upcoming slides.

When it comes to cost, CLL will typically charge you about 30% additional money. By eliminating the need for CROs, we can cut the CRO fees Additionally, our internal model has led to enhanced the trial quality. Over the past 10 years or so, we have successfully undergone over 100 inspections by 15 different health authorities in more than 10 countries and all this without any critical filing. This is a remarkable achievement.

Also direct interaction between the investigator and the sponsor provides enormous value as the investigators strongly prefer working directly with the sponsors over dealing with the CLL. Our patient enrollment strategy emphasizes diverse regions highlighting our commitment to global representation. We ensure broad global enrollment across various regions with increasing representation from emerging markets.

This strategy helps us gathering valuable data and insights from a wide range of population. And in certain cases, the access to hard-to-reach patient populations, which I will touch on later. It is worth pointing out that our China enrollment in 2025 only accounts for 1/4 of our total enrollment globally. All the examples, I will share with you later, really represents our global capability, not just the China capability.

At BeOne, we are dedicated to streamlining the drug demand with a focus on excellence. On this slide, you will see metrics from our fast-to-proof-of-concept efforts, and we are applying across all early programs. I truly believe this is important for our success. For instance, if you look at the middle column, we hold the safety monitoring committee meetings only 2 to 4 days after the last patient finished their dose-limiting toxicity evaluation.

Our medium time to complete a dose escalation cohort is only about 7 weeks, slightly over 1.5 months. This is well below industry standards. This speed can save us more than 1 year with dose escalation alone in the drug development. Time is truly of the essence.

To further illustrate our efficiency, let's look at the CDK4 inhibitor program as an example. We have enrolled over 300 patients and evaluate 2 dose cohorts, including both mono and combo in just 18 months. Do you know how quickly we initiate the first-line letrozole combination in CDK4/6i patients after completing the DLT evaluation combo in the second line patients? I have the answer here. You already see it. It's just 13 days. This is remarkable, seriously, if you think about it.

We accomplished this by strategically opening sites in regions with very limited CDK4/6 access, including Brazil, Malaysia, Maldova and Thailand. Also for the BTK CDK, we successfully enrolled over 600 patients in the last 3 years. A lot of people are comparing us to another small biotech company. We entered the clinic only about 6 months ahead of the other company, but now we are way ahead.

We effectively use the backfill and the safety expansion cohort to gather those response data. And remarkably, it took us only 4 weeks to go from the recommended dose for expansion. So basically, it's the time you're picking a few dose to expand. So only 4 weeks from that time point to start our pivotal Phase II trial. Now this CLL Phase II has already enrolled more than 100 patients. I hope I have demonstrated to you that we have made significant strides in our pursuit of operational excellence through our internal operational model.

I firmly believe the next wave of efficiency will come from the integration of AI and automation. Such advancements are not attainable using a CLL model. Clinical trials are essentially a data journey. By incorporating cutting-edge technologies into our process, we can streamline the operations, reduce manual labor and boost accuracy. Under this approach not only accelerates the clinical development, but also ensure we delivered the highest quality results.

Here are a few examples to give you a flavor how much efficiency we have already gained. This is what we've already done with our AI and automation. BeOne's [R&D] strategy is anchored in 4 foundational principles. This has really set us apart from probably our peers in this industry.

Number one, we're leveraging our diversified technology platforms to build a robust pipeline in targeted disease area for synergistic outcomes. Number two, accelerating the development of molecules towards value inflection points and achieving clinical proof of concept to inform data, keep in mind, data-driven decisions. Number three, initiating proprietary combination therapies early to maximize the potential for our assets and then enhance patient outcomes.

And then number four, exercising discipline by advancing only transformative medicine into late-stage clinical development. Our industry however, on the other hand, especially some of the large pharmaceutical companies often fall short into investing sufficiently in discovery and early development and by lacking principle in late-stage development, typically driven by commercial interest rather than data.

In contrast. We focus on strengthening early development while being highly selective in late-stage investments. Our strategies are supported by our highly productive discovery capabilities and our CRO-free clinical operational model. We're committed to pursuing these principles urgently and with a firm resolve to challenge the status quo.

Next, let us to update you our hematology portfolio. Over the years, we have witnessed remarkable advancements in CLL treatments. Key FDA approvals for therapies like Gazyva, Imbruvica, Venclexta, Calquence, BRUKINSA and Jaypirca have truly revolutionized our approach to treat CLL. The market for CLL is not only substantial, but still rapidly growing.

However, it is important to note, despite the effectiveness of BRUKINSA only addresses a fraction of the available treatment opportunities. Despite this significant advancement, there remains a considerable unmet medical need for new treatment options in CLL. There is a clear demand for fixed revision treatments, particularly for treatment-naive young and fit patients.

Current venetoclax-based first-generation regimen often fall short due to various challenges, including efficacy, safety and inconvenience. Additionally, the increasing number of patients relapsing after first-line treatment underscores the necessity for innovative treatments in relapsed/refractory setting.

BeOne stands out as the only company with fully owned potentially best-in-class assets across 3 foundational MOAs in CLL. This provides a unique opportunity to comprehensively address the unmet medical needs of patients across all lines of therapy and in the different subpopulations using both monotherapy as well as our unique combinations. We are strategically positioned to tackle the unmet medical needs in CLL treatment with our wholly owned portfolio.

While BRUKINSA currently serves a portion of patients, we aim to develop regimens that cater to all patient segments. We are dedicated to relentlessly pursue best-in-class option from frontline to later lines of therapy with both continued use as well as the fixed duration treatments.

Now move on to BRUKINSA. BRUKINSA continued to deliver exceptional value for patients around the globe as the best-in-class BTK inhibitor. It serves as the cornerstone of our CLL franchise. In the U.S., BRUKINSA leading new patients starts for both frontline and the relapsed refractory CLL and across all approved indications. It is both the most comprehensive label of any BTKi, and is the only BTKi shown to offer superior efficacy and safety in a head-to-head trial against the ibrutinib. With approvals in certified markets, including recent launch in the Japan, BRUKINSA has successfully treated over 200,000 patients globally.

From its inception, BRUKINSA was designed to provide a best-in-class 24/7 BTK inhibition. Our hypothesis was achieving complete and sustained BTK inhibition would result in a superior therapeutic profile. Notably, BRUKINSA is the only BTKi maintains serum concentration significantly above IC50. I should say, only covalent BTKi.

While exposure for acalabrutinib and ibrutinib remain well below their respective IC50 for the majority of the treatment period. But we actually had this data about 10 years ago. And we shared with a lot of people, who will say, this is the best-in-class BTK inhibitor. Nobody believing us. So we'll take the hard road and did the experiments. So we did this experiment is trying to demonstrate in the head-to-head fashion. This is a better BTK inhibitor based on science, based on the design. BRUKINSA has this superior target coverage translates into exceptional clinical efficacy. In the ALPINE trial, BRUKINSA except a sustained superior progression-free survival efficacy alongside low-cardiac toxicity when compared head-to-head with ibrutinib.

In the intent-to-treat population, the PFS ratio was 0.66, with milestone PFS over 64% for BRUKINSA and 53% in ibrutinib at a 42-months mark. The treatment effect is even more pronounced in high-risk data delta 17p population where the hazard ratio was 0.48 and the landmark PFS at 42 months was 59% for BRUKINSA and 32% for ibrutinib. These results underscore the efficacy of BRUKINSA and its potential to improve outcomes for patients with relapsed refractory CLL. Maybe just add another commentary. When we began to show ORR superiority, people still don't believe this can be a better one, not until we show the PFS. So we have demonstrated you once we can make greater molecule and design right experiments. Hopefully, next time you will believe in that.

So in the treatment-naive setting, BRUKINSA has demonstrated impressive PFS outcomes for patients regardless of their data 17p status. The presence of delta 17p is associated with significant higher risk of mortality due to CLL.

The graph presents PFS curves in SEQUOIA trial from 2 separate arms of the treatment naive CLL patients with or without delta 17p. Both arms were treated with BRUKINSA mono therapy alone. In Arm C, which represents the largest prospective cohort of uniformly treated patients with delta 17p, BRUKINSA achieved a remarkable 60 months PFS ,5-year PFS rate of 72%, comparable to the 76% in dose result delta 17p.

The success of BRUKINSA reflects our rigorous approach to drug development. We focus on creating superior molecule and are not afraid of conduct head-to-head clinical trials when necessary. We are now seeing us doing that also with sonrotoclax and the BTK degrader. These efforts have placed BRUKINSA in a strong market leadership position in the U.S. within just 2 years of its launching CLL, despite being 9 and 3 years later than ibrutinib and acalabrutinib respectively. Best drug wins.

Now I'll hand the presentation to my colleague, Remus, who will share insights on sonrotoclax and our option for fixed duration treatment.

Thank you, Lai. Good morning, everyone. I am Remus Vezan, Vice President of Clinical Development at BeOne. And I'm very excited about the opportunity to share with you our clinical development plans for next -- our next-generation BCL2 inhibitors sonrotoclax.

Fixed treatment duration is emerging as an important therapeutic modality in CLL, and our company is dedicated to addressing this important issue for patients and physicians. In our view, the fixed statement duration should meet few essential characteristics in order to be ideal for patients and give the confidence to patients and physicians to stop therapy.

One, this essential element should have the capacity to achieve higher efficacy demonstrated in high rates of responses and measured by deep uMRD levels. Two, should have the capacity to achieve long progression-free survivals at least at the level of the BTK continuous therapy. Three, it is also important to have a favorable safety profile with minimal added toxicity, no TLS and low rates of high-grade toxicities and very important, no increase in that event.

And four, should be able to address the convenience factor being an all-oral regimen with no requirement for hospitalizations and minimal number of clinical visits for TLS monitoring. And all this would allow for this medicine to be accessed by most of the CLL patients.

Venetoclax is currently the only BCL-2 inhibitor approved and represents an important therapeutic agent for CLL patients. However, there are significant limitations with venetoclax. And these limitations are very oftenly being cited by the health care providers and even more pronounced in the community settings where access to laboratory fast laboratory results and hospital beds is limited.

These limitations with venetoclax are mainly due to the intrinsic clinical pharmacologic profile of this product. Venetoclax has a long half-life over 24 hours, therefore, accumulating blood and it takes a long time to achieve a steady state level. These characteristics translate into a labor-intensive TLS monitoring due to the wrap-up and to achieve the target dose and that you see represented here in the image.

The frequent lab checks like 5 to 7 clinic visits, including a 24-hour time lab check for the first 2 dose levels. And this is the low-risk patients and even more frequent visits and requirement for hospitalization and serial lab checks for high-risk patients really significantly limits the use of this product.

In conclusion, we believe that next-generation BCL2 inhibitor that overcome these important limitations and would be able to be used by the broad CLL community is highly needed. As I showed, venetoclax has important limitations and more than half of the patients -- CLL patients cannot access this medicine.

More so, the vast majority of patients treated in the community setting cannot access this medicine due to the safety concerns and the feasibility around the ramp-up. Despite of the challenges, venetoclax has a blockbuster drug status with multibillion dollar annual revenue and with opportunities to further increase in annual sales over the next few years.

Now imagine the clinical and commercial value of our next-generation BCL2 inhibitor, with superior clinical activity, better safety, the ability to be accessed by the broad CLL population, including in the community setting, but also with the broader label and more indications.

Sonrotoclax, our next-generation BCL2 inhibitor has key characteristics that position this product to be best-in-class with superior efficacy and a more favorable safety profile. On one hand, the higher potency, 14x the increased potency in preclinical models versus venetoclax may translate in superior efficacy with much deeper and longer responses.

On the other hand, the improved selectivity, shorter half-life and no drug accumulation in the blood can offer a more favorable overall safety profile with less treatment associated adverse events. Also very important, it offers the opportunity for a shorter ramp-up, a shorter and safer and more patient-friendly ramp-up that can be used by all the CLL patients, including in the community setting. This important element gives venetoclax the potential to be a superior product that could be used by the broad CLL population.

Now I'm honored to introduce you Dr. Jacob Soumerai, Assistant Professor of Medicine, Harvard Medical School, hematologists, oncologists at Massachusetts General Hospital, a key opinion leader in CLL and the B-cell malignancies and also a principal investigator in multiple sonrotoclax clinical trials.

Dr. Soumerai is going to walk through some of the most recent data with sonrotoclax in combination with zanubrutinib, and will share his perspective on this product and its results, Dr. Soumerai.

Thanks very much. So BTK and BCL2 inhibitors have distinct and complementary mechanisms of action. Besides the antiproliferative effects of BTK inhibitors in patients with B-cell malignancies, we know that BTK inhibition interacts with multiple important cellular functions. For instance, it impairs the homing of malignant B cells to lymphoid tissues where they are normally receiving growth signals and other supportive signals from the tumor microenvironment.

This results in the migration of malignant B cells into the peripheral blood, where we know that BCL2 inhibitors can more effectively induce apoptosis and kill. Indeed, combinations of BTK and BCL2 inhibitors have demented synergistic activity in preclinical models.

And importantly, the combination of BTK and BCL2 inhibitors also results in synergistic efficacy when used in patients with B-cell malignancies. Now BGB-11417-101 is a global Phase I/II open-label study of sonrotoclax alone or in combination with zanubrutinib and/or obinutuzumab in patients with B-cell malignancies, multiple combination dose expansion cohorts have been completed.

And today, I'm going to review recently updated data, including data presented at EHA in CLL and mantle cell lymphoma. Starting with the sonrotoclax and zanubrutinib combination in treatment-naive CLL. Safety outcomes are shown here on this slide. No cases of laboratory or clinical tumor lysis syndrome occurred on study, most treatment-emergent adverse events for Grade 1 or 2, few Grade 3 or 4 treatment-emergent adverse events occurred.

The most common treatment-emergent Grade 3, 4 adverse event was neutropenia, with Grade 1-2 neutropenia in 7.9% of patients and Grade 3 or 4 neutropenia in 27.9% of patients. Importantly, this was transient, did not lead to higher rates of Grade 3 or worse infections in no cases of febrile neutropenia occurred on study.

GI toxicities, which are an important class effect of BCL-2 inhibitors were relatively infrequent and predominantly Grade 1. No fatal treatment-emergent adverse events occurred on this study. In the recently updated analysis, no new safety signals were observed with longer follow-up with sonrotoclax and zanubrutinib in treatment-naive CLL.

Measurable residual disease, or MRD, outcomes are shown on this slide for patients with treatment-naive CLL receiving sonrotoclax and zanubrutinib. We observed high rates of early undetectable MRD at a threshold of 10 to the minus 4 or UMRD4 including in high-risk patients, such as those with an unmutated IGT and deletion 17p.

The median time to undetectable MRD 4 was 7.1 months for patients with unmutated IGHV, and 7.2 months for patients with mutated IGHV. This includes a 3-month lead in with zanubrutinib alone and is significantly more rapid than what one would expect based on previous data.

92% of patients with this combination achieved undetectable MRD4 at week 48 of the combination. Now these data are particularly encouraging given previous evidence that more rapid MRD responses have been associated with prolonged progression-free survival outcomes among patients with CLL receiving BTK, BCL2 based combinations.

Progression-free survival or PFS outcomes for patients with treatment-naive CLL receiving sonrotoclax and zanubrutinib are shown on this slide. With a median follow-up of 25.5 months, the median progression-free survival has not been reached. No progression-free survival events have occurred in the 320 milligrams sonrotoclax cohort. And one patient in the 160 milligrams in sonrotoclax cohort had Richter's transformation to DLBCL, which occurred at 8 months of the combination.

Now importantly, an important feature of this study was that it allowed for elective treatment discontinuation at week 96. 35 patients have reached the week 96 time point and elected to stop therapy. All remain in an ongoing remission with a median of 3 months of therapy with, sum it, 12 months of therapy. Sonrotoclax and zanubrutinib was also evaluated and relapsed or refractory CLL and safety outcomes are shown here on this slide.

Importantly, these data are very consistent with what was seen in treatment-naive CLL with no new safety signals observed in the relapsed refractory setting. Measurable residual disease and progression-free survival outcomes are shown on this slide, 80% patients treated at the recommended Phase II dose of 320 milligrams of sonrotoclax with zanubrutinib at the approved dose, achieved undetectable MRD 4.

Looking to the PFS curves, responses appear durable at a median of 19.6 months of follow-up, the median progression-free survival has not been reached. Two PFS events have occurred. These were both progression events on active therapy in patients with deletion 17p CLL, one at the 40-milligram dose and one at the 320-milligram sonrotoclax dose.

Like in the treatment-naive setting, this protocol allowed for treatment discontinuation, electively in patients reaching the 96-week time point. 13 patients have elected to stop therapy after 96 weeks of the combination and all remain in an ongoing remission after a median of 4.5 months of therapy. Sonrotoclax and zanubrutinib was also evaluated in relapsed or refractory mantle cell lymphoma, where we currently do not have an FDA-approved BCL-2 inhibitor.

Safety outcomes for this combination in mantle cell lymphoma are shown here, and we're again consistent with what was seen in CLL, notably with no cases of laboratory or clinical tumor lysis syndrome. An MTD was not reached up to a sonrotoclax dose of 640 milligrams and 320 milligrams of sonrotoclax was selected as a recommended Phase II dose for sonrotoclax when used in combination with zanubrutinib in patients with mantle cell lymphoma.

We observed deep and durable responses in patients with relapsed/refractory mantle cell lymphoma treated with sonrotoclax and zanubrutinib. At the recommended Phase II dose, the overall response rate was 82% and the complete response rate was 67%.

The median duration of response was not reached with a median follow-up of 7 months and 84% of patients remain in an ongoing response at 24 months. Importantly, of 18 patients who achieved a complete response, 16 are in an ongoing complete response at median follow-up of 13 months.

Sonrotoclax and obinutuzumab was also evaluated in treatment-naive CLL. Now these data have not previously been reported are planned to be presented at the ASH Annual Meeting. Sonrotoclax and obinutuzumab was well tolerated with a safety profile that's consistent with individual agents, suggesting no additional combinatorial toxicity and demonstrated promising efficacy in treatment-naive CLL.

80% -- 87% of patients achieved undetectable MRD4 by week 36 and 90% of patients achieved uMRD4 by week 60. In summary, the all-oral combination of sonrotoclax and zanubrutinib is a very promising fixed duration treatment combination for patients with CLL and mantle cell lymphoma.

Now this combination is associated with a favorable safety profile with a potential for a significantly more convenient ramp-up. Additionally, sonrotoclax and zanubrutinib demonstrated very promising efficacy and treatment naive and relapsed or refractory CLL and in mantle cell lymphoma in the relapsed/refractory setting. And in CLL, we observed high rates of early uMRD4, including across molecular risk factors.

This combination has the potential to become a new standard in CLL and mantle cell lymphoma. And I'd like to just take a moment to thank all the patients and their families who participated in the studies. And of course, my coauthors and co-investigators. Thank you very much for your attention.

Thank you, Dr. Soumerai. As you just heard, the impressive results observed with sonrotoclax in combination with zanubrutinib, really positions this combination to offer the best-in-class fixed duration regimen in CLL. When we look across the currently available limited duration treatment options, sonrotoclax plus zanubrutinib really demonstrates the highest level of deep responses of efficacy with deep responses over 90% U-MRD rates, unmatched PFS for the respective follow-up, but also a favorable safety profile with less high grades of adverse events and importantly, no death.

In contrast, the currently available fixed duration therapy show limitations either from efficacy or safety perspective. In regards to safety, it is important to mention a few safety concerns like the infusion reactions observed with the infusion of obinutuzumab. The toxicity, the cardiac toxicity and cardiac deaths associated with the use of ibrutinib, but also the high rates of Grade 3 or higher toxicities like infections or other treatment emerging adverse events leading to deaths or treatment of discontinuation.

From efficacy perspective, there are some important deficiencies like the low rates of undetectable MRD observed with acalabrutinib plus venetoclax combination where only 34% of patients achieved uMRD at the end of treatment, but also the underwhelming 3-year PFS rate of near 77%. And this is despite the very fit population that was studied with this combination.

For the sonrotoclax plus ibrutinib combination, in addition to the superior and favorable safety profile, I would like to remind you that we did not observe any clinical or laboratory TLS. And we are continuing to optimizing the ramp-up schedule for sonrotoclax. We are very optimistic that for the vast majority of patients, only one clinical visit is going to be required after the zanubrutinib bleed-in.

In conclusion, we believe that this therapy has the potential to be a game changer as a fixed duration treatment for CLL patients. The sonrotoclax plus zanubrutinib combination showed the highest level of uMRD. But not only that, they also achieved this uMRD in a very short time. And this element is a further testament or evidence to the potency and superior clinical activity of these 2 products.

The fast kinetics in achieving the undetectable MRD were observed with the sonrotoclax new combination regardless of the high-risk features like the mutated or unmutated IGHV status, something that was not observed with other venetoclax-based combinations like ibrutinib, venetoclax data that was recently shared from the FLAIR study where the patients with mutated IGHV seems to have a slower and lower MRD.

Now looking ahead to our clinical development plans for sonrotoclax. Currently, we have a few important Phase III registrational studies that I would like to highlight here. Celestial treatment-naive CLL 301 study is a global Phase III study that is designed to demonstrate the superiority of sonrotoclax, zanubrutinib over venetoclax obinutuzumab. This is currently the only registrational study designed to investigate the superiority of fixed duration regimen against the current standard of care. This study completed enrollment of almost 700 patients in less than 14 months.

And this achievement is a testament of the high interest, trust and excitement of investigators in this combination, but is also a testament of the unique capacity of BeOne to run large Phase III clinical trials at the highest standards. The same combination of sonrotoclax plus zanubrutinib is currently being investigated in mantle cell lymphoma.

Celestial relapsed/refractory MCL 302 is an ongoing Phase III trial that is looking to demonstrate the superiority of sonrotoclax plus zanubrutinib over zanubrutinib plus placebo. In these trials, sonrotoclax is given for 2 years and the zanubrutinib is given to progression or intolerance.

And the primary endpoint of this study is in the PFS by independent review committee. This trial is also currently enrolling. We received high interest for this trial, and we anticipate a very fast enrollment.

We are pursuing also other combinations of sonrotoclax, like with the anti-CD20 antibody. In the relapse refractory CLL setting, we have a Phase III study that is currently ongoing CELESTIAL relapse refractory 303 study that was developed and is run in collaboration with the German CLL study group.

This is an important Phase III study that is designed to demonstrate the PFS superiority of sonrotoclax, either plus obinutuzumab or rituximab versus venetoclax rituximab, which is the current standard of care in this setting. This study provides also the opportunity to run a head-to-head comparison of sonrotoclax class versus venetoclax. And we are very confident that it will demonstrate the superiority of sonrotoclax as the next-generation BCL2 inhibitor.

While CLL and MCL remain our priority indications, we are moving aggressively to expand the clinical opportunity of sonrotoclax and maximize its clinical potential.

Multiple myeloma represents an indication -- an important indication and a [vast] market and patients with the translocation 11-14, represents about 20% of these myeloma patients. Venetoclax was evaluated in this indication at higher dose levels, however, showed -- failed to show a significant clinical benefit due to toxicity and limited efficacy.

The combination of sonrotoclax plus dexamethasone has demonstrated very compelling clinical data with high response rates of 78% at -- across all dose levels and 8 -- over 80% at the 640 milligrams of sonrotoclax, data that compares favorably with the previous venetoclax results in this indication. So building on these promising results, a study of the triple combination of sonrotoclax, zanubrutinib and dexamethasone is currently ongoing with positive preliminary safety data and the pivotal Phase III study in the second-line multiple myeloma of sonrotoclax triplet is also being currently planned.

Here, we are presenting an overview of the broad clinical development plan and clinical studies with sonrotoclax that is designed to maximize the clinical and commercial value of sonrotoclax, but are also designed to further increase the clinical opportunities with our other internal assets. It is worth highlighting that we have multiple registrational studies ongoing that offer the opportunity to register sonrotoclax in multiple indications either as a single agent like MCL, CLL or Waldenstrom, but also other various combinations.

Also important to note, market applications for sonrotoclax were already initiated in China based on the preliminary results from 2 study relapsed/refractory CLL and relapsed/refractory MCL. And the applications were accepted by the regulatory authority in China. Also, a global filing for sonrotoclax in relapsed/refractory MCL indication is planned for the second half of 2025, and we are very excited about this potential first global submission and potential approval.

And with that, I hope you are as excited about sonrotoclax as we are. And I would like to hand it over to my colleague, Amit to provide you an overview of our BTK CDAC program. Thank you.

Thank you, Remus. Good morning, everyone. My name is Amit Agarwal, and I'm a VP of Clinical Development here at BeOne. It is my great pleasure to share with you an update on BGB-1673 and also walk you through why we believe this asset has the potential to be a cornerstone of our hematology pipeline.

Let's start with the why. Despite many advances, CLL still remains incurable, and there is an enduring unmet need for these patients. As the treatment landscape evolves, more patients will have received the current generation of therapies in the front line. There is an important need to develop drugs with novel mechanisms that can overcome resistance when these patients progress.

In this context, we're developing 16673 to be the potential first-in-class BTK degrader. This drug is fundamentally different than traditional small molecule inhibitors. This is the first drug from our proprietary CDAC platform. Think of it as a molecular machine that not only blocks BTK, but completely removes it. This mechanism has several advantages.

The first is because of a catalytic action, a single degrader molecule can actually degrade thousands of the target protein, which makes it much more potent. The second is that the mechanism allows for being able to not only overcome existing mutations, but also delay the emergence of new mutations.

And the third is that the degrader is able to remove the entire protein scaffold and shut down both the kinase dependent and independent signaling, which traditional small molecule inhibitors cannot do. We have seen evidence of all 3 aspects of this MOA translate into meaningful clinical benefit. This is just a better mousetrap.

We have tested this drug in a global Phase I/II study called the CaDAnCe-101 study across B-cell malignancies. Most of the data that we have shared comes from the Phase I portion of the study. The cohorts that I will present today include the relapse CLL Waldenstrom and indolent lymphoma histologies. I will point out that we are also enrolling patients in the Phase II part of the study and in particular, in the relapse CLL cohort, we have enrolled more than 100 patients now that we could file with in 2026.

Let me talk about the types of patients we have enrolled on this study so far. The study has enrolled heavily pretreated patients who have seen multiple lines of prior therapy. In case of CLL, we have patients with a median of 4 prior lines of therapy, including a BTK inhibitor, a BCL-2 inhibitor and other treatments. We have several patients who have also received a noncovalent BTK inhibitor like pirtobrutinib before coming on to the study.

An important aspect to point out here is that of the patients who have received a BTK inhibitor, most of them, 90% got off that BTK inhibitor due to progressive disease. This is an important context when we look at the efficacy in this group in a minute.

Let me start with the safety first. The safety profile here is consistent with on-target BTK degradation. The most common adverse events we've seen include cytopenias with neutropenia being the most common. There are some adverse events associated with platelet dysfunction by contusion and bruising. And we do see some infections in the form of COVID-19 and other infections. The rate of drug discontinuations due to adverse events in this late line population is less than 5%.

What we have not seen are off-target BTK directed side effects, like arrhythmias. And again, we think this is an attribute of the program as well as the mechanism. With some patients now continuing on treatment for more than 2 years, we are building long-term safety data on this molecule.

Moving on to efficacy. For the relapse CLL cohort at the 200-milligram dose, which is the dose that we're moving forward into the Phase III study with, we see that the overall response rate is 94%. This includes some complete responses, which are rare with the BTK directed treatment. These responses occurred relatively quickly. and typically at the time of the first disease assessment.

In terms of some key subgroups, you can see on the right, responses are consistently noted regardless of prior exposures or mutations. In the patients who are the so-called triple exposed patients, meaning that they have received a covalent BTK inhibitor, a non-covalent BTK inhibitor and a BCL-2 inhibitor before coming on to the study, we see response rates of 75%. These patients truly have no treatment options left and a 75% response rate in this group of patients is highly encouraging.

With longer follow-up, we have seen that these responses are also durable. In the graph on the left, you can see that in the CaDAnCe-101 trial, the durability looks very promising.

On the right-hand side, you can see the BRUIN321 resource for pirtobrutinib. With the normal caveats of cross-trial comparison in place, you could see that in this group of relapsed and refractory patients, there is a strong reason to believe that the degrader offers a much better mechanism than an inhibitor for these patients. These results give us the confidence to launch a head-to-head study against pirtobrutinib, relapsed/refractory patients will be randomized to receive either 16673, or [pirto] as a monotherapy. We have engaged several health authorities for this trial and have an agreement on the design and the dose. We're planning to start the study later this year.

We're also seeing a strong signal in other B-cell malignancies. For Waldenstroms in a group of heavily pretreated patients, we have seen an impressive response rate of close to 85%. Interestingly, the responses occur quickly and also deepen over time. We now have VGPRs in almost 1/3 of these patients. The responses are seen in particularly hard-to-treat populations based on both the types of prior treatments that they have received, but also genetic risk factors.

And as you can see in the PFS curve on the right, these responses also appear to be durable. We have now opened enrollment on the Phase II expansion of the Waldenstroms cohort and are planning the next steps for registration in this setting.

Moving to other indolent lymphomas. In this study in follicular and marginal zone patients, we're seeing meaningful responses, including complete responses. As a single agent, this activity is very promising and could allow us to develop this drug in these diseases, particularly as a combination.

Finally, I'm going to share clinical vignette from this trial that illustrates what this drug can do. This is a 69-year-old gentleman who was diagnosed with CLL in 2009 and received multiple rounds of standard treatment. In 2024, his disease progressed, and he was diagnosed with Richter's transformation. Richter's represents a serious, often fatal complication and progression of CLL. He initially received standard treatment of R-CHOP for this, but had no response. He came on to the study in early 2025, and you can see a significant disease burden at the time of study entry. This is the response after being on the trial for 3 weeks, 3 weeks of an oral treatment. You can see that his lymph nodes have dramatically reduced. This case nicely highlights the transformative potential of this drug.

We have a broad clinical program designed to establish BGB-16673 as a foundational therapy. You heard earlier from Lai, we're moving fast with this program. This is driven not only by our own conviction in the drug, but also great enthusiasm that we've seen from our investigators on these studies. We plan to file for an accelerated approval in 2026. We already have ongoing registration studies as a monotherapy and the head-to-head against [pirto] will start later this year. We're also looking at the combination of the BTK CDAC and sonrotoclax as a fixed duration for CLL.

In the front line, we have started some work looking at the monotherapy as well as combination settings for proof-of-concept data that will inform our front-line strategy. Beyond CLL, we're also actively assessing other indications, both as a monotherapy as well as combinations. We believe that 16673 has the potential to reshape the treatment landscape of B-cell malignancies.

Now let me take a moment to recap where we are and where we are headed. We've built a comprehensive registrational program that spans the full spectrum of CLL from the treatment naive to the relapse and refractory settings. In the frontline setting, BRUKINSA has already established itself as the leading BTK inhibitor with this best-in-class profile. With the combination of BRUKINSA and sonrotoclax, we're now advancing what we believe will be the best-in-class fixed duration regimen.

For relapse patients, we will bring forward several options both as a continuous monotherapy as well as in combinations. Our BTK degrader should become a foundational therapy in this setting. We're also advancing fixed duration regimens, including CD20 antibody and sonrotoclax and evaluating the CDAC plus sonro combination as a potential next-gen option. This program is designed to offer patients important options throughout their CLL journey and make BeOne medicines the leader in CLL.

You've heard the details of our oncogenic signaling cluster drugs that will provide near-term value. Now I want to zoom out and talk a little bit about our research efforts. We are focused on developing several novel modalities. We're developing modalities that have orthogonal mechanisms and should allow us to make a broad impact on B-cell malignancies.

I would like to talk about the T cell engager cluster and our cell therapy platform. We're developing 3 different T cell engagers, a CD19x20 trispecific, a BAFFR CD22 trispecific and the CD79 with an undisclosed target trispecific. We're also develop co-stimulatory drugs with CD20xCD28 and CD2x4-1BB, the leading drugs.

Often, the cost for disease progression in the context of bispecifics has been the loss of tumor antigen. To obtain broader coverage with the initial response and to avoid antigen loss, we're developing trispecifics that will bind to distinct tumor antigens. To complement this approach, we are also looking at co-stimulatory drugs have shown significant synergy with the T cell engagers.

As shown here, our CD19/CD20 trispecific and the CD20/CD28 co-stimulatory drug have compared favorably to the competitor molecules and also demonstrated great synergy together in preclinical models. The CD19/CD20 trispecific is on target to enter the clinic in 2026 and the CD20xCD28 drug in the early '27.

Finally, I want to introduce our cell therapy platform. We all know that autologous cell therapies have made a major impact on the outcomes in hematologic malignancies, but have faced several challenges that have limited their wide adoption. Initial efforts to address some of these challenges with allogeneic cell therapies have not been successful. We're developing an iPSC-derived platform that we believe will address some of these challenges.

The platform has been developed to address CMC issues around differentiation and expansion, and there are several key genetic changes that provide hyperimmunity, prolonged survival as well as potency. A unique aspect of this platform is a proprietary signal converter that provides these cells with significant potency. I'll show a little bit of the impact of a signal converter with the experiment on the right.

What you can see in blue is what we typically have in a preclinical killing assay with some of the older generation of allogeneic cell therapies. But with the signal converter on board as well as our entire platform, you can see that we see continuous killing of these cells without any evidence of exhaustion. We think that these are optimistic changes. And if successful, this will lead to a highly differentiated cell therapy solution which we're planning to enter the clinic within 2026.

To summarize, we're not just building a pipeline, but rather systematically building a franchise. We're doing it with a sense of urgency, scientific rigor and a clear focus of delivering impact for patients and value for investors.

With that, I thank you for your attention. I think next on the agenda, we're going to take a 10-minute break. You will want to come back because Mark has some very exciting updates on the solid tumor portfolio as well. Thank you.

[Break]

Okay. Great. Welcome back, everybody. My thanks as well for joining today, come for hematology and stay for solid tumors. My name is Mark Lanasa. I'm the Chief Medical Officer for Solid Tumors at BeOne. Today, I will be providing an update on our solid tumor portfolio focusing on our progress and future plans.

Indeed, Lai and I were chatting before today's session, and we were commenting on how since our last R&D day 2 years ago, about essentially everything that I'm about to share with you is new since our last R&D Day. Our pipeline includes diverse modalities and mechanisms across 3 franchises: breast and gynecologic cancers, lung cancer and gastrointestinal cancers.

Today, I am extremely excited to share updates from each of our core disease area franchises with a focus on emerging data, new targets and exciting in-portfolio combinations. Let's begin with our breast and gynecologic cancer franchise. We are establishing an innovative approach to these cancers with several promising candidates in our pipeline, most notably our potent and selective CDK4 inhibitor.

We are committed to advancing research and bringing new treatments to market for breast and gynecologic tumors. It is important to recognize that breast cancer has been a clinical area of focus for BeOne Medicines for only approximately 18 months. In each of our franchises, the research organization focuses on both established and novel targets that enable in-portfolio combinations that can maximize patient impact.

In these overview slides, these areas of focus are highlighted as clusters. Key to our breast cancer programs are the investigational molecules in the cell cycle cluster, including our CDK4 selective inhibitor, our clinical stage CDK2 targeting small molecule as well as our novel CDK2 targeting CDAC that will enter the clinic by the end of this year.

There is also a growing body of work in our estrogen receptor cluster, where we are exploring agents that can bring benefit in combination with estrogen blockade, including a novel BCL-2 inhibitor and a selective CAT 6AB molecule. ADCs are also an important modality across the portfolio with our B7-H4 being most advanced with additional multispecific ADCs progressing through preclinical development.

And while not a focus of today's presentation, we recently achieved first human dose of our Claudin6 by CD3 bispecific, which is our first internally discovered clinical stage CD3 conjugated T-cell engager. I'd like to begin with our CDK4 selective inhibitor, which is the foundational molecule in our breast cancer franchise. CDK4/6 inhibitors are one of the largest commercial markets in solid tumor oncology valued at approximately $13 billion and continuing to grow.

One of the primary issues with CDK4/6 inhibitors is hematologic toxicity, which leads to dosing interruptions, resulting in suboptimal target coverage. Additionally, there are safety concerns due to off-target inhibition. In an effort to address these limitations, we developed a selective and potent CDK4 inhibitor designed to address the limitations of current CDK4/6. It aims to provide superior therapeutic benefits by reducing hematologic toxicity and off-target inhibition. The bar graphs on the right panel of the slide show the potency and selectivity of 43395. In a preclinical cellular assay, our CDK4 inhibitor more potently inhibits proliferation than any of the approved CDK4/6 inhibitors. It is approximately fourfold more potent than Pfizer's atirmociclib.

This potency conveys a 38-fold 4 versus 6 selectivity, almost twice as selective as atirmociclib. Although we were second to enter the clinic, we have moved very quickly through Phase I development, enabling first-in-class potential. We have closed the development time gap with Pfizer's atirmociclib from 3.5 years from first human dose to less than 18 months to a Phase III start in frontline hormone receptor-positive breast cancer.

Today, we are honored to have Dr. Shom Goel, a key opinion leader in breast cancer, presenting the CDK4 data update. Dr. Goel is an associate professor and clinician scientist at the University of Melbourne and the Peter McMillan Cancer Center. He serves as the global PI and translational PI for 4 randomized clinical trials in breast cancer and has over 60 publications, including recent works and high-impact journals such as nature, cancer cell and nature cancer.

We're excited to hear Dr. Goel's insights on our selective CDK4 inhibitor and its potential impact on breast cancer treatment. Dr. Goel?

Good morning, everyone. It's a pleasure to be here. So CDK4/6 inhibitors in a nutshell, they work by inhibiting the CDK4/6 enzymatic complex. And this leads to prevention of phosphorylation of the RB tumor suppressor protein. Ultimately, this stops cancer cells from dividing, leading to cessation of tumor growth and over time, tumor regression.

We have 3 approved CDK4/6 inhibitors, but each comes with toxicity issues and also the problem of resistance, which ultimately emerges with ongoing treatment. Common side effects include neutropenia with all the drugs and diarrhea with some and hematologic toxicity as well, which is thought to be largely driven by inhibition of CDK6. So BGB-43395, which is a potent and selective CDK4 inhibitor, aims to provide this select inhibition of CDK 4 minimizing toxicity and preventing the emergence of resistance.

So I'd like to start by sharing with you the study design for the first in-human study of BGB-43395, the selective CDK4 inhibitor. As of June 9, this Phase Ia study has enrolled a total of 284 patients with 178 of them treated in 1 of 3 dose escalation arms, the CDK4 monotherapy or combination with fulvestrant or combination with letrozole. And a fourth arm combining this medicine with elacestrant will initiate soon.

The remaining 106 patients have been enrolled into combination dose optimization arms. And based on PK and PD data, which I'm going to share with you, we've selected 3 dose levels for that dose optimization, 240 milligrams, 400 milligrams and 600 milligrams orally twice a day. I'd also like to point out that this is truly a global study with the France and U.S. leading enrollment.

So BGB-43395. Here, I'm showing you the PK and it has shown favorable PK characteristics. The panels at the bottom showed dose proportional and linear pharmacokinetics within the dose range of 240 up to 600 milligrams twice a day. The mean elimination half-life is 13 hours.

And importantly, exposures are not impacted by co-administration of either fulvestrant or letrozole. Also, there were no notable difference in exposures observed between non-Asian and Asian populations. So on this slide, we present some pharmacodynamic data. We observed a dose-dependent and durable reduction in TK1 activity. This is a biomarker of cellular replication at doses 240 milligrams twice a day or higher.

And that's what led us to select the 240, 400 and 600-milligram twice-daily doses for the dose optimization. And I highlight the dose-dependent nature of this PD effect with less TK1 inhibition seen at doses below 240 milligrams and that this PD effect is sustained with no rebound observed at cycle 2 day 1.

In the bottom right panel, early ctDNA decrease, which is another potential response biomarker was also observed starting from the 240-milligram dose level in the fulvestrant combination. So both the TK1 data and the ctDNA data suggests that doses of 240 milligrams twice a day and above are biologically active making these the doses for further development -- for focus on for further development.

So here, I'm showing the safety data for almost 100 patients who received BGB-43395 in combination with fulvestrant during both the dose escalation phase and dose optimization. And the safety data I'm showing here again limited to those 3 dose levels, which are under consideration for further studies. Overall, the tolerability is excellent with related grade 3 or higher events observed in approximately 20% of patients and only a single patient in each study phase discontinuing due to a related adverse event.

When we look at some specific adverse events, diarrhea was frequent. However, these events were predominantly low grade and straightforward to manage with once daily administration of loperamide. None of the cases of grade 3 diarrhea observed in the dose optimization phase resulted in a dose reduction or discontinuation. When we look at the heme toxicity, the rates of hematologic toxicity are very favorable in regards to any grade of anemia, neutropenia or thrombocytopenia and these rates compare favorably to the rates of hematologic toxicity with the approved CDK4/6 inhibitors and to atirmociclib.

And these hematologic AEs are important because they can result in dose interruptions, dose reductions and thereby ultimately reducing effective CDK4 target coverage. So here, we're presenting the tumor burden change from baseline in patients treated in combination with fulvestrant during dose escalation. Please note that we are only sharing efficacy from the dose escalation phase here rather than the dose optimization phase because that latter data, the optimization data is still quite immature and will be used to identify a recommended Phase III dose.

So the data that you can see on the screen here shows preliminary antitumor activity in extensively pretreated dose escalation patients. During this dose escalation phase, 37 patients, including 29 with breast cancer were treated with the fulvestrant combination at doses from 240 up to 600 milligrams twice a day. Now during that dose escalation phase, breast cancer patients were permitted to have bone-only metastatic disease, and therefore, 10 of those patients are not response evaluable. It's a heavily pretreated group of patients, as you can see.

The median number of prior lines of therapy in the metastatic setting was 4, all patients had received prior chemotherapy or an ADC as well as prior endocrine therapy. And the median follow-up at the moment is limited at 3 months. And given the cytostatic mechanism of action of these drugs, the response rate may improve over time. The objective response rate was 11% amongst the patients with breast cancer and 15% in the full cohort.

And time-to-event endpoints such as PFS are immature at the moment and will be presented at a future meeting. But it's important to note that my opinion, the response rate is also immature at this point. This is a class of drugs where traditionally median times to response sits somewhere between 3 or 5 months. And so with our median follow-up of only 3 months, we may expect the response change over time. Nonetheless, what we can see here is that among this advanced patient population heavily pretreated, the results show that BGB-43395 in combination with fulvestrant does show meaningful antitumor activity.

So in summary, these data show that BGB-43395 has a strong pharmacogenomic effect across a range of well-tolerated doses. The safety data show a potential best-in-class hematologic safety profile with low grade and readily manageable diarrhea. Emerging evidence also shows clinical efficacy in extensively pretreated post-CDK4/6 patients at those doses with pharmacodynamic activity.

And this positions BGB-43395 as a promising candidate for further development. We're excited about the clear path forward towards registration-enabling studies and look forward to initiating these studies within the next 6 to 12 months.

So with that, I'd like to thank the study patients, my co-investigators on this Phase I 101 study, and I'd like to pass the presentation back to Mark. Thank you.

Thanks so much, Shom. Next, I'd like to share an update for our promising B7-H4 targeting ADC. B7-H4 is frequently expressed in breast and gynecologic cancers. And as you can see in the lower right panel, B7-H4 has minimal expression in normal tissue. This high tumor versus normal selectivity makes B7-H4 an attractive ADC target.

Additionally, the drug linker design enhances the therapeutic profile of this ADC while the non PGP substrate payload with a DAR of 6 yields strong bystander effect contributing to its efficacy. We recently made the initial data disclosure at ASCO. Today, I will share updated data and new analyses. These data indicate a favorable safety profile and compelling emerging efficacy.

Here, we're sharing data across selected dose levels. The most frequently reported adverse events include low-grade nausea, neutropenia and fatigue. Neutropenia and thrombocytopenia were the most common grade 3 or greater AEs. The dose-limiting toxicities were principally hematologic and were observed at the higher dose levels.

However, there have been no related AEs that have led to study drug discontinuation. Overall, the early clinical data indicates a favorable safety profile as monotherapy across a broad range of dose levels. Here, we are showing the updated efficacy data as of earlier this month for our B7-H4 ADC showing its promising antitumor activity in breast and gynecologic cancers. A total of 95 patients were treated across 9 different dose levels with a meeting of 4 prior lines of therapy.

This waterfall plot is limited to the 68 patients with breast, endometrial and ovarian cancer. These are currently the target tumor types for subsequently development. The confirmed objective response rate is 24%, and the unconfirmed response rate is 29%, with 14 out of 20 responses ongoing.

We observed an emerging dose response relationship. For example, if the analysis is limited to the 6-milligram per kilogram dose level, the confirmed response rate increases to 43% and unconfirmed to 48%. We also observed an association between B7-H4 expression in efficacy. Among the enrolled breast and GYN patients, the unconfirmed response rate overall is 29%. If we limit to the half of patients with higher B7-H4 expression, the response rate increases to 42.4%.

In conclusion, our B7-H4 ADC shows favorable safety and compelling early efficacy. Dose optimization expansions and biomarker selection for breast and gynecologic cancers will initiate in the third quarter and planning is underway for Phase III study starts in 2026.

I'd next like to present BG-68501, a potent and selective CDK2 inhibitor. CDK2 is an important target in breast cancer because CDK2 activation may convey resistance to CDK4 inhibition. Preclinically, 68501 shows strong potency in selectivity, which may lead to improved efficacy and safety profile. 49 patients with pretreated solid tumors were recently presented at ASCO. These data indeed reveal a favorable hematologic toxicity profile with no dose-limiting toxicities. Common adverse events included nausea, vomiting and fatigue.

Nausea and vomiting are mitigated with antiemetics and a food effect study is ongoing, which may further improve nausea. The preliminary efficacy results show a 6% unconfirmed response rate and a 39% stable disease rate which supports our core development intent for combinations in breast cancer. Our breast cancer franchise will soon add 2 additional innovative molecules that promise improved patient outcomes in hormone receptor-positive breast cancer, a CDK2 CDAC and a KAT6A/B inhibitor, both molecules will begin clinical studies prior to the end of this year.

This is our potential first-in-class CDK2 selective CDAC. We believe that this CDAC has 3 potential key advantages over a small molecule inhibitor of CDK2. First, the catalytic mechanism that you heard about from Amit convey superior target inhibition. Preclinical potency of our CDK2 CDAC is 30x that of Pfizer CDK2 and 5 to 10x that of our first-generation CDK2 small molecule inhibitor.

Second, because of the target binding geometry, our CDK2 degrader has much greater selectivity for CDK2 over CDK1 compared to any small molecule inhibitor. The IC50 for CDK1 inhibition is greater than 10 micromolar, a greater than 4 log difference from the IC50 for CDK2 inhibition. Finally, this molecule is anticipated to have a longer half-life than small molecule inhibitors, which will enable more continuous target coverage with relatively flat PK, which may in turn further improve safety.

To conclude the update on our breast cancer franchise, BG-75202 is a potent and selective KAT6A/B inhibitor. In the upper right figure, we show greater potency than the Pfizer KAT6A/B against a number of different hormone receptor-positive breast cancer cell lines. Importantly, 75202 also has a greater than tenfold higher selectivity for KAT6 over KAT7, which is intended to improve the hematologic toxicity profile when compared to Pfizer's molecule.

In just 18 months, we've made significant strides establishing an innovative breast and gynecologic franchise with an initial focus on hormone receptor positive breast cancer growing to 8 clinical molecules by the end of this year. And again, just to reinforce the point that Lai made earlier, 8 molecules in less than 24 months CDK4, CDK2, CDK2 CDAC, KAT6A/B, BCL2, B7-H4, our Claudin6 x CD3, and MUC1 x CD16 bispecific antibodies.

The emerging data for our CDK4 inhibitor shows a differentiated hematologic safety profile with a promising benefit/risk balance as we move towards Phase III trials. The B7-H4 ADC shows substantial efficacy with manageable toxicity, and we are planning subsequent registration-intent studies in ovarian, endometrial and breast cancer.

These lead molecules, along with CDK2, KAT6A/B and BCL2 provide unique development opportunities in breast and gynecologic cancers.

Next, I'd like to provide an update on our emerging lung cancer franchise. I'm excited to share our vision for building a truly industry-leading lung cancer franchise. We are dedicated to advancing the field and improving outcomes for patients with lung cancer, featuring innovative and intentionally designed molecules. Our current focus is on 3 driver mutation populations in innovative ADCs.

The 3 biomarker clusters include: first, targeting tumors with MTAP deletion; second, targeting EGFR mutations with our EGFR targeting CDAC and third, oncogenic KRAS mutations. I will present our MTAP cluster and the EGFR targeting molecules in this section and will cover KRAS as part of the GI franchise overview.

We also believe that the full potential of ADCs has not yet been met in non-small cell lung cancer. We have monospecific ADCs in clinical development, including a B7-H3 and CEA targeting ADC, and we have additional candidates with multi-targeted ADCs and in the future, ADCs with novel payloads. We are very excited to show the early progress of our MTA cooperative PRMT5 inhibitor and MAT2A inhibitor.

First, let's discuss our potential best-in-class PRMT5 inhibitor. This compound has demonstrated superior preclinical potency and selectivity when compared with essentially all clinical stage competitor molecules. I will provide our first clinical update for this molecule today. MAT2A has mechanistic synergy when combined with PRMT5 and induces robust efficacy in animal models.

Both of our compounds are highly brain-penetrant, which is an important characteristic for lung cancer and other tumor types that unfortunately have frequent brain metastases. Let's begin with the emerging data for our PRMT5 inhibitor. Here are the initial pharmacodynamic data for our PRMT5 inhibitor.

The left panel shows serial biopsy of a metastatic lesion of esophageal squamous cell carcinoma that has spread to the lung. In the middle of the figure, the change in SDMA between screening and cycle 2 day 1 is shown. By cycle 2, day 1, the tumor cell SDMA score has dropped to 0 indicating effective target engagement at the first tested dose level. On the right, we also observed rapid plasma SDMA reduction in the first 2 patients enrolled in the study. The first 2 patients enrolled at dose level 1. Taken together, the pharmacodynamic data for our PRMT5 inhibitor demonstrates potent target inhibition as detected in both tumor and plasma. Although we achieved our first human dose in only January of this year, just 5 months ago, the Phase I study is progressing very well with 27 patients enrolled to date.

Regarding the safety profile, the most common treatment-related adverse events are nausea and anemia. Importantly, we have observed no significant hematologic toxicity, no dose-limiting toxicities, no serious adverse events and no AEs leading to discontinuation or treatment modification.

For efficacy, we have achieved target efficacious exposure at only the second dose level due to a better-than-anticipated clinical PK. Despite the short follow-up, we have already observed 3 objective responses in 3 histologic distinct tumor types at the second dose level. In summary, the early clinical data and efficacy data for 58067 are very promising, which support its potential as a best-in-class brain-penetrant PRMT5 inhibitor.

Our PRMT5 and MAT2A are strongly synergistic combination, and we are currently the only company with both clinical stage PRMT5 and MAT2A. We will begin enrolling patients to the PRMT5 and MAT2A combination as early as the third quarter of this year. In light of the encouraging early safety, PK, PD and efficacy data we are observing with our PRMT5, we will start testing standard of care combinations in various tumor types.

Next, I will share our EGFR targeting molecules, starting with our EGFR CDAC. This first-in-class compound has a truly differentiated mechanism of action designed to completely and selectively abolish EGFR signaling. It is highly potent against all typical primary and resistance mutations in EGFR while sparing wild-type EGFR and demonstrating excellent proteomic selectivity. The EGFR CDAC is currently a monotherapy dose escalation, and we have again observed a strong pharmacokinetic profile with good oral absorption and a very long elimination half-life. The emerging safety profile is consistent with the EGFR sparing -- EGFR wild-type sparing design. There have been no skin or GI toxicities reported to date. Dose escalation is in the early stages, and we're planning to start a combination study with a third-generation TK1 in the second half of 2025.

In summary, the EGFR CDAC is a highly promising compound with unique mechanism of action, strong preclinical efficacy and encouraging early progress.

Next is our EGFR x MET trispecific antibody. This compound has best-in-class potential with a unique design that offers superior and optimal MET inhibition through a biparatopic MET antibody construct that is, again, EGFR x 2 different epitopes of MET. T187 has demonstrated stronger efficacy than amivantamab and MET-driven in EGFR-TKI resistant models.

Importantly, T187 was also designed for lower EGFR on-target skin toxicity due to weaker killing of primary keratinocyte when compared to amivantamab. Regarding the clinical progress, T187 is currently in monotherapy dose escalation, and we're planning to initiate dose escalation with subcutaneous formulation by the end of third quarter of this year.

In summary, T187 is a highly promising compound with unique design and mechanism of action, strong preclinical efficacy and potential for clinical differentiation. Having a focused and deep portfolio in specific tumor types and specific oncogenic drivers naturally creates the opportunity to develop potentially synergistic in-portfolio combinations. Here, we have -- here, I'm sharing preclinical combination studies for the 2 molecules that I've just shared, our EGFR CDAC and our EGFR x MET trispecific antibody.

On the left, the combination of the CDAC and T187 yields near complete and sustained reduction in tumor volume and in EGFR TKI responsive tumor model. On the right, this combination also yields deep and sustained tumor volume reduction in EGFR TKI-resistant with superior activity when compared to the combination of amivantamab and lazertinib. Planning is underway to test this combination clinically.

Our growing and comprehensive lung cancer portfolio features a diverse and differentiated array of molecules designed to address lung cancer segments with substantial residual unmet medical need. Our PRMT5 and MAT2A are foundational molecules for an MTAP-deleted non-small cell lung cancer and other MTAP-deleted tumors. Early data support their differentiated and best-in-class profiles highlighting their potential to make a significant impact in this area.

Next, we have the EGFR cluster. Our differentiated and first-in-class molecules provide substantial opportunities for patient impact through in-portfolio combinations and through combinations with third-generation tyrosine kinase inhibitors. Finally, multispecific ADCs have the potential to broaden the eligible patient population and improve the therapeutic window. With novel payloads, we aim to further advance tumor selective targeting. In summary, our lung cancer portfolio is built on a foundation of innovation and differentiation. We are committed to advancing the field and improving outcomes for patients with lung cancer. Okay. So I will conclude the solid tumor section with a discussion of our GI franchise with a specific focus on innovation for patients with KRAS mutations.

So hang in there sort of last lap, a lot of information in this section. For this final disease area franchise, I will focus on KRAS targeting, which is mutated in virtually all cases of pancreatic cancer and almost half of the cases of colorectal cancer. While I will not revisit the specific molecules, MTAP, EGFR and MET are also important targets for GI cancers. MTAP deletion is present in approximately 20% of pancreatic cancers and up to 10% of esophageal and gastric cancers. Similarly, EGFR is an established target in RAS wild-type colon cancer and MET biology is relevant in both colon and gastric cancers. We are also excited about the development potential of our ADCs and immune cell engagers including our potential first-in-class FGFR2b targeting ADC for gastric cancer and the GPC3 x 4-1BB bispecific antibody for hepatocellular carcinoma.

KRAS plays a crucial role in self-signaling pathways. KRAS cycles between 2 states, the inactive GDP-bound off state and the active GDP-bound on state. While there have been advancements in developing small molecules to target specific KRAS mutants, challenges remain due to the presence of undruggable mutants in the emergence of secondary mutations.

Given these challenges, we are taking a multipronged approach to hitting RAS to maximize clinical benefit through new modalities and rational combinations. Our first KRAS targeting molecule, BGB-53038 is a non-covalent inhibitor of both the on and off states. This molecule is progressing well through early dose escalation. We will build upon this molecular framework by developing a second-generation KRAS-CDAC, which will both improve potency and likely also have a long half-life, thereby improving target coverage. We are also actively working to deliver RAS on-targeting molecules from discovery to the clinic. The most advanced molecule is an internally discovered potent brain-penetrant RAS(ON) inhibitor.

We are also planning to use this molecule as a non-cytotoxic drug antibody conjugate to improve tumor targeting with the intent of reducing systemic toxicities associated with broad RAS inhibition. Finally, we're also progressing a G12D specific RAS(ON) inhibitor through preclinical development.

This slide provides more detail regarding the KRAS CDAC and RAS(ON) inhibitor. In the left panel, the KRAS CDAC shows high and improved potency across various KRAS mutations, while retaining strong selectivity for KRAS over H&N RAS. The pharmacological properties suggested it can be dosed daily, which is a significant advantage for patient compliance and may improve the safety profile by delivering constant exposure.

The brain penetrant, RAS(ON) demonstrates impressive potency. The panel on the right shows similar preclinical efficacy to RMC-6236 at 125th of the dose. The middle panel shows that dual RAS inhibition via concurrent blockade of both the off and on forms delivers substantial preclinical synergy. Both these molecules are scheduled to enter the clinic in the second half of 2026, again, providing a unique opportunity for in-portfolio combinations to maximize patient benefit.

The final compound I would like to present today is BG-C137 in FGFR2b targeting ADC that has the potential to be first-in-class with a best in modality design. C137 has shown stronger efficacy in xenograft models when compared to bemarituzumab, an unconjugated monoclonal antibody. The safety profile of C137 is designed to be differentiated. Bemarituzumab causes cordial toxicity as an on-target effect that is due to the blockade of the interaction between FGFR2b and its ligands.

The parent antibody of C137 spares cordial toxicity by binding a unique epitope with much weaker ligand blockade. Our FGFR2b ADC is progressing very well through early dose escalation. With over 20 patients enrolled, there have been 0 ocular adverse events reported to date, including at dose levels where we're observing early evidence of efficacy.

We are encouraged by the early clinical progress of C137 and are likely to begin the dose optimization prior to the end of this year. We are committed to developing multiple differentiated pathway targeting therapies to address KRAS mutations, which are prevalent in several GI cancers. Our goal is to develop innovative therapies with the potential for synergistic in-portfolio combinations and improved patient outcomes.

Next, the MTAP deleted cluster presents an important combination opportunity with PRMT5 and MAT2A and MTAP deleted pancreatic cancer. And finally, we have multiple first-in-class and best-in-class ADCs. Our FGFR2b ADC is emerging with a superior safety profile. It has the potential to be first-in-class in gastric cancer.

So to conclude the Solid Tumor section, we have completely reshaped the clinical stage solid tumor portfolio over the past 2 years with almost 20 new clinical-stage molecular entities designed and selected to enable in-portfolio combinations, which we believe is critical to making the next step change in solid tumor oncology. This innovation continues with the intent to bring 2 to 3 additional clinical stage molecules per year into each of our 3 disease focus areas.

Through our internal delivery model, we are progressing our portfolio with unparalleled speed with multiple Phase III starts in planning for 2026, including CDK4 and B7-H4. In the light of very encouraging early data, PRMT5 and FGFR2b ADC may also be on an accelerated path to registration-intent studies. Our approach highlights our commitment to improving patient outcomes by driving innovation in solid tumor oncology. Thank you.

And with that, I'd like to hand back to Lai.

Thank you, Mark. Before I conclude, I'll skip this slide because I do want to also talk about some data. Just have a chance to talk about data at my R&D day. I'd like to share an update on our IRAK4 CDAC program, BGB-45035 was designed to achieve faster and more profound target degradation compared to KT-474. A molecule developed by Kymera Sanofi while also avoiding the cardiovascular risks associated with KT-474.

You might have heard from Sanofi, just I think yesterday, they will no longer advance KT-474, instead to focus on a new molecule, which won't be in clinic until next year. So now our molecule is not only potentially best-in-class but also a first in class. The clinical program has advanced smoothly with the successful completion of both single ascending those escalation multiple ascending dose escalation studies.

We are currently conducting our Phase Ib in patient with PN and AD, a notable feature of 45035 has extended half-life in humans ranging from 60 to 96 hours, leading to a sustained IRAK4 degradation. Please look at the top graph on the right, the green line, that's the second dose. We're testing the SAD 7 days after just a single dose of 45035, you can observe -- we still observed complete IRAK4 degradation in the blood.

We're anticipating the -- initiating the Phase II in the second half of this year and with the proof of concept of IRAK4 degradation in the tissue is expected by the end of the year. So in summary, I remember 2 years ago, we made a promise that we will deliver 15 new more entities in 18 months. I just counted when I was listening to my colleagues. We actually -- the promise we made was succeeded. We delivered 18 molecules at that time point in 18 months. I do believe BeOne's oncology is truly a pipeline and truly a game changer in the industry. First, our unprecedented research output and the clinical advancements underscores our leadership in R&D.

I hope that what we have presented today has convinced you that we are at inflection points on where the capabilities we have diligently built are now converging. Our historical performance does not define our future productivity. We're not simply following the trends. We're partnering both first-in-class as well as best-in-class therapies. Second, BRUKINSA is a cornerstone asset for our strategy for CLL. Now with sonrotoclax and BTK CDAC, we're expanding treatment options for all CLL patients across all segments, offering both continuous treatment as well as fixed duration therapies.

Third, our approach to solid tumor reflects our successful strategies in the hematology, emphasize continuous innovation and proprietary combination to build the breast, GYN, lung and the GI cancer franchises. It is indeed a very exciting time for BeOne.

Finally, I'd like to highlight a few key milestones within our pipeline. We have successfully achieved all critical goals we set at the beginning of the year with some complete ahead of schedule such as the CLL/MCL filing for sonrotoclax in China. In the latter half of this year, we anticipate several significant milestones, including Phase III readout from the [indiscernible] study, which is frontline mantle cell lymphoma for BRUKINSA and also the global filing for sonrotoclax in mantle cell lymphoma.

Turning to our early stage pipeline. As you have heard, we have a number of proof of concept catalysts expected for our early-stage pipeline across multiple modalities and the disease franchises. We look forward to share more data with you in the future updates.

With that, I'd like to hand over to Aaron.

Thank you. This morning, we're really looking forward to a great Q&A. While we set up the stage or we're going to get some charter for our panelists. Let me ask participants in the room and online for some quick feedback. If you look at the screens, you'll see a QR code on the slide.

And what this will be is a quick 4 question survey, won't take more than 1 minute. The team told me 30 seconds, but I guarantee it won't take more than a minute. And it's anonymous. This session is to provide valuable information to our investors. And we really would like feedback so we continue to improve as we move forward in future settings.

And there is one very interesting bonus question at the end, and we definitely want your feedback on that. So we're going to skip the room set up. And as we do so, let's just do some housekeeping items.

So for the guests in the room, if you want to ask a question, please just raise your hand. We have people walking around with microphones. Ask your question after you have the microphone. If you're joining us virtually, submit using the Ask a Question button on top right corner of your screen.

And so while we'd love to take a variety of questions, today is an R&D meeting, if you didn't notice, we'd love to spend the time maximized on our R&D portfolio. So we please ask you to stay on topic and ensure questions are related to R&D. [Operator Instructions]

So I think we are all set. Let me just pull this back. And let's open it up to questions.

Andrew Berens, Leerink Partners. Just a couple. The CDK4, did you guys actually declare a dose yet? And then can you also give some color on your combination strategies. It looked like fulvestrant in the second line, but what would the frontline combination strategy be?

And then on the fixed-dose combination strategies, would you be looking -- do you think that it will be in patients that have relapses, will they get retreated with a fixed-dose combination or move on to something like potentially the degrader? And then any color on the NCCN efforts to get endorsed there for the compendia?

Mark, do you want to go ahead?

Sure. Thank you very much, Andy. So to start with CDK4. We have not yet selected a dose. We have this dose optimization phase that's ongoing, both in combination with fulvestrant as well as in letrozole. Each of those cohorts is randomizing 60 patients across 3 dose levels. Those data are maturing. We hope to share those data in the not-so-distant future and declare a dose, that is the key gating event that will enable Phase III studies. Insofar as a combination, as you heard from Shom, we are combining with fulvestrant, but we're also about to start combining with elastrant or elacestrant which could also enable novel combinations in the second line.

In the front-line setting that we're going to combine with aromatase inhibitor, which is why we're combining with letrozole in the Phase I study.

I can take on the fixed-duration questions. In terms of the fixed duration, I think you're referring to sonrotoclax plus the zanubrutinib. So certainly, our 101 study, we plan to test retreating the patients if they relapse. That study is going to take a while, unfortunately, because almost nobody progressed. So it will be a while before we can really be challenging any of the patients.

Certainly, I think that's will be one of the option. But as you heard today, that besides the SC combination, we're also exploring potentially sonrotoclax plus our degrader. And if you think about it, the sonrotoclax plus degrader can potentially be even better of fixed-duration treatment in the relapsed refractory setting because even for patients who had continuous BTKi in the front line, you can potentially get on this type of fixed-duration treatment.

So we do believe rechallenged data is critical. As for your question about NCCN, I think you're referring to our -- the [indiscernible] in our SEQUOIA study. We're certainly working very actively in that front. We'll keep you updated.

Great. Jess Fye, JPMorgan. So a couple more on CLL. For sonrotoclax, I think there was a comment that you're continuing to optimize the ramp-up. What specifically are you optimizing, and where could you improve there. For the CELESTIAL 301 frontline study for the fixed-duration combo, with that completing enrollment earlier this year, when should we be thinking about top line data? And lastly, maybe just following up with the last one. For the BTK CDAC, which you're looking at in combination with sonrotoclax for fix duration treatment. It sounds like you're kind of positioning that for relapsed/refractory setting right now. Could that one day move up and be the frontline fixed-duration regimen?

I love all those questions. It's definitely great. Maybe just initially in terms of your first question, what are we optimizing. I was prohibited by our lawyer to share too much because we are still in the process of filing our IPs, but what I can share with you, we have tested various different ramping up in our Phase I as well as actually in the Phase III, we used the 2 different regimens.

We actually -- based on everything we have seen so far, that gives us the confidence, which Remus has mentioned during the presentation that we are very optimistic. In the end of the day, patients take on sonrotoclax will only need one clinical visit, we're not seeing that lightly. It's because based on everything we have seen, we have confidence we'll be able to achieve that.

Then in terms of the readout for CELESTIAL-301, it's an events-driven study. So I hope I can predict exactly when they will read out, but it's going to take a little bit of time. But certainly, in that study, we also have UMRD as a point to which we're going to look at. Hopefully, we'll be able to share the data earlier than the PFS readouts.

Then in addition to that, I assume your question -- is another fascinating question about taking the greater and the sonrotoclax combination potentially into the front line. I'm sure someone is going to ask another question associated with that is about the degrader itself going to frontline. I assure you, I've been getting that question almost on a daily basis. This is an amazing drug, and it's truly amazing. This is one drug, I never need to spend a minute to convince PI expert. Just everyone was telling us, it's a good job. We're definitely contemplating about degrader going to frontline and either in a mono or in a combination formats. We accumulated data, go to frontline is now the buy is really high, very high. If you look at our zanubrutinib continue to use 3-year PFS, COVID adjustment is 86%. That's really high. Then the fixed duration today, you have seen our combination of the 320 dose level plus zanubrutinib plus the sonrotoclax, that's the ES regimen, we haven't had a single disease progression.

We have 86 patients treating a cohort. So we will see how the data pan out, but that's certainly will be the option for BeOne.

Rosy Liao with Guggenheim. A couple of questions on the solar tumor franchise. So first one on CDK4. In the frontline, CDK4/6 naive setting, how are you thinking about the bar for efficacy in terms of making a Phase III goes down the line? I know we've seen some data from Pfizer in that frontline setting. So curious how we should be thinking about benchmarking there.

And then separately on B7-H4, regarding your Phase I trial, can you comment on whether those patients have previously been treated with another triple 1 ADC. I'm just curious on potential cross resistance and whether that's a factor that you're considering for the Phase III planning.

So for the second question first, these patients by understanding is that all of them are top 1 ADC naive. So we want to understand what this molecule would look like in a top 1 naive patient population because that's fundamentally our development intent for the molecule. For CDK4 in frontline, certainly, the frontline standard of care with the CDK4 inhibitors is quite high. It would be virtually impossible to run a conventional randomized Phase II study. And therefore, we've enrolled this cohort of 60 patients, we're going to follow those patients closely for surrogate endpoints that will help us to inform that decision in terms of response rate, ctDNA reduction, tolerability, discontinuations. So it will be holistic based upon that body of evidence to give us sufficient confidence to proceed to Phase III.

Yigal Nochomovitz with Citi. So 2 sort of big picture questions for John and Lai and then one specific one for Mark. So you mentioned AI, Lai, and you mentioned using it for data prep and visualization and efficiencies, but are you actually using it for drug discovery projects in terms of optimizing molecules at the preclinical level? That's the first one.

Yes. We definitely are embracing this. This is a game changer. But just to be on the practical side of it, I think that things will take step-by-step in terms of where you can apply AI for discovery. I do believe -- my personal belief on the large molecule side of it, that the application will be probably even more advanced compared to the small molecule side of it. Because end of the day, AI has to do the deep learning from whatever is available out there. So we're already -- definitely, we are already starting doing those type of works.

Obviously, basically every modality, there is for drug development, small molecule, large molecule bispecifics, ADCs and you mentioned cell therapy. Again, the one that seems to be missing or intentionally you're not pursuing is radio pharma. Just wondering if you could give any thought to that and whether radiopharma could feature in the development scheme at some point?

Do you want me to answer the question?

Please.

Yes. Good question. I got that question quite a bit as well. So we have been thinking about that. I'm not saying we're definitely not going to do it. But as you know, there's certain things associated with radio pharmaceuticals, which is due to the transportation, preparation and all the things you have to associate with that. It is not an easy task.

And one of the fundamental question is, can you do something else achieving the same effect with all the hassles? I think that's a critical question for that particular field. If you don't have a choice, certainly that's an option. But if we have another more convenient choice, maybe that's not the best option. But right now, we don't have that. I'm not saying for sure, we won't do it.

Okay. And quickly for Mark. So the argument on the central milligram versus the 400-milligram data for the CDK4, I'm assuming the point there is that you potentially don't have enough durability to really be able to show responses at 600? Or is there potentially some bell-shaped dose response? Could you just clarify? I noticed what the ctDNA was consistent with the response data too.

Yes. So we're disclosing data today from our dose escalation phase. I would highlight that these are very small cohorts. So part of this also is statistical power and wanting to have more patients that are, should we say, more homogenous, treated in the same way with contemporaneous randomization to inform that decision. So we just think that it's primarily related to the fact that these are late-line patients in a limited data set.

And there is the possibility, as you heard from Dr. Goel, that this data set could continue to evolve in a favorable way over time.

I just wanted to comment on your AI question. You asked specifically about discovery. But if you actually look at what you saw today, we are using the tools, but our issue isn't really can you make a molecule that completely degrades something. Or can you make a really good inhibitor or a really good ADC. We're quite good at that. And the cost of doing that is quite small, and we do it pretty quickly.

Will AI make us better in that area? Are there certain areas where it's very hard to make something that maybe the industry can be better perhaps. But the huge problem again, is clinical development. This is the huge area of opportunity for applying this technology.

And because the industry is so cut off in the way we do clinical trials because most companies are outsourcing this and most companies have 5 or 6 different platforms, a clinical operations platform, the safety platform, an EMR platform, it's very, very hard to have that information in high quality in a place, in a system that you can use these incredible that are now available to optimize the system.

I think this is where our company is very uniquely positioned because we don't have all the legacy nightmares of a big pharmaceutical company, but we have the breadth and we're doing everything internally. So from our perspective, we're really looking at how can you apply this to be infinitely better in the area, which is 75% to 90% of the cost and 75% to 90% of the time in which we're incredibly uniquely positioned to move in that area.

And I think Marcelo is here. If he is, he can wave. But he has come on board as our CTO and is certainly helping us look and drive forward in that area. And I think that's a place where 5 years from now, we have the potential to be game-changingly different than most organizations, and there's a lot of promise there, and we're certainly investing in that area.

I also want to add one comment on the CDK4 questions. We certainly don't believe there's a hook effect. The ctDNA should correlate with some of the tumor. That's not really truly pharmacodynamic PD biomarker. It's more of like an efficacy PD biomarker. If you think about it, the TK1 is the one truly is a pharmacodynamic PD biomarker.

So we don't see hook effects. And so far, the 600-milligram is well tolerated. And I think that like Mark said, just more sample sizes, the heterogeneous kind of population we have enrolled, yes.

600 is certainly still in play for selection.

Hello, everyone. Welcome to BeOne Medicine's 2025 Investor Research and Development Day. My name is Liza Heapes, I'm Senior Director of Investor Relations at BeOne. We are very excited to host our investor event today both in person in New York City and online for our global attendees.

Thank you all very much for joining us. This is truly an exciting time at BeOne and we are thrilled to walk you through recent progress to date and provide a sneak peek of what looks ahead. I would like to remind all participants that during this presentation, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy.

Actual results may differ materially from those indicated in the forward-looking statements. You can find more details in their filings with the SEC, Hong Kong Stock Exchange and Shanghai Stock Exchange. I'm delighted that joining us to present today are John Olyler, our Co-Founder, Chairman and CEO; Dr. Lai Wang, Global Head of R&D; Dr. Ramos Bizon, VP of Hematology Clinical Development to take us through our BCL-2 program, Dr. Jacob Soumerai from Massachusetts General Hospital, who will share [indiscernible] data. Dr. Amit Argawal, also our VP of hemo clinical Development, walking us through our BTK degrader programs and early research assets; Dr. Mark Lansa, Chief Medical Officer for solid tumors; Dr. Shom Goel who came in from Peter Mac in Australia to share the latest on our CDK4 clinical development data.

At the conclusion of the slide presentations, our speakers will be joined by Aaron Rosenberg, our CFO and moderator for today's Q&A session. Now please let's welcome, John Heller, BeOne Co-Founder, Chairman and CEO.

Thanks so much, Liza. And if you didn't notice, there was a small break in the middle, which probably will make all of you happy in about 45 minutes. So I just really want to thank everyone for joining us. We know that everyone's very busy. There's time and energy taken to try to understand our company. And we really appreciate all of the effort that you have made to date in helping us in this fight against cancer, and we really, really appreciate it.

This is our first investor meeting under the name BeOne Medicines. And I think our company BeOne, it was never simply about making one medicine to fight cancer. A lot of biotechs are, we were not. It was about trying to entirely transform the R&D process to do that to be able to make medicine more affordably and more excessively for cancer patients here in the United States and all around the world.

We also believed in doing that, we had to fight cancer, do it in a better way to improve the R&D process; and thirdly, provide superior returns to investors so that we'd be able to continue to fund the next generation of medicine for cancer patients. I think you'll see we're well on our way in all those areas.

The name BeOne, likewise, is very purposeful. B is because the single goal of any cancer patient is simply to be. One, because we all need to work together as one and no patient, no family, no clinician, no hospital, no company, no policymaker, no country can fight the formidable cancer enemy alone. We all need to work together. We need to change the process to be better at what we do.

Of course, within One in red, you can see Oke. And this represents our commitment to oncology, which I think we wanted to reiterate to the world. Because right now, given some policy that's occurred, given success in other areas like diabetes and weight loss, some companies are pulling away from cancer. We're not. We were built to fight cancer. We will be here fighting cancer with patients, with clinicians forever. That's what we're here to do.

We were built differently from day 1. We remain mission-driven. We remain founder-led. We have a tremendous sense of urgency in everything we do. And I think that will flow through in what you see today. We're fighting cancer through scientific innovation, [ un rational-ably ] , and that's what you will see today. But we're also fighting it through R&D business process innovation, and we're doing that because we really want to drive broader accessibility, again, here in the U.S. and around the globe. And we want to be able to provide superior returns in an industry that struggled to do that to any investment dollar that's coming in so we can continue to make great oncology medicines for the future.

So it's great to have a noble vision and it's great to have one that's really hard, but success isn't about a vision, it's so much more. It requires incredible people, and I think you'll see some of those from our team here today. It requires tremendous teamwork because this is one of the hardest things you can possibly do. There's so many different areas of expertise that need to work together to make a medicine.

And of course, it requires a lot of hard work some of which is not glamorous at all to get things done that need to get done. And I think you'll see we're an organization that isn't afraid to roll up our sleeves and do that work. Sustainable success also requires building strategic competitive advantages. And since day 1 of this company, we've been investing very heavily to build these. It's now been 15 years.

The simple and biggest example is clinical development. Clinical development is the vast majority of time and the vast majority of costs associated with making an oncology medicine. Yet it's largely been outsourced and is not a core competency of most oncology companies. We have built this internally over 15 years. And we now have this spectacular global team of over 3,700 people that is operating largely CRO free. They're doing the hard work and the heavy lifting that you will see the results of here today and what we're able to do as an organization, which I think will shock you at the speed and the quality of what we're doing.

We also have incredible internal manufacturing and research teams. They enable us further cost and speed advantages. Each of these capabilities, strategic advantages are incredibly hard to build. They took every penny that we ever generated in this company of revenue, reinvested or upfront licensing fee or financing that we raised to build these capabilities. It also took every penny we ever pinched, and we pinched a lot of pennies so we could spend it building capabilities and running programs.

This only exists these capabilities because of the tremendous efforts of the people that are here today and here with our company today and that have collaborated with us and also those who have previously worked at BeOne who really built these through brilliance, through dedication and through hard work, driven by their commitment to fighting cancer.

Today, BeOne has already helped 1.7 million patients, 1.7 million patients and their families fighting cancer. To me, that's something that makes me unbelievably proud, grateful and thankful that there's such a wonderful group of people within our company and around us working with us to help have that impact for patients. And what I can say unquestionably is this is just the very beginning of BeOne.

It goes without saying that if you want to build a sustainable business, it's critical to continue to be sustainable. It's critical to have the right core values and have them across your organization. And we have that. We simply live our core values. And with that, we always strive to have positive influence in every environment in which we're working, and we strive to work cooperatively with all elements of the industry.

So what are we going to share today? First, we're going to share how our unique R&D model has already proven that we can deliver quality, speed and cost sustainable advantages. And we can do that in a manner that provides superior returns to investors so we can continue to build the medicines for the future. From that perspective, this is core to everything we're doing, and I really think you'll see a wealth of information today that give you the confidence to have that true belief.

Our goal is to be the most impactful oncology company in the world. And I think when you see what we're doing, we're well on the way to that. Secondly, we're going to talk about hematology. And we have built a hematology franchise over the last decade, and we have 3 incredible medicines that can be combined to create the solutions for patients, not only today but in the future for the next 5 years and the decade beyond. And we are sure that we can continue to grow into the hematology leadership we already have in CLL and that it's highly sustainable and that we do have the right medicines for the future.

And we can build more broadly in hematology outside of CLL and some of the other indications we're already approved in to become a broad hematology leader. And third, in solid tumors. Although it took us a decade to build this franchise in hematology, we believe now we have several opportunities to build franchises that are similar in solid tumors and that we can do so in roughly half the time, and we're very excited to share this information with you.

The data associated with some of these programs, which in their own right, if they weren't in BeOne, if they were in a small biotech company, I think there'd be huge excitement and a lot of value attributed to them. So we're glad to share some information about them.

So with that said, I think that you will see there's new data being presented to. And that's highlighted on the right-hand side of the slide. I know you come, you want to see new things. There's new programs that are disclosed here at a wealth of new data. So I know you want to get to that. And I think that the magnitude of what we're about to share to me is honestly a bit overwhelming. But I think as you can see, it's tremendously exciting. It has the potential to be massively impactful for patients all around the world.

So we really should get to the heart of things. So with no further ado, and I think Liza said we should see what lies ahead. And I'd like to introduce Lai Wang, who is a good friend of mine, and he's also well known for being BeOne's second biggest Dallas Cowboys fan. So here he is, Lai.

Thank you, John. Good morning. It's really nice to see the turnout. Thanks for coming. I'm really excited to share that BeOne R&D is at a pivotal moment in its journey over the years. We have built a strong research, global clinical development and the manufacturing capabilities from the ground up, allowing us to deliver, develop and discover novel oncology medicines much quicker and more cost efficiently than the industry standards.

The strategic advantages capabilities are now scaled and fully functional across R&D. This inflection point signifies the dawn of new era for BeOne, where our commitment, excellence and the pursuit of scientific breakthroughs will enable us to profoundly impact the field of oncology. Since 2019, we have transformed from a middle-sized setup into a scaled and highly efficient research powerhouse.

Our discovery team now comprises over 1,200 research centers making us one of the largest oncology-focused discovery team in the world. We have made substantial investments in a variety of the modalities, including putting the greater record, chimeric, degradation, activation compound CDAC, bispecific trispecific antibodies, antibody drug conjugates and cell therapies.

As illustrated on the graph on the right, our new arrow is marked by a significant increase in preclinical programs and diversified modalities. CDACand the Gamba biologics, including bispecific, trispecific and antibody drug conjugates now constitute the majority of our portfolio. Capably, it will take 2 to 5 years to progress from target identification to a new motentity-engin clinical trial.

With our recent investment, we observed a substantial rise in the number of AMEs entering the clinic, especially starting from the second half of 2023. In 2024 alone, we had 10 new molecule entities entering clinic really function as a strong testimony about how strong and how productive is our discovery team. At BeOne, we prioritize quality over quantity. The rigorous innovation approach we have applied to BRUKINSA is now being used across multiple programs. We focus on conducting the crucial experiments and only move high-quality molecules into the clinic, stopping any programs that does not meet our standards.

Over the last 3.5 years, we have terminated 60 programs that did not make the cuts. This disciplined approach ensures that only the best candidate move forward. For instance, sonrotoclax was designed to be more potent and more selective than venetoclax. And also address venetoclax's associated convenience issue by designing a short half-life molecule. This will be easier for ramp-up.

The FGFR2b ADC has the potential to spell ocular toxicity associated with maratuzumab by preserving ligand signaling. Additionally, IRAK4 CDACcan achieve complete target agitation in tissues by facilitating a very fast ternary complex formation involving IRAK4 CDACand [indiscernible]. Next, I would like to highlight some of the technology platforms in which we have heavily invested in recent years, beginning with putting the graders. We currently have 23 degrader programs in our pipeline, including [indiscernible] the clinic, BTK, EGFR and IRAK4, which are designed for hematologic [indiscernible] , solid tumor and autoimmune disease, respectively.

Preclinically, we have 17 small molecule programs, including 2 we are introducing today, the CDK2 and KRS. In addition, there are 3 greater antibody conjugates VACs at the discovery stage. Our dedication to protein degradation is evident in the scope and the depth of our pipeline. The biology underlying the CDACplatform is fascinating.

As illustrated in this circular diagrams, CDACprovides many unique advantage across multiple dimensions, some of which we foresee -- we did not see at the beginning of exploring these modalities. Later in our discussion, we will dive into strategies such as increasing potency, enhancing selectivity, reducing on-target resistance and impairing scaffold with specific examples.

For now, I would like to briefly highlight 2 additional advantages. First, targeting undrugable protein is conceptually straightforward. As long as the CDAC molecule combined target, it has the potential to degrade the target protein. The binding does not need to neutralize the protein function. Secondly, by utilizing a tissue-specific [indiscernible] , we can potentially minimize the degradation in the normal tissue, therefore, enhance the safety profile.

Now let's turn to ADCs. We currently have 25 ADC programs, including 4 already in the clinic. Today, we will provide updates on a couple of those programs. Our initial wave of ADC assets consult [indiscernible] ADCs. The second wave starting from the end of this year, we're going to bring a set of the bispecific TA ADCs interconnect, although still using the tool isomes the payload.

Moreover, this [indiscernible] as well as bispecific TA antibodies can serve a building block for future novel payload ADCs, including DACs. Our investment in the technology platforms go way beyond just greater and ADCs. We believe that technology is fundamentally tied into innovation in our industry.

Since cancer is such a complex disease, it requires a multi-facet approach to target the various pathways as well as many different targets within their pathway. So choosing the right modality for each target is vital to create a perfect job and then to create a deep portfolio for certain disease area, you really need to draw from a diverse range of technology platforms.

Our journey with CIL began in 2012 when we started our BTK program, followed by BCL2 in 2017 and BTK degrader in 2019. We are anticipating the first CRL approvals for sonrotoclax and BTK CDAC in at least one of the major markets within the next 2 years. For the -- so for the sale franchise, we leveraged only 2 technology platforms, our traditional small molecule inhibitor and protein degrader platforms.

This journey, spent 15 years is a tremendous success by an industry standard, but we feel it is long. Now with our expanded discovery capabilities in both people, team and the technology platforms, we believe we are in a much better positioned to build a similar franchise across our disease area of focus which are listed here.

And more importantly, we can do it much faster. Our goal is to create a deeper pipeline by introducing 8 to 10 new mode entities for each dose area over the next 3 to 6 years. For example, I'm going to use the breast cancer and the oncological cancer franchise as the example. Our first molecule, a CDK4 inceptor which we're going to give you some update today enter the clinic at the end of 2023. So only 18 months ago. Take a guess, by the end of this year, how many molecules we have in the clinic for this franchise, 8. We have 8 new molecule entities in the clinic just for this franchise in just 2 years. This is what now we can do.

And certainly, you will hear a whole lot more about our breast cancer oncological cancer franchise in marked sections. The competition in oncology has heated up in the past 10 years. For almost any target you pick, there are so many competitors work on it. We firmly believe the future of oncology really relies on innovative combinations. Our deep pipeline empowers us to develop unique and proprietary combinations that address our mathematical needs in cancer treatment.

This slide presents several examples we will discuss throughout the presentation, Using BRUKINSA and sonrotoclax, as example, I strongly believe this might become the best treatment option ever for [indiscernible] patients. You will hear a lot more about this in the later sections. This strategy enables us to maximize the potential of our assets and ultimately enhancing the patient outcomes.

Our philosophy of rigorous scientific innovation, combined with our scale and the sense of urgency, sense of urgency is really important, has led to an industry-leading pipeline. This slide showcases our extensive portfolio, ranging from proven therapy like BRUKINSA, TEVIMBRA to very promising early candidates in early stage development.

Our pipeline reflects our unwavering commitment to advancing transformative medicines and improve patients' lives worldwide. Currently, we are executing 96 trials, ongoing trials involving 30 assets across various phases, modalities and disease areas. This slide illustrates the breadth and depth of our clinical portfolio. I will spend the next few minutes also to share with you how we are building our clinical development capability to handle this large and growing clinical portfolio.

Building our global clinical development organization has been a significant undertaking. It is hard. The time line highlights our journey forming section in 2013 to our current state and beyond. We began laying the groundwork in 2013. And from 2017 to 2024, we're concentrating on establishing our global capabilities.

Today, after streamlining and optimizing our process over the past few years were not only operational but thriving. In addition, we have ongoing plan to further enhance our efficiency through the integration of AI and automation. Our global chemical team consists of over 3,700 professionals, covering a wider range of functions to drive our efforts.

Each scale on the slide represents a different function within our team, recruiting specialized talent and assembling this formidable team of clinical developers is no trivial task. This visualization highlights the collaborative and the integrated nature of what we do. At BeOne, we harness our internal global clinical capabilities to drive speed, cost, quality and site access. We will showcase some speed examples in the upcoming slides.

When it comes to cost, typically charge you about 30% additional money. By eliminating the need for CROs, we can cut the CRO fees Additionally, our internal model has led to enhanced the trial quality. Over the past 10 years or so, we have successfully undergone over 100 inspections by 15 different health authorities in more than 10 countries and all this without any critical filing.

This is a remarkable achievement, also direct interaction between the investigator and the sponsor provides enormous value as the investigators strongly prefer working directly with the sponsors over dealing with the CRO. Our patient enrollment strategy emphasizes diverse regions highlighting our commitment to global representation. We ensure broad global enrollment across various regions with increasing representation from emerging markets.

This strategy helps us gathering valuable data and insights from a wide range of population. And in certain cases, the access to hard-to-reach patient populations, which I will touch on later. It is worth pointing out that our Chinese enrollment in 2025 only comes for 1/4 of our total enrollment globally. All the examples, I will share with you later, really represents our global capability, not just the China capability.

At BeOne, we are dedicated to streamlining the drug demand with a focus on excellence. On this slide, you will see metrics from our fast-to-proof-of-concept efforts, and we are applying across all early programs. I truly believe this is important for our success. For instance, look at the middle column, we hold the safety monitoring committee meetings only 2 to 4 days after the last patient finished their dose-limiting toxicity evaluation.

Our medium time to complete a dose escalation cohort is only about 7 weeks, slightly day over 1.5 months. This is well below industry standards. This speed can save us more than 1 year with dose escalation alone in the drug demand, time is truly of the essence. To further illustrate our efficiency, let's look at the CDK4 inhibitor program as an example.

We have enrolled over 300 patients and evaluate 22 dose cohorts, including both model and combo in just 18 months. Do you know how quickly we initiate the first-line letrozole combination in CD469 patients after completing the DLT evaluation combo in the second line patients? I have the answer here. You already see it. It's just 13 days.

This is remarkable seriously if you think about it. We accomplished this by strategically opening sites in regions with very limited CDK4/6 access, including Brazil, Malaysia, Madova and Thailand. Also for the BTK CDEC, we successfully enrolled over 600 patients in the last 3 years. A lot of people are comparing us to another small biotech company. We entered the clinic only about 6 months ahead of the other company, but now we are way ahead.

We effectively use the backfill and the safety expansion cohort to gather those response data. And remarkably, it took us only 4 weeks to go from the recommended dose for expansion. So basically, it's the time you're picking a few dose to expand. So only 4 weeks from that time point to start our pivotal Phase II trial. Now this CLL Phase II has already enrolled more than 100 patients. I hope I have demonstrated to you that we have made significant strides in our pursuit of operational excellence through our internal operational model.

I firmly believe the next wave of efficiency will come from the integration of AI and automation. Such advancements are not attainable using a CRO model. Clinical trials are essentially a data journey. By incorporating Carnage technologies into our process, we can streamline the operations, reduce manual labor and boost accuracy. And this approach not only accelerates the clinical development, but also ensure delivered the highest quality results.

Here are a few examples to give you a flavor how much efficiency we have already gained. This is what we've already done with our AI and automation. BeOne's [indiscernible] strategy is anchored in 4 foundational principles. This has really set us apart from probably our peers in this industry.

Number one, we're leveraging our diversified technology platforms to build a robust pipeline in targeted disease area for synergistic outcomes. Number two, accelerating the development of molecules towards value inflection points and achieving clinical proof of concept to inform data, keep in mind, data-driven decisions. Number three, initiating proprietary combination therapies early to maximize the potential for our assets and then enhance patient outcomes.

And then number four, exercising discipline by advancing only transformative medicine into late-stage clinical development. Our industry However, on the other hand, especially some of the large pharmaceutical companies often fall short into investing sufficiently in discovery and early development and by lacking principle in late-stage development, typically driven by commercial interest rather than data.

Interest. We focus on strengthening early development while being highly selective in late-stage investments. Our strategies are supported by our highly productive discovery capabilities and our CRO clinical operational model. We're committed to pursuing these principles urgently and with a firm resolve to challenge the status quo.

Next, let us to update you our hematology portfolio. Over the years, we have witnessed remarkable advancements in CR treatments. Key FDA approvals for therapies like Gazyva, Ebuveca, Fencluster, Calquence, BRUKINSA and IMBRUVICA have truly revolutionized our approach to treat CLL. The market for CLL is not only substantial, but still rapidly growing.

However, it is important to note, despite the effectiveness of BRUKINSA only addresses a fraction of the available treatment opportunities. Despite this significant advancement, there remains a considerable on mathematical need for new treatment options in CLL. There is a clear demand for fixed revision treatments, particularly for treatment-naive young fit patients.

Current finance-based fixation regimen often fall short due to various challenges, including efficacy, safety and convenience. Additionally, the increasing number of patients relapsing of the first-line treatment underscores a necessity for innovative treatment in relapse refractory.

BeOne stands out as the only company with fully owned potentially as-in class assets across 3 foundational MOAs in CLL. This provides a unique opportunity to comprehensively address the medical needs of patients across all lines of therapy and in the different subpopulations using both monotherapy as well as our unique combinations. We are strategically positioned to tackle the macro medical needs in CLL treatment with our wholly owned portfolio.

While [indiscernible] currently serves a portion of patients, we aim to develop regimens that cater to all patient segments, were dedicated to relentlessly pursue best-in-class option from frontline to later lines of therapy with both continued use as well as the fixed duration treatments.

Now move on to BRUKINSA. BRUKINSA continued to deliver exceptional value for patients around the globe as the best-in-class BTK inhibitor, it serves as the cornerstone of our CLO franchise. In the U.S., BRUKINSA leading new patients starts for both frontline and the relapsed refractory CLL and across all approved indications. They are both the most comprehensive label of NBKI, and is the only BTKI shown to offer superior efficacy and safety in a head-to-head chart against the ibrutinib with approvals in certified markets, including recent launch in the [indiscernible] , BRUKINSA has successfully treated over 200,000 patients globally.

For men's inception, BRUKINSA was designed to provide best-in-class 24/7 BTK inhibition. Our hypothesis was achieving complete and sustained BTK inhibition would result in a severe therapeutic profile, notably Bookings is the only BTKI maintains serum concentration significantly above SIC 50. I should say, only proven BGC.

While exposure for acalabrutinib and ibrutinib remain well below their respective IC50 for the majority of the treatment period. But we actually had this data about 10 years ago. And we shared with a lot of people, we say, this is the best-in-class BTK inhibitor. Nobody believe in us. So we'll take the hot road and did the experiments.

So we did this experiment is trying to demonstrate in the head-to-head fashion. This is a better BTK inhibitor based on science, based on the [indiscernible] BRUKINSA has this superior target coverage translates into exceptional clinical efficacy. In the ALPINE trial, BRUKINSA except a sustained superior progression-free survival efficacy alongside lowcardiac elasticity when compared head-to-head visit [indiscernible]

In the intent-to-treat population, the PFS ratio was 0.66, with milestone PFS over 64% for BRUKINSA and 53% in ibrutinib at a 42- month. The treatment effect is even more pronounced in high-risk data Delta 7P population where the hedge ratio was 0.48 and the landmark PFS at 42 months was 59% for BRUKINSA and 32% for ibrutinib.

These results underscore the efficacy of BRUKINSA and its potential to improve outcomes for patients with relapsed refractory CLL. Maybe just add another commentary. When we began to ask people still don't believe this can be a better one, not until we show the PFS.

So we have demonstrated you once. We can make greater molecule and the design life experiments. Hopefully, next time you will believe in that. So in the treatment-naive setting, BRUKINSA has demonstrated impressive PFS outcomes for patients regardless of their data 17-minstatus. The presence of data 7p is associated with significant higher risk of mortality due to CLL.

The graph presents PFS curves in SEQUOIA trial from 2 separate arms of the [indiscernible] cell patients ways or way out data 17. Both arms were treated with BRUKINSA monotone. In the Arm C, which represents the largest prospective cohort of formerly treated patients with Delta 7P. BRUKINSA achieved a remarkable months PFS 5-year PFS rate of 7%, comparable to the 76% in those results Delta 7P.

The success of BRUKINSA reflects our rigorous approach to drug development, are focus on creating superior molecule and are not afraid of conduct head-to-head clinical trials when necessary. We are now seeing us doing that also with sonrotoclax and the BTK grader. These efforts have placed BRUKINSA in a strong market leadership position in the U.S. within just 2 years of its launching CLL, despite being 9 and 3 years later than ibrutinib and cabinet respective, best drug wins.

Now I'll hand the presentation to my colleague, Ramos, who will share insights on sonrotoclax and our option for fixed ovation treatment.

Thank you, Lai. Good morning, everyone. I am Ramos Vasant, Vice President of Clinical Development at BeOne. And I'm very excited about the opportunity to share with you our clinical development plans for next -- our next-generation BCL2 inhibitors on [indiscernible] .

Fixed treatment duration is emerging as an important therapeutic modality in CLL, and our company is dedicated to addressing this important issue for patients and physicians. In our view, the fixed statement duration should meet few essential characteristics in order to be ideal for patients and give the confidence to patients and physicians to stop therapy.

One, this essential element should have the capacity to achieve higher efficacy demonstrated in high rates of responses and measured by deep UMD levels. Two, should have the capacity to achieve long progression-free survivals at least at the level of the BTK continuous therapy. Three, it is also important to have a favorable safety profile with minimal added toxicity, no TLS and low rates of high-grade toxicities and very important, no increase in that event.

And four, should be able to address the convenience factor being an all-oral regimen with no requirement for hospitalizations and minimal number of clinical visits for TLS monitoring. And all this would allow medincine to be accessed by most of the CLL patients.

Venetoclax is currently the only BCL-2 inhibitor approved and represents an important therapeutic agent for CLL patients. However, there are significant limitations with venetoclax. And these limitations are very oftenly being cited by the health care providers and even more pronounced in the community settings where access to laboratory fast laboratory results and hospital beds is limited.

These limitations with venetoclax are mainly due to the intrinsic clinical pharmacologic profile of this product. Venetoclax has a long half-life over 24 hours, therefore, accumulating [indiscernible]. And it takes a long time to achieve a steady state level. These characteristics translate into a labor-intensive TLS monitoring due to the wrap-up and to achieve the target dose and that you see represented here in the image.

The frequent objects like 5 to 7 clinic visits, including a 24-hour time lab check for the first 2 dose levels. And this is the low realizations even more frequent visits and requirement for hospitalization and serial lab checks for high-risk patients really significantly limits the use of this product.

In conclusion, we believe that as generation BCL-2 inhibitor that overcome these important limitations and would be able to be used by the broad community is highly needed. As I showed, the networks has important limitations and more than half of the patients of CLL patients cannot access this medicine.

More so, the vast majority of patients will communicate setting cannot access this medicine due to the safety concerns and the feasibility around the ramp-up. Despite of the challenges, venetoclax has a blockbuster drug status with multibillion dollar annual revenue and with opportunities to further increase in annual sales over the next few years.

Now imagine the clinical and commercial value of our next-generation BCL2 inhibitor, with superior clinical activity, better safety the ability to be accessed by the broad CLL population, including in the community setting, but also with the broader label and more indications.

Sonrotoclax, our next-generation BCL2 inhibitor has key characteristics that position this product to be best-in-class with superior efficacy and a more favorable safety profile. On one hand, the higher potency, 14x the increased potency in preclinical models versus venetoclax may translate in superior efficacy with much deeper and longer responses.

On the other hand, the improved selectivity, shorter half-life and no drug accumulation in the blood can offer a more favorable overall safe profile with less treatment associated adverse events. Also very important, it offers the opportunity for a shorter ramp-up, a shorter and safer and more patient-friendly ramp-up can be used by all the CLL patients, including in the community setting.

This important element gives venetoclax the potential to be a superior product that could be used by the broad CLL population. Now I'm honored to introduce you Dr. Jacob Samra, Assistant Professor of Medicine, Harvard Medical School, hematologists, oncologists at Massachusetts General Hospital a key opinion leader in CLL and the B-cell malignancies and also a principal investigator and multiple sonrotoclax clinical trials.

Dr. Samray is going to walk through some of the most recent data with sonrotoclax in combination with zanubrutinib, and will share his perspective on this product and its results, Dr. Samray.

Thanks very much. So BTK and BCL2 inhibitors have distinct and complementary mechanisms of action. Besides the antiproliferative effects of BTK inhibitors in patients with B-cell malignancies, we know that BTK inhibition interacts with multiple important cellular functions. For instance, it impairs the homing of malignant B cells to lymphoid tissues where they are normally receiving growth signals and other support signals from the tumor microenvironment.

This results in the migration of malignant B cells into the peripheral blood, where we know that BCL2 inhibitors can more effectively induce apoptosis and kill. Indeed, combinations of BTK and BCL2 inhibitors have demented synergistic activity in preclinical models.

And importantly, the combination of BTK and BCL2 inhibitors also results in synergistic efficacy when used in patients with B-cell malignancies. Now BGB-11417, 101 is a global Phase I/II open-label study of sonrotoclax alone or in combination with zanubrutinib and/or obinutuzumab in patients with B-cell malignancies, multiple combination dose expansion cohorts have been completed.

And today, I'm going to review recently updated data, including data presented at EHA in CLL and mantle cell lymphoma. Starting with the sonrotoclax and zanubrutinib combination in treatment-naive CLL. Safety outcomes are shown here on this slide. No cases of laboratory or clinical tumor lysis syndrome occurred on study, most treatment-emergent adverse events for Grade 1 or 2, few Grade 3 or 4 treatment-emergent adverse events occurred.

The most common treatment-emergent Grade 3, 4 adverse event was neutropenia, with grade 1/2 neutropenia 7.9% of patients and grade 3 or 4 neutropenia and 27.9% of patients. Importantly, this was transient, did not lead to higher rates of Grade 3 or worse infections in no cases of febrile neutropenia occurred on study.

GI toxicities, which are an important class effect of BCL-2 inhibitors were relatively infrequent and predominantly Grade 1 no fatal treatment-emergent adverse events occurred on this study. In the recently updated analysis, no new safety signals were observed with longer follow-up with sonrotoclax and zanubrutinib in treatment-naive CLL.

Measurable residual disease, or MRD, outcomes are shown on this slide for patients with treatment-naive CLL receiving sonrotoclax and zanubrutinib. We observed high rates of early undetectable MRD at a threshold of 10 to the minus 4 or UMRD4 including in high-risk patients, such as those with an unmutated IGT and deletion 17p.

The median time to undetectable MRD 4 was 7.1 months for patients with unmutated IGHV, and 7.2 months for patients with mutated IGHV. This includes a 3-month lead in with zanubrutinib alone and is significantly more rapid than what one would expect based on previous data.

92% of patients with this combination achieved undetectable MR2 at week 48 of the combination. Now these data are particularly encouraging given previous evidence that more rapid MRD responses have been associated with prolonged progression-free survival outcomes among patients with CLL receiving BTK, BCL2 based combinations.

Progression-free survival or PFS outcomes for patients with treatment-naive CLL receiving sonrotoclax and zanubrutinib are shown on this slide. With a median follow-up of 25.5 months, the median progression-free survival has not been reached. No progression-free survival events have occurred in the 320 milligrams in sonrotoclax cohort. And 1 patient in the 160 milligrams in sonrotoclax cohort had Vector's transformation to DLBCL, which occurred at 8 months of the combination.

Now importantly, an important feature of this study was that it allowed for elective treatment discontinuation at week 96. 35 patients have reached the week 96 time point and elected to stop therapy. All remain in an ongoing remission with a median of 3 months of therapy with Summit 12 months of therapy. Sonrotoclax and zanubrutinib was also evaluated and relapsed or refractory CLL and safety outcomes are shown here on this slide.

Importantly, these data are very consistent with what was seen in naive CLL with no new safety signals observed in the relapsed refractory setting. Measurable residual disease and progression-free survival outcomes are shown on this slide, 80% patients treated at the recommended Phase II dose of 320 milligrams of sonrotoclax with zanubrutinib at the approved dose, achieved undetectable MRD 4.

Looking to the PFS curves, responses appear durable at a median of 19.6 months of follow-up, the median progression-free survival has not been reached. Two PFS events have occurred. These were both progression events on active therapy in patients with deletion 17p CLL, 1 at the 40-milligram dose and 1 at the 320-milligram sonrotoclax dose.

Like in the treatment-naive setting, this protocol allowed for treatment discontinuation, electively in patients reaching the 96-week time point. 13 patients have elected to stop therapy after 96 weeks of the combination and all remain in an ongoing remission after a median of 4.5 months of therapy. sonrotoclax and zanubrutinib was also evaluated in relapsed or refractory mantle cell lymphoma, where we currently do not have an FDA-approved BCL-2 inhibitor.

Safety outcomes for this combination in mantle cell lymphoma are shown here, and we're again consistent with what was seen in CLL, notably with no cases of laboratory or clinical tumor lysis syndrome. An MTD was not reached up to a sonrotoclax dose of 640 milligrams and 320 milligrams of sonrotoclax was selected as a recommended Phase II dose for sonrotoclax when used in combination with zanubrutinib in patients with mantle cell lymphoma.

We observed deep and durable responses in patients with relapsed/refractory mantle cell lymphoma treated with sonrotoclax and zanubrutinib. At the recommended Phase II dose, the overall response rate was 82% and the complete response rate was 67%.

And the median duration of response was not reached with a median [indiscernible] 7 months and 84% of patients remain an ongoing response at 24 months. Importantly, of 18 patients who achieved a complete response, 16 are in ongoing complete response at median fall of 13 months.

Sonrotoclax and obinutuzumab was also evaluated in treatment-naive CLL. Now these data have not previously been reported are planned to be presented at the ASH Annual Meeting. sonrotoclax and obinutuzumab was well tolerated with a safety profile that's consistent with individual agents, suggesting no additional combinatorial toxicity and demonstrated promising efficacy in treatment-naive CLL.

80% -- 87% of patients achieved undetectable [ MRD-4 ] by week 36 and 90% of patients achieved [ UMRD-4 ] by week 60 In summary, the all-oral combination of sonrotoclax and fanibrutinib is a very promising fixed duration treatment combination for patients with CLL and mantle cell lymphoma.

Now this combination is associated with a favorable safety profile with a potential for a significantly more convenient ramp-up. Additionally, sonrotoclax and zanubrutinib demonstrated very prominent efficacy and treatment naive and relapsed or refractory CLL and in mantle cell lymphoma in the relapsed/refractory setting. And in CLL, we observed high rates of early UMRD-4, including across molecular risk factors.

This combination has the potential to become a new standard in CLL and mantle cell lymphoma. And I'd like to just take a moment to thank all of the patients and their families who participated in the studies. And of course, my coauthors and co-investigators. Thank you very much for your attention.

Thank you, Dr. Sumray. As you just heard, the impressive results observed with sonotoclax in combination with zanubrutinib, really positions this combination to offer the best-in-class fixturation regimen in CLL. When we look across the currently available limited duration treatment options, sonrotoclax plus zanubrutinib really demonstrates the highest level of deep responses of efficacy with deep responses over 90% U-MRD rates, unmatched PFS for the respective follow-up, but also a favorable safety profile with less high grades of adverse events and importantly, no debt.

In contrast, the currently available fixed ration therapy show limitations either from efficacy or safety perspective. In regards to safety, it is important to mention a few safety concerns like the infusion reactions observed with the infusion of obinutuzumab. The toxicity, the cardiac toxicity and cardiac deaths associated with the use of ibrutinib, but also the high rates of grade 3 or higher toxicities like infections or other treatment emerging adverse events leading to that or treatment of discontinuation.

From an efficacy perspective, there are some important deficiencies like the low rates of undetectable MRD observed with acalabrutinib plus venetoclax combination where only 34% of patients achieved UMRD at the end of treatment but also the underwhelming 3-year PFS rate of near 77%.

And this is despite the very fit population that was studied with this combination. For the sonrotoclax plus ibrutinib combination, in addition to the superior and favorable safety profile, I would like to remind you that we did not observe any clinical or laboratory TLS. And we are continuing to optimizing the ramp-up schedule for sonrotoclax.

We are very optimistic that for the vast majority of patients, only one clinical visit is going to be required after the zanubrutinib bleeded. In conclusion, we believe that this therapy has the potential to be a game changer as a fixed duration treatment for CLL patients. The sonrotoclax plus zanubrutinib combination showed the highest level of UMRD.

But not only that, they also achieved this UMRD in a very short time. And this element is a further testament or evidence to the potency and superior clinical activity of these 2 products. The fast kinetics in achieving the undetectable MRD were observed with the Sondotoclaxanio combination regardless of the high-risk features like the mutated or unmutated IGHV status, something that was not observed with other venetoclax-based combinations like hybrid in venetoclax data that was recently shared from the FLARE study where the patients with mutated IGHV seems to have a slower and lower MRD.

Now looking ahead to our clinical development plans for sonrotoclax. Currently, we have a few important Phase III registrational studies that I would like to highlight here. Celestial treatment-naive CLL 301 study is a global Phase III study that is designed to demonstrate the superiority of sonrotoclax zanubrutinib over venetoclax obinutuzumab. This is currently the only registrational study designed to investigate the superiority of fixed duration regimen against the current standard of care. This study completed enrollment of almost 700 patients in less than 14 months.

And this achievement is a testament of the high interest, trust and excitement of investigators in this combination, but is also a testament of the unique capacity of BeOne to run large Phase III clinical trials at the highest standards. The same combination of sonrotoclax plus zanubrutinib is currently being investigated in mantle cell lymphoma.

Celestial relapsed/refractory MCL 302 is an ongoing Phase III trial that is looking to demonstrate the superiority of sonrotoclax plus zanubrutinib over zanubrutinib plus placebo. In these trials, sonrotoclax is given for 2 years and the zanubrutinib is given to progression or intolerance.

And the primary endpoint of this study is in the PFS by independent review committee. This trial is also currently enrolling. We received high interest for this trial, and we anticipate a very fast enrollment. We are pursuing also other combinations of sonrotoclax, like with the anti-CD20 antibody. In the relapse refractory CLL setting, we have a Phase III study that is currently ongoing Celestial relapse refractory 303 study that was developed and is run in collaboration with the German CLL study group.

This is an important Phase III study that is designed to demonstrate the superiority of sonrotoclax, either plus obinutuzumab or rituximab versus venetoclax rituximab, which is the current standard of care in this setting. This study provides also the opportunity to run a head-to-head comparison of sonrotoclax class versus venetoclax.

And we are very confident that it will demonstrate the superiority of sonrotoclax as the next-generation BCL2 inhibitor. While CLL and MCL remain our priority indications, we are moving aggressively to expand the clinical opportunity of sonrotoclax and maximize its clinical potential.

Multiple myeloma represents an indication -- an important indication in [indiscernible] market and patients with the transportation 1114, represents about 20% of these myeloma patients. Venetoclax was evaluated in this indication at higher dose levels, however, showed -- failed to show a significant clinical benefit due to toxicity and limited efficacy.

The combination of sonrotoclax plus dexamethasone has demonstrated very compelling clinical data with high response rates of 78% at -- across all those levels and 8 -- over 80% at the 640 milligrams of sonrotoclax, data that compares favorably with the previous venetoclax results in this indication. So building on these promising results, a study of the triple combination of sonrotoclax, zanubrutinib and dexamethasone is currently ongoing with positive preliminary safety data and the pivotal Phase III study in the second-line multiple myeloma of sonrotoclax triplet is also being currently planned.

Here, we are presenting an overview of the broad clinical development plan and clinical studies with sonrotoclax that is designed to maximize the clinical and commercial value of sonrotoclax but are also designed to further increase the clinical opportunities with our other internal assets. It is worth highlighting that we have multiple registrational studies ongoing that offer the opportunity to register sonrotoclax in multiple indications either as a single agent like MCL, CLL or Waldenstrom, but also other various combinations.

Also important to note, market applications for sonrotoclax were already initiated in China based on the preliminary results from 2 study relapsed/refractory CLL and relapsed/refractory MCL. And the applications were accepted by the regulatory authority in China. Also, a global filing for sonrotoclax in relapsed/refractory MCL indication is planned for the second half of 2025, and we are very excited about this potential first global submission and potential approval.

And with that, I hope you are as excited about sonrotoclax as we are. And I would like to hand it over to my colleague, Amit to provide you an overview of our BTK CDAC program. Thank you.

Thank you, Remus. Good morning, everyone. My name is Amit Agarwal, and I'm a VP of Clinical Development here at BeOne. It is my great pleasure to share with you an update on BGB-1673 and also walk you through why we believe this asset has the potential to be a cornerstone of our hematology pipeline. Let's start with the why.

Despite many advances, CLL still remains incurable, and there is an enduring unmet need for these patients. As the treatment landscape evolves, more patients will have received the current generation of therapies in the front line. There is an important need to develop drugs with novel mechanisms that can overcome resistance when these patients progress.

In this context, we're developing 16673 to be the potential first-in-class BTK degrader. This drug is fundamentally different than traditional small molecule inhibitors. This is the first drug from our proprietary CDAC platform. Think of it as a molecular machine that not only blocks BTK, but completely removes it. This mechanism has several advantages.

The first is because of a catalytic action, a single degrader molecule can actually degrade thousands of the target protein, which makes it much more potent. The second is that the mechanism allows for being able to not only overcome existing mutations, but also delay the emergence of new mutations.

And the third is that the degrader is able to remove the entire protein scaffold and shut down both the kinase dependent and independent signaling, which traditional small molecule inhibitors cannot do. We have seen evidence of all 3 aspects of this MOA translate into meaningful clinical benefit.

This is just a better mousetrap. We have tested this drug in a global Phase I/II study called the CADENCE 101 study across B-cell malignancies. Most of the data that we have shared comes from the Phase I portion of the study. The cohorts that I will present today include the relapse CLM Walden strokes and indolent lymphoma histologies. I will point out that we are also enrolling patients in the Phase II part of the study and in particular, in the relapse CLL cohort, we have enrolled more than 100 patients now that we could file with in 2026.

Let me talk about the types of patients we have enrolled on this study so far. The study has enrolled heavily pretreated patients who have seen multiple lines of pliatherapy. In case of CLL, we have patients with a median of 4 prior lines of therapy, including a BTK inhibitor, a BCL-2 inhibitor and other treatments. We have several patients who have also received a noncovalent BTK inhibitor like pertebrutinib before coming on to the study.

An important aspect to point out here is that of the patients who have received a BTK inhibitor, most of them, 90% cut off that BTK inhibitor due to progressive disease. This is an important context when we look at the efficacy in this group in a minute. Let me start with the safety first. The safety profile here is consistent with on-target BTK degradation.

The most common adverse events we've seen include cytopenias with neutropenia being the most common. There are some adverse events associated with platelet dysfunction by confusion and [indiscernible] . And we do see some infections in the form of COVID-19 and other infections. The rate of drug discontinuations due to adverse events in this late line population is less than 5%.

What we have not seen or off-target BTK directed side effects, like arrhythmias. And again, we think this is an attribute of the program as well as the mechanism. With some patients now continuing on treatment for more than 2 years, we are building long-term safety data on this molecule.

Moving on to efficacy. For the relapse CLL cohort at the 200-milligram dose, which is the dose that we're moving forward into the Phase III study with, we see that the overall response rate is 94%. This includes some complete responses, which are rare with the BTK directed treatment. These responses occurred relatively quickly. and typically at the time of the first disease assessment.

In terms of some key subgroups, you can see on the right, responses are consistently noted regardless of prior exposures or mutations. In the patients who are the so-called triple exposed patients, meaning that they have received a covalent BTK inhibitor, a non-covalent BTK inhibitor and a BCL-2 inhibitor before coming on to the study. we see response rates of 75%.

These patients truly have no treatment options left and a 75% response rate in this group of patients is highly encouraging. With longer follow-up, we have seen that these responses are also durable. In the graph on the left, you can see that in the CADENCE-101 trial, the durability looks very promising.

On the right-hand side, you can see the Brent 321 resource for portabrutinib. With the normal caveats of cross-trial comparison in place, you could see that in this group of relapsed and refractory patients, there is a strong reason to believe that the degrader offers a much better mechanism than an inhibitor for these patients. These results give us the confidence to launch a head-to-head study against portabutinib, relapsed/refractory patients will be randomized to receive either 16673, or portabutinib as a monotherapy. We have engaged several health authorities for this trial and have an agreement on the design and the dose. We're planning to start the study later this year.

We're also seeing a strong signal in other B-cell malignancies. For Waldenstroms in a group of heavily pretreated patients, we have seen an impressive response rate of close to 85%. Interestingly, the responses occur quickly and also deepen over time. We now have VGPRs in almost 1/3 of these patients. The responses are seen in particularly hard to treat populations based on both the types of prior treatments that they have received, but also genetic risk factors.

And as you can see in the PFS curve on the right, these responses also appear to be durable. We have now opened enrollment on the Phase II expansion of the Waldenstroms cohort and are planning the next steps for registration in this setting. Moving to other indolent lymphomas. In this study in follicular and marginal zone patients, we're seeing meaningful responses, including complete responses. As a single agent, this activity is very promising and could allow us to develop this drug in these diseases, particularly as a combination.

Finally, I'm going to share clinical veneer from this trial that illustrates what this drug can do. This is a 69-year-old gentleman who is diagnosed with CLL in 2009 and received multiple rounds of standard treatment. In 2024, his disease progressed, and he was diagnosed with Richter's transformation. Richter's represents a serious, often fatal complication and progression of CLL. He initially received standard treatment of our SHOP for this but had no response.

He came on to the study in early 2025, and you can see a significant disease burden at the time of study entry. This is the response after being on the trial for 3 weeks. Three weeks of an oral treatment. You can see that his lymph nodes have dramatically reduced. This case nicely highlights the transformative potential of this drug. We have a broad clinical program designed to establish BGB-16673 as a foundational therapy.

You heard earlier from Lai, we're moving fast with this program. This is driven not only by our own conviction in the drug, but also great enthusiasm that we've seen from our investigators on these studies. We plan to file for an accelerated approval in 2026. We already have ongoing registration studies as a monotherapy and the head-to-head against Porto will start later this year. We're also looking at the combination of the BTK CDAC and onto as a fixed duration for CLL.

In the front line, we have started some work looking at the monotherapy as well as combination settings for proof-of-concept data that will inform our front-end strategy. Beyond CLL, we're also actively assessing other indications, both as a monotherapy as well as combination. We believe that 16673 has the potential to reshape the treatment landscape of B-cell malignancies.

Now let me take a moment to recap where we are and where we are headed. We've built a comprehensive registrational program that spans the full spectrum of CLL from the treatment naive to the relapse and refractory settings. In the frontline setting, BRUKINSA has already established itself as the leading BTK inhibitor with this best-in-class profile. With the combination of BRUKINSA and sonrotoclax, we're now advancing what we believe will be the best-in-class fixed duration regimen.

For relapse patients, we will bring forward several options both as a continuous monotherapy as well as in combinations. Our BTK degrader should become a foundational therapy in this setting. We're also advancing fixed duration regimens, including CD20 antibody and solotoclax and evaluating the CDACplus cracasndro combination as a potential next-gen option. This program is designed to offer patients important options throughout their CLL journey and make BeOne medicines the leader in CLL.

You've heard the details of our oncogenic signaling cluster drugs that will provide near-term value. Now I want to zoom out and talk a little bit about our research efforts. We are focused on developing several novel modalities. We're developing modalities that have orthogonal mechanisms and should allow us to make a broad impact on B-cell malignancies.

I would like to talk about the T cell engager cluster and our cell therapy platform. We're developing 3 different T cell engagers, a CD19x20 trispecific a BAFAR CD22 trispecific and the CD79 with an undisclosed target trispecific. We'll also develop co-stimulatory drugs with CD20 by CD28 and CD2x41BB, the leading drugs.

Often, the cost for disease progression in the context of bispecifics has been the loss of tumor antigen. To obtain broader coverage with the initial response and to avoid antigen loss. We're developing trispecifics that will bind to distinct tumor antigens. To complement this approach, we are also looking at co-simulati that have shown significant synergy with the T cell engagers.

As shown here, our CD19/CD20 trial specific and the CD20 CD28 co simulated drug have compared favorably to the competitor molecules and also demonstrated great synergy together in preclinical models. The CD19/CD20 trispecific is on target to enter the click in 2026 and the CD20xCD28 drug in early '27.

Finally, I want to introduce our cell therapy platform. We all know that autologous cell therapies have made a major impact on the outcomes in hematologic malignancies, but have faced several challenges that have limited their wide adoption. Initial efforts to address some of these challenges with allogeneic cell therapies have not been successful. We're developing an iPSC-derived platform that we believe will address some of these challenges.

The platform has been developed to address CMC issues around differentiation and expansion, and there are several key genetic changes that provide hyperimmunity prolong survival as well as potency. A unique aspect of this platform is a proprietary signal converter that provides these cells with significant potency. I'll show a little bit of the impact of a signal converter with the experiment on the right.

What you can see in blue is what we typically have in a preclinical killing assay with some of the older generation of allergenic cell therapies. But with the signal converter on board as well as our entire platform, you can see that we see continuous killing of these cells without any evidence of exhaustion.

We think that these are optimistic changes. And if successful, this will lead to a highly differentiated cell therapy solution which we're planning to enter the clinic within 2026. To summarize, we're not just building a pipeline, but rather systematically building a franchise. We're doing it with a sense of urgency, scientific rigor and a clear focus of delivering impact for patients and value for investors.

With that, I thank you for your attention. I think next on the agenda, we're going to take a 10-minute break. You will want to come back because Mark has some very exciting updates on the solid tumor portfolio as well. Thank you.

[Break]

Okay. Great. Welcome back, everybody. My thanks as well for joining today for hematology and stay for solid tumors. My name is Mark Lease. I'm the Chief Medical Officer for solid tumors at BeOne. Today, I will be providing an update on our solid tumor portfolio. focusing on our progress and future plans.

Indeed, Lai and I were chatting before today's session, and we were commenting on how since our last R&D day 2 years ago, about essentially everything that I'm about to share with you is new since I was last R&D Day. Our pipeline includes diverse modalities and mechanisms across 3 franchises: breast and gynecologic cancers, lung cancer and gastrointestinal cancers.

Today, I am extremely excited to share updates from each of our core disease area franchises with a focus on emerging data, new targets and exciting in portfolio combinations. Let's begin with our breast and gynecologic cancer franchise. We are establishing an innovative approach to these cancers with several promising candidates in our pipeline, most notably and selective CDK4 inhibitor.

We are committed to advancing research and bringing new treatments to market for breast and gynecologic tumors, it is important to recognize that breast cancer has been a clinical area of focus for BeOne medicines for only approximately 18 months. In each of our franchises, the research organization focuses on both established and novel targets that enable in-portfolio combinations that can maximize patient impact.

And these overview slides, these areas of focus are highlighted as clusters. Key to our breast cancer programs are the investigational molecules in the cell same cluster, including our CDK4 selective inhibitor, our clinical stage CDK2 targeting small molecule as well as our novel CDK2 targeting CDAC that will enter the clinic by the end of this year.

There is also a growing body of work in our estrogen receptor user, where we are exploring agents that can bring benefit in combination with estrogen blockade, including a novel BCL-2 inhibitor and a selective CAT 6AB molecule. ADCs are also an important modality across the portfolio with our B7-H4 being most advanced with additional multispecific ADCs progressing through preclinical development.

And while not a focus of today's presentation, we recently achieved first human dose of our cloud 6 by CD3 bispecific as our first internally discovered clinical stage CD3 conjugated T cell engager ager. I'd like to begin with our C4 selective inhibitor, which is the foundational molecule in our breast cancer franchise. CDK4/6 inhibitors are one of the largest commercial kits in solid tumor oncology valued at approximately $13 billion and continuing to grow.

One of the primary issues with CDK4/6 inhibitors is hematologic toxicity, which leads to dosing interruptions, resulting in suboptimal target coverage. Additionally, there are safety concerns due to off-target inhibition. In an effort to address these limitations, we developed a selective and potent CD4 inhibitor designed to address the limitations of current CDK4/6.

It aims to provide superior therapeutic benefits by reducing hematologic toxicity and off-target inhibition. The bar graphs on the right panel of the slide show the potency and selectivity of 43395. In a preclinical cellular assay, our CDK4 inhibitor is more potently inhibits proliferation than any of the approved CDK4/6 inhibitors. It is approximately fourfold more potent than Pfizer's at termaciclib.

This potency conveys a 38-fold 4/6 versus selectivity, almost twice as selective as termacicline. Although we were second to enter the clinic, we have moved very quickly through Phase I development, enabling first-in-class potential. We have closed the development time gap with Pfizer's obinutuzumab from 3.5 years from first human dose to less than 18 months to a Phase III start in frontline hormone receptor-positive breast cancer.

Today, we are honored to have Dr. Shom Goel a companied leader in breast cancer, presenting the CDK4 data update. Dr. Goel is an associate professor and clinician insist at the University of Melbourne and the Peter McMillan Cancer Center.

He serves as the global PI and translational PI for 4 randomized clinical trials in breast cancer and has over 60 publications, including recent works and high-impact journals such as nature, cancer cell and atria cancer. We're excited to hear Dr. Goel's insights on our selective CDK4 inhibitor and its potential impact on breast cancer treatment. Dr. Goel.

Good morning, everyone. It's a pleasure to be here. So CDK inhibitors in a nutshell, they work by inhibiting the CDK4/6 enzymatic complex. And this leads to prevention of phosphorylation of the AB tumor suppressor protein. Ultimately, this stops cancer cells from dividing, leading to cessation of tumor growth and over time, tumor regression.

We have 3 approved CDK4/6 inhibitors, but each comes with toxicity issues and also the problem of resistance, which ultimately emerges with ongoing treatment. Common side effects include neutropenia with all the drugs and diarrhea with some and hematologic toxicity as well, which is thought to be largely driven by inhibition of CDK 6. So BGB-43395, which is a potent and selective CDK4 inhibitor, aims to provide this select inhibition of CDK 4 minimizing toxicity and preventing the emergence of resistance.

So I'd like to start by sharing with the study design for the first-in-human study of BGB-43395, the selective CDK4 inhibitor. As of June 9, this Phase Ia study has enrolled a total of 284 patients with 178 of them treated in 1 of 3 dose escalation arms, the CDK4 monotherapy or combination with fulvestrant or combination with letrozole. And a fourth arm combining this medicine with elacestrant will initiate soon.

The remaining 106 patients have been enrolled into combination dose optimization arms. And based on PK and PD data, which I'm going to share with you, we've selected 3 dose levels for that dose optimization, 240 milligrams, 400 milligrams and 600 milligrams early twice a day. I'd also like to point out that this is truly a global study with the France and U.S. leading enrollment.

So BGB-43395. Here, I'm showing you the bay and it has shown favorable PK characteristics. The panels at the bottom showed dose proportional and linear pharmacokinetics within the dose range of 240 up to 600 milligrams twice a day. The mean elimination half-life is 13 hours.

And importantly, exposures are not impacted by co-administration of either fulvestrant or letrozole. Also, there were no notable difference in exposures observed between non-Asian and Asian populations. So on this slide, we present some pharmacodynamic data. We observed a dose-dependent and durable reduction in TK1 activity. This is a biomarker of cellular replication at doses 240 milligrams twice a day or higher.

And that's what led us to select the 240, 400 and 600-milligram twice-daily doses for the dose optimization. And I highlight the dose-dependent nature of this PD effect with less TK1 inhibition seen at doses below 240 milligrams and that this PD effect is sustained with no rebound observed at cycle 2 day 1.

In the bottom right panel, early ctDNA decrease, which is another potential response biomarker was also observed starting from the 240-milligram dose level in the fulvestrant combination. So both the TKI data and the ctDNA data suggests that doses of 240 milligrams twice a day and above are biologically active making these the doses for further development -- for focus on for further development.

So here, I'm showing the safety data for almost 100 patients who received BGB-43395 in combination with fulvestrant during both the dose escalation phase and dose optimization. And the statin data I'm showing you are again limited to those 3 dose levels, which are under consideration for further studies. Overall, the tolerability is excellent with related grade 3 or higher events observed in approximately 20% of patients and only a single patient in each study phase discontinuing due to a related adverse event.

When we look at some specific adverse events, diarrhea was frequent. However, these events were predominantly low grade and straightforward to manage with once daily administration of loperamide. None of the cases of grade 3 diarrhea observed in the dose optimization phase resulted in a dose reduction or discontinuation. When we look at the heme toxicity, the rates of hematologic toxicity are very favorable in regards to any greater anemia, neutropenia or thrombocytopenia and these rates compare favorably to the rates of hematologic toxicity with the approved CDK4/6 inhibitors and to a [indiscernible] .

And these hematologic AEs are important because they can result in dose interruptions, dose reductions and thereby ultimately reducing effective CDK4 target coverage. So here, we're presenting the tumor burden change from baseline in patients treated in combination with fulvestrant during dose escalation. Please note that we are only sharing efficacy from the dose escalation phase here rather than the dose optimization phase because that latter data, the optimization data is still quite immature and will be used to identify a recommended Phase II dose.

So the data that you can see on the screen here shows preliminary tumor activity in extensively pretreated dose escalation patients. During this dose escalation phase, 37 patients, including 29 with breast cancer were treated with the fulvestrant combination at doses from 240 up to 600 milligrams twice a day. Now during that dose escalation phase, breast cancer patients were permitted to have bone-only metastatic disease, and therefore, 10 of those patients are not response evaluable. It's a heavily pretreated group of patients, as you can see.

The median number of prior lines of therapy in the metastatic setting was 4, all patients had received prior chemotherapy or an ADC as well as prior endocrine therapy. And the median follow-up at the moment is limited at 3 months. And given the cytostatic mechanism of action of these drugs, the response rate may improve over time. The objective response rate was 11% amongst the patients with breast cancer and 15% in little cohort.

And time-to-event endpoints such as PFS are immature at the moment and will be presented at a future meeting. It's important to note that my opinion, the response rate is also immature at this point. This is a class of drugs where traditionally immune times to response sits somewhere between 3 or 5 months. And so with our median follow-up of only 3 months, we may expect the response change over time. Nonetheless, what we can do here is that among this advanced patient population heavily pretreated, the results show that BGB-43395 in combination with fulvestrant does show meaningful and tumor activity.

So in summary, these data show that BGB-43395 has a strong pharmacogenemic effect across a range of well-tolerated doses. The safety data show a potential best-in-class hematologic safety profile with low grade and readily manageable diarrhea. Emerging evidence also shows clinical efficacy in extensively pretreated post-CDK4/6 patients at those doses with pharmacodynamic activity.

And this positions BGB-43395 as a promising candidate for further development. We're excited about the clear path forward towards registration-enabling studies and look forward to initiating this study within the next 6 to 12 months. So with that, I'd like to thank the study patients, my co-investigators on this Phase I 101 study, and I'd like to pass the presentation back to Mark. Thank you.

Thanks so much, John. Next, I'd like to share an update for our promising B7-H4 targeting ADC. B7-H4 is frequently expressed in breast and gynecologic cancers. And as you can see in the lower right panel, B7-H4 has minimal expression in normal tissue. This high tumor versus normal selectivity makes B7-H4 an attractive ADC target.

Additionally, the drug linker design enhances the therapeutic profile of this ADC while the non PGP substrate -- and non PGP substrate payload with a DAR of 6 yields strong by standard effect contributing to its efficacy. We recently made the initial data disclosure at ASCO. Today, I will share updated data and new analyses. These data indicate a favorable safe profile and compelling emerging efficacy.

Here, we're sharing data across selected dose levels. The most frequently reported adverse events include low-grade nausea, neutropenia and fatigue. Neutropenia and throubocytopenia were the most common grade 3 or greater AEs. The dose-limiting toxicities were principally hematologic and were observed at the higher dose levels.

However, there have been no related AEs that have led to study drug discontinuation. Overall, the early clinical data indicates a favorable safety profile as monotherapy across a broad range of dose levels. Here, we are showing the updated efficacy data as of earlier this month for our B7-H4 ADC showing its promising antitumor activity in breast and gynecologic cancers, a total of 95 patients were treated across 9 different dose levels with a meeting of 4 prior lines of therapy.

This waterfall plot is limited to the 68 patients with breast, endometrial and ovarian cancer. These are currently the target tumor types for subsequently development. The confirmed objective response rate is 24%, and the unconfirmed response rate is 29%, with 14 out of 20 responses ongoing.

We observed an emerging dose response relationship. For example, if the analysis is limited to the 6-milligram per kilogram dose level, the confirmed response rate increases to 43% and unconfirmed to 48%. We also observed an association between B7-H4 expression in efficacy. Among the enrolled breast and GYN patients, the unconfirmed response rate overall is 29%. If we limit to the half of patients with higher B7-H4 expression, the response rate increases to 42.4%.

In conclusion, our B7-H4 ADC shows favorable safety and compelling early efficacy, dose optimization expansions and biomarker selection for breast and gynecologic cancers will initiate a third quarter and planning is underway for Phase III study starts in 2026. I'd next like to present BG-68501, a potent and selective CDK2 inhibitor. CDK2 is an important target in breast cancer because CDK2 activation may convey resistance to CDK4 inhibition.

Preclinically, 68501 shows strong potency in activity, which may lead to improved efficacy and safety profile. 49 patients with pretreated solid tumors were recently presented at ASCO. These data indeed reveal a favorable hepatologic toxicity profile with no dose-limiting toxicities. Common adverse events included nausea, vomiting and fatigue.

Nausea and vomiting are [indiscernible] mitigated with antiemetics and a food effect study is ongoing with a further improve nausea. The preliminary efficacy results show a 6% unconfirmed response rate and a 39% stable disease rate which supports our core development intent for combinations in breast cancer. Our breast cancer franchise will soon add 2 additional innovative molecules that promise improved patient outcomes in hormone receptor positive breast, a CDK2 CDACand a CAT6 AB inhibitor, both molecules will begin clinical studies prior to the end of this year.

This is our potential first-in-class CDK2 selective CDAC. We believe that this CDAChas 3 potential key advantages over a small molecule inhibitor of CDK2. First, the catalytic mechanism that you heard about from Amit can be superior target inhibition. Preclinical potency of our CDK2 CDAC is 30x that of Pfizer CDK2 and 5 to 10x that of our first-generation CDK2 small molecule inhibitor.

Second, because of the target binding geometry, our CDK2 degrader has much greater selectivity for CDK2 over CDK1 compared to any small molecule inhibitor. The IC50 for CDK1 inhibition is greater than 10 micromolar, a greater than 4 log difference from the IC50 for CDK2 inhibition. Finally, this molecule is anticipated to have a longer half-life in small molecule inhibitors, which will enable more continuous target coverage with relatively flat PK, which may in turn further improve safety. To conclude the update on our breast cancer franchise, BG-75202 is a potent and selective CAT 6 AB inhibitor.

In the upper right figure to show greater potency than the Pfizer CAT 6AB against a number of different hormone receptor-positive breast cancer cell lines. Importantly, 75202 also has a greater than tenfold higher selectivity for CAT 6 over CAT 7, which is intent to improve the hepatologic toxicity profile when compared to Pfizer's molecule.

In just 18 months, we've made significant strides in establishing an innovative breast and gynecologic franchise with an initial focus on hormone receptor positive breast cancer growing to 8 clinical molecules by the end of this year. And again, just to reinforce the point that Lai made earlier, 8 molecules in less than 24 months CDK4, CDK2, CDK2 CDAC, CAT 6 AB, BCL2, B7-H4, our CD3 CD6CD3 and MUC1 by CD16 by specific antibodies.

The emerging data for our CDK4 inhibitor shows a differentiated hematologic safety profile with a promising benefit/risk balance as we move towards Phase III trials. The B7-H4 ADC shows substantial efficacy with manageable toxicity, and we are planning subsequent registration intensities in ovarian, endometrial and breast cancer.

These lead molecules, along with CDK2, CAT 6 AB and BCL2 provide unique development opportunities in breast and gynecologic cancers.

Next, I'd like to provide an update on our emerging lung cancer franchise. I'm excited to share our vision for building a truly industry-leading lung cancer franchise. We are dedicated to advancing the field and improving outcomes for patients with lung cancer, featuring innovative and intentionally desired molecules. Our current focus is on 3 driver mutation populations in innovative ADCs.

The 3 biomarker clusters include: first, targeting tumors with MTAP deletion, second, targeting EGFR mutations with our EGFR targeting CDAC and third, oncogenic KRAS mutations. I will present our MTAP cluster in the EGFR targeting molecules in this section and will cover KRAS as part of the GI franchise overview.

We also believe that the full potential of ADCs has not yet been met in non-small cell lung cancer. We have monospecific ADCs in clinical development, including a B7-H3 and CEA targeting ADC, and we have additional candidates with multi-targeted ADCs and in the future, ADCs with novel payloads. We are very excited to show the early progress of our NTA cooperative PRMT5 inhibitor and MAT2A inhibitor.

First, let's discuss our potential best-in-class PRMT5 inhibitor. This compound has demonstrated superior preclinical potency and selectivity when compared with essentially all clinical stage competitor molecules. I will provide our first clinical update for this molecule today. MAT2A has mechanistic synergy when combined with PRMT5 and induces robust efficacy in animal models.

Both of our compounds are highly brain-penetrant, which is an important characteristic for lung cancer and other tumor types that unfortunately have frequent brain metastases. Let's begin with the emerging data for our PRMT5 inhibitor. Here are the initial pharmacodynamic data for our PRMT5 inhibitor.

The left panel shows serial biopsy of a metastatic lesion of esophageal squamous cell carcinoma that has spread to the lung. In the middle of the figure, the change in SDMA between screening and cycle 2 day 1 is shown. By cycle 2, day 1, the tumor cell SDMA score has dropped to 0 indicating effective target engagement at the first tested dose level. On the right, we also observed rapid plasma SDMA reduction in the first 2 patients enrolled in the study.

The first 2 patients enrolled at dose level 1. Taken together, the pharmacodynamic data for our PRMT5 inhibitor demonstrates potent target inhibition as detected in both tumor and plasma. Although we achieved our first human dose in only January of this year, just 5 months ago, the Phase I study is progressing very well with 27 patients enrolled to date.

Regarding the safety profile, the most common treatment-related adverse events are nausea and anemia. Importantly, we have observed no significant hematologic toxicity, no dose-limiting toxicities, no serious adverse events and no AEs leading to discontinuation of treatment modification.

For efficacy, we have achieved target efficacious exposure at only the second dose level due to a better-than-anticipated clinical PK. Despite the short follow-up, we have already observed 3 objective responses in 3 histologic distemper types at the second dose level. In summary, the early clinical data and efficacy data for 58067 are very promising, which support its potential as a best-in-class main-penetrant PRMT5 inhibitor.

Our PRMT5 and MAT2A strongly are strongly synergistic combination, and we are currently the only company with both clinical stage PRMT5 and MAT2A. We will begin enrolling patients to the PRMT and MAT2A combination as early as the third quarter of this year.

In light of the encouraging early safety, PK, PD and efficacy data we are observing with our PRMT, we will start testing standard of care combinations in various tumor types. Next, I will share our EGFR targeting molecules, starting with our EFRA CDEC. This best in class compound, a truly differentiated mechanism of action designed to completely and selectively abolish EGR signaling.

It is highly potent against all typical primary and resistance mutations in EFR while sparing wild-type EGFR and demonstrating excellent proteomic selectivity. EGFR is currently a monotype dose escalation, and we have again observed a strong pharmacokinetic profile with good oral absorption and a very long elimination half-life. The emerging safety profile is consistent with the EGFR sparing -- EGFR sparing wild-type sparing design. There have been no skin or GI toxicities reported to date. Dose escalation is in the early stages, and we're planning to start a combination study with a third-generation TKI in the second half of 2025. In summary, the EGFR CDAC is a highly promising compound with unique mechanism of action, strong preclinical efficacy and encouraging early progress.

Next is our EGFR by-MET trispecific antibody. This compound has best-in-class potential with a unique design that offers superior and optimal MET inhibition through a biparatopic met antibody construct that is, again, EGFR by 2 different epitopes of met. T187 has demonstrated stronger efficacy than ibrutinib and MET-driven and EGFR-TKI resistant models.

Importantly, T187 was also designed for lower EGFR target skin toxicity due to weaker killing of primary keratinocyte when compared to amivantamab. Regarding the clinical progress, T187 is currently in monotherapy dose simulation, and we're planning to initiate dose escalation with subcutaneous formulation by the end of third quarter of this year.

In summary, T 87 is a highly promising compound with unique design and mechanism of action, strong preclinical efficacy and potential for clinical differentiation. Having a focused and deep portfolio in specific tumor types and specific oncogenic drivers naturally creates the opportunity to develop potentially synergistic in portfolio combinations. Here, we have -- here, I'm sharing preclinical combination studies for the 2 molecules that I've just shared, our EGFR CDACand our EGFR bymet/trispecific antibody.

On the left, the combination of the CDAC and T17 yields near complete and sustained reduction in tumor volume and in each GFR TKI relative tumor model. On the right, this combination also yields deep and sustained tumor volume reduction in EFAR TKI-resistant with superior activity when compared to the combination of amavantimab and [indiscernible] planning is underway to test this combination clinically.

Our growing and comprehensive lung cancer portfolio features a diverse and differentiated array of molecules designed to address lung cancer segments with substantial residual unmet medical need. Our PRMT5 and MAT2A are foundational molecules for an MTAP-deleted non-small cell lung cancer and other tableted tumors. Early data support their differentiated and best-in-class profiles highlighting their potential to make a significant impact in this area.

Next, we have the EGFR cluster. Our differentiated and first-in-class molecules provide substantial opportunities for patient impact through ampiocombinations and through combinations with third-generation tyrosine kinase inhibitors. Finally, multispecific ADCs have the potential to broaden the eligible patient population and improve the therapeutic window.

With novel payloads, we aim to further advance tumor selective targeting. In summary, our lung cancer portfolio is built on a foundation of innovation and differentiation. We are committed to advancing the field and improving outcomes for patients with lung cancer. Okay. So I will conclude the solid tumor section with a discussion of our GI franchise with a specific focus on innovation for patients with KRAS patients.

So hang in there sort of last lap, a lot of intent in this section. For this final disease area franchise, I will focus on KRAS targeting, which is mutated in virtually all cases of pancreatic cancer in almost half of the [indiscernible] colorectal cancer.

While I will not revisit the specific molecules, NFR and MET are also important targets for GI cancers in a present in approximately 20% of pancreatic cancers and up to 10% of esophageal and gastric cancers. Similarly, EFR is an established target in RAS wild-type colon cancer and met biosis relevant in both colon and gastric cancers. We are also excited about the development potential of our ADCs and immune cell engagers including our potential first-in-class FGFR2b targeting ADC for gastric cancer and the GPC3 4-1BB bispecific antibody for hepatocellular carcinoma.

KRAS plays a crucial role in self-signaling pathways, KRAS cycles between 2 states, the inactive GDP-bound off date in the active GDP-bound on state. While there have been advanced with in developing small molecules to target specific KRAS mutants, challenges remain due to the presence of undruggable mutants in the emergence of secondary mutations.

Given these challenges, we are taking a multipronged approach to hitting RAS to maximize clinical benefit through new modalities and rational combinations. Our first KRAS targeting molecule, BGB-53038 is a non-covalent inhibitor of both the on and off states. This molecule is progressing well through early dose escalation.

We will build upon this molecular framework by developing a second-generation KRAS-CDAC which will both improve potency and likely also have a long half-life, thereby improving target coverage. We are also actively working to deliver RAS on-target molecules from discovery to the clinic. The most advanced molecule is an internally discovered potent brain-penetrant Raston inhibitor.

We are also planning to use this molecule as a non-cytotoxic drug antibody conjugate to improve tumor targeting with the intent of reducing systemic toxicities associated with broad RAS inhibition. Finally, we're also progressing a G12D specific RAS-on inhibitor through preclinical development.

This slide provides more detail regarding the KRAS CDAC and RAS-on inhibitor. In the left panel, the KRAS deck shows high and improved potency across various KRAS mutations, while retaining strong selectivity for KRAS over H&N RAS. The pharmacological properties suggested it can be dosed daily, which is a significant advantage for patient compliance and may improve the safety profile by delivering constant exposure.

The brain penetrant RAS-on demonstrates impressive potency. The pet on the right shows similar preclinical efficacy to RMC-6236 at 125th of the dose. The middle panel shows that dual RAS inhibition via concurrent blockade of both the off and on forms delivers substantial preclinical synergy. Both these molecules are scheduled to enter the clinic in the second half of 2026, again, providing a unique opportunity for in-portfolio combinations to maximize patient benefit.

The final compound I would like to present today is BGC 137 in FGFR2b targeting ADC that has the potential to be first-in-class with a best in modality design. C-37 has shown stronger efficacy in xenograft models when compared to bemarituzumab, an unconjugated monoclonal antibody. The safety profile of C137 is designed to be differentiated. But marituzumab causes cordial toxicity as an on-target effect that is due to the blockade of the interaction between FGFR2b and its ligands.

The parent antibody of C137 spares cordial toxicity by binding a unique epitope with much weaker ligand blockade. Our FGFR2b ADC is progressing very well through early dose escalation. With over 20 patients enrolled, there have been 0 ocular adverse events reported to date, including at those levels where we're observing early evidence of efficacy.

We are encouraged by the early clinical progress of C137 and are likely to begin the dose optimization prior to the end of this year. We are committed to developing multiple differentiated pathway targeting therapies to address KRAS mutations, which are prevalent in several GI cancers. Our goal is to develop innovative therapies with the potential for synergistic in portfolio combinations and improve patient outcomes.

Next, the MTAP deleted cluster presents an important combination opportunity with PRMT5 and MAT2A and MTAP deleted in pancreatic cancer. And finally, we have multiple first-in-class and best-in-class ADCs. Our FGFR2b ADC is emerging with a superior safety profile. It has the potential to be first-in-class in gastric cancer.

So to conclude to resection, we have completely reshaped the clinical stage solid tumor portfolio over the past 2 years with almost 20 new clinical-stage molecular entities designed and selected to enable in-portfolio combinations, which we believe is critical to making the next step change in solid tumor oncology. This innovation continues with the intent to bring 2 to 3 additional clinical stage molecules per year into each of our 3 disease focus areas.

Through our internal delivery model, we are progressing our portfolio with unparalleled speed with multiple Phase III starts in planning for 2026, including CDK4 and B7-H4 in the light of very encouraging early data, PRMT5 and FGFR2b ADC may also be on an accelerated path to registration intent studies. Our approach highlights our commitment to improving patient outcomes by driving innovation in solid tumor oncology. Thank you. And with that, I'd like to hand back to Lai.

Thank you, Mark. Before I conclude, I screen this slide because I do want to also talk about some data just have a chance to talk about data at my R&D day. I'd like to share an update on our IRAK4 CDACprogram, BGB-4505 was designed to achieve faster and more profound target accusation compared to KT-474. A molecule developed by Camera Sanofi while also avoiding the cardiovascular risks associated with KTM.

You might have heard from Sanofi. Just I think yesterday, they were no longer advanced KT-474 [indiscernible] to focus on a new molecule, which won't be in clinic until next year. So now our molecule is not only potentially best-in-class but also a first in class. The clinical program has advanced smoothly with the successful completion of both single ascending those escalation multiple ascending dose escalation studies.

We are currently conducting our Phase Ib in patient with PN and AD, a notable feature of 450 has extended half-life in humans ranging from 60 to 96 hours, leading to a sustained ardegadation. Please look at the top graph on the right, the green line, that's the second dose. We're testing the SAD 7 days after just a single dose of 45035, you can observe -- we still observed complete work for degradation in the blood.

We're anticipating the -- initiating the Phase II in the second half of this year and with the proof concept of the work for degration in the tissue is expected by the end of the year. So in summary, I remember 2 years ago, we made a promise that we will deliver 15 new more entities in 18 months.

I just counted when I was listening to my colleagues. We actually -- the promise we made was succeeded. We delivered molecules at that time point in 18 months. I do believe BeOne's oncology is truly a pipeline really a game changer in the industry. First, our unpresent research output and the clinical advancements underscores our leadership in R&D.

I hope that what we have presented today has convinced you that we are at inflection points on where the capabilities we have diligently built are now converging. Our historical performance does not define our future productivity. We're not simply following the trends.

We're partnering both first-in-class as well as best-in-class therapies. Second, for Kansas a cornerstone asset for our strategy for CLL. Now with Soro and BKCC, we're expanding treatment options for all CLL patients across all segments, offering both continuous treatment as well as fixed duration therapies.

Third, our approach to solid tumor reflects our successful strategies in the hematology, emphasize continuous innovation and the property combination to build the breast GYN, lung and the GI cancer franchises. It is indeed a very exciting time for BeOne.

Finally, I'd like to highlight a few key milestones within our pipeline, we have successfully achieved all critical goals we set at the beginning of the year with some complete ahead of schedule such as the CLO MCL filing for Sono in China. In the later half of this year, we anticipate several significant milestones, including Phase III readout from the MEMO study, which is only mental cell lymphoma for BRUKINSA and also the global filing for surrender class inventory cell lymphoma.

Turning to our early stage pipeline. As you have heard, we have a number of approved concept catalysts expected for our early-stage pipeline across multiple modalities and the disease franchises. We look forward to share more data with you in the future updates. With that, I'd like to hand over to Erin.

Thank you. This morning, we're really looking forward to a great Q&A. While we set up the stage or we're going to get some charter for our panelists. Let me ask participants in the room and online for some quick feedback. If you look at the screens, you'll see a QR code on the slide.

And what this will be is a quick for question survey, won't take more than 1 minute. The team told me 30 seconds, but I guarantee it won't take more than a minute. And it's anonymous. This is -- this session is to provide valuable information to our investors. And we really would like feedback so we continue to improve as we move forward in future settings.

And there is one very interesting bonus question at the end, and we definitely want your feedback on that. So we're going to skip the room set up. And as we do so, let's just do some housekeeping items.

[Operator Instructions]

And so while we'd love to take a variety of questions today is an R&D meeting, if you didn't notice, we'd love to spend the time maximized on our R&D portfolio. So we please ask you to stay on topic and ensure questions are related to R&D. [Operator Instructions] So I think we are all set. Let me just pull this back. And let's open it up to questions.

Andrew Berens Link Partners. Just a couple. The CDK 4, did you guys actually declare a dose yet -- and then can you also give some color on your combination strategies. It looked like fulvestrant in the second line, but what would the frontline combination strategy be?

And then on the fixed-dose combination strategies, would you be looking -- do you think that it will be in patients that have relapses Will they get retreated with a fixed-dose combination or move on to something like potentially the greater? And then any color on the NCCN efforts to get endorsed there for the compendia?

Mark, do you want to go ahead?

Sure. Thank you very much, Andy. So to start with CDK4. We have not yet selected a dose. We have this dose optimization phase that's ongoing, both in combination with fulvestrant as well as Electrical. Each of those cohorts is randomizing 60 patients across 3 dose levels. Those data are maturing. We hope to share those data in the not-so-distant future and declare a dose -- that is the key gating event that will enable Phase III studies. And so far as a combination, as you heard from John, we are combining with full veteran, but we're also about to start combining with elastin or elacestrant which could also enable novel combinations in the second line.

In the front-line setting that we're going to combine with aromatase inhibitor, which is why we're combining with letrozole in the Phase I study.

I can take on the fixed duration questions. In terms of the fixed revision, I think you're referring to sonrotoclax plus the zanubrutinib. So certainly, our one-one study we plan to test retreating the patients if they relapse. That study is going to take a while, unfortunately, unfortunately because almost nobody progressed. So it will be a while before we can really be challenging any of the patients.

Certainly, I think that's will be on the option. But as you heard today, that besides the SC combination, we're also exploring potentially sonrotoclax plus our degrader. And if you think about it, the sonrotoclax plus degrade can potentially be even better of fixed duration treatment in the relapsed refractory setting because even for patients who had continuous BTK in the front line, you can potentially get on this type of fixed duration treatment.

So we do believe we challenge is critical. As for your question about NCCN, I think you're referring to our -- the MD in our study. We're certainly working very actively in that front. We'll keep you updated.

Great. Jess Fye, JPMorgan. So a couple more on ZL. For sonrotoclax, I think there was a comment that you're continuing to optimize the ramp-up. What specifically are you optimizing, and where could you improve there. For the CELESTIAL 301 frontline study for the fixturation combo, with that completing enrollment earlier this year, when should we be thinking about top line data?

And lastly, maybe just following up with the last one. For the BTK CDAC, which you're looking at in combination with sonrotoclax for fix duration treatment. It sounds like you're kind of positioning that for relapsed/refractory setting right now. Could that one day move up and be the frontline fixturation regimen?

I love all those questions. It's definitely great. Maybe just initially in terms of your first question, what we are optimizing. I was prohibited by our lawyer to share too much because we are still in the process of our filing, but what I can share with you, we have tested various different ramping up in our Phase I as well as actually in the Phase III, we used the 2 different regimens.

We actually -- based on everything we have seen so far, that gives us the confidence, which Rimas has mentioned during the presentation that we are very optimistic. In the end of the day, patients take on sonrotoclax will only need one clinical visit, we're not seeing that lightly.

It's because based on everything we have seen, we have the confidence we'll be able to achieve that. Then in terms of the readout for [indiscernible], it's an events-driven study. So I hope I can predict exactly when they will read out by, it's going to take a little bit of time. But certainly, in that study, we also have UMD as a point to which we have been look at it.

Hopefully, we'll be able to share the data earlier than the PFS readouts. Then in addition to that, I assume your question is another fascinated question about taking the greater and the sonrotoclax combination potentially into the front line. I'm sure someone is going to ask another question associated with that is about the grade itself going to frontline.

I show you I've been getting that question almost on a daily basis. This is an amazing drug, and it's truly amazing. This is one drug. I never need to spend a minute to convince PI. It's good. Just everyone was telling us, it's a good job. We're definitely contemplating about degrader going to frontline and either in a mono or in a combination formats, what community data.

Go to frontline is now the buy is already high, very high. If you look at our zanubrutinib continue to use 3-year PFS COVID adjustment is 86%. That's really high. Then the fixed duration today, you have seen our combination of the 320 dose level plus Zanu plus the Sonro, that's the ES regimen, we haven't had a single disease progression.

We have 86 patients treating a cohort. So we will see how the data pan out, but that's certainly what the option for BeOne.

I'm Rose with Guggenheim. A couple of questions on the solar tumor franchise. So first one on CDK, in the frontline, CDK4/6 setting, how are you thinking about the bar for efficacy in terms of making a Phase III goes down the line? I know we've seen some data from Pfizer in that frontline setting. So curious how we should be thinking about benchmarking there.

And then separately on B7-H4, regarding your Phase I trial, can you comment on whether those patients have previously been treated with another triple 1 ADC. I'm just curious on potential cross resistance and whether that's a factor that you're considering for the Phase III planning.

So for the second question first, these patients by understanding is that all of them are top 1 ADC naive. So we want to understand what this molecule would look like in a T1 naive patient population because that's fundamentally our development intent for the molecule. For CDK4 in frontline, certainly, the frontline standard of care with the CDK4 inhibitors is quite high. It would be virtually impossible to run a conventional randomized Phase II study.

And therefore, we've enrolled this cohort of 60 patients, we're going to follow those patients closely for surrogate endpoints that will help us to inform that decision in terms of response rate, ctDNA reduction, tolerability, discontinuations.

So it will be holistic based upon that body of evidence to give us sufficient confidence to proceed to Phase III.

Okay. Can you hear me Yes, [indiscernible], Citi. So 2 sort of big picture questions for John and Lai and then one -- specific one for Mark. So you mentioned AI, Lai, and you mentioned using it for data prep and visualization and efficiencies, but are you actually using it for drug discovery projects in terms of optimizing molecules at the preclinical level? That's the first one.

Yes. We definitely are embracing this. This is a game changer. But just to be on the practical side of it, I think that things will take step-by-step in terms of where you can apply for discovery. I do believe -- my personal belief on the large molecule side of it, that the application will be probably even more advanced compared to the small molecule side of

it. Because end of the day, AI has to do the deep learning from whatever is available out there. So we're already definitely, we are already starting doing those type of works.

Obviously, basically every modality, there is for drug development, small molecule, large molecule bispecifics, ADCs and you mentioned cell therapy. Again, the one that seems to be missing or intentionally you're not pursuing is radio pharma. Just wondering if you could give any thought to that and whether radiopharma could feature in the development scheme at some point?

Do you want me to answer the question?

Yes. Good question. I got that question quite a bit as well. So we have been thinking about that. I'm not saying we're definitely not going to do it. But as you know, there's certain things associated with radio pharmaceuticals, which is due to the transportation, preparation and all the things you have to associate with that. It is not an easy task.

And one of the fundamental question is, can you do something else achieving the same effect with all the hassles? I think that's a critical question for that particular field. If you don't have a choice, certainly that's an option. But if we have another more convenient choice, maybe they not option. But right now, we don't have that. I'm not saying for sure, we won't do it.

Okay. And quickly for Mark. So the argument on the central milligram versus the 400-milligram data for the CDK 4, I'm assuming the point there is that you potentially don't have enough durability to really be able to show responses at 600? Or is there potentially some bell-shaped dose response? Could you just clarify? I noticed what the ctDNA was consistent with the response data too.

Yes. So we're disclosing data today from our dose escalation phase. I would highlight that these are very small cohorts. So part of this also is statistical power and wanting to have more patients that are, should we say, more homogenous, treated in the same way with contemporaneous randomization to inform that decision. So we just think that it's primarily related to the fact that these are late-line patients in a limited data set.

And there is the possibility, as you heard from Dr. Goel, that this data set could continue to evolve in a favorable way over time.

I just wanted to comment on your AI question. You asked specifically about discovery. But if you actually look at what you saw today, we are using the tools, but our issue isn't really can you make a molecule that completely degrades something. Or can you make a really good inhibitor or a really good ADC. We're quite good at that. And the cost of doing that is quite small, and we do it pretty quickly.

Will AI make us better in that area? Are there certain areas where it's very hard to make something that maybe the industry can be better perhaps. But the huge problem strategy again, is clinical development. This is the huge area of opportunity for applying this technology.

And because the industry is so cut off in the way we do clinical trials because most companies are outsourcing this and most companies have 5 or 6 different platforms, a clinical operations platform, the safety platform, an EMR platform, it's very, very hard to have that information in high quality in a place, in a system that you can use these incredible that are now available to optimize the system.

I think this is where our company is very uniquely positioned because we don't have all the legacy merits of a big pharmaceutical company, but we have the breath and we're doing everything internally. So from our perspective, we're really looking at how can you apply this to be infinitely better in the area, which is 75% to 90% of the cost and 75% to 90% of the time in which we're incredibly uniquely basin to move in that area.

And I think Marcelo is here. If he is, he can wave. But he has come on board as our CTO and is certainly helping us look and drive forward in that area. And I think that's a place where 5 years from now, we have the potential to be game-changingly different than most organizations, and there's a lot of promise there, and we're certainly investing in that area.

I also want to add one comment on the CDK4 questions. We certainly don't believe there's a whole fact. The ctDNA should correlate with some of the tumor. That's not really truly pharmacodynamic PD biomarker, it's more of like an efficacy PD biomarker. If you think about it, the TKI is the one this pharmacodynamic PD biomarker.

So we don't see [indiscernible] . And so far, the 600-milligram is well tolerated. And I think that like Mark said, just more sample sizes, the genius kind of population we have enrolled yes.

600 is certainly still in play for selection.

Leo from RBC Capital Markets. I wanted to stay with the CDK4 program for a minute. I've got 2 questions. I guess you mentioned that follow-up is still early and that's sort of why it's hard to maybe judge response rate. But I guess as you have longer follow-up, is it possible that you're going to have some of the AEs compound see more of the neutropenia over time? I guess how confident are you that the safety profile is going to continue to hold up and discontinuations are going to remain low? And then maybe looking ahead to the commercial market positioning, I guess, do you think a win on safety is going to be enough to convince physicians given that competitor drugs have survival data? Or do you need to show a win on efficacy and safety?

So maybe I'll start. I think as I began the CDK4 section, the whole hypothesis behind this molecule is that it is more potently inhibiting CDK4 than any of the approved molecules and with greater 4 versus 6 selectivity. So this was designed to have more continuous target coverage, deeper target coverage and therefore, better efficacy. So that is the objective for the program.

In terms of your question about safety, my understanding of our safety experience is that most of the AEs that we're observing do emerge early in the patient's treatment course, but this is a great opportunity for Dr. Goel to share his personal experience on the safety and certainly any comments you have on efficacy as well.

Yes, certainly. So actually, to the first point about safety, our clinical experience from this study and certainly my experience taking care of patients on this study is that the adverse events I described do tend to come on early. And overall, we found the safety profile of the drug over time, and there have been many patients on the study for a considerable length of time, even though the median follow-up is short, has been very favorable. I think it's -- time will tell. The data will tell, but I think the chances that a number of new adverse events would emerge later on is, in my opinion, quite low.

What I think does have a greater chance of changing over time is the response rate. And I think this is a really important point to make. If you think about what we know about CDK4/6 inhibitors as a class, if we think about the big randomized Phase III studies that we look at, the median time to response in many of these studies is several months. 3.6 months in MONARCH 3, up to 4.9 months in the RIGHT Choice study with ribociclib. Our median follow-up is 3 months. So I think I'm encouraged because as Lai said, the ctDNA data certainly shows very encouraging signs of efficacy. And as for response, I think we just need a little more time to get a full impression on that.

Sean Laaman from Morgan Stanley. My question relates to venetoclax versus sonrotoclax. And if you have some suggestions around the stratification of venetoclax use and then I think you said on Slide 16, approval of sonrotoclax fall for approval for sonrotoclax next year. How do you see with respect to the ramp, the evolution of the Venn diagram of overlap of use over time?

So yes, I can start. Maybe Remus can also add. In terms of the -- our molecule, again, I just want to emphasize probably a couple of points here. From day 1, we were trying to figure out how to solve the issue with venetoclax. We're not saying venetoclax is not a good drug. Venetoclax actually is a very powerful drug, has clearly shown great activity in the clinic.

But the problem with venetoclax lies in 2. Number one, it is very difficult to use it during the ramp-up, as you pointed out. So we are working extremely hard on that. Maybe Remus can chime on that. I just want to add one more point about venetoclax issue. It's a pretty large small molecule. Molecule weight is big. When you're dealing with a large small molecule, you're going to deal with a big PK variation between patients. The larger you get, usually absorption is worse for small molecule drug. So venetoclax does have a lot of PK variation in the clinic. So the patients who absorb well, probably hitting target okay. But there are a significant portion of patients who can't absorb that well, the PK will be low. When the PK is low, you don't hit the target hard enough. So when we designed sonrotoclax, this drug is 14-fold more potent than venetoclax. So we uplift everybody, right? So in a way, even for patients who probably have low absorptions, you still can achieve enough BCL-2 inhibition.

End of the day, about doing small molecule is about hitting the target. So we're definitely hitting target really hard. So we're seeing that now in the clinical in terms of the uMRD rate. If you say maybe it's not apple-to-apple comparison, SZ versus VI or SZ versus AV, that's a different BTK inhibitor, but we also have our internal SZ versus SV data. We have our Arm D SEQUOIA data. So you clearly see even when you combine with same BTKi, sonrotoclax is hitting the target harder, which is leading to deeper uMRD and also quicker uMRD. Maybe, Remus, you also can chime a bit more on.

I would just add that we have currently over 1,600 patients treated with this molecule in a single agent or in combination. So we have a very good understanding of the safety profile. And as we look across a single agent or combinations, we consistently see a better safety profile. In addition to the efficacy that Lai was mentioning. So we see some rates of neutropenias, maybe you said to me, but consistently, the GI toxicities are much lower than what we see the adverse events with venetoclax. So this give us the confidence that this is a much tolerable molecule, and we can combine it with our internal assets so we can address multiple indications.

I may just add one more point about ramp-up mechanistically, why can be easier for us versus venetoclax. Venetoclax has half-life of 26 hours. For a drug with a 26-hour half-life, you usually takes 4 to 5 half-life to get to a steady state. So venetoclax naturally will take a longer time to get to steady state. This is why you need to monitor patients more intensively while the drug level goes up because when drug level goes up, the TLS risk comes.

Our drug is much shorter half-life. It's 5 hours. So this story is very different from zanu story, which for us, for the zanu was about more sustained target inhibition there. But here, actually you be able to clear out the drug a little bit faster is better for your ramp-up.

And the reason why this is -- in this fashion works is because this is not like a kinase inhibitor. Kinase inhibitor is like hitting the brake. We have constantly hit the brake. Otherwise, the kinase signal goes on, cells survive. But this is induced apoptosis. It's not like hitting the brake. So once you hit the target, Cytochrome c were released from mitochondria. And on Cytochrome c released from mitochondria, cell will die. So it's not -- it's a very different mechanism of action. This is actually really beautiful kind of scientifically putting together. Yes, you are able to hit it hard, but you don't have to hit it constantly. And then in a way, you're able to induce cell death. This is why our ramp-up requires much less monitoring. We believe end of the day, patients only need one visit to the hospital to do a pre-dose check then probably 4 to 6 hours after dose check on day 1 of taking on. That's it.

Maybe you want to chime in?

Yes, I'll just chime in a little bit. The 101 data is clearly very exciting that we see a favorable safety profile, and we see high rates of early uMRD that appear quite durable. And obviously, there's -- the hope is that this holds up in the CELESTIAL Phase III study. The biggest barrier to patients are receiving and achieving deep remissions to BCL-2-based therapies right now is actually feasibility. The truth is that I use quite a bit of venetoclax, but most patients are not treated by me. They're treated in the community where the feasibility of venetoclax-based strategies has been really quite limited. And so it's really the minority of patients who actually are able to achieve this type of therapy. And so safety and efficacy is crucial. I'm looking at that, that's absolutely critical for comparing the sonrotoclax ibrutinib data against the existing landscape. But it's the feasibility that I think is really the key linchpin here in the future about getting PCL-2-based therapies into patients.

Great. And if I can have one pretty high level. So as investors, ultimately, the true measure of R&D success is commercialization and success there. But if you think about your research and development efficiency and benchmarking, where would you say you sit compared to global pharma? And where do you think you sat a few years ago?

I don't want to tell Lai that he is truly outstanding and research team is exceptional. But I think what my co-founder who's a real scientist, not a CEO would say, is you're always striving to be as good as you possibly can be and as successful as you can be. And there is no best because whatever you do, there's other people that are also trying to compete. And no matter what, we always have to strive to be the absolute best we can.

I think what I can say is I'm known for being super critical and having an unbelievably high standard and setting unrealistic expectations that people strive for. And what our R&D team is known for is actually achieving those. They actually achieve those. And I think to all of our amazement, this is a team that's able to do things that are truly extraordinary. And I think that speaks a lot to the passion and the energy and the commitment, but it also speaks to the group of people and the way they're able to work together as a team to really deliver on things.

So I feel incredibly proud of where we are at this point in time. It certainly is -- was aspirational but probably viewed by most people as impossible 5 years ago. And I think that I can tell you, we're setting just as high standards for ourselves to improve and be better 5 years from now. And our goal is to come back and do this meeting in 5 years and have all of you say, I never could have possibly imagined that, but you actually did it. So that's who we are and what we're trying to do. And I think that it is not luck it is not entirely brilliance. It's a lot of hard effort by a lot of people that are really committed and trying to fight cancer.

Great. So Yaron, and then we probably have time for 1 or 2 more after if there's others in the room. Go ahead.

Yaron Werber from TD Cowen. I have just maybe a few questions. The first one, 18 drugs into the clinic in 18 months. That's pretty good. I guess the question is, how much bandwidth do you have, especially R&D-wise as you -- I mean, you're ramping on revenues very nicely, but as you go into late-stage development. And then on CLL, what's the sonro dose that you're taking forward for 301 and 303, the CELESTIAL studies? And is 303 fixed duration? And then I have a quick follow-up.

Maybe the second question first, the dose we're taking to the 301, which is the treatment-naive CLL. That's a fixed duration for 320 milligram, same -- that's for basically the combination is only for 1 year with up to 3 months of the leading for zanu. So the 303 is the Phase III study in the relapsed/refractory CLL. In that study, we're testing a 2-year combination with either obinutuzumab or rituximab. I mean there is an interesting cohort, which we are going to do is look at after 1 year if MRD negative patient will be able to stop treatment, but that's not really a registrational cohort. So that's also fixed duration.

To your first question about how can we handle this such a big pipeline. First of all, thanks to all of you, the investor support. We appreciate it. I think to go back to our philosophy. We're going to be very disciplined in terms of how we -- which one we move to late stage. I truly believe the industry made a lot of mistake in the past, which is they're investing based on how big the market is and how close the drug is to the finish line, not based on data. So this is why during the presentation, we emphasized twice or 3 times about data.

So to be able to really make a data-based decision, you have to move to clinical POC. And I think maybe in this world and also thanks for that question asking John about it. So it's on the record now, John. So we are pretty efficient in terms of getting from target all the way to get the data, critical data points in the clinic. That's actually what's important. If you can do this well, you will be able to sit in a position to really pick the winner, the ones the others, maybe you're not so sure, you're still partner. There's many different opportunities there. So we're very excited about this potential problem because that it's a great problem to have.

And then on the EGFR MET, just given the data with EMI, how are you thinking about tox, especially rash, scalp tox, injection site reactions? And then you have a lot of Phase I data probably at ESMO or toward the back end of the year. Which ones -- some of them are going to be very early kind of Phase I looks and some are more mature, which ones are going to be a little bit more mature where the data is going to be a little bit more telling?

We will have relatively limited Phase I data this year's ESMO, just sequence and the cadence of the molecules entering the clinic, a lot entered in the fourth quarter last year, and we've already passed the abstract deadline. So most of the Phase I disclosures in terms of new data will actually be in the first half of '26.

For EGFR MET, it's very, very early days. I believe we have less than 10 patients enrolled. So as I mentioned, it was designed to mitigate skin tox, which is an important toxicity associated with the class and including amivantamab. We are hopeful that we will see mitigation of that. We are going to focus the development based on subcutaneous administration to mitigate infusion-related reactions. So we're hopeful and look forward to sharing the data. We think that molecule has a lot of potential given the impact that we're seeing with amivantamab.

Maybe I'll just add a little bit more mechanistic side of it. Part of the HAP Cys behind that was maybe similar to VEGF PD-1 bispecific idea. So the idea over there at least is not proven. The HAP Cys was the antibody, the bispecific half-life is a little bit shorter. So therefore, you don't have as much circulating times, but more you get a contributing the tumor tissues. This is somewhat a similar idea here. So we probably don't have as much kind of the systematic kind of the rash, this kind of toxicity due to the EGFR inhibition. And we also did some of the screening during the preclinical looking using a particular cell line to screen for that.

Kelly Shi from Jefferies, thanks for great presentation and discussion. I have 2 questions. First on CDK4 inhibitor. Besides the development strategy that you have elaborated, I have a question on how to better understand today's clinical data, especially on efficacy front when we're looking at ORR and stable disease rate and also with the patient baseline characteristics that with all post-chemo endocrine and also CDK4/6 inhibitors.

Yes. So this is a really important question because when we are talking about a Phase III study start in a second-line population, that would be a true second-line patient population that would be -- patients would be post CDK4/6, but they would not have had such extensive prior treatment, which is an important point. I think our efficacy data needs to be interpreted in the context that the target population for development is earlier line than the patients that we're showing today in addition to the maturity that Dr. Goel mentioned before. I don't know if there's anything more that you would like to add in that context and that's good in terms of interpretation.

ADC, following the promising ORR from this first clinical data, what are the key questions for next step of development in your consideration for achieving best-in-class position among all the B7H4 agents?

Yes. So I think what I shared today is that we're seeing efficacy that we're very excited about across a range of doses. And now we need to simply expand that experience to help us refine our final dose level selection for future studies. So we need to get into our dose optimization phase.

The other point is thinking about the patient selection. So I showed you a simple -- if we just cut patients into high low, what does that look like, but refining the biomarker for optimal patient benefit. So I think those are the 2 critical questions that we're working to address for that program to ungate registrational intent studies as early as the second half of next year.

Great. So I think that rounds out our Q&A. Thank you to the panel. Our panel is going to make their way off the stages now. In the meantime, it's a great opportunity if you haven't done the survey to take that 30 seconds to complete. And I will hand it over to John for some closing remarks.

Probably people know which choice I'd make on the survey for the last question. I hope you all did. Look, I want to thank you again for all your time and energy today. I know it's a lot, and it's a lot to digest, but there are a couple of takeaways at the highest level.

First of all, our pipeline and our company is really at an inflection point. There's 20-plus near-term milestones in the next 18 months for our company. So it's a lot to digest. In short, though, it's incredibly exciting. It's a great time to be here at BeOne. It's a great time to be in the oncology field. The data that we're seeing looks incredibly promising, and that's a great thing for patients. We also believe it's a great thing for the company and for investors.

And absolutely I think it's a tribute to the group of individuals we have that are working on this internally in the company and the collaborators that we have working with us. And I really want to thank them all. And it's great for you to have some exposure to them here today.

So again, huge thank you to everyone. Massive thank you to our esteemed guests and collaborators, Dr. Soumerai and Goel. And please join us again next year when Lai will, with his R&D team truly amaze us at what they're able to accomplish. Thank you all so much.