Incyte Aktie

Good morning, everyone. Thank you for joining us. It's my pleasure to introduce the Incyte management team. With me, I have Bill Meury, CEO; and Pablo Cagnoni, President and Global Head of R&D.

To start here, Bill, could you give us an overview of where the company stands today, including your core franchises, Jakafi and Opzelura? The pipeline priorities and just how you're thinking about, big question. But outlook and strategy for the company as we look to the next 3 years?

Sure. I mean, big picture, we're transitioning Incyte from a single cornerstone product to what we believe will be a portfolio of growth drivers. We think about the business across 3 dimensions, as you know, hematology, oncology and immunology. We also break the business down into 3 parts: a core business, a pipeline and then, of course, business development.

When we look at our core business today, all the products ex Jakafi, that business will finish this year in the range of about $1.7 billion, up 30-plus percent versus prior year. It's relevant because by the time we hit 2030, the transition, we estimate that core business will be doing about $3 billion to $4 billion. So right now, it's funding the pipeline, and it will set a floor.

Then we look at the pipeline. Today, we have 8 assets, including VGA039, the Star deal. That have the potential on an unadjusted basis to 2x the company. The -- and they're supported by 14 clinical studies, 15 clinical studies that will be underway in Phase III. We don't have to be perfect here.

The 4 assets that I think have a high PTRS, will get approved and contribute meaningfully to the company are 989, our monoclonal antibody targeting mCALR, G12D, povorcitinib and now VGA039 for Von Willebrand's disease. You don't need heroic assumptions, assuming we successfully complete the Phase III programs to get to a multibillion-dollar sales level with that group. You layer that right on top of the core business.

Business development will be used just to simply strengthen, extend the core. And what happens is the pipeline becomes the core business, and we expect has the potential to drive top quartile growth from '29, '30 out to '30, '35.

Could you touch on the business development side? So you announced the transaction for Star Therapeutics yesterday. How are you thinking about BD from here? And why Star? What are you solving for when you look at the overall pipeline? And then what are you adding as you go forward?

I'll start with your last question. What we're solving for is growth post 2029. And when we looked at the Star deal, and I've said this a few times now, it was as close to a textbook example of the type of deal that makes sense for Incyte. Its sort of checked all the boxes. First, it's novel. In other words, we're not dealing with incremental innovation. We're not in a situation where we're going to be maximizing marginal differences or we're a late entrant. It has standard of care potential in von Willebrand's disease. That's number one.

Number two, it's in hematology. That's the central identity of the company. We have differentiated knowledge and capabilities there, and we have all the R&D and commercial infrastructure we need. Number three, it has the potential to really move the needle in terms of our top line, and it could be highly growth and revenue accretive. It's in Phase III. So the timing is right. And we did a deal that was structured. The economics made sense for the seller and they made sense for us.

And so I think it's a good phenotype for the type of thing that we should be doing right now, very complementary to the business, the right risk/reward profile. We use only basically just over 20% of our go-forward balance sheet. So we still have flexibility going forward. And our view here is that we have a tight framework and criteria. If something is in the framework, we can act fast. If something is not, we are very comfortable being patient here, and that's how we're going to view it.

Great. Let's start with the myelofibrosis or the MPN business here. So for Jakafi XR, you launched the drug last month, priced at parity with Jakafi, acknowledging your expectations that 2026 will primarily be focused here on formulary coverage. What are you seeing in these early days of launch? And what do you want to see over the coming quarters to give you confidence in reaching that upper end of your 10% to 30% guidance range?

Yes, it's a good question. As it relates to formulary coverage, I can provide an update. We're about 30 days in. Optum has added XR to formulary. CVS has added XR to formulary. 14 regional plans have added XR to formulary and 4 Medicaid states. And so as it relates to formulary coverage, we are off to a good start.

Conversion or uptake for XR will be measured early and tied to formulary coverage, and we expect really a step change when you get to January 2027, and you're going to want to be converting at 1 point, 1.5 points a month. That would be this working. As it relates to what would get us to the upper end of the range, in which case we preserve north of $1 billion in Jakafi sales. It starts with coverage and really just moving prescribers and patients to think about XR before IR.

We have obviously a very large professional promotion effort in place. We cover all the major hematologist prescribers in the country. We also have a patient database, and we're able to communicate with Jakafi patients. And so as you know, with these launches, it's about execution. So far, it's set up. If we're in the middle of our range, that's good. And if we're at the upper end of the range, there's only upside in that.

Why couldn't it be higher than the range you've given?

When you're dealing with an XR conversion, remember, there's new patients and there's current patients. IR makes a great deal of sense for new patients. When you're moving someone off of a drug IR to XR when they're are current, that takes a little bit more time. And I think there's a certain amount of inertia in the market that you have to recognize. Now you can solve for that with a lot of activity, and I think that's what we're going to try to do.

Great. And should we expect you to disclose sales or other metrics over the near-term?

Yes. We'll provide an update on formulary coverage, prescriptions, and you will see the sales. Right now, we have about $10 million to $12 million in sales today. I think by the end of the year, that number could be in the range of about $50 million to $75 million.

Alright. Pablo, turning over to you on the mCALR program here. So that program remains the primary focus from a pipeline perspective and revenue replacement strategy ahead of the upcoming presentations at EHA, walk us through where the program stands today and your level of confidence in successfully bringing this to the market in both the second-line and first-line settings in MF?

Certainly. So we will have an update at EHA as you pointed out. We'll have an update on the ET population, an update on the MF population and a translational update as well. And when you look at overall what this program is, let's start with ET. We'll present an update to probably around 100 patients at EHA.

And I think what consistently we're seeing is very high rates of complete hematologic response regarding 70% or so in type 1 patients, that number is even higher. It's probably around 90%, and it's lower in patients with non-type 1 mutation. We've known that now for quite some time. Very importantly, the safety profile of 989 continues to be very clean. A lot of patients, almost all the patients are still on drug, a very, very low percentage of patients that had to discontinue.

In addition, in second-line ET, we have alignment now with FDA, and we're in the process of launching the first pivotal trial for 989. I'm highly confident that in second-line ET, when you look at the historical numbers for post-hydroxyurea interventions in the 30% to 40% complete hematologic response and not a lot of them with durability, the data that we've shown for 989 gives me a lot of confidence that this medicine will have a positive second-line ET trial and eventually, we'll get it to market.

So now the role -- the goal here is execution in second-line ET, getting that off the ground and enroll as fast as possible.

On the MF side, you have data in the abstract and we'll update it during the meeting, and there's 2 separate important messages there. In this update, it's not a true frontline population that will be updated at ASH at the end of the year. But what you'll see is post-Jakafi or post-rux, patients and a group of patients that were what we call ineligible for Jakafi.

So let's start with the first one. We have SVR35 rates that we reported before, has trended approximately the same, percentage points here and there lower. But overall, the data looks consistent with what we've shown in the past. Importantly, the anemia data continues to get better.

And when you think about what 989 does, which is basically normalizing hematopoiesis in these patients, basically suppressing, eliminating the malignant clone, allowing the benign wild-type cells to grow back, that's why the anemia continues to get better. It's getting in the 60% range or so, which we think is pretty impressive in this pretreated patient population.

The other thing you're going to see is that in the JAK [ SVR35 ] is very high. And that gives us a lot of data that we'll have later this year and about the possibility to accelerate the development of 989, both in second-line MF and first-line MF as well. In second-line MF, we're already in the process of starting conversations with FDA in order to build a new framework, a new regulatory framework for these patients, which would be a composite endpoint, which will incorporate some of the things we're talking about, including some aspect of this normalization of hematopoiesis represented by anemia.

We'll see how those conversations go. If we need to go with SVR35, I'm confident we can get the trial design with a high probability of success anyway based on the data that we already have.

And then the next step is as quickly as possible once we have all the data in-house for the first-line MF population is to launch the first-line MF trial, which we probably will initiate early in 2027. So that's the goal. By this time in 2027, probably earlier, we'll have 3 pivotal trials ongoing with 989, second-line ET, second-line MF and first-line MF. That's the goal.

Got it. If XR could get you to $1 billion at the high end of the range, what does mCALR give you in terms of revenue replacement of Jakafi?

Yes, it's a good question. We'll take ET and MF, which both can contribute equally to, let's call it, the peak sales potential of this product. In ET, the best way to think about it is 20,000 people with the mutation and ET. Half of them, roughly 50% are not fully responding to hydroxyurea, not because it's not a really good cytoreductive agent, but because people can't get to the therapeutic dose due to toxicity. That's 10,000 people.

At biologic pricing, call it, $250,000 a year, that's a $2.5 billion TAM. So what percentage of that segment does 989 get? If it gets all of it, it would be a $2.5 billion opportunity. If it gets half of it, we still have $1 billion plus coming from ET. Another way to think about it is 5,000 people in the United States have the mutation and are resistant to hydroxyurea, which is a negative prognostic indicator. You probably get most of those. Again, you kind of get to $1 billion, multiple roads there. That's half the product.

The other half is MF. I think the most important point of what Pablo said is that, we're very encouraged. We can't call it yet. We'll know more at the end of the year at ASH with the frontline performance of 989. When it's used earlier, it does better, especially in the type 1 population. Type 1 patients are 75% of MF.

There's 10,000 people with the mutation and MF. That's a $2.5 billion segment. If you're in the front line, you get more of it. If you're in the second line, you get a little bit less. Either way, I think both indications can get 989 into that $2 billion to $3 billion range. And that would be a real success for us.

Yes. That's great. Pablo, going back to you here. You have an end of Phase II meeting with the FDA later this summer to discuss the potential for a new composite endpoint for the -- for a pivotal Phase III here in second-line MF. Maybe walk us through the strategy here and how critical this is to Phase III success in both the second line and frontline and what the implications for the field and competitors are if the FDA does move forward with this? And does it really set a new bar here?

So the argument here, which I think it's important to understand is the reason why SVR35 and TSS50 are there is simply because 15 years ago or 16 years ago, it was clear that Jakafi was very good at shrinking spleen and improving symptoms. And so they were put there and everybody has had to use those endpoints in MF since then.

While 989 does shrink spleens and improved symptoms, and we've shown that data very clearly at EHA and ASH last year, it has a completely different mechanism and a different impact on this disease, which we -- the term to summarize that I use is, it normalizes hematopoiesis. But that's basically reflected in a dramatic improvement in anemia that we've seen that, again, we reported at ASH last year.

When you take that into account and about the fact that anemia, its a better correlate to long-term survival in these patients that SVR35, really reach a point that you say, well, it's time to figure it out, how to incorporate this knowledge into a novel endpoint. And this is, by the way, data has been generated independently of us. It's been published by a group of experts showing that other factors than SVR35 and TSS50 have better correlates with long-term survival in MF patients. So that's the argument that we put together.

Obviously, the data has been published. There's support from the scientific community, both in the U.S. and in Europe about really redefining how these medicines are approved. If we can't get there with FDA, I'm confident an SVR35, TSS50 focused trial is still a trial we can win.

When you look at the comparable data in second-line MF in patients with no washout from Jakafi, the SVR35 to momelotinib in that group of patients is 7%. We've been reporting rates around 30% now since ASH last year, and you'll see another update on Saturday. So that's still a trial we can win. We just think it's important to change the regulatory paradigm. But if we have to stick with SVR35 and TSS50, we'll do that and still think we're going to have a way to run a positive trial.

And just on a related point, we've been monitoring the impact of mCALR on VAF, which has been fairly modest thus far in MF. At which time point should we expect this -- or expect to see this meaningfully improve? And how critical is it to the drug's long-term success?

So let's remember what VAF tells us and what it doesn't tell us because I think it's really important. VAF is basically, VAF in peripheral blood is basically taking a pool of cells, a highly heterogeneous cell population and measuring the frequency of the variable -- the different -- the wild-type and the mutated allele in that population. It's a ratio. And the important point there is in MF, the wild-type population is smaller. So changing that ratio with a small population takes longer to grow, it's harder.

And second, it's going to be a lagging indicator to what's going on in the bone marrow. In addition, VAF measures cells that are CALR mutated positive, but thrombopoietin receptor negative, and those cells are not affected by the antibody. They have to die on their own. They're nonmalignant. They don't lead to the disease, and they have to die on their own.

When you put all that together, we think over time, VAF will continue to improve, but it's a much lower indicator of what's going on. What we pay a lot of attention, and we'll update this at EHA is the megakaryocytes in the bone marrow, which are the source of the disease. So we measure CALR mutated megakaryocytes and wild-type megakaryocytes, and thats how we're seeing a shift. The mutated ones are going down, the wild-type are going up.

Then we look at immature cells in peripheral blood, CD34-positive, CALR-mutated cells in peripheral blood, and we again see those going down. And the third, we see normal red cell progenitors in the bone marrow going up. All that is telling us the right things are happening.

When you look at VAF, the magnitude may be modest, as you pointed out, but almost all the patients are pointing down in that waterfall. So we're seeing that the malignant clone is going away as represented by that. I think over time, VAF should continue to get better. We're not too focused on VAF. I know there's a lot of interest in seeing that. I would focus more on what's going on in the bone marrow and what's going on in the peripheral blood progenitors.

Great. There's an expanding competitive landscape that's playing out within MPNs, including J&J into more of mCALR and Lilly and AJAKs on the JAK inhibition side, where we've seen more data, I guess, for the EHA abstract and expect to see initial data from the mCALR programs over the next 12 months or so. What are you monitoring most closely from a competitive perspective? And how are you thinking about differentiation and positioning relative to these assets?

I'll just make a few comments and let Pablo expand. What we're focused on right now is our programs, obviously. As Pablo said, we have an opportunity by the middle of '27 to have 3 Phase III trials. I think as it relates to the other monoclonal antibody, thoughtful antibody design, no human data. So not a lot to say there. As it relates to the opportunity that type-2 JAK2, I think that it's an apples-and-oranges comparison.

One is a symptomatic therapy, optimizing or maximizing spleen volume reduction and symptoms versus a potentially disease-modifying therapy. I don't think it's an either/or. I think in a CALR population, if we can replicate in Phase III what we're seeing in Phase I, we have a solid path to build a very important product for us. And as it relates to the T-cell engagers, more advanced disease, and it could have a role, and we have to focus on ours, not J&J's. That's my view.

Just to complete a couple of points there. Look, our goal, as we stated last year is by the end of this decade is to have a targeted therapy for every single patient on MPN. In order to do that, we need to execute on the current plan. We have the understanding of the space. We know this biology. We have the right team in place. We have these medicines that we've been talking about in the clinic and launching pivotal trials as we speak.

And we also have a number of next-generation programs that we're working on. So we're going to continue to innovate in the space. We have the critical mass in place to continue to expand our presence in MPNs, and we will. So obviously, you always follow your competitors. You don't underestimate anyone, but our goal and our focus is to execute on the current programs.

And just the last one to round out the questions on MPNs here. Where does your mutant-selective 617F program stand? And are you seeing encouraging signals with new solid dispersion formulation? And when should we expect a go/no-go decision for this lead asset?

So 058 has been a challenging program. The first thing I would say is we remain absolutely convinced that this mechanism will work. If we hit V617F hard enough, we will get positive clinical readouts in patients with V617F mutated MPNs. The program has been challenging. We've been generating data. The data right now are not trending in the direction that we would love to see. So we will reassess the program later this year, and then we'll make decisions.

We have next-generation programs that look much better, molecules that look much better than the lead. We also have the option agreement with Prelude. We're following -- we're tracking the progress, and we can execute the option whenever we think it's the right time. So we're unlikely to present meaningful data later this year, but we will continue to update you as the program progresses.

Bill, moving over to povo here. You have framed this opportunity as a $500 million to $1 billion peak sales outlook in HS across both pre- and post-biologic patients. Walk us through the launch strategy and how you plan to target both of these sub-populations and what needs to play out to reach that upper end of the guidance range?

Yes. We do believe, given the data set, which 70% is in a pre-biologic population and 30% is in the post-biologic patient population that we can capture or garner utilization at sort of both those inflection points. When you look at the data on povo and compare it to that of a biologic, you see high score 50, 75, 90, 100; pain relief, draining tunnel clearance, flare control that rivals the 17s. I think it's indisputable.

The one thing that a JAK inhibitor does is it relieves pain, I think, perhaps as good or better, and it's definitely faster. There's no FDA-approved oral option. Someone gets put on or gets diagnosed with HS, they get an antibiotic or steroid on one end, and then they have to leap over to an IL-17. And so I think this will be an important treatment option for dermatologists and NPs and PAs. The benefit-risk profile in HS, I think, is very attractive.

The most important part of what we're going to do at launch is to educate them on the data, of course, and then garner utilization in both those places. And you're talking about 150,000 patients who are diagnosed and treated. I think some estimates are higher with HS that are not taking any advanced systemic therapy. There's only about 50,000 to 60,000, which is growing on the IL-17s.

HS is unlike IL-13-mediated AD or IL-23-mediated psoriasis. It's a multi-cytokine disease. JAK inhibitors are multi-cytokine inhibitors. And so I think there's real potential here. The most important thing for us to do is to get trial at launch. And if the drug performs in the real-world setting like it did in the clinical trial setting, I think it's going to be a needle mover.

And from a payer perspective, is there any hindrance to really kind of dominating that prebiologic set?

Yes. I think, usually what you worry about in this situation is prior authorizations and steps through, for example, a biosimilar Humira. But it's really difficult to mandate that type of medical exception if the label doesn't. And it is important that we have a label that covers both the pre- and post-biologic setting. If it was to happen and there were drug utilization management measures put in place, they wouldn't be widespread. They wouldn't be universal.

And I think more and more cross-subsidization and bundling agreements are less and less effective given the push for transparency. And even on the PBM side, they want to manage their budgets on a line item-by-line item basis. I believe there's a price point in the end that we can charge that makes sense for the PBMs and the plans and makes sense for Incyte, and we'll manage that during the launch.

And speak to your confidence here for expansions into vitiligo and asthma and PN as you look to growing this product further.

Very high confidence in vitiligo. We have the data. I think the key there, whether it's AbbVie, Pfizer or Incyte is you have to medicalize vitiligo. It has to be perceived, understood as a chronic immune disorder, not an aesthetic or a cosmetic problem. And that does take some time. But it's a -- prevalence is very, very high. We know, given our experience with Opzelura, what it's going to take to commercialize povorcitinib for vitiligo. And that could be $0.25 billion that you're adding on.

There is a bull case there what's bigger just based on the prevalence numbers. But I think you have to be clear-eyed about where that category is in terms of diagnosis and treatment. PN is an itch disease. We'll have those data at the end of the year. There's one thing JAK inhibitors do well, and that's relieve itch and they do it fast. And so I think that is of equal significance to povo as vitiligo is. I mean I think those 2 indications could be $0.5 billion, maybe a little bit more. As it relates to asthma, wait for the data at the end of the year, it's not in our model.

Maybe just a final question here. You continue to sound very confident regarding the profile of your G12D KRAS program and PDAC post the data that we've seen, not just from you, but also from competitors in this space. What drives this level of confidence? And how do you see the drug existing within the landscape with other therapies?

So it's an amazing time in pancreatic cancer research, right? I mean the data -- the data from RevMed was pretty extraordinary. Now when it comes to specifically even G12D mutations, we think we have what looks in our hands, whether you want to call it best-in-class as good as anybody else in class -- we can debate that when we show the data.

What we've been doing over the past few months is, number one, we've been executing on putting in place a frontline Phase III trial of our G12D in combination with chemotherapy, both types of chemotherapy, FOLFIRINOX and GemNab and previously treated pancreatic cancer. The trial is getting off the ground. It's already enrolling patients and it's going quite well.

In parallel with that, we generated data, 2 cohorts or cohort of 50 patients, give or take, half with GemNab, half with FOLFIRINOX. We'll present that data at ESMO, assuming it gets accepted. And we'll have a fair amount of follow-up in order to give you an idea, not just the responses, but the durability. We're very happy the way that data are evolving. Hopefully, you will agree when we show it later this year.

What we've also done is combine a G12D with Erbitux, which is something that daraxonrasib can't do because of the rash. So we thought that angle in colorectal cancer was very important. And we've also combined it with chemotherapy plus Erbitux. All that data as part of the potential expansion into colorectal cancer will be presented later this year as well.

So we're really excited how the program is trending. We really like the way the data are evolving, and you should expect not just continued evolution in first-line pancreatic, but also an expansion of the program to other indications.

Great. Maybe just one last question. Anything else I did not ask about that you want to highlight as you look forward here?

I think on Niktimvo, which has become a nice incremental growth driver for the company, we'll have data at the end of the year looking at Niktimvo in combination with Jakafi, which would result in a steroid-free regimen for patients with GVHD. And I think that is an important outcome to watch.

Great. And Opzelura seems to be on track?

The Opzelura looks good. The AD launch in Europe, I think, will be important to keeping that product on a solid growth trajectory. And also, we have Opzelura -- we have a study with Opzelura in HS that will report out in the fourth quarter. And there's no FDA-approved topical treatment. It would be for mild-to-moderate disease. Our Phase II study, the HiSCR50 rate in HS was 79%. Now vehicle was high, too. The Phase III study, we're using an HiSCR75 endpoint to have Opzelura as a topical for mild-to-moderate and to have povo for moderate-to-severe creates a franchise and a sequencing strategy that could be very valuable.

Great. Well, with that, thank you so much. Appreciate the time.

Thank you.

Greetings, and welcome to today's Incyte conference call and webcast. [Operator Instructions] As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Alexis Smith, Vice President, Head of Investor Relations. Alexis, please go ahead.

Good morning, everyone, and thank you for joining us today. The press release and presentation for today's call can be found on the Investors page of our website. Today, I'm joined by Bill Meury, Chief Executive Officer; Pablo Cagnoni, President and Global Head of R&D; and Dave Gardner, Chief Strategy Officer, who will offer prepared remarks; Suketu Upadhyay, Chief Financial Officer; and Steven Stein, Chief Medical Officer, will join us for the Q&A portion of today's call.

Before we begin, I would like to point out that we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors in our SEC filings for additional details.

With that, I'll hand it over to Bill.

Good morning, and thank you for joining us. Today, we're announcing Incyte's acquisition of Star Therapeutics Vega program centered on VGA039, a first-in-class Phase III asset in von Willebrand disease that we believe can become an important new growth driver for Incyte. I'll briefly cover why this deal makes sense strategically and financially, and then Pablo will walk through the data and development path, and Dave will discuss the market opportunity and commercial framework. We conducted extensive due diligence on this asset across scientific, translational, clinical, safety, regulatory and commercial dimensions and came away with a high level of conviction in both the strength of the data and the attractiveness of the opportunity.

VGA039 checks all the boxes we look for in a business development opportunity. It's squarely within our core, hematology, the science, the disease and the R&D and commercial operating models are all areas where Incyte has real expertise. Second, VGA039 is supported by a high-quality, consistent data package with 3 layers of validation, mechanistic validation through target engagement, translational validation through restoration of thrombin generation and clinical validation with strong early human efficacy and safety data.

Third, the development path is clear and manageable with alignment already in place with regulators who granted VGA039 breakthrough designation for the treatment of von Willebrand disease earlier this year. And importantly, it has the potential to be highly accretive to sales and growth post '29 with approximately $1 billion or more in net sales potential. Taken together, we believe this structured transaction is strategically aligned, financially meaningful and consistent with our framework for capital allocation and value creation. The acquisition fits directly into our broader strategy, transitioning Incyte beyond a single cornerstone product. We're constructing a portfolio of multiple growth drivers rather than making one oversized bet, and VGA fits this strategy well. It strengthens our pipeline and represents a smart use of capital with an attractive upside and manageable risk profile.

On a product level, as you'll hear from Pablo and Dave, VGA039 is designed to restore normal thrombin generation and reduce bleeding by modulating Protein S activity. Current treatments for von Willebrand disease are burdensome, inconvenient and are often failed to adequately control bleeding. If successful, VGA039 has the potential to become the standard of care for a sizable underserved patient population and to be for von Willebrand disease, what HEMLIBRA has been for hemophilia A.

With that, let me turn it over to Pablo.

Thank you, Bill, and good morning, everyone. Our interest in this opportunity begins with a significant medical need and a novel first-in-class therapeutic approach that we believe could address key limitations of existing therapies. Von Willebrand disease is the most common inherited bleeding disorder, affecting 135,000 diagnosed patients in the U.S. and many more worldwide. The disease is highly heterogeneous, encompassing multiple subtypes and a broad spectrum of clinical severity. As a result, patients can experience a wide range of bleeding complications with the most common clinical manifestations, including gastrointestinal bleeding, other mucosal bleeds and heavy menstrual bleeding.

Many of these bleeds can be managed outside the hospital setting. However, recurrent or severe episodes, especially GI bleeding and in rare cases, critical organ bleeding can be clinically significant and are the leading causes of emergency visits and hospitalizations. Patients with more severe disease can also experience hemophilia-like bleeds, including joint or muscle bleeds. The underlying cause of von Willebrand disease is a deficiency or dysfunction of von Willebrand factor or VWF, a key protein involved in normal blood clotting or hemostasis. VWF plays a dual role in hemostasis by helping platelets adhere to sites of vascular injury and by stabilizing clotting Factor VIII.

When VWF is absent, reduced or dysfunctional, both platelet function and coagulation can be impaired, resulting in prolonged recurrent or spontaneous bleeding. Diagnosis includes bleeding history and specialized testing that measures the amount and function of von Willebrand factor with the latter determining disease subtype. In the United States, an estimated 35,000 patients have clinically significant disease burden and receive care at specialized hemophilia treatment centers or HTCs. Current management includes on-demand treatment for acute bleeds and prophylaxis, which is based primarily on von Willebrand factor replacement. While prophylaxis can be effective, it requires frequent infusions and breakthrough bleeding is still common.

Despite guideline support, prophylaxis remains underutilized, primarily due to the onerous nature of the schedule of infusions. These limitations underscore the need for novel prophylactic therapies that can provide effective bleed prevention while reducing treatment burden. That brings us to VGA039, an anti-protein S monoclonal antibody designed to modulate endogenous anticoagulant activity and support more effective hemostasis. Protein S serves as a cofactor for 2 key anticoagulant pathways, TFPI alpha, which regulates the initiation phase of coagulation and activated protein C or APC, which regulates the propagation phase by inactivating Factors Va and VIIIa. By modulating protein S cofactor activity for both pathways, VGA039 is designed to normalize thrombin generation in a controlled manner. The goal is to improve clot formation and stability without replacing von Willebrand factor and without driving excessive systemic coagulation.

This mechanism is particularly compelling in von Willebrand disease where the bleeding phenotype is heterogeneous. By enhancing thrombin generation downstream, independently of the underlying von Willebrand factor defect, VGA039 has the potential to provide broad prophylactic coverage across von Willebrand disease subtypes and bleed types. VGA039 has been evaluated in 4 clinical studies, including VIVID-3, a Phase I/II multi-dose safety and efficacy study in adults and adolescents. In the trial, patients received a monthly subcutaneous dose of VGA039 over a 17-week treatment period with the option to continue into VIVID-5, an open-label extension trial. Enrolled patients had a history of serious and/or frequent bleeding episodes, including mucosal bleeds, GI bleeding and hemophilia-like joint and muscle bleeds.

Pre-study historical annual bleed rates or ABRs range from 0 to 431, reflecting the heterogeneity of the population. Most patients had a baseline ABR of greater than or equal to 12, which is consistent with the high bleed population we are evaluating in Phase III. In this study, VGA039 demonstrated a substantial median annualized bleed rate reduction of 81% across all participants, including those with no prior IV prophylaxis and switch patients. The depth of the response was also significant. 2/3 of patients with a non-0 baseline achieved at least a 75% reduction with 1/4 of them achieving 0 qualifying ABR during the multi-dose treatment period.

Notably, activity was observed across all von Willebrand disease subtypes and bleeding manifestations, consistent with the hypothesis that enhancing thrombin generation downstream of the underlying VWF defect may provide benefit across the heterogeneous VWD population. In precedent clinical trials with other investigational therapies across bleeding disorders, including VWD, ABR reductions from early studies like VIVID-3 were highly concordant with registrational study results. The safety and tolerability profile to date is also encouraging. VGA039 was well tolerated in VIVID-3 with no withdrawals on therapy and no thromboembolic events reported.

Taken together, this data support the potential of VGA039 as a novel once-monthly subcutaneous prophylactic therapy for patients with von Willebrand disease and were the basis for FDA granting breakthrough therapy designation. We have regulatory alignment on the registrational program for VGA039. And the Phase III study is designed as an open-label intra-patient comparison study with a 6-month observational baseline period followed by 12 months of active prophylaxis. Patients will receive monthly subcutaneous VGA039 using a weight banded flat dosing. The primary endpoint improvement in total ABR, including both treated and untreated bleeds comparing each patient's active treatment period against that patient's own observational baseline.

The study is expected to enroll approximately 60 patients and is on track to deliver top line data in early 2029, supporting a potential launch shortly thereafter. As Bill mentioned, our conviction is supported by the convergence of mechanism, pharmacodynamic evidence, early clinical activity and a Phase III design aligned with both the biology of the disease and the needs of the patient population.

I will now turn it over to Dave, who will discuss the commercial opportunity for VGA039 and why this asset is a strategic fit for Incyte. Dave?

Thanks, Pablo. VGA039 checks all the boxes when we think about our business development strategy at Incyte. It is highly adjacent to our core hematology franchise, leveraging existing commercial and R&D capabilities. It has established human proof of concept and is in Phase III with the potential to launch in the peri-LoE time frame for Jakafi. And the commercial opportunity is needle moving in magnitude for Incyte with blockbuster potential. But most importantly, this represents a novel step change for patients who have yet to experience the exciting innovation that has been brought to other bleeding disorders.

Let me start with the last point, which is how impactful VGA039 could be for von Willebrand disease patients from a practical perspective. Today, the prophylaxis options available for von Willebrand are primarily IV factor replacement therapies. These products can reduce bleeding, but they require frequent infusions, often 2 to 3 times per week. This burden is a major reason prophylaxis remains underutilized even among patients with severe and frequent bleeds where benefit risk favors bleed prevention. VGA039 has the potential to change that paradigm.

On the left of the slide, you can see that the current prophylaxis model requires frequent IV infusions with replacement therapy. Patients have to make a choice, deal with frequent infusions or treat acute bleeds as they happen. In many cases, patients will need both. On the right side is the proposed VGA039 regimen, a once-monthly subcutaneous injection. This difference matters. In hemophilia, we've seen that effective subcutaneous prophylaxis can transform treatment patterns and patient expectations. We believe a similar dynamic could be in play in the high unmet need segment of VWD.

Our commercial focus for VGA039 is not on the entire diagnosed population of 135,000 in the U.S., but rather a focused defined population within von Willebrand disease who experienced severe or frequent bleeding. As Pablo mentioned earlier, today, roughly 35,000 patients are treated in HTCs and other specialty settings. At least 7,000 to 10,000 of them have severe frequent bleeding and are eligible for prophylaxis today. This is our initial target market. Due to the limitations of the current options, only around 2,000 of them are on prophylaxis or prophylaxis-like regimens today. Our target population is not the average von Willebrand disease patient. It is a high burden segment characterized by recurrent GI bleeding, clinically significant mucosal bleeding, joint or muscle bleeds and other patterns.

In severe von Willebrand disease, annual bleeding rates can be very high, in some cases, reaching 30 or more events per year. From a market development standpoint, we believe VGA039 will do 2 things. First, it will convert patients currently receiving IV prophylaxis to a less burdensome monthly subcutaneous option. Second, it will expand the prophylaxis eligible treated population by making prophylaxis more practical for patients and physicians who today may avoid regular IV therapy because of administrative burden. We have seen in hemophilia A that when prophylaxis becomes more practical, adoption can become the norm with rates approaching 90% versus only 25% in severe or recurrent von Willebrand disease today.

There is a real opportunity to close the gap between those who need prophylaxis and those who are receiving it. Our pricing assumptions are anchored to existing prophylactic regimens and supported by the severity of disease in this target population. Severe von Willebrand disease is associated with meaningful health care utilization, including iron replacement, transfusions, emergency visits, hospitalizations and ambulatory care, which supports the health economic rationale for more effective and convenient prophylaxis.

Finally, Incyte is well positioned to launch VGA039 successfully given our deep hematology expertise and established commercial infrastructure. In short, VGA039 gives us a late-stage hematology opportunity with a differentiated mechanism, a practical monthly subcutaneous profile and the potential to meaningfully improve care for a clearly defined high-need von Willebrand population. Taken together, we believe these attributes support both the potential to establish a new standard of care and a significant blockbuster peak sales opportunity.

Back to Bill.

Thanks, Dave. Ultimately, this transaction reflects how we think about business development at Incyte. We're focused on opportunities that can create asymmetric outcomes where the upside materially outweighs the downside. We structured the deal with a combination of upfront consideration of $1.25 billion and up to $750 million in sales milestones, which aligns economics with value creation, preserves balance sheet flexibility and supports the potential for a strong return on invested capital. Just as importantly, we do not view this as incremental innovation. Based on the data generated to date, we believe this asset has the potential to establish a new standard of care. Opportunities like that are rare, and they create a fundamentally different value proposition than assets that simply offer modest improvements over existing therapies.

Before we move to Q&A, I want to recognize the work of Star Therapeutics. They've built a differentiated program in an area of real need, and we are excited to carry that work forward with their team. Our focus now is on ensuring smooth integration and executing the Phase III study.

With that, operator, please open the line for questions.

[Operator Instructions] Our first question is coming from Salveen Richter from Goldman Sachs.

This is Lydia on for Salveen. Could you just speak to strategically the timing of the deal? And then also any risk related to the VGA039's mechanism, particularly around thromboembolic events.

Sure. As it relates to the timing of the deal, I don't think we tie BD to a calendar. We have 2 sources of developing our product line, internal R&D and then external BD. And we looked at this opportunity, it was highly differentiated. The timing was right in terms of what we're solving for post '29. We have a Phase III ready asset, and we looked at the risk-adjusted returns on this, and we were ready to act. I think that this is probably as close to a textbook example of the type of deal that makes sense for a company like Incyte. And we also still have balance sheet flexibility if we see other deals. And we're patient right now. If we see something that makes sense, we'll do it. If not, we'll wait. Thank you.

Okay. So let me take the second part of the question. So we believe the risk here is very low. Let me tell you why. We -- number one, we reviewed it with more than 60 patients' worth of data and we reviewed all the data from the open-label expansion study, there were no relevant treatment-emergent adverse events of thrombosis. Furthermore, we saw no evidence of clinically relevant D-dimer elevations in any of these patients. And we think that's for a couple of really important reasons.

Number one, the dosing of VGA039 and the dosing strategy that the Star team put in place was a PD-driven, pharmacodynamic-driven dose selection. By measuring the amount of thrombin generation, we know that if the exposures to 039, the concentrations are between 25 and 100 micrograms per ml, there is normalization of thrombin generation. And that is the key word here is normalization of thrombin generation without overshooting thrombin generation. By doing that, we think the risk of clinically relevant thrombotic events are very, very low, and we were comfortable as we reviewed all the data that I described.

Our next question is coming from Etzer Darout from Barclays.

Congrats on the deal. Just a couple of -- just one question really on the blockbuster potential for VGA039, particularly around pricing. I think about once-monthly prophylactic product like Takhzyro for hereditary angioedema. Is that the right way to look at that from a pricing standpoint? And any color you can provide on how you can get to the $1 billion peak potential, that would be great.

Thanks for the question. I'll turn it over to Dave.

Sure. Thanks for the question. So if you look at not only VWD prophylaxis regimens, but prophylaxis across bleeding diseases, you come up with price points in the $500,000 all the way to upwards of $1 million a year. I would say that we're not banking on the upper end of that, but I would think about a net price point in that kind of $500,000 per year range is how to think about it.

Yes. What I would just add, Etzer, is think about what David talked about during his prepared remarks, if you have a hemophilia A-like segment of von Willebrands, meaning severe frequent bleeders. And we looked at claims data, we looked at the literature. We surveyed a very high percentage of the hemophilia treatment centers in the United States. You have 7,000 to 10,000 people. If you use annual cost of therapy of $500,000, the lower end of the range, you're looking at a market between $3.5 billion and $5 billion. That doesn't assume that you achieve, for example, what has been achieved in the hemophilia A market where prophylaxis has garnered 90% of the population. So there's a credible path here to a product that can move the needle at Incyte and generate north of $1 billion.

Our next question today is coming from Derek Archila from Wells Fargo.

This is Jacob on for Derek. So just from your diligence process, how are you thinking about this approach targeting protein S compared to others aimed at stabilizing VWF.

Pablo, go ahead.

So first of all, this is a completely different mechanism. The mechanism of modulating protein S, which is such a key element in the coagulation cascade, we think it's highly differentiated and uniquely suited for the most severe forms of von Willebrand disease. Now because it normalizes thrombin generation regardless of clotting factor levels, potentially it could work across other indications. But we believe it's uniquely suited for the group of patients that are more in need of better prophylaxis, and that's type 3 and a lot of type 2 von Willebrand disease patients. I think other approaches that have been recently advanced are very different because they're more focused on stabilizing and elevating existing levels of von Willebrand factor, which would not solve the problem of patients with type 3 and many type 2 von Willebrand disease. So as we looked at this, we think the highly differentiated nature, the fact that it's likely to address and it does in the work that we reviewed, the needs of the most severe patients with VWD, we thought that was a very differentiated approach.

Our next question today is coming from Ash Verma from UBS.

Congrats on the deal. Maybe just in terms of like the Phase III focus here, is this on the high bleeders with no prior IV prophylaxis. And I see that like in this data, it shows that you also generated 75% to 100% reduction in patients who switched from prior prophylaxis treatment. So is that a market segment that you want to follow up at a later point of time? Just help us understand like what are the different pieces of the market and how you want to pursue them.

That's most definitely a group of patients we will address as well. We have very early data in some of those patients already from the MAD study that we reviewed. They're not included in the current pivotal trial, but will be absolutely a focus of a future pivotal trial. It's a very important group of the population, and we intend to address their need.

Thanks for the question.

Our next question today is coming from Evan Seigerman from BMO Capital Markets.

So Bill, in the past, a multiplier in how you think about the world in terms of -- to acquire. Aside from indication -- aside from expansion beyond just VWD and kind of other bleeding indications, how else could this be a multiplier? And what else might you be looking for in a next asset beyond this company?

Well, I think as it relates to VGA039 being a multiplier, I think Incyte is at a size right now where if we have a credible path to $1 billion or $2 billion, that is a real needle mover. I mean we're not a giant diversified company where you need $2.5 billion to $5 billion in peak sales potential for a product to be highly material. And we're going to get a lot of leverage out of this business because we have all of the infrastructure we need in R&D and commercially. And as I said, I think this is about as close to a textbook type deal that we could do. It really checks all the boxes.

As it relates to other things that we're going to do, you know our 3 areas, Evan. We have hematology, oncology and immunology. And I don't think it's going to be the case that we replace Jakafi with one big swing. I think often those types of deals, whether it's a large company or a small company, can often destroy value. And we're not trying to meet a deal quota. We're not trying to count the number of deals we're doing. We're looking for things like this, which I think are differentiated. It's got an acceptable risk-reward profile, and it's right in our core. And if we see those things in those areas, we'll act. And if we don't, we're going to be patient. Thanks for the question.

Our next question today is coming from Michael Schmidt from Guggenheim Partners.

This is Rosy on for Michael. Congrats on the deal. So on the patient population, you've called out roughly 5,000 to 8,000 patients who have recurrent bleeds but aren't currently on prophylaxis. I guess what do we know about why those patients are on treatment today? And what kind of market share do you expect VGA039 to capture in that subgroup specifically? I guess if I may add another question, how do you think about the relative size of the U.S. versus ex U.S. opportunity here?

Thanks for the question. I'll turn it over to Dave.

Yes. Thanks for the question. So in terms of penetrating the population who have severe frequent bleeding, but are not currently on a prophylactic or prophylaxis-like regimen, I think that's the gist of the first question. When we surveyed physicians and spoke to dozens of KOLs about this, the indication is that it's multiples of that initial 2,000. So if you ask physicians, they would say it might get up to 4 to 5x. So when we define the population in the way that we did of severe current frequent bleeders, we expect high penetration in that subset. I think that all you need to do really is take that 2,000 and double it to have a really, really meaningful $1 billion to $2 billion opportunity for us.

The physicians are telling us it would be more like 4 to 5x. So I think we're in relatively good shape there. In terms of how to think about the U.S. versus ex U.S., we've modeled the ex U.S. as a relative minority in the total peak sales opportunity. If you look at other examples such as HEMLIBRA and other bleeding diseases, the ex U.S. can be a very, very meaningful portion of the total sales. So I think if anything, we might be being conservative on the ex U.S. front, but we absolutely anticipate this being a global launch.

And Rosy, I would just add, if you think about how you segmented the market, there's 2,000 people taking prophy, which is with replacement therapy, and it's multiple times a week. VGA039 gets approved, there's a high likelihood that the majority of those 2,000 patients could be put on VGA039. Right there starts at roughly $1 billion. And then there's the expansion of the prophy market. And as Dave said in his prepared remarks, it's only 25,000 of that severe frequent bleeding, 25% of that frequent severe bleeding subset. In hemophilia A, different disease, more serious, it's 90%. If we get prophy utilization up to 45% of that overall segment, you're talking about 3,000 to 4,500 patients. And so that is going to be a sizable opportunity for us. Thank you.

Our next question today is coming from Jessica Fye from JPMorgan.

Maybe following up on kind of the theme of a couple of the other ones. So of the 7,000 to, I think, 10,000 U.S. patients eligible for prophylaxis today, would all of those patients who are not currently on infusions meet the enrollment criteria for the VIVID-6 Phase III trial? Or can you tell us kind of what proportion would? And then recognizing the differentiated dosing frequency here, what's the primary comparator or benchmark you're going to hold your Phase III data up against when it reads out.

So let me take the first part of the question, and then I think Dave and Bill may want to comment. So the eligibility, as I mentioned, is ABR of 12 or greater. So patients are going to be followed for 6 months. They have to capture the bleeding episodes. If the ABR is 12 or greater, that's what they need to move to the prophylaxis phase of the study. Each patient is his or her own control here, Jess. There's no comparison with other approaches since there's nothing similar to this. Obviously, von Willebrand disease patients that they are managed with conventional prophylaxis, which is basically factor replacement therapy.

And as Dave reviewed, this is very onerous for patients. The rates of reduction that we've seen were over 80% in terms of ABR reduction in the clinical data that we reviewed even in the open-label expansion. And a lot of the patients, as I mentioned in my prepared remarks, had ABRs of basically 0 once they were switched to VGA039. So that profile that I just described and the statistical design are fully aligned with the FDA. So we're comfortable with the design of the study, and we're very comfortable based on the review of the open-label extension data that we had.

Dave, do you want to add?

So yes, I think it's a good question, Jess. In order to isolate the treatment effect and measure the magnitude of bleed reduction, you're right, not all 7,000 to 10,000 would qualify for the Phase III protocol to state that clearly. In terms of who we would compare to, there's, as you know, a handful of approved agents in VWD. We know that they all have impressive bleeding reductions. We think those are one relevant benchmark. The feedback we get is that because these are relatively small studies and estimates can move around with just individual patients that -- it's key to show that you reduce bleeding by more than 50%. It's key to hit the primary endpoint. By the way, it's designed with the agency. And after that, we think the profile will win.

Thanks, Dave. Thanks, Jess.

Our next question today is coming from Eric Schmidt from Cantor Fitzgerald.

This is Imogen on for Eric. Congratulations on the deal. I guess a question on recruitment. So the time lines here. Given the relatively small size of the study and a fairly small number of sites open, do you see potential to accelerate the early '29 time line now that it's in Incyte's hands?

Yes, Imogen, thank you for the question. A couple of comments on that. The first part is we need to remind you the design of the study. So when a patient is enrolled, they first have to be followed for 6 months in order to capture the ABR, then they get started on therapy. The treatment is a year in order to be able to assess the ABR reduction in those patients. So immediately from -- when the last patient is enrolled, you have an 18-month period that you have to wait. The Star team has done a fantastic job implementing the study.

We reviewed the screening logs and enrollment and the site opening schedule. Obviously, we bring to bear a larger organization with a much larger footprint, and we'll do everything we can to accelerate the enrollment in the trial. And there might be ways to do that. We'll provide further guidance as we transfer all the obligations to Incyte, but we'll obviously try to accelerate the enrollment of the study. But I just want to remind everyone, there's that 18-month period that patients had to be followed for 6 months for the baseline ABR and then 1 year of therapy to capture the reduction in bleeds.

Thanks for the question, Imogen.

Our next question today is coming from Matt Phipps from William Blair.

Congrats on this deal. I think it fits nicely. Just wanted to quickly ask, I know the trial excludes patients with low -- very low levels of Factor VIII. How many does that -- how many patients might have that exclusion criteria? And then just confirming that the same weight banded dosing is going to be used in the Phase III trial that was shown the PK in the ASH presentation.

Matt, thanks for the question. Yes, the answer to the weight banded dosing is yes. The same dosing that we used in earlier trials that was implemented in earlier trials and that were used in the open-label extension will be used in the Phase III trial. There's 3 doses, 225, 300 and 450 depending on the weight of the patient.

On the Factor VIII levels, Matt, just to clarify, we want to make sure patients don't have high Factor VIII levels. So we're limiting to patients needing to be at the lower limit of normal. If you look at the population, we did extensive work on this, the patients who fall into the category of severe frequent bleeders that we have defined as our target patient population, virtually all of them are going to have low Factor VIII levels.

Thanks, Matt.

Our next question today is coming from Jay Olson from Oppenheimer.

Congrats on the deal. Just to follow up on Bill's earlier comment. What's the level of interest you're seeing amongst patients and prescribers to move away from factor-based prophylaxis and switch to a more convenient and potentially more effective, safer option for prophylaxis like 039. And then also, if you could please comment on your appetite for moving into adjacent bleeding disorders like hemophilia.

Great. Go ahead, Dave.

Sure. Thanks, Jay. So the physician interest is incredibly high in this. I'd say it starts with a discussion around how patients on IV prophylaxis would prefer a simple monthly subcutaneous option. But very quickly, it goes to how much this can expand the population. I think a lot of patients really consider going on prophylaxis, but opt against it because of the onerous profile. Most of the physicians we spoke to commented that patients, including those in the VIVID-3 program who had opted out of getting IV prophylaxis didn't actually realize how bad their disease was until they had experienced some relief. So I think we'll just -- if we produce the product profile that we're looking for, the interest in this will be incredibly high, both in the current population on prophylaxis and beyond it.

Pablo, do you want to take the second question?

I'll be happy to. Thanks for the question, Jay. So theoretically, let me take a step back. So VGA039 increases thrombin generation regardless of clotting factor levels. So mechanistically, there's no reason why it could not work in other bleeding disorders as well. The Star team, and we agree with their approach, addressed von Willebrand disease first because there is a bigger need as we've been discussing during the call, particularly in patients with severe von Willebrand disease for better, more effective prophylaxis. So that approach is something we fully agree with, and we're going to drive this forward as fast as possible.

They have presented, the Star team, preclinical data in other bleeding disorders, and we'll have conversations internally and then with key opinion leaders about initiating potential trials in other potential bleeding disorders. But mechanistically, VGA039 should work regardless of the bleeding disorders we're talking about because what it does is it normalizes thrombin generation regardless of clotting factor levels.

Thanks for the question, Jay.

Our next question today is coming from Judah Frommer from Morgan Stanley.

Congrats on the deal. Maybe just first, can you give us a little more detail on overlap in call sites for your hem/onc sales force and kind of hematologists treating these bleeding disorders? And then just assuming this will be a chronically dosed antibody, any evidence of any drug antibodies or neutralizing antibodies that you've seen thus far?

Great. Thanks for the question, Judah. As it relates to the market or the target audience, you're talking about roughly 150 hemophilia treatment centers. In fact, the program here is going to look very similar in size and shape to what we're already doing at bone marrow transplant centers all across the country, where there's roughly the same number. And so we have a pretty good sense of what it will take to commercialize this product.

Let me take the second part of the question. We have not seen any evidence of ADAs in the ongoing open-label extension trial or any of the trials for that matter.

Thanks for the question.

Our next question today is coming from Kripa Devarakonda from Truist.

Congratulations on the deal. So from the data that you've seen so far, do you have a good sense of what the average duration of treatment could be, especially when we think about the real-world use of the drug. And what's your level of confidence that this could be a chronic therapy? And how does that play into your estimate of the peak opportunity.

Dave will start off and then Pablo will add.

Thanks, Kripa. So between VIVID-3 and the open-label extension, we have not seen any evidence that patients won't take this chronically. And so we have yet to give you an estimate on duration of therapy, and that's good news because virtually everyone is ongoing, and we don't see any signs of -- any reasons for discontinuation.

Let me complete that. I don't see why a patient with severe von Willebrand disease that has ABRs over 12, which is enrollment criteria for this study, and some of these patients have 30, 40, 50, an ABR of 30, 40, 50 and that is receiving a once-a-month subcutaneous injection that is well tolerated and has no major side effects that we know at this point, why would that stop at any point in time. So I think what we're looking here is a chronic ongoing therapy, particularly for the patients with more severe von Willebrand disease.

Great. Thanks for the question, Kripa.

Our final question today is coming from Salim Syed from Mizuho Securities.

Congrats on the deal. Just one from us. Given that this is an open-label study, are you guys -- how are you guys handling the data internally? Is this something that you plan to sort of look at as you go and you'll have knowledge to that? Or is there some sort of blinded protocol even for you guys, even though it's open label? And related to that, if you wanted to change the protocol to build an interim, if you saw good data, is that something that you could do?

Thanks for the question. Pablo?

Yes. Thank you for the question. So the way we will handle, as you described, is an open-label study is the same way we handle other open-label studies, whether they're randomized or not. And there is a team within the company that is -- that basically monitors the study, but we are blinded to the ongoing results of the study. So this is treated with a level of regulatory rigor that it has to for a pivotal trial. So the answer is we will not have access to obviously the data as the study is ongoing.

When it comes to modifications to the protocol, I think it's a little bit too early to comment on that. We will obviously transfer all the obligations to Incyte. The process basically starts today to do that. And then we'll make decisions as you usually do in any pivotal trial, whether there's any need for interim analysis. Now very importantly, we have full alignment with FDA here on the design of the study. And so we would take any change. We will be very cautious about making any changes to the ongoing study or the statistical analysis plan because of the agreements we have with the FDA.

Thank you for the question.

We've reached the end of our question-and-answer session. And ladies and gentlemen, that does conclude today's teleconference webcast. You may disconnect your lines at this time, and have a wonderful day. We thank you for your participation today.

[Audio Gap] featured company Incyte, presented by their Chief Medical Officer, Steven Stein. So thanks so much for joining us, Steven.

Thanks for having me. It's good to be here.

So a lot to cover. So -- and I don't want to spend the whole time on 989 because I know you have just a few other things in your pipeline. But I do want to start there just because I know it's a topic of high interest, and there's a lot of recent data and developments of late. Maybe just on the 989 for ET you guys recently announced Phase III plans after speaking with the FDA, and that program is going to start midyear. Can you walk us through some of the unique elements in that design and in particular, the ability to shorten the typical registration requirements and the implications of having BAFF as a secondary endpoint here?

Yes. Thanks, Brian. I'll try to get to all your questions. So obviously, just in terms of stepping back for a second, if you look at the sort of company 3 verticals, there's hematology, solid tumor, oncology and then immunology. In the hematology vertical, if I can put it that way, obviously, myeloproliferative neoplasms are front and center. It's something that has been the DNA of the company since the beginning and something, in the correct way, we sort of want to own going forward. And the sort of research frame mindset there is mutation-specific therapies now.

So moving beyond more broad, sort of, JAK-STAT inhibition, even in terms of nuances there but really going to mutation-specific therapies. And the first one in that journey is the mutant CALR antibody 989. And to talk about specifically on ET on this question, I'm sure you'll come to MF next. But ET is where we went first with the antibody. It's about -- if you look at mutant CALR in that setting, it's about 25% of all of ET. It's a very clean environment to study it in because we have such a sensitive pharmacodynamic market in platelets. It just gives you a very quick clean read. And it's something we utilize to the meat of your question going forward with the FDA on the study design, and it really helped us.

I just want to also, in terms of stepping back, in the nearly 30 years I've been dealing with regulators and with the FDA, this is about the most collegial interactions I've ever had, and they're really interested in working with us and helping us. We have breakthrough designation as well. But I think the step back there is 16 years ago, we were the inventors of the endpoints here and certainly in myelofibrosis with SVR35 and symptoms, those were ruxolitinib driven and have remained the endpoints over the last 15-plus years. So there's a recognition from the FDA that this is a space we know well and can work well together.

So with the 989 antibody in ET, we'll have an update at EHA. At ASH, we had approximately, I think, 50 patients of data and 35 of those had 24 weeks follow-up. At this EHA update, it's quite substantive. There are 110 patients and about 60 of those have doses greater than 750. So it's a really substantive data set. And if you look deeper into that data set, and you're not looking at doses per se but for the type 1 mutation, there's about a 92% complete hematologic response rate in the abstract. And then for the non-type 1s, it's in the 30% to 40% range, which is something we knew straight off.

So it comes to your question, what happened with the study design. The principle we wanted to get to was to make a very user-friendly study for physicians and patients. So we wanted an all-comer study, and we wanted to try encompass both type 1s, which are uniquely sensitive but non-type 1s in the same study and then use a dose schema that could be rapidly titrated. So what we did and worked with the FDA to get to is it's an all-comer. So sites don't have to worry about whether they're type 1, type 2, non-type 1, type 1 like, it's quite a complicated arena. We put everybody on. We'll do the mutation-specific testing, obviously, and the stratifications there. Everybody starts at 750 milligrams. It's those control rates I talked about in type 1.

And then at cycle 2, day 1, day 29, if they haven't hit the 400 or below threshold, they immediately dose escalated to 2,500. So we expect all the -- just about all type 1s will be okay at 750. And then for the non-type 1s, a great proportion will need that dose escalation. And then it's -- the other -- so that was a great achievement. It's very user-friendly. It's easy to operationalize.

The second thing was we get control very quickly. So we managed to convince the FDA that we don't have to wait what is standard with other sponsors 52 weeks. We can actually measure the endpoint at 24 weeks. So it's complete hematologic control for at least 12 weeks. So you have to then -- if you think that through, you have to have control by 12 weeks to get to 24 weeks. And then -- so platelets below 400, white cells below 11,000, no thrombosis, no bleeding. So we're confident in that design. We like the setup. It's second-line ET versus BAT arm, which we estimate will be HYDREA, anagrelide and interferons and actually quite a decent proportion, we think will be retreated with Hydrea. In certain parts of the world, interferon use is increasing as well. So we like the setup, it's a good study, and it's literally about to start.

Excellent. And I guess where do you stand with the regulatory alignment in MF? I know there's maybe some principles from ET that can apply but there's obviously not as readily available a rapid biomarker for response. So maybe talk us through how you're thinking about the MF path forward in second line initially and what some of those discussions are entailing?

No, you're right. I mean you teed it up perfectly. It's a little bit of a different milieu, right? The -- we don't have a sensitive pharmacodynamic marker like platelets. Obviously, there's spleen control, there's symptom control, there's VAF reduction. I didn't answer your VAF question on ET. I'll come back to it. There's VAF reduction, but it's not as simple to titrate. So it's a little bit of a different construct. So at EHA, again, we have quite a substantive update. I think there will be about 80 patients of data at the meeting. A good proportion of those will have 24 weeks of follow-up in second-line MF, maybe 60-odd patients there. So -- and we're in the same territories on what are the standard responses in terms of SVR and symptoms. What we have with this drug that's unique is anemia response as well.

So in the abstract, you'll see a 58% anemia response rate, and that talks to disease modification aspects thereof. So our ongoing assumption for your question is that we'll be in the old world of SVR35 and symptoms. And in that respect, we're okay but it's not moving the field forward. What we'd like to do is have a healthy discussion with the FDA around a new endpoint in MF in terms of registration studies but it's actually been driven by the European Leukemia Network for nearly a decade. They published 3 times on what a composite endpoint could look like. And in fact, they make a very strong argument that if you do a composite on hemoglobin, on blast count, on platelets, on spleen, is actually more directly correlated with overall survival and leukemia-free survival than the old endpoints, SVR35 and symptoms. And that's been driven extraneous to insight by opinion leaders in the field. We'll see if we can get the FDA there.

Do you think the FDA is open to it?

I think they are. I think they want to try and move the field forward. They've realized that TSS50, particularly holding to that and trying to beat RUX on symptoms is proven very difficult even for us with some of the combos. So I think they are, and we'll hopefully have agreement sometime a little after the middle of the year and be able to tell you publicly on the third quarter call where we are. So that's the desire and where we want to be.

Control arms, next -- some of the...

The main interest in the field is exactly what you just said. People want to see it against JAKs. So it will probably be a BAT arm that incorporates ruxolitinib, fedratinib, momelotinib, pacritinib, maybe even HYDREA and danazol, lenalidomide, et cetera. But that will be the control arm in second-line MF. It will also be IV. So beyond the endpoint, the next thing to agree on is dose. And this is also tricky here because we don't have that PD marker. One of 2 things maybe, one is we just go with a higher dose across the board if we do an all-comer study, come to an agreement based on our modeling, we'll have extensive modeling on what a higher dose could look like or potentially in this area, do a dose by mutation. So have a dose for type 1 and a dose for non-type 1.

And so we'll have a test that can turn that around pretty quickly and be able to do that. That will be the meat of the discussion, what the best way to do that study is in terms of the dosing paradigm. Again, we'll communicate that when we have it.

Just on the VAF endpoint in ET because you asked earlier, it was the FDA who brought it up. They said, why this is disease-modifying, why don't you put it in and we have. We have pretty good data we'll show at EHA on correlating 25% or greater VAF reductions with heme response. So there's some validation going on already. So the same thing in myelofibrosis, if we get to a composite endpoint that has sort of blasts, platelets, hemoglobin, spleen control, we may have a molecular endpoint there as well to show. So that's where we'd like to be with currently.

You mentioned EHA a couple of times, and you alluded to the additional data we're going to see there, and we saw some additional data in the abstract, which looks very much aligned with what you've presented before. Anything more that we should be looking at -- looking for at EHA across the MF and ET program that you think play out? And maybe also, there's been some competitive updates as well coming out of the EHA abstract. So I'm just curious if you have any views on that.

Sure. So just very quickly, we were 3 presentations at EHA, MF oral, ET poster, translational poster is really important, has single cell sequencing data on megakaryocytes on peripheral blood mononucleosides or marrow fibrosis. So I would look at that because it talks to the disease MOA. There's also about 20 patients worth of JAK ineligible patients in that abstract. And then at the meeting, I think about 15 of those 20 have 6 months of follow-up. So you get some sense of what a first-line population looks like, although the first-line data will present at the end of the year. So that will be interesting as well.

In terms of competitors, we've seen the Ajax' abstract looks really good in terms of SVR and symptoms. What we're interested selfishly on what does it look like in the mutation-specific population, particularly mutant CALR. We know across the board, our own data and the very small public data set that JAKs don't do well in mutant CALR. They're not as active. So we'll see what Ajax does there. And we want to look at the AE profile because we know if we use high-dose RUX, for example, we could achieve very similar SVR and symptom control but you would run into quite significant anemia. So we want to just look at that profile there.

Just to be clear, we're in a different mind frame. We really think about mutation-specific therapies as the way forward, which is why we're not in that space currently. Our own V617F is sort of struggling along with the formulation. We switched to an ASD now. Hopefully, we'll get better exposure and be able to hit IC35. We have next-gen backups, and we have a prelude option deal on their lead and their backup. So this is a space we're also extremely interested in 617F specific therapies. It really opens up p-VERA extensively. So the Ajax data set we'll look at. We're not sure if J&J is going to have an abstract or not on their bispecific. We have a bispecific in the clinic as well. And then there's some earlier efforts on siRNA in the space and vaccines, but I think they're a bit too early to speak about.

Got it. I know you're starting with IV but you've made a lot of progress towards a subcu formulation. And you recently reported that this was -- you had some success in healthy volunteers. So can you just help us envision what sort of -- what are you seeing? What kind of profile will constitute -- would constitute success here? And are you doing any additional formulation work? Is there sort of a concentration goal that you have here with the -- I know you have the device that could enable at-home delivery of the subcu. I guess how are you thinking about putting all the pieces together in terms of concentration, dose level, any reformulation and what you guys are seeing so far that gets you as encouraged as you are?

Yes. No, I think you hit the main points, Brian. The subcu is really important from a patient perspective, right? In ET, particularly people are generally well, don't necessarily want to go to clinics or even infusion centers for years on end. So ultimately, getting to a subcu there is really key to our strategy and plan. We started in healthy volunteers to get bioavailability data. We completed that. We like what we've seen from a BA perspective, and we're currently going into patients now to sort of do the same thing, get more bioavailability data, et cetera. We know from the get-go, just to be clear, that we're not going to be able to encompass these doses in pens.

So we went in with the device very early. We've got this partnership with an FDA-approved device, enFuse, that can hold up to 25 ml. The amount you have in dictates how long that takes to infuse. So low amounts, 10 minutes, high amounts, 20 minutes to get it in, you take it off and dispose of it. You're right, there are 2 aspects. There's bioavailability. If you want to ballpark bioavailability, IV to subcu, people generally want in the 40% to 60% range. And so we're happy where we are without telling you what the exact number is.

But the next aspect is concentration. So you have a certain amount of milligrams per ml. And if you do those 2 calculations, you want to be able to encompass your top dose in a single device. We're comfortable we'll get to where we want in a single device but it will be towards the top end of the 25 ml, right, for you. And so we knew that going in.

If you look competitively now, and we're taking at face value what Damora said, obviously, I think the IND is about to go in. They're talking about more potency for non-type 1 and then in nonhuman primates, a 15-day half-life. So it could be a Q4 week subcu. So our next gen are thinking about that as well. So that's a good desirable profile to get to. potentially, I'm not sure they know their dose or bioavailability. It's too early, but you could start thinking about can you then encompass those in an easier-to-use Penn type formulation.

The second-line ET registration studies is IV to start, should get across the finish line and launch in '29. We have an agreement with the FDA to do bridging work. We should have a subcu available within 6 months of that launch. Second-line MF is likely to be IV as well given the timing because we want to go fast. But our first-line MF study, we want to do with the subcu from the get-go.

Great. That's super helpful. I promised I wouldn't spend the whole time on 989. So maybe we'll shift gears, but maybe stay on myeloproliferative neoplasms initially before we move to I&I. You alluded to your own V617F. You have this new ASD formulation. Can you just give us a sense of like how that's going so far in the clinic and maybe what the key signals you're going to be looking for out of that in the back half of this year to make a go/no-go decision on that asset versus moving with some of your next-gen or with Prelude?

Yes. No, I mean, firstly, again, it's incredibly important to us. So 617F opens up the rest of MF, particularly but all of p-VERA. And again, mutation-specific approaches are key. It's been frustrating. We knew we didn't have the optimal formulation. We've pushed it in the clinic. We can't get sufficient exposures to hit the target hard enough. We've just switched to ASD and we're testing that now. This year, though, if we present data at the end of the year, it will be on the old formulation. So it will be more like a '27 data set. If this doesn't get there because the target is so important to us, as you alluded to, we have next-gen and we have the Prelude option deal, which is still open, I think it was 15 months when it was signed. The IND is in there on the lead. They have backups as well. So this is not a target we want to miss out on. It's key to us. I don't know if our lead is going to be able to give us what we need. We'll see.

That's good. It sounds like you have a lot of different clinical options. And then you recently launched or in the process of launching Jakafi XR. I guess can you give us any flavor of just what the early days are looking like in terms of receptivity, any surprises in the way it's being used? And then just how are you thinking about what would get you to that kind of upper end of the, I think, 15% to 30% patient conversion range that you and have talked about.

Basically principle. So I have PTSD from this. We got a CRL, but now we all celebrately, we got across the finish line. It was not easy. But we're there, and we've launched, as you said. We priced it at parity to IR. So that's important. There's no issue for payers in that respect. The key is formulary coverage, trying to get upwards of 50% to 70% coverage as quickly as possible. This year's contribution will be modest, I don't know, $10 million, $20 million type thing. Next year will be the first full year with adequate formulary coverage, and we hope to see a year of potentially like $100 million in sales.

And then upwards of somewhere in that analog of the 10% to 30% range, you want to use 20% as a number we're using, which in 31 months, that's what we have left until the end of the LOE is going to be a lot of hard work to get there, right? If we achieve that, we then potentially have it through the early 2030s, maybe up to 2034. Bill has been talking about numbers. If you take that 20% of where we are on our top line, we could have somewhere around $500 million to $700 million product from RUX XR, and that would really help us to bridge that trough period. As Bill says, and he's right, if the company is trading on RUX XR at that time period, we've got a lot of things wrong, right? So we have to be beyond that at that point.

Yes. But even a modest piece of [ that ] is still a meaningful bridge.

Yes.

Shifting gears to, I guess, on oncology, hem-onc, you guys recently reported positive Phase III data for tafasitamab in first-line DLBCL back earlier this year. How are you guys thinking about the opportunity for the drug in that setting and the key differentiating features versus standard of care? And what should investors be focusing on for your upcoming ASCO presentation?

Right. So a quick advertisement. It's a plenary oral at ASCO on Saturday. It's a plenary oral at EHA like a week later. So obviously, the academic community is interested. It's a second positive study in first-line diffuse large B-cell lymphoma in 25 years. Hazard ratio reported in January 0.75, p-value 0.019. Different from the POLARx study in that it's a little bit of a worse population. So we're IPI 3 to 5, they were 2 to 5. We're about 30% ECOG 2 or above, they were 16%. So those are the major differentiators, 899 patients. It's a curative -- potentially curative population, really important data set. We'll show you at those presentations, all the other endpoints, event-free survival, et cetera.

Very important focus on, I guess, 2 things. One is cell of origin data. It's about 50% germinal center, 50% activated B cell. The POLARx data is good. It's on a $1 billion run rate, but it's used almost exclusively in ABC subtype because the germinal center hazards were basically one, that's in keeping with its MOA. We have good data in both data sets. So I think that's one differentiator in both cells of origin.

The other thing to look at, people are very focused on the 2-year PFS, EFS data because if you don't relapse within 2 years, you're usually cured of this condition. So we'll show you that 2-year split as well, and then we'll show you overall survival data as well. So really good for patients, really great to have a positive Phase III in this setting. Bill and the company have been conservative because of the entire market here. We know the bispecifics coming, et cetera. But we think this will add to what we already have in somewhere around the $300 million to $400 million sort of range. There are 30,000 patients every year with first-line diffuse large B-cell lymphoma in the U.S., 50% still get R-CHOP, probably the lower IPIs in the germinal centers. So there's clearly opportunity but we've been measured in how -- what we think the uptake will be.

Got it. And can you talk about your latest expectations for povo in HS and maybe just what the uptake curve there could look like, where it fits in and how potential competitor data later this year could shape that?

Yes. So I think we probably did that endpoint too early when we presented last February. I mean you can't change it once you declare a 12-week endpoint. The reason I say that is we saw the 54-week updates looking really good, right? The HiSCR rates are where biologics are. Pain control is probably the best in the class and beyond. Draining tunnel data is good. So the setup is really good. We think there are about 300,000 patients with HS, about 200,000 get treated if you want to add a branded, say, of 35,000 a year, you have a total addressable market that's upwards of between $7 billion, $8 billion.

There are 3 groups of treatment. There's conventional therapy, antibiotic steroids, there's TNF and then there's IL-17. We have data in both prebiologic and post. That's our desire in terms of getting the label in both. And we want to be potentially used in both Bill spoke about numbers on various calls of around $500 million here. We'll launch early next year. So we should have a full year in '27, and we want to be used in both settings, pre and post biologic. So that's the setup. The data looks good to support that. We don't think that's a hyperbolic number to achieve there. If you add vitiligo and then PN, the 3 indications and should we get them all, about $1 billion or north of $1 billion opportunity for povo for us.

And then lastly, where does Opzelura then fit in? And I know you recently expanded that study. Some of the doc feedback we've heard has been some intrigued just given the in elderly, in milder patients...

The anecdotal feedback is great. The study enrolled so, so well that adding 100 patients each study has made no difference on timeline. So we did that. But what we really wanted to do is control the placebo response rate. So there's no competitor in mild HS. We are the only ones going after it. It's abscess and nodules up to 10 and no draining tunnels. So there could be a significant placebo rate. So having a higher number could help there. So the driver was easy to do it to enroll in like gangbusters, control placebo response rate. Opportunity is another few hundred million on top of Opzelura. So important. And then again, will give us that topical to oral solution in HS, topical Opzelura for the mild, povo for the moderate plus.

Lots more we could cover. But unfortunately, we're out of time. So thanks so much.

Thanks for having us.

Really appreciate it. That was great.

Good afternoon, everybody. Welcome back to the Bank of America Healthcare Conference. I'm Tazeen Ahmad. I'm one of the senior biotech analysts at the bank. It's my pleasure to have our next presenting company here, Incyte. Presenting for Incyte up here on stage with me is Bill Meury, who is, of course, President and CEO. Bill, thanks for making the trip out West to see us.

Thanks, Tazeen. It's good to be here.

So it's been quite the year of transformation for Incyte. So I thought maybe we usually start off by asking for an overview of the company, but I thought I would switch it up a little bit with you. And have you tell me what it's been like to be at Incyte since you became the new CEO a while back last year.

Yes. Thank you. It's a good question. It's been about a year. And I can tell you that I did a lot of diligence before coming in. I had an opportunity to speak with the members of the Board for an extensive period of time. And there have been nothing but good surprises so far. One of the reasons I joined is I thought that the core business as well as the pipeline was somewhat underappreciated. I think there's a lot of substrate and potential for meaningful product flow over the next several years. And that's just going to be important in terms of replacing Jakafi and going beyond Jakafi with multiple growth drivers.

Second, I was impressed with the R&D and commercial capabilities of the company. And I think the discovery group, there's a talented bunch of biologists and chemists and translational researchers, the development group. We have about 10 Phase III studies underway, and they know how to execute. Commercial team is wired into the markets that we're in. And then financially, the company is in a good position. Right now, we have strong revenue growth and cash flow and a growing balance sheet. We're squarely focused on Act 2 and just going beyond Jakafi. And since I've inherited a good business, I think the company has achieved most of its major milestones over the last 12 months. And I think the growth profile of Incyte post '29 is much clearer today than it was even a year ago.

Yes. And you've been very passionate about talking about that. So we'll go into some details. So maybe let's talk about the current commercial lineup, especially Jakafi. So I think it still manages to surprise people, the uptake that it gets every quarter, given that it's a very mature asset. We're actually approaching the LOE for it. Can you talk to us about what some of the drivers you've seen over the last year that allow it to keep bringing in new patients or circling patients back?

Yes, it is pretty remarkable. It's year 15 on the market. This quarter, as you know, sales were up about 7%, 6% of that was pure demand. We see broad-based growth across the 3 indications. So MF, PV and GVHD. MF and GVHD are low to mid-single-digit growing indications. PV is plus 10%. And by the end of '26, it will be the largest indication for Jakafi. It's a standard of care treatment. It's got a lot of support from prescribers, and it has excellent formulary coverage and you put those 2 things together and you have a sustainable growth story. And this year looks strong, and we expect the same for the next couple of years when we lead up to 2028.

Okay. So how should we be thinking about the switch rate to Jakafi XR? You recently got that approved. How important is this for life cycle management?

Yes, it's a good question. XR is a bridge for the company. And in terms of conversions, and there's models out there, as you well know -- analogs, you can look at. We estimate that we can convert, let's call it, 20% of Jakafi IR. So on a relative basis, you'd say that's modest. But in absolute terms, that could be $0.75 billion in sales. It's a once-a-day version of a standard of care. We know that with a chronic symptomatic condition, when you miss doses, there can be a loss of control.

When you go to a once-a-day formulation, the adherence rate is going to be 15% to 25% better than BID. The way I think about conversion right now: in 2026, think about measured early uptake with a step-up in conversion tied to access in '27. So '26 will be about formulary coverage. Conversion rates will be in the low to mid-single digits. And then in '27, that's when we expect to really accelerate the rate of conversion. And by the time you get to early '28, we'd like to see that number around 20%.

Okay. And is there a subgroup of patients that you think will be earlier in conversion?

There's definitely a subgroup of physicians, early adopters. We also believe that in the GVHD market where patients are on multiple therapies, a once-a-day version of Jakafi may be more favorable. And there are also certain channels where we believe conversion can be accelerated. And the program is being launched right now. In fact, our sales organization, both on the East Coast and the West Coast has launch meetings this week. Interactions with health plans have already started. And the key metric, and we'll be talking to you about this on each quarterly call, will be: what does the formulary coverage look like, how rapidly can we achieve it? And at that point, you can really start to drive conversion.

Okay. And then just in general, what is the sentiment at Incyte about the time it will take to get on to formulary coverage? Is there anything complicating about this that would make it longer than what you would think?

Yes, it's a good question. It's the right question. So we priced Jakafi XR purposely at parity to Jakafi IR. And that was to enable fast formulary coverage. And I would expect that in a 6- to 9-month period, we're approaching 50% or more formulary coverage. And we'll focus on the top PBMs and the top plans. And I would hope we've made some meaningful progress by the end of the year, which gives us just over 6 months of time.

Okay. So let's talk about Opzelura. It's received phenomenal reviews when we talk to physicians about it. And all the survey work indicates like the drug is really efficacious, so efficacious that the amount of drug that patients need seems to be much smaller than we thought. So is that a good thing?

Is that a good thing? I think it's a good thing that when a dermatologist thinks about a treatment for AD that it's topical, they know that Opzelura is superior to TCI and for long-term use is superior to a topical corticosteroids. Yes.

So for the -- I guess, the patients on the milder end of, let's say, AD, for example, do you think that you could make up for it with more patients over time as opposed to us all counting the number of tubes per patient, which seems to be lower than what initially was thought?

I do. If you -- the business between now and 2030 has the potential to grow at a 10% to 15% 5-year CAGR, which means globally, we expect Opzelura to do almost $780 million this year, and we're just under $800 million. By 2030, we expect that number to be about $1.3 billion. Right now, we know that the underlying growth in the U.S. for AD and vitiligo is very strong. And there's just 2 metrics that we looked at to get to your question. What is our share of new patient starts? That will be the measure of the health of any business in biopharma. We're at 46%. You also look at what are your new patient starts on a year-over-year basis. And so in the first quarter of '26, new to brand or new to patient starts for Opzelura were up 30%.

And so the fundamentals of the business are very strong, and I think it's because of what you said, it performs well. And we have 20,000 writers, and we have very good formulary coverage at this point. And so we just have to keep our foot on the gas and continue to drive the business organically. And then, of course, we would layer in the international launch of Opzelura for AD, which is in the second half of this year, and we may have an indication for HS. And those are the 3 components of growth for Opzelura over the next 5 years.

Okay. Yes. So since you mentioned the ex U.S. launch for Opzelura, how are you thinking about that?

Internationally, Opzelura is available for vitiligo. And in 2025, it did roughly $130 million in sales. We didn't have an indication for AD. We get the indication for AD in the second half of '26, and the AD market is about 5x the size of the vitiligo market. And so I expect it could throw off $200 million to $300 million in incremental sales over the next several years. The first country we're going to launch in, in Germany, where we have reasonable pricing, and we'll also launch in the other EU 4 countries.

Okay. What is the pricing differential between U.S. and Europe just directionally?

Depending on the country, it can be about 50%. But in Germany, it's better.

Okay. So how should we be thinking about the rest of this core business? We talked about Jakafi, we talked about Opzelura. As we approach 2028, you've done a good job of letting people know where you think sales might go to. Obviously, they're going to decrease because you're going to lose exclusivity. But what is the floor? Maybe just remind us what you think it's going to be? How long it will be there, and then we can move into talking about mCALR?

On a revenue basis.

Yes.

Yes. The core business without heroic assumptions about the other products, Monjuvi and Zynyz and we put povo in there, should be at least a $3 billion to $4 billion business, which is this core business growing at roughly, let's call it, a 20% CAGR. This quarter, our core business was up 63% year-over-year. And so it is in very good shape right now. What will be key is that when we launch Monjuvi for frontline DLBCL that we garner a reasonable percentage of that market.

Now you have Polivy and you have Epkinly, but there will be a place for Monjuvi, and we'll share data on our frontline DLBCL study, and there's only been 2 positive studies, Polivy and ours. On top of R-CHOP at the ASCO meeting, and people will be able to see the PFS, which we reported in the press release, but also how the product does across subgroups, different cells of origin, ABC and GCB. This was an IPI 3 to 5 population, so a more severe population, more complex patient group. And from our perspective, a 10% share of the frontline DLBCL market, which is modest in relative terms, doubles the size of Monjuvi. Then the povo launch is going to become very, very important, which we'll introduce in early 2027. We're currently discussing with the FDA the application. But the business right now with those 5 assets I think, reliably sets, as you put it, the floor for the company.

Okay. Maybe let's spend a minute on povo for HS. So where do you think in that treatment regimen this can fall into? It's going to get crowded pretty quickly? And what do you think are the special attributes here that we should be aware of?

HS is one of the most difficult dermatological conditions you can have other than maybe advanced skin cancer. There's no FDA-approved oral anti-inflammatory. It's a multi-cytokine disease. Povo is a multi-cytokine inhibitor. I think we're going to capture patients at 2 inflection points, pre-biologic and post-biologic. If you look at the data from our Phase III, you have biological efficacy, HiSCR 50, 75, 90 and 100, pain relief, drain tunnel clearance. And so I think that the market is structurally set up for an oral anti-inflammatory and for sequencing oral to biologic.

Now that's not to say that it's only going to be used prebiologic. I think it will source patients from both the prebiologic setting as well as the post-biologic setting. We know that IL-17s work. They don't work for everybody. There are patients on those drugs with active disease, not getting pain relief. There can be some wear-off. I think they would cycle right off of 17 onto an oral anti-inflammatory in this case, povorcitinib. And so our job right now is get it approved, broad label and wire the launch for success.

What is the proper range of pricing to assume?

It's a good question. There's a corridor in the market. If you just talk about WAC prices for a minute. At the low end, it's about $7,000 a month. At the high end, it's north of $10,000. We will work within that corridor. And as we get closer to launch, understand what the label looks like, we'll decide what the final price point is. But this will be about volume and establishing povo as a legitimate option in both of those populations.

Okay. And do you get the leverage of the sales force for Opzelura for this?

Yes, it's a good question. We get a lot of leverage out of it. We'll expand the sales force to call on some HS specialists, but most of the infrastructure is in place, and there is a lot of overlap.

Okay. And from the time it gets approved, how quickly can you start marketing it?

So we expect an approval at the end of 2026. I would say we'd have a launch all raring by first quarter of 2027. And one other point is Opzelura, if it gets positive data in HS in mild-to-moderate HS, which will get those results in the fourth quarter of 2026, we have a topical to oral solution and the leverage point that you just made is highly relevant to both products.

Okay. We'll come back to povo later, but I wanted to spend some time on mCALR. So this became -- data -- you started presenting data for this a couple of years ago, and it became a little bit more prominent last year. So I think when we have conversations with investors, MF, I think largely people understand what role it could play. We could talk about that for a minute, but I also want to spend some time on the potentially bigger indication, which is ET. So maybe let's start with ET and then we can go back to MF.

Yes. So we'll start the Phase III trial in the next several weeks. We have agreement with the FDA on a Phase III study design. I think the important thing when you think about ET is to stratify that market. And you have patients, half of 20,000 patients that are doing fine on hydroxyurea. But you have the other half of patients, which is about 10,000 patients, who do not achieve a complete hematological response, not because hydroxyurea is not an effective cytoreductive agent, but because it's very difficult to get to the 1,000-milligram dose where you can get those complete responses. Those patients have residual symptoms, residual thrombotic risk and albeit low residual transformation risk. Those are patients in their 40s or 50s. They'll live with ET for a good portion of their life.

So 989 achieves a complete hematological response, as you know. It varies by type, but roughly 80% and has a disease-modifying benefit in terms of the reduction in VAF. This would fundamentally change the way ET is treated from hydroxyurea, which is a trade-off drug to a disease-modifying mutation-specific targeted therapy in 989. And I think that it will reshape the way hydroxyurea is used today, assuming we take what we produced in Phase I and replicate that in a Phase III study, and we've talked about the design of that study, as you know.

Yes. So for physicians, when we talk to them, they say that, that specific patient population may not feel the need to be on therapy because they're not as advanced as an MF patient. So what's your market data research telling you on that?

Yes. If you look at patients with a CALR mutation in ET, they have very high platelet counts. And they're not achieving a response with hydroxyurea. And so the reason why a physician would say, well, it's a small number of patients is think about all the people with ET. It's like over 100,000. But if you look at the CALR population, it's roughly 20,000. And we're saying half of that 20,000, 10,000 is the target market for 989. And I don't -- I haven't met anybody that has not commented that ET for CALR patients is like a ticking time bomb. The disease does have the potential to cause thrombosis and transform, and they want to get platelet counts into a normal range. In this case, it's less than 400. And so I think if you stratify it the right way, this targeted therapy has utility in that part of the market.

Okay. So you're going to start your Phase III.

Yes.

How long do you think it will take to enroll that study?

From first patient and the last patient, you're probably looking at a 24-month period for enrollment and then you have, of course, 6 months of treatment.

Okay. In the meantime, do you have plans to show any follow-up data from previous data sets at medical meetings?

Yes, it's a good question. So at the EHA meeting in the middle of this year, the last data set we had was 55 patients at week 24. And at the EHA meeting, we will have 110. And so you'll see more patients at week 24.

Okay. And so what metrics should we be looking at there?

Yes, complete hematological response is namely the -- and you look at VAF. And you'll see that unlike in MF, which is a much more complex aggressive condition, the VAF reductions in ET are more pronounced and are stronger than even what we showed at ASH.

Okay. So that's ET. So let's now go to MF. So you've shown impressive data for that subset of the population already. Remind us what part of MF patients have the mCALR mutation?

Yes, it's a good question. About 35% of patients with MF have CALR mutation. Roughly speaking, it's probably almost 10,000 people.

And so how easy are these patients to find? Are they already types, gene types?

Yes. That is pretty routine these days. It's a good question. And we have not had any challenges in enrolling patients in our Phase I trial. I think the NPN community is especially focused on moving away from broad pathway nonspecific treatments to -- just like in other areas of oncology to mutation-specific targeted treatments.

Okay. So for CALR patients that have been on Jakafi, what are additional challenges that they've had relative to the patients who don't have the mutation?

Yes, it's a good question. This isn't widely known. There is data in the literature, and we will share data. Response rates with JAK inhibitors in CALR patients are lower than what you see in the overall population. So for example, if you look at the label for Jakafi, it achieves an SVR35 of between 30% and 40%. I think it's 29% and 40%. But in a CALR patient, it could be like 20%. And so it is a unique population of patients where we think 989, our monoclonal antibody can have a lot of utility.

Okay. So it does look like other companies, larger companies are also looking at this subset of patients. What do you think that is?

I think -- well, it goes to what we believe is a trend in MPNs, which is the JAK-STAT pathway has been -- is fully understood and exploited. But more and more, they're looking to segment the population, match therapies with the biology. And so I think we will see more and more work being done across MPNs, whether it's 989 with CALR or our 617F, so that precision oncology enters the area of MPNs.

Okay. Are there other mechanisms outside of JAK-STAT that you think could have efficacy on CALR patients as well?

Not that's not a broad pathway blocker. I mean this is a mutation-specific targeted approach. And one of the features of 989 is it's exquisitely selective, and you see that in the benefit risk profile. We focus a lot on spleen volume reduction, symptom relief, anemia response, the translational data. Notice every other novel mechanism for MPNs or most novel mechanisms for MPNs are associated with cytopenias and other toxicities, but the benefit risk profile of a monoclonal antibody like 989 is pretty impressive.

So what is the next data update for MF?

So at EHA, we will provide an update. At ASH, we showed data at week 24 in a second-line setting, 36 patients. And when we get to the EHA meeting, it will be roughly 60 patients.

Okay. And trend-wise, numbers do you want them to look the same as they did last year?

Yes, you're looking for consistency in terms of spleen volume reduction, symptom relief and anemia response, and we'll also share where we are with translational data.

Okay. Now what about combination of Jakafi with 989?

Yes, it's a very, very good question. It should be complementary. I think hematologists look at that combination as potentially very interesting. We're going to have data at the end of the year at the ASH meeting in 2026, looking at 989 in the frontline setting as a monotherapy and as a combination therapy. There is a concept, a use case of induction and maintenance where you work with 989 and with Jakafi and then perhaps maintain with 989. That's a concept. We would have to produce data and, of course, secure approval for that.

But Jakafi is dealing with spleen volume reduction in symptoms, but no other part of the disease. 989 is dealing with those 2 things plus anemia, platelets, neutrophils and as well as all the translational data that you've heard Pablo talk about, which is megakaryocytes and CD34 positive progenitor cells. And so it's a much more holistic approach and is focused on restoring bone marrow function, not just a quality of life endpoint.

Right. And what about the survival benefit that Jakafi has? How do you think that could be complementary in combination?

It should be additive, but those are data that we have to produce in long-term studies.

Okay. So let's maybe go back in a few minutes we have, I wanted to touch on povo again. Outside of HS, what other indications do you think are going to be compelling to look at?

Yes, it's a good question because we spend all of our time on HS because we have an NDA submitted to the FDA. But we will get data this year in the middle of the year. Well, we just got the vitiligo data, and we will have data at the end of the year in PN. And so you're talking about 3 indications. I think the primary driver for povo will be HS. But when you look at vitiligo, it's the largest market of the 3, HS and prurigo nodularis. The key with vitiligo is to medicalize the treatment. And the more and more patients and physicians see it as a chronic inflammatory condition, a chronic immune condition, the more likely you can unlock more and more patients.

I think that's key, whether it's AbbVie with their product or Pfizer with their product or Incyte with povorcitinib. One of the benefits that we have in vitiligo is we already have a topical solution with Opzelura. And so we will have a topical to oral option. And what povo does is it unlocks those patients with vitiligo who are not taking Opzelura who have a BSA of greater than 5%, where applying a topical on your body is not always that practical. And in prurigo nodularis, the way I look at it, that's an itch disease. And there's one thing JAK inhibitors are really good at, itch. I think JAKs were made for PN, and they work very fast. And so between the 3 indications, we think we have a product that could do between $1 billion to $2 billion in sales.

Okay. We've talked about this. In terms of vitiligo, so if you pursue povo in this indication, how does Opzelura fit in going forward?

I think they're complementary and they work together. And that's true whether you're in HS or whether you're in vitiligo. Opzelura is very good for people that have less skin involvement. Povo is much more practical for patients who have more extensive skin involvement. I expect very little cannibalization. And whatever cannibalization we get is more than manageable.

Okay. What have you learned from the vitiligo launch so far with Opzelura outside of -- it tends to be more popular and less surface area portions of the body, face, or hands?

Yes. I think that there's a lot of education that is required, educating about the condition, also educating about the time it takes for treatments, whether they be topical or oral to repigment the skin. And I think there are some patients who are willing to live with it. And I think that's a choice. And I think there are other patients that are really looking to manage it, especially when your vitiligo is affecting your hands and your arms and your face and your neck, which are very sensitive areas. There is a major consumer activation component in a condition like this so that patients are aware of the availability of the treatment. And I think with povorcitinib and Opzelura, we can leverage both assets to -- because I do believe you could unlock diagnosis and treatment to a much greater extent with approved orals, ours and others that we haven't been able to do before.

Okay. So how should we be thinking about the catalysts over the next 12 months? So we've talked about upcoming data for a ASCO. What should we be thinking about for ESMO?

So 2 important data updates at ESMO. One is we have -- we'll have an update on our frontline study with G12D in combination with standard of care chemo. So our G12D plus mFOLFIRINOX and GEMNabP. We're very reassured by the data in terms of the objective response rate. The most important component here at this point is durability of response and an estimate on PFS. But we have...

That's in PDAC.

That's in PDAC. In fact, that's exactly right. We have a novel G12D inhibitor, very active combinable with both mFOLFIRINOX and GEMNabP, and we started a Phase III study, as you know. I believe it's an underappreciated asset. I think it's going to start to declare itself and could be an anchor for our solid tumor oncology portfolio in Incyte. We will also provide an update on our TGF-beta x PD-1 bispecific in colorectal cancer. You'll see those data on top of FOLFOX bev, bev and cetuximab. And that is also an interesting opportunity for us. As you know, PD-1s have almost no efficacy in MSS CRC. We showed in our late line or second and third line Phase I study, an objective response rate of about 15%, 23% no liver mets, 12% liver mets. This is a really unique product. No one's cracked the code on TGF-beta x PD-1. The program is still maturing. We are in a Phase III study. It was a calculated risk. It has the potential to be an outlier opportunity for the company. Let's watch the data mature, and we'll see if we have something.

Okay. So that covers ESMO. Then we talked about EHA and we've talked about ASH. So that covers 2026. Did I miss anything?

No, you didn't. Good job.

Okay. And then what data readouts just summarize top level to expect next year?

Good question. In 2027, Well, we'll have updates on the 989 program on JAK2 617, anything coming out of discovery. And we'll probably also have some updates on the solid tumor oncology program. What we'll be in launch mode in is all of our immunology business.

Okay. Perfect. And then last question for me really quickly. Your views on business development, bringing in assets?

Look, it's going to be an important part of our growth strategy like every company. And we're focused on the 3 therapeutic areas that we're in today. I think a deal for Incyte can come in 1 of 2 sizes, a smaller transaction, somewhat derisked, less upfront capital or something that may be a little bit larger that requires more upfront capital. And our balance sheet is a strategic asset right now. What we're solving for in BD is not a revenue gap. It's constructing a portfolio of multiple growth drivers so that Incyte could be a top quartile growth company post '29.

So is it important for you that anything you bring in already generates revenue? Or do you prefer it not yet be closer to it, but not yet.

It doesn't. I think business development for revenue stage assets, there's not a lot of return left for the buyer, as you know. Flip side is we're not looking to buy a lot of unbounded downside risk. I think we're looking for things that can contribute to top quartile growth when we hit 2030, '31, '32, which would be entering Phase III somewhat derisked. I think those make the most sense for Incyte.

Okay. Perfect. All right. Thank you. With that, we're out of time. Thanks, guys, for joining.

Greetings, and welcome to the Incyte First Quarter 2026 Earnings Conference Call Webcast. [Operator Instructions] As a reminder, this conference is being recorded. [Operator Instructions]

It's now my pleasure to turn the call over to Alexis Smith, Vice President, Head of Investor Relations. Please go ahead, Alexis.

Thank you. Good morning, and welcome to Incyte's First Quarter 2026 Earnings Conference Call. Before we begin, I encourage everyone to go to the Investors section of our website to find the press release, related financial tables and slides that follow today's discussion.

On today's call, I'm joined by Bill, Pablo and Tom, who will deliver our prepared remarks. Steven, Dave and Mohamed will also be available for the Q&A portion of today's call. I would like to point out that we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail.

I will now hand the call over to Bill.

Thank you, Alexis, and good morning, everyone. We're off to a strong start in 2026 with net sales up 20% year-over-year, driven by strong demand across our entire portfolio. In parallel, we advanced the pipeline with key regulatory and clinical milestones. We view '26 as a year of strategic progress as we transition Incyte beyond a single cornerstone product toward a high-quality, growth-oriented portfolio across hematology, oncology and immunology. This progress will come from multiple sources, the continued organic growth from our commercial portfolio, the execution of life cycle launches of key brands, the advancement of a broad increasingly late-stage pipeline and a focused approach to business development. The sequencing and pace of execution here matters as these efforts are intended to lay the foundation for a future beyond Jakafi.

During the quarter, the FDA accepted our regulatory application for povorcitinib in patients with moderate to severe HS. The application was submitted ahead of schedule and is supported by a robust high-quality data set across both pre- and post-biologic patient populations. If approved, we believe povo should be a significant growth driver for Incyte as the first FDA-approved oral anti-inflammatory treatment for HS, a disease which affects more than 300,000 people in the United States. We also remain on track for several regulatory decisions this year, including Jakafi XR, which has the potential to generate meaningful sales and serve as an important sales bridge and Opzelura for moderate atopic dermatitis in Europe, a key future growth opportunity for the brand and our international business.

Finally, we expect global submissions from Monjuvi in the first-line DLBCL in the first half of the year with approval and launch anticipated in early 2027. Across the pipeline, we continue to advance novel compounds that support our broader transition to a hem/onc I&I company. The pipeline reflects a deliberate balance of risk and reward, combining programs with the potential for outsized returns alongside opportunities that can deliver incremental but highly reliable growth. This work is backed by an experienced clinical development and clinical operations team and consistent execution across trials.

In hematology, we had a positive end of phase meeting with the FDA in the first quarter and are on track to initiate our Phase III study in evaluating our mutant CALR antibody 989 in previously treated CALR positive patients with ET by midyear. This represents an important step as we continue to build a portfolio of molecularly targeted therapies, which Pablo will discuss in more detail shortly.

In oncology, we now have 4 pivotal trials underway across colorectal, ovarian and pancreatic cancers, including the recent initiation of our G12D program in first-line pancreatic cancer earlier this month. These programs target areas of significant unmet need and represent meaningful long-term growth opportunities for the company.

In immunology, we are advancing registration programs in mild to moderate HS for Opzelura and moderate to severe HS, vitiligo and PN for povorcitinib. In addition to the regulatory acceptance for povo and HS mentioned earlier, today, we announced positive results from both Phase III registration studies in adults with nonsegmental vitiligo. These results will support a regulatory application in nonsegmental vitiligo expected in the first half of 2027. Over time, we believe the I&I portfolio at Incyte has the potential to become a significant contributor to the business, representing approximately 1/3 of total revenue by 2030.

Finally, I want to take a moment to talk about management. At this stage of the company, our results depend largely on the strength of our management team. Experience, judgment, decision-making and the ability to execute strategic plans. With that context, we have made several executive appointments. This morning, we announced the appointment of Suky Upadhyay as Chief Financial Officer. Suky brings deep experience leading large finance organizations, most recently Zimmer Biomet and Bristol-Myers Squibb. We also announced the appointment of Pablo Cagnoni as President, Incyte and Global Head of Research and Development; and Steven Stein as Executive Vice President and Chief Medical Officer and Head of Late-stage Development.

Additionally, Mohamed Issa was appointed as Executive Vice President and Head of U.S. Commercial, coinciding with the integration of our U.S. commercial operations into a single organization. Mohamed is an experienced executive with a track record of new product launch planning and operations. The new structure is intended to establish consistent standards and enterprise-level capabilities across analytics, market access, sales operations and patient services, creating a launch-ready organization in 2026. These capabilities can be leveraged across the portfolio to maximize the return on our commercial investments. Taken together, these appointments give us the management experience and operational oversight for the next phase of the company.

Now turning to the quarter. Total revenue in the first quarter of '26 was $1.27 billion, up 21% over prior year. Net sales in the first quarter totaled $1.1 billion, representing 20% growth year-over-year. Sales increased for every marketed product, both in the United States and internationally, and was driven by strong prescription and volume demand across the portfolio. Jakafi sales in the first quarter were $758 million, up 7% year-over-year. Prescription demand increased 6% with broad-based growth across all indications, MF, PV and GVHD. New patient starts remain strong.

The prescriber base is stable and a formulary coverage is broad, providing an important foundation for the Jakafi XR launch. We anticipate the approval and launch of XR in the middle of the year. Our immediate focus will be on securing adequate formulary coverage for XR over the next 12 months post launch. We estimate that XR can achieve 10% to 30% of Jakafi's business by 2029. We'll provide more insights on the launch in future quarters.

Sales for our core business, excluding Jakafi, were up 63% year-over-year, with contributions across hematology, oncology and immunology. This business will be supported by 4 new product launches over the next 12 months including Jakafi XR, Opzelura for moderate AD dermatitis in Europe, Monjuvi in first-line DLBCL and povorcitinib in HS. As we've discussed, our core business ex Jakafi has the potential to approach $3 billion to $4 billion by 2030, reflecting the strength of the portfolio and continued execution. It is becoming an increasingly important part of how we transition the company for long-term growth.

Opzelura continues to be the largest single contributor to the core business ex Jakafi with sales of $143 million, up 20% versus prior year. In the U.S., sales were $106 million, an increase of 12% versus the first quarter of '25. The underlying prescription demand for this business is strong, up 17% year-over-year, which is supported by the continued adoption of nonsteroidal topical therapies. Internationally, growth remains robust in vitiligo where we see strong uptake across markets. In the first quarter, sales totaled $37 million, up 56% year-over-year.

Internationally, growth remains robust in Vitiligo, where we see strong uptake across markets. As a reminder, Opzelura is under review by European regulators for moderate AD, and we expect approval and launch in the second half of the year. The moderate AD indication has the potential to contribute meaningfully to top line revenue beginning later this year. For full year '26, we anticipate that roughly 80% of revenue will come from the U.S. and 20% from international markets.

In Hematology and Oncology, net sales grew 116% to $204 million. Niktimvo, Monjuvi and Zynyz were the largest contributors to growth in the quarter. Niktimvo has now entered its second year following its launch in the first quarter of '25. Net sales were $55 million in the first quarter of '26, reflecting a strong consistent new patient start profile and solid persistency. We've built a broad growing prescriber base with virtually every BMT center in the United States using Niktimvo with all becoming repeat customers. Within 12 months, Niktimvo has captured 32% of the third line plus market. Finally, formulary and payer coverage remains strong for the brand.

Monjuvi sales were $49 million in the first quarter, up 67% year-over-year. Growth was primarily driven by uptake in follicular lymphoma following approvals in the U.S. and international markets. Looking ahead, the potential U.S. approval in first-line DLBCL represents an incremental growth opportunity starting in 2027. Finally, Zynyz sales were $41 million in the first quarter with rapid and robust adoption in SCAC.

Now I'll turn the call over to Pablo.

Thank you, Bill, and good morning, everyone. We have made strong progress year-to-date across our hematology, oncology and immunology franchises, delivering key regulatory and clinical accomplishments.

Turning to hematology. We achieved several important milestones for 989, our mutant CALR monoclonal antibody, where pivotal development efforts continue to advance. Most notably, this includes the positive end-of-phase meeting with the FDA in the first quarter. As a result, we're on track to initiate the Phase III study evaluating 989 in patients with previously treated essential thrombocythemia midyear, a key inflection point for this program. Our JAK2 V617F inhibitor program, 058, continues to progress. During the first quarter, we initiated our Phase I dose escalation study evaluating the ASD formulation of 058 in MPN patients with a JAK2 mutation. Preliminary data in a modest number of patients anticipated by year-end, which we expect will provide early evidence of clinical efficacy as well as an increased understanding of the viability of the ASD formulation for future development efforts.

In parallel, we're progressing our next-generation compounds through preclinical studies. We remain confident in the underlying thesis that the inhibition of V617F will lead to positive clinical outcomes in patients with MPNs that harbor this mutation.

Lastly, in addition to the previously announced positive top line data for tafasitamab in first-line DLBCL, we plan to present the full data set during a featured oral presentation at the upcoming ASCO Annual Meeting in June. This data supports global regulatory submissions for tafasitamab in first-line DLBCL with approval and launch anticipated early next year.

Turning to oncology. During the quarter, Zynyz was approved by the European Commission for patients who previously untreated squamous cell anal carcinoma, adding a second indication for Zynyz in Europe. In our pipeline, this month, we initiated a Phase III study evaluating our KRAS G12D inhibitor, 734 in combination with chemotherapy in first-line pancreatic ductal adenocarcinoma or PDAC patients. This marks a significant step for the program as it enters late-stage development in a setting with substantial medical need.

Finally, in immunology, we have made meaningful regulatory and clinical progress advancing our late-stage portfolio. Notably, this includes the new drug application acceptance by the FDA for povorcitinib in moderate to severe hidradenitis suppurativa as well as the positive results of our Phase III registrational program evaluating povorcitinib in patients with nonsegmental vitiligo.

I will now turn to 989. In the first quarter, we had a positive end of face meeting with the FDA on the development program in ET. The Phase III trial will evaluate 989 compared to best available therapy in both type 1 and nontype 1 mutant CALR positive patients with ET who are resistant or intolerant to at least one prior cytoreductive therapy. The trial will utilize a flexible dosing schedule starting with 750 milligrams IV every 2 weeks, with a single dose escalation option built in to allow for appropriate optimization based on early platelet response. The primary endpoint is durable complete hematologic response or DCHR at week 24. The reduction of mutant CALR VAF from baseline will be evaluated as a key secondary input in the trial, further underscoring the unique mutation-specific and potentially disease modifying profile of 989. We're encouraged by a dialogue with the FDA and have a clear and executable path towards forward Incyte second-line ET with a Phase III study on track to initiate midyear.

In parallel to ET, we're progressing our development efforts in myelofibrosis, or MF, where we are evaluating 989 as the first and second line treatment option. Data from our ongoing Phase I program will be shared throughout the year. We remain on track to initiate a Phase III trial evaluating 989 as a second-line treatment in mutant CALR policy patients with MF in the second half of 2026, pending alignment with the FDA in the middle of the year. The Phase I cohort evaluating 989 as a single agent and in combination with ruxolitinib in patients with previously untreated MF is enrolling well. Finally, we initiated and completed a Phase I study evaluating a subcutaneous formulation of 989 in healthy volunteers, supporting our strategy to expand utility and improve convenience for patients. These results enable the initiation of a Phase I study in mutant CALR positive patients in the second quarter.

I will now turn to our oncology portfolio. Starting with 734, a KRAS G12D inhibitor, which is emerging as a very important pipeline opportunity for Incyte. The Phase III trial evaluating 734 in combination with standard of care chemotherapy, gemcitabine plus nab-paclitaxel or modified FOLFIRINOX in first-line PDAC is underway. More than 200,000 patients are diagnosed with PDAC with G12D being the most common driver mutation impacting 40% of patients. Today, there are no molecular targeted therapies for patients with pancreatic cancer and chemotherapy has been the foundation of care for decades.

What we believe is particularly important is the combination profile of 734 with standard of care chemotherapy. To date, 734 has demonstrated a manageable tolerability profile we combined with either gemcitabine plus nab-paclitaxel or modified FOLFIRINOX without compromising chemotherapy dose intensity. Given how PDAC is treated in practice, especially in the first-line setting, that ability to combine effectively with both full dose chemotherapy regimens is critical. This is reflected in our Phase III development program.

Our maturing Phase I data reinforces our conviction in this opportunity, which we view as increasingly derisked. We plan to share efficacy and safety data from the Phase I study in combination with modified FOLFIRINOX and gem/nab in first-line PDAC patients in the second half of the year. The distinguishing feature of our development approach is the scale and depth of our Phase I clinical program where roughly 400 patients have been treated with 734 across PDAC, colorectal, non-small cell lung and other 12D mutated cancers. This has allowed us to build a robust and comprehensive understanding of both clinical activity, safety and tolerability across tumor types and treatment settings, which is informing our development efforts.

With a strong early clinical foundation and Phase III development now underway, our focus remains on execution as we advance this program that has the potential to become the first KRAS G12D specific inhibitor approved in first-line PDAC. In parallel, we continue to evaluate expansion opportunities in additional G12D-driven tumors, and we plan to share more about our efforts later this year.

Oncology portfolio has reached an important inflection point with each of our core programs now in registrational development and actively enrolling patients. Pivotal efforts for A90, a TGF-beta receptor 2 by PD-1 bispecific are underway. The Phase III trial evaluating A90 in combination with FOLFIRINOX bevacizumab in first-line MSS colorectal cancer patients is ongoing. In the second half of the year, we anticipate sharing additional data from the Phase I study in combination with FOLFIRINOX, in first-line colorectal patients as well as a combination with bevacizumab in previously treated patients with colorectal cancer. 667, our CDK2 inhibitors in pivotal development in patients with platinum-resistant ovarian cancer Cyclin E1 over expression, a biomarker-defined population with significant medical need.

The MAESTRO clinical program consists of 3 studies, 2 ongoing trials, a Phase II single arm study and a Phase III versus investigator's choice chemotherapy and a planned Phase III study in the first-line maintenance setting, which we expect to initiate in the second half of 2026.

Finally, in immunology, we have made significant progress advancing our late-stage development efforts for povorcitinib, our oral JAK1 small molecule inhibitor. This includes the NDA acceptance in HS and as announced today, the positive results from our Phase II/III registrational program in nonsegmental vitiligo. In HS, last month, at the American Academy of Dermatology Annual Meeting, we presented late-breaking 54-week data from our Phase III STOP-HS program, which reinforced both the durability and the breadth of response associated with long-term povorcitinib treatment. Continuous improvements in clinical outcomes were observed at week 54 and with up to 71% and 57% of patients achieving HiSCR50 and HiSCR75 respectively. Further, up to 29% of patients achieved HiSCR100, the most stringent end point in HS which represents a 100% reduction in abscess and inflammatory nodules count with no increase in draining tunnels. Up to 20% of patients achieved complete clearance of draining tunnels and nodules at week 54.

Clinically meaningful improvements in skin pain, fatigue and quality of life measures, outcomes that are highly relevant to patients and clinicians managing this chronic disease were also observed. Finally, from a safety perspective, both 45 and 75 milligram doses were generally well tolerated throughout the study, supporting the profile for chronic use in HS. This data supports the potential for povorcitinib to deliver symptom control and durable disease improvement in patients with moderate to severe HS, both before and after biologic therapy. With the regulatory application accepted, we look forward to working with the FDA towards a potential approval and launch in early 2027.

Today, we also announced positive results from our Phase III program evaluating povorcitinib in adults with nonsegmental vitiligo. Our Phase III program is evaluating the efficacy, safety and tolerability of povorcitinib compared to placebo in patients with nonsegmental vitiligo across 2 identical Phase III studies, STOP-V1 and STOP-V2 for 52 weeks. The program enrolled over 900 patients including 456 patients who received a 30-milligram dose of povorcitinib. In both trials, povorcitinib achieved the primary endpoint of greater than or equal to 75% reduction in facial vitiligo area scoring index, F-VASI, from baseline to week 52, demonstrating statistically significant and clinically meaningful reductions in facial vitiligo compared to placebo.

Statistically significant improvements were also observed in key secondary endpoint measures including total vitiligo scoring index 50 or T-VASI 50 at week 52. The 30-milligram dose of povorcitinib was well tolerated. The overall safety profile for 52 weeks is consistent with prior studies with no new safety signals observed. Across both studies, rates of treatment-emergent adverse events of special interest were low between 2% and 3% and similar between the povorcitinib and placebo treatment groups. There were no major adverse cardiovascular events. Only one TEAE of VTE was observed in the povorcitinib treatment group in a patient with multiple confounding risk factors, including smoking history, high BMI and intercurrent pneumonia. These results provide a clear and compelling path towards registration planned for the first half of 2027 and underscore the opportunity to add an oral alternative treatment for patients with vitiligo to our portfolio. We plan to share additional data from the trials in the second half of 2026.

Povorcitinib continues to produce compelling data in immune-mediated dermatological conditions. We have seen success in translating early Phase II findings into larger registrational programs with now 4 post Phase III trials across HS and vitiligo. As we look ahead, we expect data from our third indication for prurigo nodularis by end of year. In addition to povorcitinib, we are evaluating Opzelura in a Phase III registrational program for the treatment of mild to moderate HS with top line results expected end of year. If positive, this result would support a supplemental new drug application in 2027. And if approved, Opzelura would provide the first topical treatment option for patients with HS.

Our JAK/ANKO franchise is well positioned to provide topical to oral solutions across mild to severe immune-mediated dermatological conditions, and we look forward to providing more updates this year.

To close, we have a catalyst-rich year ahead with multiple late-stage data readouts, regulatory milestones and pivotal trial initiations across our 3 core franchises, underscoring the breadth, depth and maturity of our pipeline.

With that, I'll turn it over to Tom for a financial update on the quarter.

Thanks, Pablo. As Bill mentioned earlier, our total revenues and net sales for the first quarter were $1.27 billion and $1.10 billion, respectively, increasing 21% and 20% from the prior year. Our GAAP R&D expenses were $516 million for the quarter, increasing 18% from the prior year, driven by continued investment in our late-stage development assets including our mutant CALR, G12D and CDK 2 programs.

Moving to SG&A. GAAP SG&A expenses were $328 million for the quarter, increasing 1% year-over-year. Ongoing operating expenses for the first quarter of 2026 increased 14% year-over-year compared to a 19% increase in ongoing revenues during the same period, leading to a continued increase in operating leverage and margins. We reaffirm our full year 2026 total net sales, R&D and SG&A operating expense guidance.

Total net sales guidance for the full year 2026 is $4.77 billion to $4.94 billion representing a 10% to 13% increase from the prior year. This includes net sales expectations for Jakafi of $3.22 billion to $3.27 billion, Opzelura of $750 million the $790 million and hematology and oncology products of $800 million to $880 million. Total GAAP R&D and SG&A operating expenses are expected to be $3.495 billion to $3.675 billion for the full year. Finally, we anticipate cost of sales to remain relatively stable, representing approximately 9% of net sales.

I'll now turn the call back over to Bill.

Thanks, Tom. In closing, we're off to a strong start to the year. Our core business continues to deliver durable growth. Our pipeline is advancing with multiple catalysts ahead, and we've strengthened our leadership team to support the next phase of execution. As we look ahead, we see 2026 as a year of execution with multiple inflection points across the business that we believe will further strengthen both our near-term performance and long-term growth trajectory.

And with that, I'll turn the call over to the operator for Q&A.

[Operator Instructions] Our first question today is coming from Tazeen Ahmad from Bank of America.

Congrats on the positive data for povo for the nonsegmental vitiligo. I wanted to ask what your thoughts are as you prepared the next step, how do you see this coexisting with Opzelura in the commercial space? What's been your experience with marketing and this indication so far? And do you think that each of these drugs could be appealing for a different segment of vitiligo?

Yes. Thanks for the question, Tazeen. I'll make a few comments and then ask Mohamed, our U.S. commercial head, to also expand on how we're thinking about vitiligo. I think there's a real opportunity here with the FDA approvals of oral treatments to essentially unlock the vitiligo market in the same way that advanced systemic therapies unlocked AD and psoriasis. I think that these approvals will create awareness that vitiligo is a chronic inflammatory disorder. And I think that is important for everybody that's going to be in the market.

This is definitely about medicalizing the condition. Frankly, I think Incyte does have an advantage in that we have a topical to oral solution. There is a natural sequencing that sets up in the vitiligo market and we're able to cover sort of the waterfront with both Opzelura as well as with povorcitinib. And that's ultimately going to be, I think, the key to success here -- we have the advantage of incumbency. We have direct ties to the providers. We know how they think about this condition. We understand the education that's required to increase the treatment rate -- and we, of course, have interactions with payers on this front, too. And so I think it's going to be an important contributor to povo being 1 of the 3 indications that we're pursuing right now.

Mohamed, do you have anything to add?

Really well said, Bill. Look, maybe just some context to the indications. We have obviously reason to believe there's 1.5 million people living with vitiligo in the U.S. and only 20% to 30% seek treatment, like Bill mentioned, a good portion of those patients, about 35% of them have a BSA less than 5. Those are going to be really good patient segments for Opzelura. You even have a patient segment between 5 and 10 BSA. That's also a target patient population for Opzelura. And then for patients with BSA greater than 10, where systemic therapy is most likely we estimate that total addressable market to be about $1.5 billion to $2 billion, which gives povo a great opportunity to address that need as well. And like Bill mentioned, having a topical to oral continuum for vitiligo and even HS if both products get approved, puts us in a really unique position as Incyte to satisfy that patient journey from the beginning all the way to advanced treatment.

Next question today is coming from James Shin from Deutsche Bank.

I appreciate all the color on 989. But I just wanted to check in, will 989's EHA update be mostly a check-the-box kind of update? Or will there be some new wrinkles to glean? And just if I could sneak one in. I don't know if Suky is on the call, but Bill, I know you guys mentioned previously having expense discipline, but what changes, if any, will Suky brings?

Great. James, you snuck in a second question, so there may be a penalty after the call. I'll let Pablo answer the first question.

Thank you for the question. So the update at EHA it's going to be pretty substantial. We have continued to enroll in these studies. We have longer follow-up and we have continued to deepen our translational understanding of the effects of 989 in patients with both ET and MF. So you should expect continued growth in number of patients. In ET, we'll have approximately 100 patients enrolled and we'll report data in those. For MF in terms of the second line, we'll have about 45 patients, 45 patients, single agent and about 15 to 16 patients in combination with ruxolitinib. And I think, first of all, the data has continued to evolve well. We think the durability is an important point. We think the continued tolerability of 989 in this patient population is very important. And we do think that continue to see how the translational part of the story continues to evolve with clear evidence of disease eradication disease modification by 989 in patients with MPN is very important. So you should expect to see a lot more of that at EHA.

Yes. And as it relates to Suky, look, he has extensive experience at both large and small companies. We have a very strong finance department at the company. He's going to focus on the things that a CFO needs to focus on. both strategically and operationally. You want to make sure that your budget planning process is efficient and sharp. You want to make sure that capital allocation decisions are made intelligently. There's, of course, a role in terms of setting up the right systems so that we can scale the company and we're really glad to have him. So thanks, James.

Next question is coming from Stephen Willey from Stifel.

So I guess, congrats on securing the 24-week CHR endpoint in the pivotal ET trial. But just wondering if you can provide some more detail around the mechanics of dose escalation just in terms of the platelet response criteria that will be used to trigger that and then just how that works from a timing perspective. And then just as a follow-up, just given some of the flexibility here that you were given from the agency around the EP around the ET end point, just curious how you think this now kind of reads into your ability to secure additional flexibility from the agency in the pivotal second-line MF trial?

Go ahead, Pablo.

Certainly, so let me start with your last point there because I think it's very important. We had a very constructive set of interactions with FDA. So we're very, very happy how these conversations are going. And I think they recognize 989 is a fundamentally different way to treat patients with MPN. It's truly not only molecular targeted therapy but has the potential for disease modification, and that needs to be contemplated as we implement Phase III trials and as we select endpoint for these Phase III trials. So in terms of the conversations on MF, we believe, as you alluded to, that this will allow us to have a conversation with FDA about defining endpoints in MF that truly reflect the effects of 989 in terms of normalizing hematopoiesis, which we think it's a critical difference compared with existing therapies for patients with MF. So we'll provide more updates on this later in the year, but we think that dialogue is going to be very constructive as it was in ET.

In terms of your specific question about ET, if you remember the data we presented last year, with 989 does in patients with ET is a very rapid normalization in platelet count that happens very soon after the first dose. And by the end of the first cycle, it's about a month, most of the patients that will normalize plates have done so. So we believe that an early dose escalation at that point for patients that are not early responders is the right approach here to take into account the heterogeneity that we see sometimes in the response. So we believe that by this, we'll be able to cover patients with all kinds of mutations and have a treatment effect across the board in patients with ET.

Our next question today is coming from Etzer Darout from Barclays.

Great. Thanks for today's earnings update. So we noticed the updated guidance for ruxolitinib now in the second half versus early 2027 for first-line GVHD. Just -- maybe if you could talk about your expectation for that study? And given sort of the move up in time line, potential to maybe accelerate the pivotal program in combo with ruxolitinib?

I just want to -- I want to make sure your question is related to Niktimvo and the Phase III study with Jakafi?

Yes. The movement in the second half out versus early 2027 that you had previously guided to?

Go ahead, Pablo.

So let me take that. So the study -- the randomized Phase II study combining Niktimvo with rux and comparing that with rux and steroids, accrued very quickly, well ahead of schedule. As a result of that, we'll have data before the end of this year, and that will help us define the rest of the regulatory strategy to bring Niktimvo to first-line chronic graft versus host disease patients.

The next question today is coming from Ash Verma from UBS.

So just on 989, trying to understand the implications of this flexible dose escalation in ET pivotal trial design for the MF indication. So I mean how do you think that plays out? Like could this be a challenge if you have to titrate patients and some don't get the benefit of the efficacy unless you get the 2500 mg dose? And especially like how would that be relevant if you're pursuing the first line MF indication?

When you look at the data that we presented twice last year, a substantial percentage of patients with ET respond by normalizing platelet count at doses well below the dose escalation of 2,500. Based on that, we think that the starting dose of 750 milligrams IV every other week, is the right way to start because a lot of the patients with normalized platelet count with that. And that alone will support achieving the primary endpoint of the study, which is durable complete hematologic response at 24 weeks.

Now there's a percentage of patients like it tends to happen molecular targeted therapies that are less sensitive to 989. And for those patients, we thought one step up to 2,500 should cover the efficacy in that patient population. So we basically designed the study to try to cover the heterogeneity in this population. We believe that the early dose escalation step is the right way to do it. We believe that the rapid effect of 989 normalizing platelets in patients that will do so, will allow us to very quickly make that determination. And obviously, as I mentioned at the beginning, we had a very constructive discussion with FDA, and we reached an agreement on this.

Next question is coming from Michael Schmidt from Guggenheim.

I had one on 734, the KRAS G12D program. So nice to see the chemo combo study now up and running in PDAC. Pablo, just curious how you think about either potentially pursuing other registration opportunities in PDA perhaps with investigational therapies such as pan-RAS inhibitors? Or -- and then how do you think about addressing other tumor types such as lung and colorectal cancers?

Thank you for the question, Michael. So first of all, let me just say, we are very pleased how this -- the data are evolving. We'll have an update for all of you later in the year, but the combination with chemotherapy, which we showed the ability earlier this year at the ASCO GI meeting, but now the response rate data is coming in, and we'll have that as well as more durability data later in the year, and we're very pleased with the progress of this program and the implementation of the Phase III pivotal trial in first line. In parallel with that, we've done a lot of work in other contexts. First of all, in pancreatic cancer, we have a strong interest in adjuvant and we're trying to decide the right design there. You'll hear more about that in the second half of the year.

We're also then in combination with Erbitux, which I think one of the really important advantage of 734 in this competitive landscape is the absence of rash. And so the combination with EGFR inhibitors is key, and it will be key, we believe, to develop these therapies in colorectal cancer. So you'll hear more about that later in the year, which could be both in combination with Erbitux alone or Erbitux plus chemotherapy in different lines of therapy in colorectal cancer. And finally, we have enrolled a cohort of patients with non-small cell lung cancer. We'll have data on that in the second half of the year. All this gives you an idea how we're going to potentially expand this program later in the year, and we'll give you a comprehensive update when we present the updated data.

Next question is coming from Matt Phipps from William Blair.

I'll follow up on 734. I just wanted to confirm that all studies have resumed enrollment following that temporary pause a month or so ago to review those pneumonitis events? And I guess, is a history of pneumonitis and going to be an exclusion criteria for DAWN-303 Phase II study?

So let me recap on what happened here because it's important to have clarity. We had the event of pneumonitis. We reported -- we did a full program review that encounter 4 cases of pneumonitis in more than 350 patients treated. Importantly, 3 of those patients were receiving 734 in combination with chemotherapy. And 2 of the patients had concurrent infections. And an in-depth review of the data concluded there was no signal that about the incidence of 734 producing pneumonitis in these patients. But it's very important to remember. Now the Phase III study was never put in pause. We -- what we did is in order to amend consent forms and investigator brochure, Europe, it's an administrative reason, they put enrollment on hold in the Phase I study. So that -- those have been amended now. It will reopen. Nothing ever stopped in the U.S. We have continued to enroll patients. The implementation of the Phase III study continues apace without any interruptions.

The next question is coming from Judah Frommer from Morgan Stanley.

Just curious on Opzelura. If you could comment on competition, within the nonsteroidal topical market. Is that still a growing pie? Are you fighting for share just within the market kind of ex steroids? And then just curious on -- in terms of the long-term guide for Opzelura doubling, how important is it to have povo approved in those indications for those multiple tools within the tool bag for those indications?

Yes, Judah, thanks for the question. I'll start with the second question that you asked and then double back on the first. When you think about this business over the next 5 years, there's essentially 3 components to growth. And I do believe Opzelura has the potential to grow it, let's call it, a 10% to 15% CAGR over this period of time. First component is organic growth, which is what you're talking about, continued penetration of the AD and vitiligo markets.

The second component of growth is the launch of the HS indication for Opzelura and mild to moderate HS. And then there's the launch of Opzelura in Europe for atopic dermatitis, which could throw off $200 million to $300 million in incremental sales. And it doesn't require any heroic math to forecast at Opzelura can approach $1 billion -- let's call it $1.3 billion roughly by 2030.

Now as it relates to competition in the United States, I'm not so much focused on these modest market share shifts that you can see between products on a monthly basis. A few points here. In the first quarter, our share of new patient starts in the United States was 46%. And new patient starts, as you know, our NBRx is sort of the future, it's growth. TRx is tell you a lot about the base in the past. But when you're really monitoring and managing a business, you're focused on that NBRx number. NBRx volume or new patient start volume in the first quarter was up over 30% year-over-year and was at a higher rate than the market. And we had 2 to 4x more new patient starts in the first quarter than any of the other branded topicals.

I think the real key here, and this is true for us as well as anybody else that has a topical is that the use TCIs of is starting to moderate, and there is a shift from TCIs and steroids to these nonsteroidal branded topicals. And you see that month-to-month and quarter-to-quarter. I think the benefit we have is Opzelura is superior in terms of skin clearance and itch relief relative to a TCI. And it is a better long-term option than steroid. I think the product is set up perfectly over the next 5 years, and we're in a very, very strong position, and you have the benefit of operating in a market where there's a real tailwind, and that is the move away from steroids and TCIs. I think that probably covers it. I think as it relates to Povo, I think that's upside. The fact that we are able in both vitiligo and in potentially HS to offer a complete treatment solution topical to oral, that's how I think about it. Thanks for the question.

Next question today is coming from Ren Benjamin from Citizens.

Congrats on the quarter. My question is on 058 in the Phase I with the new ASD formulation. Can you talk to us a little bit more about how we should be evaluating those results? And when we see it in the second half, what you're looking for and how we view this and will the deal you made with Prelude and that molecule for which you have an option. When do you guys ultimately make a decision between the 2 and how?

Thank you for the question. So as I mentioned during my prepared remarks, we are now in the clinic with the new formulation, and we're going to have an update for you before the end of the year. What we would love to see here is that with the new formulation, if we achieve the right exposures that our preclinical data predicted were necessary to see an effect that then we will be able to confirm our conviction that inhibiting VC617F in this way with pseudokinase inhibitor, will deliver positive clinical outcomes of patients with MPNs. So that's basically the goal of the program for this year to deliver enough exposures with the new formulation to achieve concentrations that will hit the target hard enough to show clinical outcomes that matter.

Now when it comes to Prelude, we see that as a next-generation program potentially for us. We have internal next-generation programs, and we have an external next generation program, which is a Prelude 1. That's a time-based option. We'll have to make a decision at some point in time. And that data will be compared with the data from our internal programs as well as the data from the LEAD 058, and then we'll make a decision which once we move forward.

Our next question is coming from Mitchell Kapoor from H.C. Wainwright.

This is [indiscernible] on for Mitchell Kapoor. Congratulations again on the data. I was curious about povorcitinib in HP. So where do you expect to be earliest uptake to take place? Would you say in biologic naive patients post biologic failures or patients with specific disease features such as like draining tunnels pain or a high inflammatory burden?

Yes, Mitchell, thanks for the -- or excuse me, [indiscernible] thanks for the question. I'll make a few comments and then Mohamed will add. First of all, I would just step back and say that I think the HS market is tailor-made for an oral. This market is set up for sequencing oral to injectables. And that's something that's been missing. Think about all the value that's been ascribed to orals in the obesity market and povo has the potential to be the first oral anti-inflammatory. We expect to have a broad label, both in the pre- and post-biologic setting, which I think is a real advantage. 70% of our clinical data is in prebiologic patients. As it relates to early uptake, you certainly could envision that patients who are on a biologic right now, 1 of the 17s are TNF who have active disease or aren't achieving pain relief or have some injection fatigue could be an early source of utilization.

And if you think about the size of the biologic market, there's a range out there in terms of the estimates, it's 50,000 to 75,000 patients. If povorcitinib was to get 10% of 50,000 on an annualized basis, you'd have a couple of hundred million dollars in revenue. But I think the most important point here is we expect that we will capture patients at 2 distinct inflection points after an antibiotic before a biologic. And then after a biologic, whether it's a 17 or TNF alpha. And Mohamed right now is working on preparing that launch. So it is completely wired for success.

Mohamed, do you want to add anything?

Yes. Look, I mean, HS, as we know, is a large and growing market and has a significant unmet need. The disease is debilitating. It's characterized by chronic pain, drainage and flares and obviously, highly heterogeneous, right, with multiple cytokines. So when you think about the market, as Bill just described in terms of its size, 300,000 patients in the U.S., 200,000 actively seeking treatment and yet only 50,000 of them are in advanced therapy. So povo is positioned to address this market as the first and only oral treatment with biologic-like efficacy across all of the treatment parameters that are quite debilitating and by competing, like Bill mentioned, in both the pre- and post-biologic setting, povo has the potential to be somewhere between $500 million to $1 billion in peak sales. And I think at launch, you can expect an opportunity to capture patients on both sides of that inflection point.

Our next question today is coming from Srikripa Devarakonda from Truist.

And congrats on the most recent clinical data as well with povo. I have a question on the rux mutant CALR combo with the first-line data that is expected year-end. Can you remind us of data that suggests any synergistic benefit? And given how well ka is entrenched in the myelofibrosis market, if CALR mutant patients are doing well on Jakafi, where do you envision mutant CALR fitting, like is it a combo? Is it -- could it be a switch add-on?

Thank you for the question. So let me offer a couple of points. So let's start with the first part of your question about synergy. Preclinically, we saw additive to synergistic effects combining 989 with Jakafi and CALR mutated models. And I think what's important to remember is, first of all, Jakafi as well as it works and as important as a step forward, it has been in patients with MPNs as particularly in CALR mutated patients, very little, if any, disease modification potential. It controls the symptoms, some of the symptoms of the disease. Obviously, it leads to spleen responses. All those effects are much less in patients with CALR mutations. In fact, if you look at the control arms of the COMFORT study or the MANIFEST study, the SVR35 and Jakafi in CALR-mutated patients is approximately 20%. That's in previously untreated patients. So obviously, there's a need for something better for CALR mutated patients even in first-line MF.

The second part of the question is Jakafi does have a package, which is obviously produces a fair amount of anemia and thrombocytopenia. So what we're looking to do with 989 is fundamentally different. We're looking to restore normal hematopoesis. We're looking to eliminate malignant megakaryocytes from the bone marrow. We're looking to eliminate CD34 positive mutant CALR positive cells from peripheral blood. And as a result of that shift back to normal hematopoiesis, which as we've seen already, translates into improvements in anemia as well as spleen responses and symptom improvement. So when we put this whole package together, we'll show you the data by the end of the year in a larger group of first-line patients, we will have for you a regulatory strategy for 989 in first-line MF. But we think that the effect of 989 and Jakafi are fundamentally different in this patient population.

The next question is coming from Brian Abrahams from RBC Capital Markets.

Sounds like you've made a lot of progress with the 989 subcu form, having completed the healthy volunteer study. So I guess I was wondering if you could maybe tell us about the observations there. And then the scope and dose range that you're going to be testing in this ongoing Phase I study in patients and whether that in and of itself could potentially be bridging or whether you'll need integration of the subcu form into the Phase III?

Thanks for the question, Brian. Pablo?

So the data from the healthy volunteer study, as I mentioned in my remarks, has allowed us now to move very quickly into patients. We're going to test a very broad range of doses. Let me just assure you that they will cover all the potential doses that we're using in Phase III in ET and that we could conceivably use in Phase III in patients with MF. So we will have that covered.

In terms of implementing this in Phase III studies, this is a question of timing, Brian. Speed is really important here. We need to bring this medicine to market for patients with ET and MF as quickly as possible. We will not slow down the AD study. We're probably not going to slow down the second-line MF study to incorporate the subcu, and we'll have a bridging strategy at the back end -- our goal is to incorporate a subcu formulation in the first line MF study. And right now, the plan allows us to do that. We'll provide an update on both before the end of the year.

Our next question today is coming from Jessica Fye from Morgan Stanley.

I had another one on 989. I was hoping you could touch on the potential translatability of the ET design to MF as it relates to starting dose. And I guess really more specifically the potential for an up-titration approach particularly in the context of a potential 6-month primary endpoint where we're presumably going to be looking at SVR35 and TSS50 versus looking for an early platelet response like in ET?

Thank you for the question, Jess. So the journey in MF is just a little bit earlier. We need to spend a little bit more time with FDA discussing the design of the second-line MF study. So I'm going to be a little bit let's open about answering the question in detail. Now I think that the fact that we have an agreement on the potential for -- the potential on the step-up escalation in ET certainly can build -- we can build the framework around that in MF. I think the more important thing in MF to be honest, is to have a constructive dialogue with the agency on the primary endpoint of the study, which we intend to do and for which we have a lot of supporting data.

As I mentioned in an answer to a previous question, 989 is a fundamentally different type of medicine for patients with MF. This is about normalizing hematopoiesis not just a nonspecific inhibition of JAK that leads to some symptom improvement and spleen response. It's about normalizing hematopoiesis. We think that needs to be contemplated into the primary endpoint for the study in MF, and we intend to have that conversation with FDA. Conceivably, we could have the same to address the heterogeneity across the population, we could have a dose escalation step as well. In this case, it could take a little bit longer, but we'll have that conversation with the FDA as at the right time.

Thanks, Jess. Congratulations on the move to Morgan Stanley.

Our next question today -- actually our final question today will be coming from Derek Archila from Wells Fargo.

Congrats on the progress. This one is for Pablo. If you frame the setup for EHA and the update there earlier, but I guess, is the expectation we should see deepening responses in these MF cohorts at the update I just wanted to reconcile the eradication comment that you made.

So it's always -- look, we will have data that continues to show the effect of 989 as a disease-modifying therapy. And that consistently will show that we can continue to eliminate -- dramatically reduce in some patients close to eliminate the malignant population of megakaryocytes in the bone marrow and in peripheral blood. And you should see more of the translational data at EHA.

We reached the end of our question-and-answer session. Ladies and gentlemen, that does conclude today's teleconference and webcast. You may disconnect your lines at this time, and have a wonderful day. We thank you for your participation today.

Good morning, everyone. My name is Etzer Darout, Senior Biotech Analyst at Barclays. My pleasure to have Incyte joining us today, day 2 of our conference. With me, I have Bill Meury, President and Chief Executive Officer at Incyte. And to my far right, we have Pablo Cagnoni, Head of R&D at Incyte. Welcome to our conference.

Thank you.

Bill, I'm sure most of our listeners are fairly familiar with Incyte, but maybe provide some introductory remarks, maybe some of the key points around the business and the pipeline over 2026.

Yes. I mean we think about Incyte across 3 dimensions or therapeutic areas, hematology, which I would describe as the central identity of the company. We have an emerging solid tumor oncology business that really started to declare itself in 2025 at ESMO with our G12D inhibitor for pancreatic cancer and our TGF-beta/PD-1 for colorectal cancer, which are now in frontline Phase III studies. And then we have an immunology business that is anchored today by a topical JAK inhibitor called Opzelura. We expect to get an approval for povorcitinib at least by the end of 2026, early 2027.

And so in that area, we'll have a topical to oral solution, what I think is an advantage across 3 different immune-mediated skin conditions. We think about the business in 2 parts. We have a core business ex-Jakafi, which by 2030, we expect will be as big as Jakafi. That business in '25 did about $1.2 billion, was up 50% year-over-year.

Maintaining the health of that business is critical to navigating this transition in 2029 when we lose exclusivity for Jakafi. And the other part of the business is our pipeline. And we have 7 assets in development where 80% of our R&D investment is centered on. And those programs are continuing to declare themselves.

And so we take our core business, we layer on our pipeline and the company has the potential to go way beyond Jakafi and essentially set a new high watermark for Incyte. That's how we think about the business. The last point I'd make as it relates to business development, just like in any company, it will be used as a multiplier and to extend or strengthen the core business.

Great. Let's maybe start with Jakafi. And when you think about sort of -- it's a major source of revenue today, as you pointed out, but not sort of the growth engine longer term. When you think about sort of how you would internally measure sort of success maybe post Jakafi, is it about revenue replacement pipeline advancement, margin preservation. How do you think about sort of the bar for success for the replacement, if you will, ultimately of Jakafi?

Sure. It's a good question. We're not looking for a one-for-one replacement on Jakafi. If you really think about what we're solving for, it's top-tier growth post '29 and durable revenue earnings and cash flow, which is to say we want to minimize our LOE exposure. And there are 2 parts to the solution. I mentioned this core business ex-Jakafi. That business has the potential to grow at a 15% to 20% 5-year CAGR. So between now and 2030, it should approach $3 billion to $4 billion. And that is about managing the business on a day-to-day basis at a very detailed level.

Now growth is not linear. What's important in that core business is 4 product launches over the next 12 to 18 months. Jakafi XR, frontline DLBCL for Monjuvi, where we just reported top -- well, not top-line results, but released the results of our study, moderate AD indication for Opzelura in Europe, which will be an important incremental growth driver and then povcitinib.

Those 4 launches are important in terms of continuing to drive our core business. And then as we look at our pipeline, we made a lot of progress in 2025. When we started the year, we had no proof-of-concept data on 989. We had no proof-of-concept data on the G12D inhibitor, our TGF-beta by PD-1 -- we had no Phase III data on povorcitinib or combination data with Niktimvo and Jakafi at least from a safety perspective. We have all of those things now. And so what it means is we have much more visibility into the growth profile of the company in order to go beyond Jakafi.

And we'll measure our success this year, next year and the following year in terms of advancing those programs. But right now, we've fundamentally changed the shape and maturity of the pipeline. And I think it's probably more focused and strategically aligned than ever before. And then like I said, the next part of that equation is always BD, which will again will be targeted and selective and it will be used to extend the core, not looking to fill a revenue gap, looking to build the business into the 2030s that is an all-weather business essentially.

Great. And obviously, one of the areas of focus for Ensign is myeloproliferative neoplasms, right, given your position with Jakafi. You presented some NASH data suggesting benefits across spleen benefits, symptoms, anemia benefits for your mCALR program. And when you think about conversations with regulators across these different endpoints, if you will, what do you think ultimately matters most for patients, where if you think about sort of what a pivotal looks like, where you can really sort of highlight the benefits of like an mCALR program in that population of patients with [ MF ]?

Yes, it's a good question. I'll make a couple of comments and then just turn it over to Pablo to expand. First, I think with the data that we shared at ASH at the end of the year, 2025 in both MF and ET, it's a pretty sizable Phase I program. I think we've answered all the threshold questions on 989, our monoclonal antibody targeting mCALR.

On the ET side, we have a very complete -- a very high complete hematological response with pretty pronounced impact on BAF, so both the clinical and molecular end. And I think that the approval of 989 second-line ET is going to quickly reshape the use of hydroxyurea, which is an imperfect treatment. It's the best they have right now.

On the MF side, whether it's spleen volume reduction, SVR35, symptom relief, TSS50, anemia response. What you saw in that Phase I study is frontline efficacy in a second-line setting. And for hematologists out there, Jakafi has been a remarkable drug, made a big difference in patients' lives, but it's a trade-off treatment. You increase the dose, you control symptoms, but cause anemia. If you don't increase the dose, you avoid the anemia, but you don't control the disease.

And symptom relief is common in the treatment of MF, but molecular response is rare, and we have the potential for both with 989. We're going to be starting Phase III studies. We expect to start Phase III studies in the middle to the end of the year in both ET and MF, and we're currently in interactions with the FDA, and I'll let Pablo make a comment on where we're at.

So our goal, as Bill mentioned, is to start at least 2 Phase III studies this year. We started conversations already with FDA. Those conversations have taken place. And we're finalizing the protocol for the second-line ET study. And the important thing is what aspects are we reaching agreement with FDA.

So we need to agree on the population. This study is going to be in all comers, both type 1, type 2 and non-type 1 type 2 patients. We are reaching agreement with the agency on the dosing strategy. We agree with the comments that have been made that when you see the data that were presented at ASH, it seems like patients with type 1 respond at a lower dose. So we want to take that into account in this study, but we still want to keep on study.

The endpoint -- the primary endpoint is pretty straightforward here. It's going to be some version of complete hematologic response. But what we're trying to do with the agency is 2 things. We're discussing maybe accelerating the readout of the endpoint. The traditional approach has been 52 weeks. And then on the other side, incorporate in some manner, not as a primary endpoint, but in some manner, VAF as an endpoint to just get started with the clinical validation of VAF as an endpoint in patients with MPN.

So those things will be -- I'm confident will be finalized by the end of the month. At the latest, we will present the details of the next earnings call in the second half of April, we'll give you full details of the design of that study.

In the second half of the year, as Bill mentioned, our intention is to start a second-line MF study. Those conversations will take place soon with the agency, but we're finalizing a data package. And then we're making a push to start a first-line MF study, whether that's very late this year or early next year. It's a little bit in flux right now, but we're certainly moving as fast as we can.

And I would be remiss, if I don't comment real quick. The other important aspect of the development plan for 989 is a subcutaneous formulation that's going to enter the clinic this month in healthy volunteers. We're going to then move to patients as soon as possible. And by the second half of the year, probably early -- late third, early fourth quarter, we'll have not only the formulation, but we'll have the device, the subcutaneous device that we intend to use at some point. We're going to incorporate as soon as we can into pivotal trials.

And I think I wanted to talk about the anemia response, particularly in MF. When you think about that as it looks like a differentiator to us relative to sort of what you see with JAK1s. Is it really maybe a commercial story? Or could it be viewed as really just game-changing or transformative, I guess, for the patients that can see that anemia response benefit. How do you think that response gets positioned commercially?

Yes. I would say that I mentioned earlier that hematologists will sometimes describe JAK inhibitors as trade-off treatments. And it's because that anemia is a negative prognostic indicator for survival. In fact, if you look at patients with MF and severe anemia, their median survival is quite a bit shorter than those who have MF without severe anemia. The big difference is we're not just avoiding anemia.

And I think Pablo speaks to this quite eloquently, it's proof of mechanism that not only is 989 shrinking the spleen and improving symptoms, but it's restoring normal bone marrow function and red blood cell production. So I think it's a crystal ball into how 989 works.

I think the community is going to have to look at the totality of the data. It's not just about anemia. It's not just about the conventional endpoints, SVR35 and TSS50. But across the continuum, you have what appears to be a superior treatment to the current standard of care. And I think your comments about anemia are, like I said, really effectively describe the benefit that 989 provides relative to anything else to add Pablo.

I think it's an important distinction, as Bill said, because there are drugs that seem to have some impact on anemia, probably because they're less potent than Jakafi and so they're a little bit less toxic for red cell progenitors. What we showed at ASH is something fundamentally different. As you pointed out, in addition to the spleen shrink as a symptom improvement, we showed that more than 50% had really important improvements in anemia. We're talking about 1.5 gram, 2 grams improvement in hemoglobin over time.

And I think one of the questions that has come up is that because of discontinuation with Jakafi? The answer is no. We've talked about this before. We looked at patients with or without a prior washout and the impact on anemia is the same. And we looked over time and the anemia keeps getting better many months after stopping Jakafi. So this is not discontinuation of Jakafi, which is not to say that stopping Jakafi is not a good thing for the anemia, but the effect we're seeing is not Jakafi discontinuation.

And the other important part of the story is when you look at in detail of what's going on in the bone marrow, we showed that we are shifting back to normal production of red cells. And that is basically one of the key elements of disease modification that we're seeing with 989. The bone marrow is starting to normalize again and starting to make normal red cells again, and that's why hemoglobin goes up.

Great. And maybe on the 058 program, the JAK2V617F, I think in our discussions, there doesn't seem to be questions around sort of mechanism or rationale, maybe more around sort of the formulation and whether or not this formulation can overcome limitations of the prior work. Maybe your thoughts around maybe level of confidence for the new formulation for 058 as you think about being able to kind of show, again, clinical benefit with that program.

Let me start. I am confident on the mechanism. V617F is a driver mutation in these diseases. When you hit driver mutations hard enough, you get positive clinical outcomes. I mean we've seen that over and over the past 25 years.

So the question is, how do we hit it hard enough? 058, we knew entering the clinic, there are a couple of challenges, and we made this very clear. The therapeutic window for 058 is relatively narrow. It's not ideal. We thought it was good enough and still do to achieve what we need to achieve. We knew there was a solubility problem. We put a formulation initially in the clinic that we thought addressed it. It turns out we need something different. We introduced a solid dispersion formulation this quarter, and we will have data by the end of the year.

Based on the healthy volunteer data, I'm cautiously optimistic that we'll get to the exposures that we need to see evidence of clinical activity. Now we have 2 backup plans, one internal. We have backup molecules that we think have improved properties over 058. Those are being advanced as fast as possible.

And as you probably know, we signed an agreement with Prelude last year that gives us access to their V617F inhibitor programs. They are managing those programs. We have an option agreement. If at some point in the future, they share the data with us. If the data looks strong, we have the option to acquire -- fully acquire the program. So that's how we are addressing V617F. I think one or more of these approaches is going to get us what we need.

Maybe switch gears to lymphoma and tafasitamab with the update you provided for the frontline treatment in DLBCL. You mentioned R-CHOP is still very much used in that frontline setting. And I guess, how do you see the role of tafasitamab involving in that frontline setting?

Sure. The goal, as most people know, in frontline DLBCL is cure. 40% of people still don't achieve cure. As you know, that space is evolving. You have R-CHOP, which is just 50% of treatment. You have Polivy and then, of course, at some point in the future of Epkinly or this year, we should know whether or not it has utility in the frontline setting.

We have a strong efficacy signal in terms of PFS. We'll release more data in 2026 in terms of activity in subgroups and a manageable safety and tolerability profile. And so when you think about Monjuvi, think about the community setting, high-risk patients, aren't on our trial, and it simply represents an add-on or intensification strategy.

And to put in perspective for Incyte, if we were to get a modest portion of the frontline DLBCL market, call it, 10% or 15%, we could 2x the sales of Monjuvi on an annualized basis. And so I think it's going to play an important role. We don't need to take over the frontline DLBCL market. The data set that we're going to release in 2026 is a fairly competitive or very competitive data set. We'll submit to the agency in the first half of 2026, and we could have an approval at the end of '26, early '27, give or take.

Great. Maybe the I&I franchise with povorcitinib, you have a couple of important pivotal data points this year. Maybe first in PN, how much better does povo need to be relative to a Dupixent, if you will? And just if you think about sort of level setting expectations around that data set and how that can sort of play out or evolve?

I'll make a first comment and then turn it over to Pablo. I don't see whether it's HS, PN or vitiligo sort of a fight to the death or a market share battle or an either/or. I think what's lacking right now in those conditions is an oral anti-inflammatory. And HS, you can take a topical or systemic antibiotic and they got to jump all the way to an IL-17.

In PN, there's no FDA-approved oral. And I think there's an expectation of the dermatology community as it relates to sort of clearance and itch with all these conditions in PN, I think it was made for JAK inhibitors. And so I don't really look at it versus Nemluvio or versus Dupixent, but get the first FDA-approved oral JAK inhibitor for PN, and that's going to have a meaningful role in the treatment of that condition. I think the same is true in HS. And the same is true in vitiligo. Do you want to add anything?

I'll just add one quick comment on PN. I obviously agree with Bill's comments. I think one of the things that povorcitinib does very well, and we've seen that both in HS and in the Phase II and III and in the Phase II in PN is it works very fast.

When you look at itch, 2/3 of the effect that by about 2 weeks. And if you look at the median time to 4 points or greater itch improvement at the higher doses, that's 19 days. That's a lot faster than Dupi. And when you talk to dermatologists, they will tell you that Dupixent works, but it takes a long time to work, particularly when it comes to itch relief. And that's the key symptom in PN patients.

So I think povo is a great drug for PN. Obviously, we're very optimistic about the vitiligo results that we'll have in the middle of the year. And the speed at which it works, both in HS and PN, I think, are going to be, obviously, in addition to the fact that it's oral is going to be a key difference, I think for patients.

And in vitiligo relative to Opzelura, is it going to be a different patient population, complementary treatment? How do you see those 2 sort of evolving in vitiligo?

Yes, it's a good question. We'll have the only topical to oral backbone. And Opzelura has penetrated a fairly high percentage of the diagnosed and treated vitiligo patients, who have a BSA involvement of less than 5%. But for people with a BSA of greater than 5%, clearly, an oral treatment is more practical than a topical one.

And I think we have an advantage going into vitiligo. We're there now. We, of course, have the topical, assuming the data in Phase III are convincing, I think we'll expand that market in terms of diagnosed and treated because you have an oral versus a topical.

Maybe quickly on the TGF-beta PD-1 bispecific program, moving into a pivotal study in colorectal cancer. I think that was a bit of a surprise, if you will, to jump from Phase I to Phase III. Maybe again, talk about sort of what we could see from a differentiation or just data update that can maybe give us more confidence around sort of the pivotal plan around the molecule?

Please go ahead.

So I agree that historically, you sometimes take an intermediate step. The reason why we did this, when you look at the Phase I data, there's a couple of things that are unique. #1, we treated 100 with MSS colorectal cancer. I mean this is not the usual small 12-patient data set that -- so the point estimate for the response rate in that population, I think, is a pretty solid number, which is about 15%, including a lot of patients with liver metastases.

And again, this is third, fourth-line MSS colorectal. When you compare that with every other piece of data published with PD-1, PD-L1 inhibitors, pembro, nivo, atezo, the response rate to those agents is 0, not low, it's 0. There are no responders. And even if you look at the recent combinations with novel CTLA-4 inhibitors in addition to PD-1s, they've seen responses, but none in patients with liver metastases. We have about half of our responders have liver mets.

So that's the strength of the data. We think we have a drug in this population of patients. We combined with chemotherapy with FOLFOXbev, and we showed that the safety is there, they're well tolerated together. So then the question came, is there enough substance here to initiate a pivotal trial? When you look at the history of development of PD-1 inhibitors over the past 15 years, you'll see that a number of times that they have response rate of single agents in the low -- in the single digits to low teens.

When combined with chemotherapy in early lines of therapy, that has delivered about 8 or 9 different approvals. That's the path we're following. We think that the strength of the single-agent responses we've seen in late line, combined with chemotherapy in first line will deliver a positive trial. So at the end of last year, we initiated the study. The study is now accruing patients. And we will provide an update on the data set in combination with chemotherapy towards the middle of this year, just to give you more clarity what we've seen.

And when you think about portfolio construction, the company is going to take some calculated risks. If we're right, it's transformational. If we're wrong, we haven't bet the farm. I think Pablo's point about an intermediate step, given the breadth and depth of the Phase I data set, it made a lot more sense in this case to go into Phase III.

Great. Just maybe lastly on the KRAS program. The early data suggests meaningful activity. How are you thinking about sort of maybe going into maybe earlier line settings, particularly, where you may see lower tumor burden for those patients? How are you thinking about that?

So the data that we showed, as you point out, is a single agent second, third line. We also showed early data in combination with chemotherapy, ASCO GI, showing that we can combine our G12D inhibitor with both main types of chemotherapy in first-line pancreatic cancer, Genmab and FOLFIRINOX. So that's been established.

On the basis of that, we are initiating a Phase III trial in first-line pancreatic. We think that is the most important indication. We obviously are in a race with some competitors are going the same path, and we need to get there as fast as possible. We'll provide an update on that data in the second half of the year, again, just to give you clarity what we're seeing in terms of the combination with chemotherapy. At the same time, we're discussing internally what other indications should we prosecute with the 12D.

And I think you alluded to much earlier lines like adjuvant therapy and perhaps other combinations. We're doing a lot of that background work, and you should expect an update on how we expand this program in the second half of the year.

Great. Bill, Pablo, thank you for joining us, for your participation. And hopefully, you enjoyed the rest of the conference.

Thank you very much.

Thank you very much.

Thank you to our listeners as well. We'll be back shortly with our next session.

Good morning, everyone. I'm Andy Berens, senior biotech analyst at Leerink Partners on day 2 of our Global Healthcare Conference in Miami. We're very happy to have with us Incyte. We have Pablo and Bill. Thank you, gentlemen, for joining us.

Thank you for having us.

It's good to be here.

Yes. It's beautiful weather. Why don't we start? I mean, obviously, I think a lot of people know Incyte, but maybe just a general overview. I mean, you assumed the helm recently, and maybe we could talk a little bit about how the company, what's changed and what's remained the same, I guess, since you joined.

Sure. We're focused on the company against, I think, 3 dimensions. There's a core business ex Jakafi that we estimate over the next 5 years has the potential to reach about $3 billion to $4 billion in sales. So our core business ex Jakafi, which is all FDA-approved marketed products, should be as big as Jakafi by 2030. That's important. And that namely is Opzelura, Niktimvo, Monjuvi. And then we also put in there XR and povorcitinib, which will be approved over the next 12 months. That's sort of priority #1.

Then of course, we have a pipeline of 7 assets where about 80% of our R&D investment is focused. It's in hematology, oncology and immunology. We have 14 clinical studies that will be underway in 2026 against these 7 compounds and that, of course, builds the next growth phase for Incyte, and we'll continue to progress these programs in '26 and beyond. And more and more, I think there's visibility into what the potential of that pipeline will be. It hasn't completely declared itself yet.

But on an unadjusted basis, that pipeline has the potential of 2 to 3x our top line sales unadjusted. And then the third dimension is business development, which like at any company, will play a role in supplementing our growth and extending the core franchise. And that's how we think about the business. That's how strategic operational and financial decisions are made against those 3 areas.

Okay. Why don't we start, I guess, with Jakafi, and then I think we'll probably very quickly shift to the pipeline and things in development that you mentioned. But Jakafi has been a huge success for Incyte. There have been other JAK inhibitors for a while. There were concerns about competition. You have an XR formulation. You have other compounds that are -- we'll talk about in the pipeline in myelofibrosis and myeloid diseases. But how should we think about Jakafi over the next several years importance to the company and the investment thesis?

Yes, it's a good question. In 2025, it was up just around 10% year-over-year. Keeping it healthy is a priority because it's a funding vehicle for the new product launches and for the pipeline. It's got 3 indications, as you know, MF, PV and GVHD. All of 3 are growing. Our focus right now is maintaining a mid-single-digit growth rate on Jakafi between now and the end of 2028. We'll launch Jakafi XR in the middle of this year, and that will preserve a portion of the Jakafi revenue after it loses exclusivity.

In terms of conversions, and Andy, you know these models, you can assume based on analogs that we could convert about 15% to 30% of Jakafi. I'd like to use a sort of point estimate that's just below the midpoint of about 20%, which means we could preserve about $0.75 billion in Jakafi as we go through the LOE. And then, of course, the more important piece of our whole franchise as it relates to MPNs is in 989, the monoclonal antibody.

Okay. Yes, we'll definitely talk about that one. I just want to kind of get there because I know when we start talking about it, there's a lot to talk about. In terms of pricing, how should we think about pricing for Jakafi going forward?

Yes. We -- the company has done an exceptional job of managing gross to net and the average selling price for Jakafi. It's largely a Medicare Part D product as well as there's some 340B there. It's a relatively stable environment with the exception of migration of the 340B program, which can have an impact on every company's average selling price. I think we have it fairly well managed.

As it relates to XR, it should be in the parity ZIP code. In order to get XR put on formulary, we're going to have to set a price that makes sense, most importantly, for PBMs and health plans and at the same time, makes sense for Incyte. And I think there's a price point that is going to be agreeable to the PBMs and the health plans.

The key thing is to make sure that out-of-pocket costs for patients are not changed and that the net cost of the plan is not higher with XR than it is for IR. It will take us about 6 to 12 months to get formulary coverage. And then most of '27 will be about conversion. The second half of '26 when we launch will be about formulary coverage.

Okay. Well, like I said, Jakafi has been very, very successful. It's been the foundation the company has been built on and generated tremendous free cash flow. One of the things that Jakafi was successful at was you basically defined the regulatory goalposts for myelofibrosis with the SVR35, the splenic volume reduction and then also TSS50, which is a measure of quality of life and symptom improvement. So how difficult is it to then come along? A lot of companies have tried with other compounds to beat Jakafi at those 2 endpoints were essentially created for the molecule.

Specifically today, compounds that are looking to enter the MF space you're talking about?

Yes.

I think when you look at other JAK inhibitors that are out there or other mechanisms that are in development that could be introduced, I think they can be important treatments, but they're really tools for subpopulations, I think more niche in nature and refitting around the margins. I don't believe that there's going to be anything that disrupts the standard of care. In this case, Jakafi over the next couple to several years. I think that's how I see the competitive landscape.

Okay. And your program, so you've got several targeting different subgroups. We'll talk about the CALR. Do you think that those interventions can be Jakafi in symptom improvement and splenic reduction?

I think you have to look at the totality of the evidence when you look -- you're talking about 989 our targeted treatment.

Yes, yes.

And there are both clinical and molecular endpoints that matter in this whole equation. If you look at the data that we produced in Phase I in the second-line setting with 989 in both ET and in MF, it looks like first-line efficacy in a second-line study. That's whether you're talking about conventional endpoints like the SVR35, TSS50 or anemia response when you're talking MF, when you look at the results for 989 in the ET population in terms of complete hematological response or VAF reductions, that is a superior profile on paper to anything that's out there today, including Jakafi.

And if we could replicate the results from the Phase I study in Phase III in both ET and MF, there's a potential for a real changing of the guard in the treatment of both those MPNs. We'll start those Phase III studies this year, midyear and then end of the year. And I think the key piece about Jakafi, Jakafi is an important product and made a big difference in patients' lives. It's a quality of life drug, makes people feel better, but it's also a trade-off product. If you increase the dose to control the symptoms, you can cause anemia. If you keep the dose low, you avoid the anemia, but you don't control the symptoms.

On the ET side of the house with hydroxyurea, which is decades old, there hasn't been a change in the standard of care there. It's also sort of a product that requires a trade-off. Most patients with hydroxyurea can't get to 1,000 milligrams a day, which is dose needed, particularly for patients with high platelet counts to control the condition. I think 989 solves the trade-off with both the standard of care in MF, Jakafi and the standard of care in ET, which is hydroxyurea.

Okay. So why don't we pivot and start diving into 989 and the CALR pathway? What is the role of CALR in MF and ET?

I mean I think in the long run or not even long, in the medium term, our goal is to establish molecule-targeted therapies as a standard of care across all NPNs, Andy. We're starting with ET and MF with 989, which is, as you pointed out, a CALR antibody. And the data that we showed last year in 2 meetings and more recently at ASH clearly shows not only there is an improvement in clinical endpoints, which is what's going to matter for regulatory purposes and what matter to patients on a daily basis, as Bill mentioned, spleen reduction, improvement in symptoms and perhaps more distinct compared with other available therapies, the improvement in anemia that we saw, which was pretty dramatic in over 50% of the patients.

As important as that is, I think the other bucket that is really important is the translational data shows very clearly that 989 is eradicating the disease. It's a molecular targeted therapy eradicating cells that have the driver mutation. We saw that in the bone marrow reduction of mutated karyocytes. We saw that in peripheral blood with the elimination of CD34 positive CALR positive cells. And we see that in the progressive VAF reductions more dramatic so far in ET, but also present in MF.

So the way disease -- the word disease modification gets a little bit overused, but I think what we're seeing is truly disease modification in the sense that 989 can selectively eradicate the burden of disease in patients with ET and MF. I think that's the most important way to look at it in the long run because I think in the long run, that will translate in all kinds of benefits for patients even beyond what we've seen so far in terms of spleen reduction, symptom improvement and anemia improvement.

And Pablo, do you want to comment on the frequency of the mutations?

Yes. So the CALR, which was described, as you know, in 2013, is present in about 25% of patients with ET and about 35% of patients with MF. Now we need to spend a minute on this type 1, non-type 1 story. Type 1 is very clear. That happens probably in about 55% of those mutated patients with ET, maybe 55% to 60%. In MF, we think that frequency is higher. It's probably 65% to maybe upwards to 70%. Those are non-type 1.

The best way to characterize, and there's a small group that is type 2, and then there's a group that is non-type 1, non-type 2. And that is a very heterogeneous group of patients that has characteristics, some of those non-type 1, non-type 2 look more than type 1, some are non-type 2. So it's not as straightforward. I'm now for short, I call them type 1 and non-type 1 just because it's simpler. And the important part is, I think the type 1 is about 65% to 70% of MF and about 55% in ET.

Okay. And the difference between type 1 and type 2 and ET versus MF in terms of what we've seen, and we'll talk about the data with 989 and maybe we can talk about it now if you want. But it seems like there is a difference in activity targeting CALR and why would that be?

So 989, which is our first entry into the space, we've known from the beginning has different affinity for type 1 mutations than non-type 1, specifically type 2 in this case. So we knew there will be a difference in dosing. And we think largely that difference in affinity can be addressed with difference in dosing, but just increasing the dose. That's not to say that the efficacy in non-type 1 will be identical to type 1, but we can get pretty close simply by increasing the dose, which is what we intend to do in pivotal trials.

We are discussing -- we're in the middle of conversations with the FDA, and we're discussing a dosing strategy that we think will in part address this difference in affinity. I think it's important to note also that by the time of our quarterly call in April, we will have clarity and we'll be able to provide clarity on the design of the first Phase III trial in ET, which will be in second-line ET when it comes to population, which we intend to enroll all comers, dosing strategy in order to be able to address the differential affinity for type 1 and non-type 1 as well as the endpoints, including the incorporation of some molecular endpoints in the study.

Okay. And the endpoint, the molecular endpoints could be a pathway for accelerated approval or you don't know yet?

We think that in ET, based on the conversations we've had with the agency, hematologic response will be the approval endpoint. We intend to incorporate VAF as a molecular endpoint whether it's the hierarchy, we'll disclose that in April, but we think there's a way to incorporate VAF as one of the endpoints in the pivotal trial. The other conversation we're having with the FDA is the timing for the assessment of the primary endpoint where there's 52 weeks, which is what's been used traditionally in ET or it can be done sooner.

Okay. And what do you see when you target CALR, when we talked -- you mentioned the SVR35, the TSS scores. What about bone marrow changes? And you mentioned anemia, too, is improving. But what about some of the bone marrow changes? -- the hallmark of the disease?

What we saw and reported at ASH is there's 3 things that are important for, I would say, we see a very clear and very fast reduction of malignant megakaryocytes in the bone marrow. That's really part of the source of the disease, and they lead to the fibrosis in the bone marrow, which we also see improvement on. We saw improvement in fibrosis in the bone marrow. The second part is in peripheral blood, there's very mature cells in these patients that you don't see in normal population that are malignant CD34-positive progenitors. We saw dramatic reduction in those as well.

The third part is we saw an increase of normal erythropoiesis. So basically, cells that make normal red cells increase in these patients on treatment of 989. And that supports the improvement in anemia. So improvement in anemia is truly because of normalization of hematopoiesis in these patients, normal production of red cells in these patients. And then the fibrosis improvement is also important to note in a subset of patients. So overall, every measure of the disease, it's getting better on patients undergoing treatment of 989, and that's reflected on the spleen shrinkage, on the symptom improvement and the anemia improvement.

Is the fibrosis improvement is just to stop it from happening and then it starts to remodel on its own? Or is there some direct impact on this fibrosis reverse?

So malignant megakaryocytes produce mediator cytokines that basically trigger fibrosis. And by reducing those, I think fibrosis start to improve through remodeling. There's no direct targeting of the fibrosis by 989. It's just the reduction and hopefully, over time, elimination of malignant cells in the bone marrow that then allows the bone marrow to regrow normal hematopoiesis and remodel over time.

Okay. And I think you mentioned before that there's no way -- I mean, the FDA is difficult to biopsy, obviously, the bone marrow and there's inconsistencies because you're only getting a small segment. And there's no modality to measure with imaging the fibrosis yet.

We've continued to -- we're receptive to ideas. We've interacted with a number of institutions that have claimed to have a method that can be reproducible and widely applicable because if you're going to run a worldwide study, you need for this imaging assessments to be done everywhere. We haven't seen it, and I don't think biopsy is reliable enough. I don't think the FDA is going to agree to that.

Besides, I'm very happy if we can incorporate VAF and then as exploratory endpoints, we can have things as megakaryocytes and more important perhaps the peripheral. But those are really time-consuming cumbersome. I think they're very important to understand what the drug does, but they are not necessarily the right regulatory endpoints. I think in the molecular side, I think reduction in VAF might be the most -- the one that's going to be most widely applicable.

How much of a reduction in VAF do you think you need to have to see clinical benefit?

I don't think there is a line. What we saw in the ET trial, which is easier to measure because platelet normalization is such an easy to measure and reproducible marker. There is a clear correlation between degree of VAF reduction and degree of platelet normalization. That is pretty clear in ET. I think in MF, we need more data and more patients because VAF reduction in MF is lower.

Those patients have higher VAF at the beginning. They have lower residual normal hematopoiesis. And since VAF measures a ratio, if the residual hematopoiesis is lower, that ratio takes longer to reverse. So we've seen changes in VAF in MF. It seems to be taking longer than in ET. I think ET is a cleaner story. And in that one, there is a clear correlation between hematologic responses and VAF reduction.

Okay. Can we talk a little bit about ET because it seems to be a less well-defined disease right now. What we hear from physicians is a lot of patients are watch and wait compared to MF. But what's your sense of how these patients are treated now? And how could a CALR agent change that?

Yes. So I think the standard of care first-line ET today is hydroxyurea. I think a lot of patients are intolerant to hydroxyurea. It requires multiple dose adjustments because of the white cell count. I mean, basically, hydroxy is cytotoxic, right? It just happens to kill platelets and white cells. That's why it gets used in ET. Second line is in patients that are intolerant, which is very common or cannot quite maintain an adequate platelet count or they have a thrombotic event on hydroxyurea, the options are anagrelide or interferon and interferons have been developed as well in first line.

I think the important part with interferon is in second-line patients that are post hydroxyurea, the complete hematologic response to interferon is probably under 40%. So it doesn't seem to work very well. And anagrelide is probably under 10%. I'm talking about platelet normalization. So that's what's available, nonspecific therapies that just happen to normalize platelet count in some patients with some safety concerns and some cumbersome dose adjustments. I think what 989 brings to the table is a completely different value proposition. It is the first molecular targeted therapy, not just for ET, but for MPNs as a whole.

It showed very clearly not just platelet reduction, but platelet normalization. What we see in the graph that we presented at ASH is the platelets drop and they -- without those adjustments, they stop dropping once they normalize. The reason for that is 989 is killing the malignant cells and completely sparing the normal megakaryocytes. So then you normalize the platelets and you keep dosing the patients and those platelets don't move from there, don't keep going down. Also, we saw no leukopenia and really no anemia to speak of. So I think it's a different value proposition that would exist. And in general, when you look at hematology, malignant heme the last 25 years, going back to Gleevec, going through CD34 antibody, molecular targeted therapies, when they work, they really take over segments of the market based on that.

I would just add that because I've heard the indolent component of the ET population in the watch and wait group. Patients with a CALR mutation ET, there's about 20,000 of them. You remove watch and wait. They're not in that group. Real-world evidence studies with hydroxyurea, only about 25% to 50% of people get to a complete hematological response. Non-989 makes it to market. Someone has a CALR mutation, is not getting a response with hydroxyurea usually because they can't reach the dose, highly likelihood that they get put on 989.

If you stratify that population just one more level, about 25% of people are resistant to hydroxyurea, which is a negative prognostic indicator. That's about 5,000 patients. They're also going to be immediate candidates for 989. So I think even in a second-line setting, what's likely to happen is the use of hydroxyurea gets completely reshaped. Anyone that doesn't have control or isn't tolerating it because almost 40% of people have Grade 3 AEs would get put on 989. I think it's an underappreciated indication for 989, and it will be the first one.

Okay. And the natural course of the disease, the patients that don't get therapy, what percentage of them progress and then ultimately either get worse with more aggressive disease or end up getting treated?

So look, I think that there's a high-risk population from the beginning, which are patients that are older and they had either a thrombotic or bleeding event. I think the important thing to understand, let me put it this way, Andy, about ET is -- and this is more clear even in CALR-mutated patients. There is a point where this disease starts to progress towards MF. And when that happens, it doesn't happen in everyone, but it's hard to predict who is it going to happen on and when is it going to happen. But it does happen in a big group of patients.

What we're trying to do with 989 in that population and one of the many arguments for using 989 once approved in this population is that you can reset the clock another, let's say, 10 years. So if you're diagnosed with ET and you're in your 60s or 70s and all of a sudden, we add another 10 years to that clock, then ET becomes a solved problem for a very large group of patients just by a very well-tolerated injectable that patients can self-administer at home once the subcu is available, which is something we should discuss. Our subcu development starts this month, and we expect to have a subcu device and formulation ready for pivotal trials in the second half of this year.

Okay. And you also have several other compounds you said in development. You have a TC, but you also have another -- sounds like another MAB too.

Look, our MPN is an area where we're going to continue to innovate and continue to raise the bar of what we can do. We have a T cell engager in the clinic that's going through dose escalation. We'll present data at the appropriate time. We have continued to try to improve on the properties of 989 because we realized that the different affinity for type 1 and non-type 1 was something we could continue to improve even further.

And of course, we have the whole effort in V617F inhibition. We have a lead program in-house. We have a backup program in-house, and we have an external backup of our agreement with Prelude. MPN is an area where we want to bring a molecular targeted therapy for every single patient with these diseases by the end of the decade.

Okay. Can you talk a little bit about the JAK selective program you just mentioned, your internal programs and then the option you have with Prelude?

Our internal program is a pseudokinase inhibitor. 058 is a short name, entered the clinic a little over a year ago. We had some challenges with the original formulation. The solubility of this molecule is not ideal, and we knew that. The initial formulation did not solve the problem. We paused. We switched to another solid dispersion formulation that is entering the clinic. We'll have data later this year with that formulation. If that formulation solves the problem, then we'll proceed as fast as possible with 058.

We have a backup program that we think solves some of the problems of the lead. That is a pre-IND work is ongoing. We'll have more clarity towards the end of the year. Now we're constantly scanning the landscape for great ideas when it comes to molecule targeted therapies in MPNs. And it just so happens that Prelude, we thought had a really interesting idea in a different chemical space. So we basically did an option deal. They are running this program. We're not involved up to a certain point. At that point, we have the option to basically buy the program and bring it in-house. It will be a question of which one of these programs has the best data, but that's an option that we have on the table.

Okay. I know we have a couple of minutes left. We really didn't get deep into the pipeline. But what else in the pipeline would you I mean you have povo coming very shortly commercially probably. Do you want to talk about that a little bit and the time we have left?

Listen, we expect to be launching it in the first quarter of 2027. If we get a priority review, it would be the second half of 2026. You have a 3-indication JAK inhibitor, the first and only for HS initially. AbbVie will be shortly behind us with Rinvoq, probably first and only for prurigo nodularis and then it will be 1 of 3 in vitiligo. The indication for HS is probably the most important right now. That category, that condition is simply lacking in treatment options.

On one hand, you have oral antibiotics or topicals. And then the other, you have IL-17s, and there's no stepping stone in between. We have data both in pre- and post-biologic patients. If you look at HiSCR 50 or HiSCR 75, pain relief, draining tunnels, flare control, the data on povorcitinib are very, very convincing. I think we should be able to capture patients at 2 inflection points in the treatment of HS before a biologic as well as after a biologic.

You got a couple of hundred thousand people out there with HS. Only about 50,000 of them are taking an IL-17. The rest are on all off-label steroids or antibiotics. It will be an important first indication for the drug and important just from the big picture of shoring up our core business ex Jakafi. So when we hit the transition, you have a JAK inhibitor that's producing well over several hundred million dollars in sales and has the potential to be a $1 billion opportunity when you look across the 3 indications.

When we compare it to some of the biologics, what are the attributes? I mean, obviously, it's oral versus IV, but it sounds like there are other attributes to that you think are commercially appealing.

If you ask dermatologists when they look at it, you see biologic efficacy when you look at skin clearance and pain relief. Of course, it's an oral, which patients still prefer over a biologic. The other thing about JAK inhibitors to remember is they work fast. rapid. In other words, if you look at the pain relief in the studies with povo, about 30% of people had a 30% improvement in pain. Half of that benefit came in the first 3 weeks on the drug. And so it's a much more intuitive sequencing approach to go antibiotic, JAK, IL-17.

Now we'll have to deal with policies at the health plans. But if you use psoriasis as an analog, Otezla was a stepping stone before an IL-23. And I think in this case, povo has better efficacy on a relative basis than, for example, Otezla did versus the IL-23s. I think there's a real opportunity here. There's certainly going to be a lot of trial of the compound given the lack of treatment options in HS right now. This is going to get used.

And we expect data on Opzelura in HS in the fourth quarter, which is not really on a lot of radars right now, but we'll have a topical to oral backbone for the treatment of HS if we can get positive results with Opzelura and povo approved by the FDA. So I think we have a competitive advantage going into that category.

Okay. Let me see if there's any questions from the audience before we wrap up the session. Anybody have a question for Pablo or Bill? All right. Well, thanks, gentlemen. Congrats on all the progress.

All right. Welcome back to the 46th Annual TD Cowen Healthcare Conference. Really happy to have the next session here with -- I'm Marc Frahm from the biotech team here at TD Cowen, and we're really happy to have the next session, Incyte with Bill Meury, the CEO, to join.

Maybe just start off with, Bill, do you want to just give a kind of high-level kind of status update of the company? What do you think the kind of key value creation events for investors will be over the next 12 to 24 months?

Yes, sure. Thanks, Marc. I think about the business in three parts. Part one is we're focused on our core business ex Jakafi, which in 2025 finished at about $1.2 billion. We estimate by the end of '26, it could approach about $1.7 billion.

When you go out to 2030, we have a target for that business of $3 billion to $4 billion, which is to say that the core business ex Jakafi has the potential to be as big as Jakafi is today by 2030. It replaces it. Key to that growth will be products like Opzelura, Niktimvo, Monjuvi, povorcitinib and XR, namely. That's where the majority of our growth over the next 5 years will come from.

Second, of course, is pipeline execution. We have 7 products that are in late stages of development. That's where 80% of our R&D investment is in those 7 products. On an unadjusted basis, we estimate peak sales for that group of 7 products could be roughly $10 billion unadjusted.

Now not all of them are going to work. But I think the point here is we have much more visibility into the growth profile of our pipeline at the end of '25, beginning of '26 than we did at the start of 2025.

And so for example, we had no proof-of-concept data on 989. We had no proof-of-concept data on G12D for pancreatic cancer or TGF-beta by PD-1 for colorectal cancer. We had no Phase III data on povorcitinib. We had no frontline data in DLBCL with Monjuvi, and we had no combination data of Niktimvo and Jakafi from a safety set.

We have all of that now. We have more work to do in 2026, of course, and beyond. But I think the depth and maturity of our pipeline is stronger today than it was a year ago.

And then third is business development. And we'll use business development like any company to strengthen our core. We're not going to use business development to fill a revenue gap, but rather to create long-duration revenue earnings and cash flow.

And those are the three priorities of the company. We'll, of course, manage our cost base very carefully, both R&D and SG&A. In 2026, our SG&A is -- it's only going to be up about 4%, with G&A down 10%. And R&D, of course, is where we're leaning into to build a pathway to growth in that post-2030 period.

Okay. Great. Thanks for that overview. Maybe we'll start on the commercial side. The biggest longer-duration asset for you guys right now in terms of sales is Opzelura and your background on the commercial side. So now that you've been in the job for 6 months.

What -- as you've kind of looked into that franchise and looking forward, what has insight gotten right about the commercial effort? What needs to be tweaked and is being tweaked now? I think we saw a little -- one piece of it with there's some pricing concessions this year, but what else beyond that?

Yes, it's a good question. Fundamentally, that business is in a good position. And what I mean by that is strong demand, 250,000 patients take Opzelura annually in the United States. Prescription volume is going to be up 15% to 20% year-over-year. There's 20,000 writers of Opzelura, and you have exceptional formulary coverage.

What you're going to see in '26 is we'll expand the size of the target audience, which means we'll expand our sales force to drive growth of Opzelura at some point in 2026. We'll call on more physicians. That's number one.

Second, the NPPA specialty in atopic dermatitis is very important. That segment, it accounts for roughly 40% of all prescriptions. It will be bigger than dermatology in AD probably this year. And it's also the fastest growing. And so we'll relaunch or launch a new program to NPs and PAs, dedicated sales, dedicated MSLs, dedicated peer-to-peer program, dedicated materials. And I think that focuses us on the first priority, which is continue to drive AD vitiligo use in the United States with Opzelura, all right?

I think the other thing is the moderate AD indication in Europe is going to be a real value driver. And just to sort of put it in perspective, first of all, in the moderate AD study, the drug had an EASI50 rate of 70%. And there was itch relief in a large percentage of patients at 8 weeks. In fact, its relief in some patients, about 10% to 15% of patients was in 15 minutes. It's a really, really good topical antibiotic, topical anti-inflammatory.

In Europe, we did $130 million with vitiligo. We didn't have the AD indication. AD is 3 to 5x the vitiligo market. And so you could see revenue from Opzelura in Europe in AD approaching $200 million to $300 million over the next several years.

And then the last point I'd make about Opzelura is we expect to have data on the use of Opzelura and HS at the end of 2026. An indication for HS for Opzelura could be as big as both AD or vitiligo is in the United States, which is a couple to $300 million.

And then one of the guidance pieces was on the other oncology portfolio, which implied about 45% growth year-over-year in '26 versus '25. As we look at that kind of bucket of assets, what -- is there an asset in there that's like that's the one investors should pay attention to that's the real growth asset, that's going to drive it over the longer term?

Yes, it's a good question. I would focus on 2, and that is Monjuvi and Niktimvo. The majority of the growth in that business in '26 and even beyond is going to come from Monjuvi and Niktimvo.

As it relates to Monjuvi, we have a 2-indication drug today, CD19. We will release data in the second half of the year on our frontline DLBCL study. A modest share of the frontline DLBCL market because you do have Polivy out there and you have EPKINLY, there'll be others, but a modest share for Incyte, call it, 10% would double the annualized sales of Monjuvi today.

And so frontline DLBCL will be an important approval and new indication. Think community setting, think unfit patients, think a simple add-on to R-CHOP. And R-CHOP is still 50% of the frontline DLBCL market.

As it relates to Niktimvo, it's year 2, arguably the most important year in a launch. I'd say even more important than year 1, off to a very, very good start. We have to continue to expand use, not just in fourth line, but in third line.

Over the longer term, demonstrating efficacy on top of Jakafi or a steroid will be important to the long-term peak sales potential of Niktimvo. And so when you think about that other oncology business, that -- those are the two products that I focus on.

Okay. Just for the first-line DLBCL indication, is the marketing angle mostly going to be kind of the ease of use and convenience for the -- for -- particularly in some of the settings of community? Or is it a real efficacy differentiation versus some of the others besides R-CHOP that obviously you've beaten on a top line basis?

Yes, it's a good -- I think it's both. Here's what we know. We have a hazard ratio of 0.75. You'll see when we release the data of Monjuvi plus R-CHOP versus R-CHOP what the PFS percentages look like and the delta versus R-CHOP. And we'll also show activity in subgroups, ABC and GCB. And I think there is a benefit risk proposition for Monjuvi in frontline DLBCL in the community setting for certain patients that is as compelling as the alternatives.

And all we need to do to move the needle here is collect sort of as a base case, an incremental $200 million to $300 million in sales. It could be bigger. As you know, that frontline market is large. The unmet need there is cure, but only 40% of people are cured with current treatments. And so I think when you see the data in the second half of 2026, you'll look. And the totality of the evidence is fairly compelling.

But as you know, that landscape over the past couple of years has really started to evolve. And so I think we're focused on where the drug will most likely be used. And I think for a lot of people, it's going to be a simple intensification strategy tafa when on top of R-CHOP versus a replacement, which is what you do with Polivy or when you use a T cell engager, that benefit risk equation changes a bit.

Okay. And then XR should be launching later this year. I guess maybe can you walk through what the kind of value proposition is for that franchise versus traditional Jakafi, maybe from here to '28, '29 when the LOE happens? But then what's the value proposition to keep using it on the back end of the LOE?

Yes, it's a good question. You have a more convenient form of the standard of care. So just start with that. And I think that's clear. Once-a-day formulations and providers know this, payers know, will usually deliver an adherence gain of 15% to 25%, right? So there's the second sort of element of the proposition. Third, the price point is going to be economical for providers, for patients and ultimately for payers.

Most important with this XR is, one, generate demand; two, we'll activate consumers. We have a database of Jakafi users that is sizable that we've built over the past decade plus. Then you have to get formulary coverage and secure enough formulary coverage that moving patients from IR to XR is frictionless. And we will find a price point that makes sense for PBMs, payers and one that makes sense for Incyte.

Now this is a sprint. There's 2.5 years between now and when we lose exclusivity on Jakafi, and we're targeting a conversion rate in the range of about 15% to 20%. I focus just below the midpoint and call it 20%. When generic forms of Jakafi are available, there is going to be some headwinds on XR.

At that point, Incyte is not chasing the XR number. XR is simply a bridge in the 2030 period. And when you hit that period, we should be launching several products from the pipeline, which will shorten the duration of this trough and build essentially a glide path to growth. And certain formularies or certainly payers will keep XR and formulary. Others will want a discount. Others will remove it from formulary. I think all we need to do is get it to about 20%, and it gives us the bridge that we need.

And that's probably a good bridge now to talk about CALR. And 989, so obviously, we saw some data late in the year presented at ASH. But I guess what are, in your view, the questions that have clearly already been answered by 989? And what are the big remaining questions that you need to answer this year and beyond with that asset?

Yes. I think the threshold questions in terms of 989 utility in ET and MF have been answered. In ET, we have a complete hematological response of roughly just over 80%. real-world evidence data with hydroxyurea, which is the standard of care, the CHR is like 25% to 50%.

And unlike hydroxyurea, which has 7 warnings and precautions, 40% of people have Grade 3 AEs, the benefit risk profile of 989 is compelling. And I think the availability of it, even in the second line, will reshape the use of hydroxyurea. Anyone that's not getting complete hematological response who's in their 50s, going to live with the disease for 30 years is likely to get a targeted treatment. That's ET.

On the MF side, you know the data from ASH. We have an SVR35 that's roughly 33%, TSS 50 of 40% anemia response in 50% of people in a second-line setting. VAF reductions will take more time in MF because it's more complicated biology than ET.

Right now, the focus is complete our interactions with the FDA. By the first quarter earnings call, I would expect we'll be able to provide clarity on the Phase III program in ET second line. We've been having constructive interactions. The goals are still the same, type 1, non-type 1. If it's not 1 dose, it's 2 doses, that's not an issue. Both clinical and molecular endpoints, we're still talking about the length of the study, conventional is 52 weeks. That's most important.

We'll have that same conversation with the FDA on MF in the middle of the year. And I would expect by the third quarter call, which will be sometime in October, we'll provide more clarity on starting our second-line study in MF. Those are -- that is the regulatory milestones.

In terms of frontline, which is very, very important, I do believe there's a feasible path to frontline in MF, whether it's frontline mono or frontline combo, we will share data in the second half of the year, towards the end of the year on 989 in a frontline setting, both mono and combination with the expectation that if those data stand up, we could be starting a frontline study sometime in early 2027.

Okay. I think before we get to that presentation at the end of the year, there's also planned a more Q2 midyear update on the second-line patients. Maybe you want to frame that, the size and scope of that presentation. And I think you were able to get a few Jakafi ineligible people in back end of the ASH presentation. Are there more of those patients coming, which maybe gets a little bit of a flavor of what to expect at ASH?

Yes. So the data update for middle of the year with 989 second line, we had roughly 36 patients at the ASH in the -- at 24 weeks evaluable for efficacy. That number could be between 40 and 50, let's call it 45 patients. In the ET, I believe we had -- there were about 30 patients that were evaluable for efficacy. That number is going to be probably almost twice that, right? I'm just talking about at week 24.

As it relates to the frontline data, which was effectively a frontline population, JAK-naive, we're focused on the true frontline mono and combo study. And so you'll get a few more patients in that. What I would say about it is definitely a strong signal of efficacy.

It -- as you know, though, it's mathematically fragile. One patient moves across the line and you could move the SVR35, which was 57% in that population by 14 points. I think it was certainly encouraging, but the frontline data that we'll share will be the most important piece.

Okay. And maybe you started to touch on the design question for ET, just dose to address all mutations. How important is it to -- maybe for convenience and ease of prescribing, have one dose even if it means you're kind of overdosing some patients versus really optimizing the dose for the right dose for the right patient?

Yes, it's a good question. I think that one dose is always ideal. I think two doses is not an issue at all. If there was a -- the framework we've been working with, and all of this is subject to discussions with FDA, which are happening right now; if there's a starting dose and then an escalation dose, we'll have a subcu device on the market. I think that makes a great deal of sense for providers. And that is a framework that we're focused on.

Okay. And thinking back to going to frontline, when these trials started, there was this combo approach, particularly for the frontline, a concern that maybe the CALR antibody would take some time to really develop efficacy for patients and you'd want the kind of rapid action of Jakafi.

But I mean, given the data we've seen and that there are some fairly rapid responses happening, what's the rationale for that combination still? Is it -- or is it more like, look, this was just going and but -- so we'll see, but most likely, it's the monotherapy?

Listen, what you're -- I think what you're describing is an induction and maintenance approach. And in fact, if you ask most hematologists, put aside the regulatory environment and what you have to study how they would use 989, several have said to me, I can envision a world or a future where I'm using Jakafi and 989 together for induction and then maintaining patients with 989 for obvious reasons.

One, it's going to provide spleen shrinkage, symptom relief and improvement in anemia, not just less anemia, which I do think is proof of mechanism. And then, of course, you have the disease-modifying benefits, which clearly are going to take a little bit more time in MF.

Our view is given the results we produced in a heavily treated population, second line. I mean I remind people that the average spleen volume size for people in that study was [ 23 50 ], right, which is almost the same spleen volume as the COMFORT-I and II trials, and we had an SVR35 of about 25%, a small number of people. It seems to me that you're probably going to get better results if you take a combination and move it into a pure frontline setting.

And so all the options are on the table right now. When we get the results from our frontline studies, mono combo in the second half of the year, we'll make a decision about exactly how to prosecute this.

Okay. And maybe -- we're starting to get a little close on time. Just we'll turn to ET. We get a lot of questions about the IV formulation and how acceptable that is there or how much it really relies on ultimately getting the subcu of the on-body to work. Just what are your -- is IV a viable formulation if that's ultimately what you need? Or do you absolutely need the subcu?

In this population, I think a subcu is going to be really important. We've already started the healthy volunteer study. Our aim is that within the first 6, 12 months of the launch of 989 for ET, we follow with a subcu device. I think the gold standard for a fast follow IV to subcu was J&J's Darzalex. I think we'll do the exact same thing here.

There is the potential in ET to reach a several thousand patients. There are many patients out there that are not in the watch-and-wait bucket that are not low risk, but are actually high risk, and they don't have complete hematological control and a targeted treatment that's easy to take is going to produce for us a meaningful revenue stream. And I believe the subcu will be available as we continue to move this program forward.

I think investors are used to with subcu like auto-injector pens and stuff, but this is a little bit different with the on-body. You want to talk through kind of the format and what that experience, what do you expect it to be for patients.

Yes. It would -- it's a disc, and it's a very elegant disc. It looks -- the company is an able and it was -- it looks like Apple produced it. It's not a big, clunky device at all. And we believe the admin you fix it on to a part of your body, and we believe the infusion time is going to be roughly 15 minutes.

And so -- and you do it twice a month. Do it 15 minutes, take it off, 2 weeks later, you do it again. If I was -- like I mentioned, if I was 50 years old with ET and was going to live with the disease for 30 years rather than taking hydroxyurea, I'd rather take an infusion every 2 weeks. And I think that's the aim.

Maybe you started to touch on a little bit of how the treatment paradigm may evolve in ET with this drug. Just what is that vision for what ET looks like on the back end of the second-line trial you're reading out? Because you have hydroxyurea, but also potentially in between you starting and finishing that trial, we'll also get bomedemstat data potentially for Merck. Just what does the ET paradigm look like in, call it, 2030 or something?

We have a targeted treatment that has high CHRs and fairly dramatic, deep, rapid VAF reductions. that you'll get more data on VAF with our update in the middle of the year. And I think you'll find those data in ET, which is a pure setting. I think it's a crystal ball into how the drug works on mutant CALR. It gets more complicated, as we know, in MF.

And I don't see a reason or a version of the world where 989 can't become standard of care relative to hydroxyurea or anything else that's out there for both hematological response and molecular response. And I think the control rates with hydroxyurea are very, very low, not because it's not a good cytoreductive agent, but because people can't get to the therapeutic dose of 1,000 milligrams a day.

And what's important to remember is that patients who have CAR and ET have very high platelet levels. like 1 million versus 600,000 or 700,000 with other mutations. And so 989 in a CALR population is going to be, I believe, differentiated relative to other alternatives.

Okay. And is there a first-line opportunity in ET? And what does that drug profile need to look like to really support that?

I do believe there is a first-line opportunity. We're starting second line. And I say that because of the point that we just talked about, which is CALR patients have very high platelet levels, dosing hydroxyurea high enough to control counts is more difficult. And in a first-line study, we may be able to show that in CALR.

That said, I think when a second-line agent -- the second-line study comes out with 989, I think hematologists -- someone said to me the other day, hydroxyurea is what we have, and it's important and it helps patients, but it's the equivalent of Tylenol for a fever.

And he went on to say that ET, while there's a large group of people that are in this watch-and-wait bucket or taking aspirin, there's many people that have gotten a partial response. They have residual symptoms, residual thrombotic risk, residual transformation risk and it's the equivalent of a ticking time bomb.

And so I believe the second-line data will be enough, but I think we're going to still look at whether or not we could do a first-line study.

Okay. And then the other mutation that's quite important in these diseases is the actual JAK2 mutation where you do have an inhibitor there. What is the bar for success? Is there any -- look like for a mutant selective JAK inhibitor? Is there any difference than how we thought about CALR just based on the biology being a little different? Or is it just the same kind of 30-ish percent response rate?

I think the framework, if you have both clinical response like you talked about SVR35, TSS50 and then molecular response, I think the framework, Marc, is the exact same thing as we see for CALR with 617. It's just that if you believe in 989, 617 is twice the size of 989, given the mutation frequency.

And maybe explain how -- you have a couple of different assets in the space. Just how they fit or rights to a couple of different assets in the space? How they fit together?

Sure. We actually have essentially four programs. We have a lead. We have an ASD formulation of the lead to improve solubility, dissolution and bioavailability. We have a backup 617 internally, and then we have the option on Prelude. And there's four horses in the race. And we're prepared to progress as many as we need to in order to solve what we think is not a PD problem, but a PK problem.

In other words, when you look at preclinical data with 617F, the very same models that predicted the utility of 989 in MF and ET also predict utility of 617 in MF, PV and ET. And I think we need to solve this PK problem, whether it's a prelude compound, I'm really impressed with the work that they're doing or whether it's one of our internal programs, we want to get to the finish line sooner than later.

Maybe we are running out of time. So maybe on povo, just so we get a lot of investor pushback of it's another JAK, like aren't they just going to lose out to other JAKs, even if people want to take that mechanism in some of these diseases you're developing? Just what are people missing about povo in your view?

HS is the most challenging dermatological condition you can have. There is no FDA-approved oral treatment for mild -- moderate to severe disease. If you look at the data, whether it's ours or even AbbVies, I don't think it's -- if I'm in a 1 of 2 situation in a market that does really well, that's excellent. It's a multi-cytokine inhibitor. Clearance rates, itch relief, flare control, draining tunnel clearance is as good with a JAK povo as it is with the biologics. It's oral. And the most important thing is it works faster.

What is missing today in HS? There is nothing in the moderate to severe that's oral. You can use an antibiotic, physician will tell you keep your skin clean, all right? And then you have to jump right to an IL-17. I believe there's an opportunity for povo to be positioned in a pre-biologic setting, which would be a natural sequencing from antibiotics, whether they're oral or systemic before you go to an IL-17.

There's, of course, the post-biologic opportunity, which is rather than sequencing through IL-17, you can move to a JAK inhibitor. But our data are very compelling. The most important thing for us right now is complete the NDA review with the FDA, assess the benefit risk, assuming it works in both pre- and post-biologic, we have a broad label. And I think there's a lot of potential there.

And then maybe quickly on G12D, obviously, a competitive space. You're towards the front of it. But how do you win long term? Is it just about being first to market? Do you think 734 is actually a differentiated G12D versus other G12D inhibitors?

Well, as you know, it's an on-off inhibitor, 80x more selective for G12D. And we know that we can combine it with standard-of-care chemo. I think the most important thing for us to do right now with G12D is complete the Phase III, demonstrate a PFS of call it, 9 months, hazard ratio of 0.7 and low grade 3 toxicity. And if we're 1 of 2 in pancreatic cancer, I think we're going to be just fine.

Okay. Unfortunately, that's all the time we have for today. We're already over a minute, so we'll have to stop there. But thanks a lot for joining, Bill. Thanks, everybody, in the room and online.

Greetings, and welcome to the Incyte Fourth Quarter and Year-End 2025 Financial Results Conference Call and Webcast. [Operator Instructions] As a reminder, this conference is being recorded. [Operator Instructions] It's now my pleasure to turn the call over to your host, Alexa Smith, Vice President, Investor Relations. Please go ahead.

Good morning, and welcome to Incyte's Fourth Quarter and Full Year 2025 Earnings Conference Call. Before we begin, I encourage everyone to go to the Investors section of our website to find the press release, related financial tables and slides that follow today's discussion. On today's call, I'm joined by Bill and Tom, who will deliver our prepared remarks. Steven, Dave Matteo and Mohammed will also be available for the Q&A portion of today's call. I would like to point out that we will be making forward-looking statements, which are based on our current expectations and beliefs.

These statements are subject to certain risks and uncertainties, and our actual results statements to differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. I will now hand the call over to Bill.

Alexis, thank you, and good morning, everyone. I'll cover 2 topics today. First, I'll give an overview of our performance in 2025 and then I'll turn to our outlook for 2026 and beyond and the steps we're taking with our core business and pipeline to transition Insight. As I touched on at JPM, there are several achievements in 2025 that stand out. First, our business exceeded expectations on 3 levels: total sales, Jakafi sales and our core business sales ex Jakafi Second, we fundamentally changed the shape and maturity of our pipeline. We moved multiple assets from early to late-stage development.

We now have several outlier opportunities for the treatment of MPN and pancreatic cancer, colorectal cancer and HS that have the potential to drive revenue, earnings and cash flow into the next decade. Finally, regulatory applications for Jakafi XR, Opsilora for moderate AD and povacitinib for HS in Europe were submitted on a timely basis. The point here is we have much greater visibility into the potential growth we file of the company now than we did at the start of 2025. Everything we accomplished this past year commercially, scientifically and operationally has created the foundation for an inflection point in '26 and beyond.

Now I'll speak to our performance in '25 and the outlook for '26. Turning to revenue. The business performed exceptionally well this past year. Revenues in the fourth quarter totaled $1.51 billion, up 28% versus the prior year. For full year '25, revenue totaled $5.4 billion, up 21% year-over-year. This was driven by strong commercial performance and an increase in milestone and contract revenue. Net sales in the fourth quarter totaled $1.22 billion, representing a 20% increase versus the prior year. For full year '25, net sales were $4.35 billion, also up 20% year-over-year. exceeding both expectations and our guidance.

Growth was broad-based with nearly every product contributing meaningfully. Focusing on our core business, ex Jakafi sales totaled $1.26 billion, representing over $400 million in growth and a 53% increase versus 2024. OpoloraNictimbo and Monjuvi, with the largest absolute growth contributors. This core business is expected to grow over 30% in '26 and has the potential to grow at a 15% to 20% 5-year CAGR and approach $3 billion to $4 billion by 2030. Now a few comments about the key products, Jakafi, Opselora and our hematology and oncology products.

Starting with Jakafi on Slide 9. Fourth quarter and full year sales exceeded expectations. In the fourth quarter, sales were $828 million, an increase of 7% versus prior year. Full year sales totaled $3.093 billion, representing an 11% increase year-over-year. Jakafi remains an integral part of our business and keeping it healthy is a priority. It continues to serve as a funding source for our pipeline and for future product launches.

A few comments on the fundamentals of this business. First, prescriptions increased 11% in the fourth quarter and 9% for the full year 2025 despite a growing base and competition. Second, demand was up across all 3 indications. TV will be the largest and fastest-growing indication in '26 and with a penetration rate of only 30% versus 6% to 7% and in frontline MF. It should be a reliable and significant source of growth going forward. And finally, formulary coverage for Jakafi remains excellent with near complete coverage across plans.

In '26, we expect net sales to be $3.22 billion to $3.27 billion. Prescriptions are expected to grow at a high single-digit rate, representing mid-single-digit sales growth compared to 2025. In terms of Jakafi XR, we expect to receive an approval and launch in the middle of '26. Given this timing, the second half of the year will be mostly about formulary access and '27 will be focused on conversion. We will share more about our launch plans and future calls. Now I'll turn to Slide 10 for Opel. Net sales in the fourth quarter totaled $207 million, an increase of 28% and full year net sales were $6.78, up 33% versus 2024.

Growth was driven by increased penetration in the U.S. AD and vitiligo markets, where Opsalora prescriptions climbed 24% and 15%, respectively. The pediatric launch for OpsilorAD is off to a strong start in the United States with sales already annualizing around $30 million. both dermatologists and parents are increasingly seeking nonsteroidal options for atopic dermatitis, driven by concerns about long-term steroid use. International sales for Opalora in Vitiligo doubled to $130 million in 2025. In '26, we expect sales of $750 million to $790 million, representing roughly a 15% increase at the midpoint.

This estimate is based primarily on continued double-digit volume growth in the United States for AD and Vitiligo, partially offset by price actions to expand formulary coverage as well as sustained double-digit growth internationally off of a larger base as we lap the strong full year launch for Vitiligo in Europe. Most of the benefits of the moderate AD launch in Europe in the second half of this year are expected in '27 and beyond. As I've said, our aim long term is to nearly double the size of this business. The nonsteroil segment of the AD market is growing 20% year-over-year, creating a significant tailwind as prescribing migrates from topical steroids to nonsterile options.

We still have a modest share of each of those segments, so there is substantial headroom for growth. In addition to this, our international business and new indications will serve as meaningful catalysts for the next phase of expansion. And now on Slide 11, we'll turn to our hematology and oncology products. Net product sales in the fourth quarter were $187 million, up 121% compared to prior year. Full year '25 sales were $583 million, representing an 83% increase compared to 2024, driven by Nictimbo, Monjuvi and Xina. Nic Timo finished its first year at $152 million. We achieved broad penetration deep utilization of BMT centers, and we've reached more than 1,400 patients with 13,000 infusions, in line with expectations Victim is being used widely in the fourth-line setting with increasing preference in the third line.

As it relates to Monjuvi sales were up 20% versus prior year based on a strong launch in follicular lymphoma in the middle of 2025. As you know, we released data in January in frontline DLBCL where Monjuvi plus lenalidomide showed a 25% improvement in PFS, improving an R-CHOP chemotherapy, which is a regimen that still accounts for 50% of the first-line DLBCL market. This year, we plan to present the data at an upcoming medical meeting, work to incorporate Monjuvi into appropriate guidelines and submit an sBLA in the first half with a potential FDA approval by early '27.

Looking ahead, we've set our full year guidance for the Hematology & Oncology business at $800 million to $880 million for the year, representing approximately a 40% to 50% increase compared to our performance in '25. Now 3 takeaways about '26 that I'd like to reinforce before turning over the call to Pablo. First, our core business, excluding Jakafi, has the potential to be as large as Jakafi is today by 2030. And A key part of that growth will come from product launches we expect late this year and early '27. I mentioned XR, Opilor and Monjuvi earlier, so I want to make a few comments about where we are with vatinib.

The NDA for povasitinib in HS has been submitted and we anticipate filing acceptance this quarter. As you know, HS is the first of potentially 3 indications: the others being PN and Vitiligo. Pogo has the potential to be the first FDA-approved oral treatment for HS. Here, we have an opportunity to capture patients at 2 critical inflection points: first, in the pre-biologic setting, a population with no FDA-approved treatments today. These patients are cycling through antibiotics and steroids that don't address the underlying disease biology.

Second, in the post-biologic setting where IL-17 and TNFs are used but where partial responses are common. An effective oral option could be transformative in both treatment settings. We'll talk more about launch plans and future calls. Second, our pipeline has the breadth and depth to support top-tier growth and the potential of 2 to 3x our top line over time. In '26 alone, we will have 14 pivotal trials underway across 7 assets by end of the year and multiple data catalysts.

Paul will walk through the status of our key programs. and the potential to double our business over time. And finally, we view BD as a multiplier, a way to extend and strengthen the core. we have the capacity to pursue a broad range of opportunities. Ultimately, the size and nature of any deal will be dictated by a strategic fit and the potential for durable revenue earnings and cash flow.

Now I'll hand it over to Pablo.

Thank you, Bill, and good morning, everyone. As Bill mentioned earlier, in 2025, the pipeline reached a new level of breadth and maturity setting up a materially different outlook for the company going forward. First, our approved portfolio and regulatory footprint broadened with approvals for Monjuvi in follicular lymphoma, sinus and squamous cell anal carcinoma and Opsilura in pediatric atopic dermatitis and alongside regulatory submissions for Jakafi XR, Opsalura and poricitinib. Second, positive clinical data meaningfully advance multiple programs including Phase III registrational data for pobasitinib in hydronatis supertivarHS and early-stage results supporting pivotal development for the mutant color program in MET KRAS G12D in pancreatic cancer and TGF-beta receptor to you by PD-1 bispecific in MSS colorectal cancer. .

In 2026, we will continue to build on this momentum through additional approvals, regulatory filings, pivotal data readouts and trial initiations. For our late-stage pipeline, we anticipate FDA filing acceptance for pobacitinib in HS this quarter, and we plan to submit an sBLA for tafasitamab in first-line DLBCL in the first half of 2026. With these submissions underway, we expect the potential approval and launch of 4 products in late 2026 and early 2027. The emphasis in '26 shift to advancement across the portfolio, as we expect 7 data readouts this year, including the positive tafacitamab data already shared in January and 14 pivotal trials underway across hematology, oncology and immunology by year-end.

Together, this reflects a pipeline that is increasingly focused, more mature and positioned to translate scientific progress into meaningful impact and long-term value creation. Our hematology portfolio is 2 priorities: expanding the addressable market of established products such as tafacitumab across a false spectrum of B-cell lymphomas and axatilimab in graft-versus-host disease and advancing novel therapies in myeloproliferative neoplasms via our MPM portfolio of targeted therapies. In GVHD, we're advancing Nick time in 2 first-line studies evaluating it in combination with ruxolitinib as well as in combination with steroids. Data from these trials are expected in early 2027 and early 2028, respectively.

Our MPM pipeline remains a key area of focus where we're advancing 3 targeted therapies: 989, our mutant collar monoclonal antibody, 784 are mutant collar by CD3 bispecific antibody and 058, our JAK2 V617F small molecule inhibitor. Each of these programs is designed to address a well-defined disease driver with the potential for disease-modifying activity and the opportunity to fundamentally change how MPNs are treated. Looking ahead to upcoming milestones. We expect to report Phase I data for 058 in the second half of this year. and Phase I data for 784 in 2027. With that context, I would like to turn to Slide 17 to review our progress with 989 and the breadth of development efforts for this program.

As a reminder, last year, we presented Phase I data evaluating 989 in color positive patients with essential thrombocythemia and myelofibrosis. The data presented at EHA and ASH in 2025 reinforce the potential of our approach to directly target the oncogenic driver mutation addressing both the underlying disease and key clinical manifestations. Importantly, this proof-of-concept results provide a strong foundation to advance 989 into pivotal Phase III development. We expect to initiate our Phase III trial evaluating [indiscernible] in second-line color positive ET patients in mid-2026, following regulatory alignment in the first quarter. Turning to myelofibrosis. We expect to initiate a Phase III trial in second-line MF in the second half of 2026 following regulatory alignment midyear.

In parallel, we continue to advance our ongoing Phase I study, which is enrolling second-line ET, second-line MF and first-line MF cohorts. We plan to share updated data in second-line ET and second-line MF midyear and new data from our cohort evaluating [indiscernible] as a monotherapy and in combination with ruxolitinib as a first-line therapy in the second half of 2026. Finally, we're advancing a subcutaneous formulation of 99 we aligned with the FDA on this development strategy last month, and we plan to initiate a Phase I study during the first quarter of 2026. The -- in December, tafacitamab was approved in both Europe and Japan in combination with lenalidomide and rituximab for the treatment of adult patients with relapsed or refractory follicular lymphoma following at least 1 prior line of systemic therapy further expanding its global footprint. In January, we reported positive top line results from the pivotal Phase III frontline trial, which evaluated tafacitumab and lenalidomide in combination with our CHOP as a first-line treatment for newly diagnosed high-grade DLBCL with IPI of 325.

The study met its primary Empeno progression-free survival and achieved its key secondary endpoint of event-free survival by investigator assessment with no new safety signals observed. We plan to present additional data from the frontline study, including overall survival and subgroup analysis at an upcoming Medical Congress this year. Based on these results, the SBLA for Pristine DLBCL remains on track for submission in the first half of 2026. If approved, Monjuvi has the potential to address the full spectrum of B-cell lymphomas. Turning now to oncology. Our oncology portfolio focuses on advancing novel therapies that target well validated by historically difficult pathways in high incidence cancers including colorectal, pancreatic and ovarian cancer. Starting with 890, our first-in-class TGFBeta receptor 2 by PD-1 bispecific antibody.

Based on data we presented at ESMO and following alignment with the FDA, we initiated a Phase III study in December, evaluating AO in combination with FOLFOX and bevacizumab compared to placebo in combination with all Fox bevacizumab in first-line MSS colorectal cancer patients. Next, 667, our CDK2 inhibitor has been evaluated in patients with platinum-resistant ovarian cancer with cycling E1 over expression, a biomarker-defined population with significant medical need. The Maestra clinical program consists of 2 ongoing trials, a Phase II single-arm study and a Phase III study versus investigator choice chemotherapy as well as a planned Phase III study evaluating 667 in the first-line maintenance setting in combination with bevacizumab.

734 is a highly selective KRAS G12D inhibitor that has demonstrated promising antitumor activity in G12D mutated solid tumors, including pancreatic adenocarcinoma or PDAC. Last month, at ASCO GI, we presented new efficacy and safety data evaluating 734 both as a monotherapy and in combination regimens in patients with PDAC. At the planned Phase III dose of 200 milligrams a day, 734 as a monotherapy demonstrated a 37% overall response rate in a predominantly third line and later population. -- with a disease control rate of 78%. In combination with standard of care therapies, 734 demonstrated a manageable tolerability profile when combined with gemcitabine plus nab-paclitaxel and modify FOLFIRINOX without compromising chemotherapy intensity.

Taken together, this data support the potential for 734 to be meaningfully integrated into frontline treatment for patients with PDAC. Earlier this year, we gained alignment with the FDA on the registrational program and are on track to initiate our Phase III trial in first-line PDAC in the first quarter 2026. If approved, 734 would represent the first G12D targeted therapy for the treatment of patients with pancreatic cancer. With pivotal trials now underway for CDK2, TGFb receptor by PD-1 and KRAS12, our strategic focus is turning to how we can expand these programs across additional tumor types and clinical settings.

Our objective is to broaden the potential impact of these programs and reach more patients over time. We expect to provide updates during 2026. Finally, in IAI, we have a JAK Anchor franchise with topical to oral solutions across mild to severe immune-mediated dermatological conditions. First, an update with Opsalura. In early 2025, we shared results from the Phase III program in prurigo nodularis, where obsolurametid primary endpoint demonstrate statistically significant improvement in itch compared to placebo in 1 of 2 registrational studies. In January, we received FDA feedback indicating that an additional clinical efficacy study will be required to support registration for this indication. As a result, we have decided to pause for the development of SalurnPN at this time.

Operas also been evaluated in a large Phase III registrational program as a topical treatment for mild to moderate Huttsuprativa, with results expected from the 2 HS1 and IH2 trials later this year. Haneda Suprativa is also the most advanced indication for povasitinib, our novel JAK1 small molecule inhibitor. Earlier this year, we presented 24-week Phase III data that further reinforce the differentiated clinical profile of povasitinib, demonstrating deep and sustained improvements across multiple key end points. Importantly, povacitenib also showed a rapid and robust reduction in skin pain and draining tunnels, a defining symptom for patients and a critical treatment goal for clinicians.

From a regulatory standpoint, we submitted the MAA to the EMA during the fourth quarter of 2025 and anticipate acceptance of the NDA filing by the FDA in the first quarter of 2026. Beyond HS, our Phase III registrational trials in vitiligo and PN continue to progress well. In vitiligo, we anticipate data from our 2 registrational Phase III trials STOP V1 and STOP V2 in mid-2026. In PN, we anticipate data from our STELPN1 and STOP PN2 studies expected by year-end. Finally, we continue to explore its broader potential with Phase II proof-of-concept data in asthma anticipated in the second half of 2020. Overall, 2026 is a pivotal year for opsolurand poblacitinib, with important key regulatory and clinical milestones across all evaluated indications.

To close, we have a catalyst-rich year ahead with multiple late-stage data readouts, regulatory milestones and pivotal trial initiations across our 3 core franchises, underscoring the breadth, depth and maturity of our pipeline. We look forward to an exciting year of execution and to providing continued visibility as these milestones unfold. With that, I'll turn the call over to Tom for a financial update on the quarter.

Thanks, Pablo. As Bill mentioned earlier, our total revenues and product revenues for the quarter were $1.51 billion and $1.22 billion, respectively, increasing 28% and 20% from the prior year. For the full year, our total revenues and product revenues were $5.4 billion and $4.35 billion, respectively, increasing 21% and 20% from the prior year. Our GAAP R&D expenses were $611 million for the quarter increasing 31% from the prior year. Our GAAP R&D expenses were $2.05 billion for the year. Ongoing R&D expenses increased 8% year-over-year, driven by continued investment in our late-stage development assets. Moving to SG&A. GAAP SG&A expenses were $390 million for the quarter, increasing 19% year-over-year. .

Our GAAP SG&A expenses were $1.38 billion for the year, increasing 11% year-over-year, primarily driven by costs associated with the U.S. oncology product launches in 2025 and timing of certain other expenses. Ongoing operating expenses for the full year 2025 increased 11% year-over-year compared to a 19% increase in ongoing revenues during the same period, leading to a continued increase in operating leverage margins.

I'll now turn the call back over to Bill.

Thanks, Tom. Before we close, I want to reiterate our revenue guidance and address our expense outlook for 2026. As mentioned earlier, we have set full year '26 revenue guidance of $4.77 billion to $4.94 billion, representing a 10% to 13% increase from prior year. This includes net revenue expectations for Jakafi of $3.22 billion to $3.27 billion, OpSalura of $750 million to $790 million; and hematology and oncology of $800 million to $880 million. Sales for our core business ex Jakafi will range between $1.57 billion and $1.69 billion representing roughly a 30% growth rate at the midpoint in 2026.

As it relates to expenses, I think we've achieved the right balance between maintaining financial discipline and ensuring we are not underfunding strategic initiatives or compromising our growth prospects. We will continue to get leverage out of this business where we can so that we can create financial breathing room to invest where it matters most. Ultimately, what we're solving for is the steepest possible growth curve post 29% and durable earnings and cash flow. We expect total GAAP R&D and SG&A operating expenses to be $3.495 billion to $3.675 billion in '26. At the midpoint, this represents a 4% increase versus prior year. driven primarily by targeted investments in our late-stage pipeline and launch readiness while maintaining tight control elsewhere.

We expect R&D to be up roughly 10% from last year, consistent with advancing programs that we believe can meaningfully shape the company's future. 80% of our investment in R&D is concentrated in the 7 programs Pablo reviewed earlier. As it relates to SG&A, G&A will be down 10% compared to last year. While sales and marketing is modestly higher to support the key launches in the second half of the year.

Together, SG&A will remain relatively flat year-over-year, reflecting deliberate reallocation rather than broad-based spending. Finally, we anticipate cost of goods to remain relatively stable in the 8% to 9% range of net sales. We have an excellent set of opportunities in front of us and a path to replace Jakafi. What matters most right now, like at any company is execution, getting things done, which means orchestrating product launches, running multiple Phase III trials to tight time lines and managing the business at a detailed level.

With that, I'll turn the call over to the operator for Q&A.

[Operator Instructions] Our first question is coming from Marc Frahm from TD Cowen.

Congress on progress. Maybe sort of with Pablo, for the CAR pivotal programs, just your latest thoughts as you've gotten into designing the Phase III, that's just kind of how do address the potential differences for 989 and dosing for some of the different CALR mutations to ensure full potency. That approach to start low, titrate up for those that need it. or maybe prospectively kind of wrap people to different starting doses?

Or is it just simplify things and max out dose for everyone. And then maybe just a quick clarifying thing on the commentary around obsolete pricing. Just how much of that was driven by the entry into -- your entry in new markets and needing to access those versus maybe some of the competitive launches putting pressure on the existing indications?

Go ahead, Paul. Paul we'll take the first one. Thanks for the questions, Mark.

Okay. So we're going to discuss this with FDA this quarter. So I just -- I'm going to try not to go far ahead of ourselves. What we're proposing in principle for the ET second-line study, which we intend to initiate this half in the first half of 2026.

First of all, the enrollment would be in all patients, patients with all types of mutations, both type 1 and nontype 1 mutations. And we're going to discuss with FDA a dosing strategy, which we think will address the differential potency of 989 across the range of mutations that you brought up in your question. We're confident that we have a good strategy. We're also going to discuss the primary endpoint of the study, which obviously will be some version of hematologic response, but the question there is the timing for the valuation of the primary endpoint, which we would like to discuss with the agency. .

So all in all, I think we're in a good position. We submitted a good package. We look forward to interacting with the agency, and we'll provide an update later this year.

Thanks, Pablo. And Mark, as it relates to Opsalura, not a competitive issue. We take a very long-term view of Opsilor. We have exclusivity to the end of the next decade. We just launched a pediatric indication. We potentially could have an HS indication. The market is really moving, as you know, as I mentioned, prescribing migrates from steroidal topicals to nonsterile topicals. This was about improving formulary coverage for the long term at the major PBMs so that it's a frictionless experience for dermatologists and patients. And I would expect the impact on ASP in '26 to roll off in 2027 and beyond. We'll be providing fewer discounts in the future than we did in the past. That's it. Thanks for the question. .

Your next question is coming from Tazeen Ahmad from Bank of America. .

Also 1 on obselura. So can you just give us your sense of what the uptake is in the current approved indications and the average number of tubes that are being used. We understand the importance of being on formulary, but we'd also like to get a better sense of how to better model sales on a go-forward basis.

I can break this down a little then. First, the AD business is growing at almost 20% year-over-year. And you saw that in our '25 results. And then you have a [indiscernible] business that's growing in the mid-teens. And roughly 60% of our business is AD and roughly 40% of it is vitiligo. I would also comment that we launched for pediatrics in 2025. And that business, when you look at prescription data on a weekly basis is already annualizing at $30 million. So when you're thinking about modeling [indiscernible] that business is going to grow over the next 5 years at about a 10% CAGR. That's how I would think about net sales.

The other piece of Opole you have to think about is the international business. Now internationally, we finished '25 with $130 million in sales in Vitiligo. We're launching for moderate AD in that same market in the second half of the year. Most of the benefit will be in '27. The AD market is 5x the size of the vitiligo market. So I estimate there's probably $300 million in incremental revenue for Opsalora internationally over the next 5 years. So we're going to -- we finished the year at roughly $700 million, give or take, just below, $300 million of that could come from the United States, driven by AD Vitiligo and then $300 million internationally just by the -- just with the launch in moderate AD.

What I haven't factored into this is we get an indication for HS, for Opsilor at the end of 2027. Most of our growth will be volume. We expect some modest price actions over the next several years. I think most of the heavy lifting as it relates to securing formulary coverage and the investment in that is behind us. and that's how you think about this business. Essentially, you're going to grow at a CAGR of, call it, 10% to 15%. Thanks for the question.

Next question today is coming from Michael Schmidt from Grogan Securities. .

This is Bose on for Michael. So just some questions on front line. I guess with Monjuvi succeeding in frontline DLBCL Bill, you had mentioned that 50% of patients are receiving R-CHOP, but can you help us understand how you're thinking about the overall opportunity for Monvisetting and just positioning versus Polivy. And then a quick follow-up, on the trial, with the IPI eligibility criteria, it seems like the trial would maybe have a higher enrichment of patients with a poor prognosis.

So I guess in this context, how should we think about the PFS benefit that you reported? And are there any implications here for 1 potential use across a broader family population?

Great questions. I'll have Pablo answer the second question, and then we'll double back and answer the first question. Thanks, Pablo.

So you're correct. The study was focused on patients with an IPI 3 to 5. And that is a group with the worst prognosis that what has been reported by some of our competitors in the frontline DLBCL setting. I also would encourage you, what we know today, obviously, as mentioned in the script, that about half the patients are still getting our top -- and the recently introduced competitors in this space do not address the need of all patients with DLBCL. As you know, there's an entire subset of patients here with GCB DLBCL that are not currently addressed by 1 of the more recent entries in this space.

We look forward to showing the full benefit of Monjuvi in this patient population. We think that the benefit in PFS that we reported is very competitive. As you know, the safety profile of Monjuvi is very well established in this context. So we'll discuss the results in more detail over the course of the year. but we're very encouraged by what we're seeing across the entire spectrum of patients with DLBCL with IPI 3 to 5.

Yes. I'll just make a couple of comments, and then I'll ask Mohamad who runs Monjuvi to finish up. Right now, we're going to have by the end of '21, early 27 at 3 indication products. And we'll finish this year somewhere in the range of the mid-$200 million. with an indication of frontline DLBCL, and I don't see it as a fight to the death between Polivy and Monjuvi. We have a very positive study in frontline DLBCL, clear separation in terms of PFS. It's simply an intensification strategy with Monjuvi being added to LEN and R-CHOP versus a substitution or replacement strategy with Polivy. And so there's incremental revenue associated with Monjuvi that will support building this core business in 2030 to $3 billion to $4 billion.

Mohamad, do you have anything to add?

Yes. Thanks, Jose, for the question. First-line DLBCL represents the largest potential opportunity for Monjuvi with approximately 30,000 patients treated any. And 50% of those patients, as was mentioned, are still being treated with R-CHOP today. And as Bill just described, Monjuvi is in addition to R-CHOP versus replacing R-CHOP. And as Pablo mentioned, full spectrum of efficacy across all different types of patients with the PFS benefit has been communicated, I think, positions Monjuvi, not just for short-term growth, but continues to make Monjuvi a meaningful contributor, as you heard from Bill and others around our growth rate in 2029 and beyond -- thanks for the question, Ross.

Next question today is coming from Eric Schmidt from Cantor pit. .

Maybe I'll ask about 890 your bispecific for colorectal cancer. Are we going to see any additional Phase I/II data in 2026? And does the pivotal study have an interim analysis? .

Thanks, Eric. Probably why don't -- Stephen, do you want to take that? .

Yes, Eric. So yes, you will see additional data over the course of the year. That program, as I mentioned in my prepared remarks, was initially -- the Phase III study was initiated already. We're in the process of expanding the footprint. We have identified more than 200 sites globally to execute this study. And we look forward to sharing updated data both in combination with altoxpevacizumab as well as other combinations that we are implementing for that program. So you'll see more data over the course of the year. We'll give more clarity on the specific timing of those as the year progresses, depending on submissions to different conferences.

Is coming from Salim Syed from Missile.

This is Eric Lavington on for Salim. I was just wondering if we could get a little bit more color on the OpsalurainPN and why the FDA was asking for another Phase III or recommending it. If that has any read-through to the Obsolor in HS? Or if perchance might have to do with trial designs for HSN?

Great. Thanks for the question. Steve and Stein will answer that for you.

Eric, thank you. You asked a few questions related to both PN and HS -- so just in Pablo's prepared remarks, if you remember, we conducted 2 large Phase IIIs in Parago nodularis. The 1 study was positive and statistically significant. The second study just missed -- based on comments during the year that the FDA made, we approached them if the combined analysis could suffice to get across the finish line. Because we have conducted 2 studies and 1 was negative, they strongly recommended that an additional trial, a third study would be needed in the setting and would obviously have to be positive to get it across the finish line.

So it's a unique situation where we had 2 studies 1 positive, 1 negative. And as Pablo said, that's why the programs currently pause while we debate whether or not to conduct an additional study. There is no read through to -- in our HS studies, we're doing standard regulatory development. Again, 2 large Phase IIIs accruing very well. As you know, our proof-of-concept data is very strong there. And obviously, we want those studies to be part and get across the finish line. And I don't know if Pablo wants to add anything else.

No, I will just add just a small comment on PN. While the second study did barely miss the primary import of itch, it was very positive for the Investigo Global Assessment or treatment success. So we're convinced that Obsolura has strong efficacy in patients with perianal areas. As I mentioned in my prepared remarks, we paused further development there. We're discussing whether we do -- we will or will not do an additional trial to try to support that indication. I obviously agree with Stephen. I don't think there's any read-through to the HS indication.

Your next question is coming from Saba Richter from Goldman Sacral .

Could you speak to the MLR bispecific here? You've guided to Phase I data next year. Maybe tell us more about this asset and how it could be differentiated from your current MCLR program. And then on 6 17F, where we'll see initial Phase I data in the second half -- what is your current level of conviction for this asset and walk us through the profile you want to see here to make that go, no-go decision? .

Thanks, Alvin. Pavel will take that.

Thank you, Salveen. So let me take first call or by CD3 bispecific program. So that study is really now accelerating. So we're very core the enrollment is going well. As you might remember, we designed our color by CD3 T cell engager, bispecific purposefully with the collar arm binding to a different epitope from our Color antibody. The reason for that is, obviously, if patients, for some reason, do not respond to the color antibody, there would be ideal targets for the bispecific -- now in terms of understanding where exactly will place a bispecific in the treatment paradigm for patients with MPNs, I think it's too soon for me to elaborate too much there.

We believe that there might be some patients that require more potent approach or that require a molecule that produces faster responses or perhaps that after initial responses to the color antibody for some reason, progress. As we generate the efficacy data that we will have next year for the bispecific, we will get more clarity into work the position in the treatment paradigm in patients with MPNs. As you know, and I reiterated at ASH last year, our goal by the end of the decade is to have a treatment solution for every single patient with MPN. That's why we think the bispecific could play a role.

Now in terms of the V617F program, we remain fully convinced that if you hit this driver mutation, the V617 mutation patient PN, if we hit it hard enough, we will get the same type of outcomes that we sell with the color antibody in [indiscernible] .

This is a driver mutation. We have a small molecule inhibitor. We have very strong preclinical package that we presented repeatedly. And we believe that if we hit it hard enough, we will get the same kind of transformative clinical effects and molecular effects that we saw with 989. We just need to generate that data. We are now entering the clinic with a new formulation that we discussed recently a solid dispersion of formulation. We will have data later this year. And once we have that data, we'll tell you what the next steps of the program are. .

And Pablo, also the key is that with 6 17F, we'll cover 3 MPNs, MF and PV not just MF and ET and the mutation frequency, as you know, Salveen, is 2x, 3x what it is for Callar. And so you'd essentially with 617 cover 80% of MF and ET and PV.

Our next question today is coming from Jay Olson from Oppenheimer. .

For patients as you plan your KRAS G12D CDAC study, can you share your thoughts on the trial design? And how are you doing the competitive landscape that's evolving in PDAC and potential advantages for your program? And do you plan to run any additional Phase III studies beyond PD ?

I'm going to have Stephen comment on the trial design, then I can come back with the competitive landscape and the expansion of this program. Go ahead.

Jay, thank you for the question. So as Pablo said, in the updated ASCO GI, we had that 37% response rate with very encouraging data on duration of response, potentially read through from duration of treatment to PFS. So we're really encouraged. I think the second really important point there was the ability to combine our 12D inhibitor with both standard of hair chemotherapy regimens in the frontline, so gem Abraxane plus modified filfurinox and the ability to deliver those regimens with the dose. .

So you can read through to that. Obviously, the study will go up on Krinal.gov as soon as it's open, that we intend to do a first-line study in combination with both chemotherapy regimens, we'll stratify accordingly, it will probably be 50-50 percent approximately each use, and it will be a comparison to the chemotherapy with standard time-to-event end points. We may look at things along the way in terms of response rate, et cetera. but it's a time to event study in that setting.

In terms of other studies beyond PDAC, obviously, this is a compound that we really like. I just alluded to the activity in PDAC. We have interest in activity in other tumor types with 12 Dis important, our colorectal cancer and lung, et cetera. So stay tuned to developments there. And including in PDAC as well, there's potential to potentially do things like adjuvant or neoadjuvant studies as well, which we'll outline as soon as we're ready to do so. So it's an important compound to us. We may well be the first 12 D to get across the finish line in terms of mutation specific therapy in a large tumor with massive unmet need and the ability to combine with both first-line standard of care chemotherapy.

And Jay, just regarding the competitive landscape, and I think this is true not just for 734 or G12D, but also TGF-beta PD-1. Both these cancers, response rates are low, survival times are short, and there haven't been novel treatments in the frontline setting in decades. G12D as a target was the Everest of oncology. TGF-beta by PD-1, no one's crack the code. Now we have to convert Phase I to Phase III. But I don't think this is about competition. These are the largest wide open white spaces in cancer, we could be first or early in pancreatic, and we could be first and only in colorectal.

So right now, we have to execute this program. And as Pablo talked about and Stephen expand these programs. And we have the capabilities and the resources to maximize both assets. If we ever needed a partner who would think about that carefully, expand our geographic reach, and we would do it on our terms. But we are sort of locked in on both of these, and I think competition is less important Phase III execution is most important.

Our next question is coming from Matt Phipps from William Banner.

This is Madeline on for Matt Phipps. On Poo in HS, did the pre-NDA discussions with the FDA discuss the potential to include biologic-naive patients in the labeled indication. .

Yes. Thank you for the question. I'll let Steven Stein answer it.

Yes. So obviously, our study included both populations, prebiologic and post-biologic. In fact, about 33% to 36% of patients had biologic exposure. You saw the activity which we updated during the year, showing extremely encouraging Hisar response rate that increase over time, excellent pain control upwards of 70% of patients over time having little to no pain and excellent data on draining tunnel. And that includes included in both populations. The post biologic activity is a little higher. We submitted the MDA, as we alluded to in our remarks, and that will be by the end of this first quarter should be signed off by the FDA, and we are seeking a label in both populations. .

Our next question today is come from Judah Farmer from Morgan Stanley.

Part on for Judah. We just wanted to get incremental color on expectations for the 99 readout and frontline MF later this year. What are you guys looking for in order to kind of move forward in that setting?

Pablo?

So by the second half of this year, we'll have a pretty substantial data set in patients with previously untreated myelofibrosis. And we're randomizing patients to 9 versus a combination of 9 ruxolitinib. So we'll have a very good idea of what the efficacy is in that population. Now let me make something very clear. I believe the data we have today with 989 that we presented at Asta we have with 989 most in previously treated patients with MF, a little bit of naive patients that were not legal for Jakafi. I am convinced that the efficacy and safety of 989 will support development in the first-line setting.

We do need the data set that we'll present later this year in order to discuss with the FDA how to design and implement the Phase III trials, -- but I'm fully convinced that this medicine will be developable in first-line MF. And we'll give you more clarity later this year.

Your next question today is coming from Andy Chan from Wolfe Research. .

This is Brandon on for Andy. Regarding the XR, any preliminary conversations with payers on formulary access or early signs that give you confidence on the eventual launch here? .

Yes, it's a good question. We absolutely have had conversations with every major PBM. Here's how I would think about it. I think that Jakafi is the perfect product for an X formulation because if you think about it, it treats a chronic symptomatic disease, the twice 8-day drug with a 3-hour half-life. And we know that once-a-day formulations produce an adherence gain of 15% to 25%. So there is a medical reason why this product should be put on formulary. That's point number one.

Point number 2 is we have to set a price that makes sense to the PBMs and the health plans for the patients and for insight. And there is a price point that's going to make sense. We think about it in 3 contexts. One is what is the net cost of the plan. two, what is the coinsurance and patient out-of-pockets and then three, what will be rebates. Now a new product, your goal is to get 80% to 100% coverage. -- with an extended-release formulation like Jakafi, you're probably not going to reach into that top tier of formulary coverage. But we should get enough formulary coverage to enable a conversion rate of 10% to 30%. And pick the midpoint. Most of '26 will be about that, you'll start to see meaningful conversion in 2027. Thanks for the question.

Next question is coming from Evan Singerman from BMO Capital Markets. .

When you're thinking about the Phase III HS data for solar in 4Q talk to me about how you plan to manage the placebo response for this trial, especially with it being tested in kind of the mild to moderate patient population, which you could have a more exaggerated dynamic with the placebo?

Thanks, Evan. Go ahead, Stephen.

Yes. Evan, thanks for the question. You're right. So when you have a lower burden of absence and nodules, you can get an inflated placebo response rate. The 2 ways, we're managing that in the Phase IIIs, a larger study, a greater end and setting the minimum number of requirement on absentees which should manage an artificial placebo response rate and then also looking at higher rates of Hisco control like Iscar75. So all of the above.

Larger study minimum number of absent nodules and a higher Hisco control rate and then obviously, 2 studies as well. And that's the main ways we're trying to control the placebo response rate.

Next question is coming from Derik Garcia from Wells Fargo.

Just quickly, so how much revenue contribution from RXR are you really baking into the Jakafi guide -- and I just wanted to clarify, so you highlighted 30% penetration for Jakafi in PV right now? I guess what level do you think you can get to before LOE? .

As it relates to the guidance for 2026, there's no incremental revenue associated with XR in that number. And so we expect that Jakafi in '26 between PV and GVHD will grow in the high single digits, and there is going to be some modest price actions, and that gets us to the current guidance. When you think about this business over the next 3 years, the 2 indications that are growing at a double-digit rate, PV and GVHD. And I would look at this as a mid -- maybe mid- to high single-digit grower between now and 2028, the end of 28 when we actually transition and generics are introduced. I think it's the best way to model and think about the business.

I think I've been pretty consistent about how to think about Jakafi. And as it relates to conversion, if we can pick up, take the mid-20%, 20%, you're going to have almost $0.25 billion sitting in XR when we get to the '29 here. Thank you.

Next question is coming from Brian Abrams from RBC Capital Markets.

So on 989, now that you have some alignment with the FDA. I was wondering if you could give us a sense of just the potential volumes and injection times that you're going to be testing for the subcu bioequivalent study? And -- maybe talk about the most probable path for integrating the subcu into the broader program and potential time lines there?

So let me make a couple of comments on the subQ development. And it's a little bit early for me to answer your question with a lot of precision. So let me try this. The study will test -- the first thing we need to answer is what's the bioavailability of the formulation that we're going to test subcu. We obviously have per clinical data, but now we need human data to really understand exactly what that is. So that's point number one. The second, and as I mentioned, related to the first Phase III trial in second-line ET is we need to align with the FDA which we'll do this quarter on the dosing strategy for patients with ET. .

Once we have those 2 pieces of data, by availability of the subcu formulation and dosing strategy, I will be able to answer your question about volume and infusion time. As you remember, we signed a collaboration with Enable late last year, I believe, in October of last year to use the infused device. -- which will allow very high volumes of infusions by the patients at home without the need to go to the doctor's office as a self-applied device. It takes about 10, 15 minutes. -- and the patient does it without any major discomfort. It's not a device that patients have to work continuously. They just do it at the time of infusion and then they can remove it and throw it away.

So we believe that, that device will give us the alternative to really have a very simple subcutaneous infusion experience for patients pretty much regardless of the dose. But in terms of specifics, we need a little more data to fully answer the question. We'll have that data over the course of the year.

Our next question is coming from Stephen Willey from Stifel. .

On the in selective JAK inhibitor. I know you've made some comments recently about IC 35 being the exposure target that's needed to see clinical benefit. Can you just elaborate on why you think that's the right target exposure, if that's somehow limited by cross reactivity on wild type and just whether you think the new formulation can get you meaningfully higher than C35. .

Yes, it's an excellent question. So the reason the I-35 focus with the 058 program is because that's specific to 58 is not about the target. It's about the selectivity of the molecule that we have in the clinic. And that's what the animal model data suggests that there is a window -- the ideal window of selectivity between the effect on the mutant -- the V6 mutant and the wild type is around the IC 35. So we believe that with the current formulation, based on preclinical data, we should be able to achieve that level of exposure. That question will be answered relatively quickly over the course of this year, and we believe we'll then have clinical data in the second half of 2026. But the IC 35-point is related to the selectivity of the molecule.

Now -- as I mentioned, I think towards the end of last year, and we reiterate our JPMorgan earlier this year. We do have backup programs in this space. We are fully committed to this target. We believe hitting this target hard will translate into clinical benefit in this -- in this patient. So whether it 058 in the second half of this year, we'll provide clarity on addressing this target or 1 of the backup programs remains to be seen, but we're fully committed to answering this question.

Our final question today is coming from Kripa Devarakonda from Truth Securities.

I wanted to just get your expectations for poborsitinib and OSA with the Phase II readout coming up? And also, maybe you can help us understand where you see a place for this drug in the therapeutic landscape? Is it prebiologic oral or for patients who are refractory. I know it's a little early ahead of the data, but any color you can give would be helpful?

Yes, I'll take the second part of your question, which I think relates to povacitinib and HS, and then I'll turn it over to Pablo. I think the key here with povacitinib. Think about what's happening in the obesity market right now with an oral pill. There is a lot of energy around agovi.Now I'm not suggesting that HS is like obesity. But there's a couple of hundred thousand people in the United States being diagnosed and treated with HS. Only about 25% of those patients are taking an advanced systemic and the only advanced systemics available or the IL-17s and T&F -- that's 50,000 people. The 150,000 people using products that are not approved for HF, antibiotics and steroids.

Our ability to drive sales of pobacitinib is to get to that group, that's 75% of the market where they have an advanced to a biologic, they're not getting complete control with an antibiotic or a steroid. And so I think the path here is to get to this prebiologic population and 70% of our data are in that population. Pova is tailor-made for this group of patients. And I do expect that there'll be a great deal of trial and adoption. Once that happens, there's, of course, the post biologic and half the people that are on IL-17 don't get a full response, and so there are going to be patients there.

Next thing we have to do as a company is create an experience for patients and physicians and make it easy to get the product. And that means making sure we verify benefits, we get the time to first fill is really short. We clear PAs and we reduce the abandonment rate. And if we do those 2 things, povacitinib is going to be a major driver of revenue for this company in HS. And then of course, you layer in PN and vitiligo, and we have a very sizable product. That's how I would think about it.

And if you want to turn to the asthma piece.

So look, we know from all the data that we've been generating over the past several years across a range of indications that povacitinib is a very strong, very potent tent inflammatory medicine. In that context, knowing that asthma is an inflammatory disease, I think this is a strong rationale. There was a strong rationale that the study we started to develop oversidnib in asthma, particularly in patients, obviously, that don't respond to inhaled corticosteroid to long-acting beta agonist and particularly in patients with low synophelic asthma. Now we are conducting a well-designed, randomized Phase II study -- we will have the data later this year. And based on that, we'll decide next steps. But obviously, there was a strong scientific rationale to do that, and we look forward to showing the data later this year. .

We reach the end of our question-and-answer session. And ladies and gentlemen, that does conclude today's teleconference and webcast. You may disconnect your lines at this time, and have a wonderful day. We thank you for your participation today.

Great. Good morning. Welcome, everyone. My name is Jess Fye, biotech analyst at JPMorgan, and I'm delighted to be continuing conference this morning with Incyte. First, you're going to hear a presentation from the company's CEO, Bill Meury, then we're going to open it up for Q&A. If you have a question, you're sitting in the room, someone will bring you a mic.

[ Audio gap ]

If you want to ask it, over the portal, internet to me on the iPad, you can do that too. But with that, let me pass it over to Incyte's CEO, Bill Meury.

All right. Good morning, everyone. Thanks for being here. What I want to try to do with our time this morning is give you a clear and balanced picture of Incyte and talk about how we're thinking about building the company. As I was walking in the room, someone asked me what makes Incyte unique? The way I think about it is we're not a diversified giant or a small start-up. We have the innovation and growth potential of a biotech company and the capabilities and resources of a large pharma company. I would say the sweet spot of scale. What we're trying to solve for right now is top-tier revenue growth and durable revenue earnings and cash flow.

Now in order to navigate the transition of Incyte from a Jakafi company to a hem/onc and IAI company, we have to do these three things right. You see them on the slide. First, scientific innovation. As you know, return on R&D investment in biopharma has been stubbornly challenging and persistently difficult to unlock. And Incyte is not necessarily immune to that reality. But what I would say is that our pipeline is stronger, deeper and more strategically aligned than ever before. It's not consumed by moonshots or safe low return bets. It has the right balance in terms of risk and reward. We focus on compounds where our science gives us an edge in areas where we can lead that specialized high-value markets.

In terms of operational execution, there's plenty of biologic risk in the industry, and so we have to control execution risk. Operationally, department heads at Incyte, R&D, manufacturing, commercial are expected to run their business at a detailed level. And in terms of execution, we're focused on doing three things well: first, setting priorities. We focus on the vital few things that can create value. So for example, our R&D investment in 2026 will be just north of $2 billion. 80% of that investment is in seven priority compounds. So there's no diffuse spending. We're not scattershot, and we've gotten rid of what I call limbo projects. Second, set deadlines and commit to meet those deadlines. Deadlines inspire productivity in the company probably more than compensation, and they create urgency. And then finally, we make sure that long-term strategic growth initiatives are fully funded and resourced. Last point here is value creation. We're not the National Cancer Institute. We're not the National Institute of Health, and we have to convert science into FDA approvals and cash flows.

We think about our business across three dimensions or therapeutic areas: hematology, oncology and IAI. We're not looking to configure a loose unrelated group of products. We're trying to build franchises because franchises give strategic, operational and financial advantages. This informs what we do, what we don't do, what we invest in, what we don't invest in, gives employees clarity and should give investors some predictability. Hematology is a central identity of the company, and we have a window of opportunity to transition the treatment of MPNs from non-specific symptomatic therapies to mutation-specific disease modifying therapies. In oncology, I think we've quietly and systematically built what could be a high-impact oncology portfolio. And of course, in IAI, we have a jacket franchise with topical to oral and mild-to-severe solutions. There are two achievements in 2025 on this list that stand out to me. The first one is our core business is exceeding expectations on three levels. Total sales, Jakafi sales, which is important because Jakafi is a funding vehicle for our pipeline and for new product launches. And then in terms of the core business, ex Jakafi, we expect is going to be up over 40% in '25 over 2024. Second, we fundamentally changed the shape and maturity of our pipeline in 2025. We moved multiple assets from early-stage development to late-stage development. So to put this in context, when we started 2025, we had no proof-of-concept data on 989. No proof-of-concept data on G12D, TGF-beta by PD-1, no Phase III data on POVO. No safety data of Niktimvo in combination with Jakafi. And we had no frontline DLBCL data on Monjuvi. We have all of those things right now. The point here is that we have much greater visibility into the potential growth profile of the company and our ability to set a new high more mark for Incyte.

Three simple but important points for 2026, and I'll break each one of these down. First, our core business ex Jakafi has the potential to be as big as Jakafi is currently by 2030. Key part of that growth story will be product launches for Jakafi XR, Opzelura, POVO and Monjuvi. Second, our pipeline has the breadth and depth to support top-tier growth and potentially 2 to 3x our top line. We have seven assets being supported by 14 pivotal trials in 2026.

And then finally, in terms of business development, we see it as a multiplier to extend or strengthen the core. We're not looking to chase deals, fill a revenue gap or buy unbounded downside risk. We want high fit opportunities that have the potential to create durable revenue earnings and cash flow into the next decade. Now this is a road map essentially for what I would call [ Act 2, ] and I'll start at the end and work our way backwards. If you see the top right. What we want to do is configure a company that can achieve top-tier revenue growth, call that a 15% to 20% 5-year CAGR is diversified in terms of number of products, indications and markets has minimal LOE exposure, has healthy operating margins on a balance sheet that could approach $7 billion to $8 billion by 2030. Now if we start at the beginning on the far left of this chart, we have a core business that will fund the pipeline and reduce the depth of the trough. We have product launches and a pipeline that will become the core business, reduce the duration of the trough and build a glide path post-2029.

Let's take a look at the core business. You can read this from bottom to top. Dark blue is Jakafi, light blue is the core business. You can see in 2024, we had sales of $3.62 billion. We expect to finish 2025 at or a tick above the upper end of our guidance of $4.32 billion. In terms of Jakafi, it had a very strong fourth quarter and a good year, and we're very focused on the health of that business given the fact, as I mentioned earlier, it is a funding vehicle.

Now here, I'm zooming in on the core business. And the core business is defined in the right, the list of products Opzelura, Niktimvo, Monjuvi, Zynyz, Pemazyre and Iclusig. And you read this from left to right. If you take a look at 2024, sales were approximately $827 million. We expect to finish '25 million at $1.26 billion, which is the midpoint of our range, up 45%. Two comments about this. If you look at the products on the right, every single one of them were up in 2025 over '24. That's number one. Number two, Opzelura, Niktimvo and Monjuvi with the largest absolute growth contributors to our core business ex Jakafi.

We can read this slide right here from left to right. On the left, you have Opzelura, Niktimvo, Monjuvi, Zynyz. And then 2025 sales, what I want to focus on is the third column from the left, which is the growth drivers. Our estimation is Opzelura has the potential of 2x over the next five years. Growth from Opzelura is going to come from three sources: first, increased penetration of the AD and vitiligo markets in the United States. 2025, Opzelura in AD was up between 20% and 25%, and vitiligo was up between 15% and 20%, that's number one. Number two, we'll be launching Opzelura for AD in Europe in second half of 2026. Most of the benefit of that launch will be in 2027. In Europe with Opzelura in vitiligo today, we finished '25 just south of $150 million. The AD market in Europe is 5x the size of the vitiligo market, that's going to be an important growth driver. We're also pursuing indications for prurigo nodularis and hidradenitis, that's number one. As it relates to Niktimvo, had an excellent first year. It's annualizing at over $200 million. We penetrated roughly 20% of the third-line plus population. So there's still a lot of headroom. I think one of the most important facts about the launch is that the persistency rate with Niktimvo is between 60% and 70%. That is patients who started at the beginning of the launch for the year and are still on therapy at the end of the year, and what that equates to is compounding revenue. We're pursuing combinations of Niktimvo with steroids and ruxolitinib, which could 2x the addressable population for Niktimvo, important product. We have an excellent partnership with Syndax. As it relates to Monjuvi, we released data in frontline DLBCL last week and presented it. We just released it last week. This is a very positive large Phase III trial in DLBCL. There were clear improvements in PFS, EFS in a high-risk population defined by IPI 3 to 5, and in patients with complex biology. Not a winner-take-all market. It's not a battle between Monjuvi and Polivy in my opinion. 50% of the market is still in R-CHOP. So Monjuvi plus lenalidomide represents an intensification strategy versus a substitution strategy with Polivy. The point is that this will sustain the growth of Monjuvi. Over the next five years, we now have not just a: two-indication drug, relapsed and refractory and follicular, but also frontline DLBCL. And we'll be sharing more information about Monjuvi including activity in various subgroups.

Now this is a snapshot of our pipeline. And there are five points I'll make here. The first one is, these seven assets form three franchises: hematology, oncology and immunology, number one. Second, what you see here are novel and/or first-in-class agents. That is there are no me-toos or late entrants. Third, six of the seven programs are in Phase III, and the majority of these programs were homegrown. Fourth, this pipeline has the potential to achieve top-tier growth, net peak sales opportunity of north of $10 billion. Naturally, that is not a hard target. It's indicative of the substrate in the pipeline. Well, of course, refine our view of the potential of this pipeline as more information is collected on each asset as we derisk it, it becomes less opaque and more transparent. And then lastly, each one of these assets has strong IP and an exclusivity period that extends to the end of the next decade or the beginning of the following one.

This is our MPN portfolio. We're developing three targeted therapies you can read from left to right that shut down the driver mutation and don't just manage the disease, but modify the disease. So if you think about MF, PV and ET, standard of care treatments, Jakafi, hydroxyurea and interferon. They block pathways. They manage symptoms, they're blunt instruments, very different in what you see other areas of oncology. In other areas of oncology, immunotherapy, precision medicine and targeted therapies are the standard of care, not the case here with MPNs. We have an opportunity to trigger a changing of the guard in the treatment of these blood cancers. In 2027, we'll provide an update on 784, which is our T cell engager. In the second half of '26, we'll provide more information about our 617F small molecule. Right now, I want to focus on 989 and give you an update of what's happened since the ASH meeting about 30 days ago. To remind you, this is an all-comer strategy, type 1, non-type 1, front line, second line, mono and cabo, at least as it relates to myelofibrosis.

I'll move from left to right on this slide, you have important updates. First, we'll have a meeting with the FDA this quarter, and we expect to gain alignment on our program in terms of endpoints, dose and design. By the middle of 2026, we'll start a second-line study in ET, and we'll provide updated data from the ongoing Phase I program. So that's ET. In MF, in the middle of 2026, we expect to have alignment with the regulators on a second line study in MF, and we'll share updated data from our ongoing Phase I second-line MF cohort. Then in the second half of 2026, we expect to start second-line MF study as well as provide data from the Phase I cohort examining 989 and 989 ruxolitinib frontline MF. And then finally, we gained agreement about a week ago with the FDA on a subcu development program for 989.

A couple of comments about ET. The practice-changing thesis or the blockbuster thesis on 989, I think is predicated on two things. First, on the left, high clinical and molecular response rates, relative to the standard of care, which is HU. and then on the right, a large chronic underserved market. And I think the best way to think about the ET market is to stratify it. So we have 20,000 patients in the United States with a CALR mutation ET. That excludes the watch and wait group. 50% of them achieve only a suboptimal response, not because hydroxyurea is not an effective cytoreductive agent, it is. But most patients can't reach a therapeutic dose due to side effects. Ask any hematologist, and there is a therapeutic squeeze with hydroxyurea. Now our partial response means residual symptoms, residual thrombotic risk and the potential risk of transformation, although it is low. That is one sort of segment. 25% of patients with hydroxyurea or with ET a resistant hydroxyurea. An HU resistance is an independent negative prognostic indicator for survival. 989 has the potential to reshape the use even with second-line data of the use of hydroxyurea and becoming standard of care. MF shares the same biology as ET, but it's more complex, more aggressive and linked with shorter survival. We shared data at the ASH meeting this year, second-line MF, what I would describe on the left is first-line efficacy in a second-line study. If you look at the right, there are roughly 10,000 patients in the United States with a CALR mutation and MF. As remarkable and as important as Jakafi is, it's essentially a quality of life drug, but only 30%, 40% of people achieved an SVR35. At diagnosis, about 1/3 of people are anemic and after treatment, that number almost doubles. And probably the most important point on this chart is that 20% of people are at risk for transformation to AML. So the potential for 989 in both ET and MF is significant.

Our strategy in oncology right now is threefold. First, we focus on novel biologic targets and pathways. So think TGF-beta by PD-1, G12D, CDK2. High-incidence cancers that miss the IO revolution, colorectal cancer, pancreatic cancer and ovarian cancer. And we're developing treatments that can be used frontline in combination with standard of care chemo, which can have the most immediate medical impact and commercial impact for Incyte. We're running four Phase III trials across these compounds. I'm going to focus on G12D and provide you with an update there. This was long considered as many people in this room know the Everest of oncology, considered an undruggable target. Today, it's probably one of the most scientifically compelling targets in oncology, and Incyte has a credible path having the first selective G12D inhibitor for pancreatic cancer. Standard of care has been chemo for decades. There are no targeted therapies, as you know. The 5-year survival rate is quite low. 734 is a highly selective G12D inhibitor. We ran a large Phase I trial of approximately 300 patients, including 200 in PDAC. This weekend, we presented data at ASCO GI, and there is an update on our monotherapy arm, 1,200 milligrams daily. The objective response rate was 37%. The disease control rate was 78%. There are very few discontinuations or dose reductions due to side effects. And the swimmer plot in terms of durability of benefit is very, very encouraging. We also shared data on 734 in combination with both standard of care chemo regimens, GEMNab and FOLFIRINOX. We have a manageable safety profile without compromising dose intensity. We are starting a Phase III program in frontline PDAC in first quarter, very encouraged by what's happened with this compound over the past year.

Turning to povorcitinib. We're developing it for hidradenitis, vitiligo and prurigo nodularis. It could be the first oral JAK inhibitor for HS. It will open up a large market in vitiligo that is patients with a BSA involvement of greater than 5%, which is a market we can't get to with Opzelura, practically speaking. And it could be the first and only JAK inhibitor in prurigo nodularis. The NDA for povorcitinib is expected to go in the first quarter of 2026, we expect to launch at the end of '26 early 2027. We'll have data from our vitiligo and prurigo nodularis programs in the second half of 2026. A couple of comments about povorcitinib. I think the HS market is primed, not only for povorcitinib, but for an oral anti-inflammatory that has biologic efficacy. And there are other JAK inhibitors out there. I don't think it's a fight to the death, winner take-all market either. Hydradenitis is one of the most challenging dermatological conditions that you can have. Pain is the defining symptom. Today, if you think about what is available to dermatologists and patients, you have an antibiotic on one side, which does very little for inflammation, and you have an IL-17 on the other side, which is effective, but works about half the time. JAK inhibitor like povorcitinib is a multi-cytokine inhibitor. And in HS, that matters. This is very different than IL-23-mediated psoriasis or IL-4/13-mediated atopic dermatitis advantage. We achieved clearance rates in the 50% to 60% range by week 24. That's as good as a biologic. Pain relief in 60% to 70% of people by week 2024, most of that relief comes in the first three weeks. We have an opportunity to capture patients at two inflection points, after antibiotic were prebiologic and post biologics. We have a path to replace Jakafi and set a new high watermark. And these are three strategic priorities that we're focused on in running the company, build the core business, advance the pipeline and use business development to strengthen and extend the core.

Thank you very much.

Great. Thanks for the presentation. And as a reminder, if you've got questions in the audience, you can internet me over the iPad or just raise your hand, someone will bring you the mic. So you spent a lot of time kind of outlining the plan to address the Jakafi LOE. Can you double-click a little bit on how you're going to balance managing expenses during that kind of LOE period called the trough period, how you balance that with kind of investing to support growth as you come out the other side?

Yes, it's a good question. We will get leverage out of this business over time. Right now, we're solving for -- what we're solving for is the steepest possible growth curve post 2029 that we can create. We approach budgeting and allocating operating expenses in a very sort of bottoms-up way. And our first call on capital right now is that core business. So that business is as big as Jakafi when we hit 2029. And then the second call on capital are the R&D programs. And we're not -- as I mentioned, we're not spreading our bets everywhere. We're focused on seven compounds that some of them are calculated risks, but that we think can create outsized returns. And we will manage our margins between now and then, but what we want to solve for is not the next three years, we may trade a little bit of margin, a little bit of R&D burn, so that we can create a glide path to growth. But I will tell you, the company will be disciplined in terms of how we're managing OpEx. Our G&A in 2026 will be down 5% to 10%. Sales and marketing, growth, operating expense growth will be managed. Of course, in R&D, our operating expenses there will be up north of 10%.

A question in the audience?

Yes. I'm Martin [ Versace, ] I'm a biotech entrepreneur, but I'm here because I'm also patient in PV taking Jakafi. And I just wanted to share that I had to get Jakafi prescribed in Europe because at MSK in New York and Cornell in New York, they wouldn't prescribe it to me, because they said I didn't meet all the criteria of PV, and they said -- like I saw them very resistant to prescribing a medication that for the last two years has been the best thing that ever happened to me. I mean it's -- compared to all the other alternatives is -- I mean, I'm better than I ever was. I don't know what it does, but not only controlling the hematocrit, but it seems to be very good for the immune system and anything else. Why are doctors resistant, and I can give you names, Dr. Rampal, [ Robos, ] reluctant to prescribe it, saying that I didn't fill all the criteria of PV. When in Europe, they just gave it to me.

Well, first of all, if you give me the name of the physician, I will go visit that physician. Pablo, do you want to take that?

Look, I think that when you look at the trajectory of Jakafi and PV over the past 10 years since initial approval, I mean, it's been the fastest-growing segment of the market. So it's unfortunate to hear that some physicians is still resistant. And I don't know the specifics of the case. But the adoption of Jakafi in PV in the U.S. has been excellent across the board. Sometimes, I think the same physicians are more conservative about when they initiate Jakafi versus other interventions like phlebotomy and other things. But I think in general, we're quite happy the way the community -- and 2 years ago, 2.5 years ago, we presented the magic PV data that basically show that there's an improvement in thrombosis free survival in patients with polycythemia vera that take Jakafi. I think that has really led to an inflection point in adoption. So maybe your experience precedes the availability of that data and maybe that explains why those particular physicians were too conservative.

So turning to the pipeline, 989 got a lot of focus last year. Thinking about frontline MS, what would you need to see in the data to justify moving into frontline?

In our frontline Phase I results?

Yes.

You're going to want to -- well, in a monotherapy scenario, you're going to want to see the SVR35 at a clinically meaningful level, nice improvements in TSS50. We expect to see continued anemia response. So if you can replicate what we've observed in that Phase II, or excuse me, in that Phase I trial, second-line patients, we'll have to talk to the FDA about a path for generating a frontline indication, but I think all the information is there. Obviously, in combination, you're going to have to see additive benefit in terms of 35 -- SVR35 symptoms, and we'll see how the anemia response looks. And we'll learn more when we get the Phase I data in the second half of '26. Pablo?

I think Bill made the comment during his remarks that what we've seen so far, just to remind everyone, is basically first-line efficacy in second line patients. When you look at the results we presented at ASH in terms of SVR35, TSS50, they're comparable with historical benchmarks for Jakafi in first-line patients with MF. So that's really a really good start. The additional thing we've seen, there are two additional things are: number one is anemia improvement. 56% of the patients have improvement in hemoglobin, which is very, very meaningful in this population. And the final piece is that the safety profile is a lot more benign than Jakafi. As good as Jakafi is, and we just heard a testimony, it's -- CALR has been -- 989 has been extremely well tolerated. So other question in first line is, is it going to be a single agent, or is it going to be a combination. We're doing both. As you know, we're randomizing patients through 989 versus 989 plus Jakafi in previous untreated MF. Once we have that data, we'll make that decision. It could very well be a three-arm study, with Jakafi as a control and two other arms running combination with one single agent. And the endpoint is something we'll need to discuss with FDA. I think I'm particularly excited about the data in terms of anemia improvement and maybe bringing the FDA forward to say that maybe that is a more relevant endpoint for patients with MF, perhaps in symptoms. So we'll see how we balance those things once we have more data.

We're committed to developing this front line, but we need data. An important point, 60% to 70% of patients on Jakafi ultimately end up on the second line of progress. So even the second-line data, whether it's in ET or in MF and this is not meant to lower expectations, is going to have an immediate impact, one in the hematology community and then in terms of what 989 can mean to Incyte when we launch it.

I have a question. As you think about core business pipeline, capital allocation strategically on a high level, how do you think about China as a competitor and partner?

It's, one, a source of innovation for sure, and it can also be a partner. I think it's exactly what you said. Today, obviously, we're 90% U.S. We have an emerging business in Europe. I would expect over the next couple of years, not only our presence, but our work in China is going to continue to expand.

So coming back to 989, how should we think about the time lines for second-line development in MF and also ET?

So the -- we presented the updated data in ET at ASH, and I think it was a very compelling data set in terms of complete hematologic response and the molecular impact of 989 in terms of reducing the size of the malignant clone in patient. So we're really, really excited about that data. And as Bill mentioned in his remarks, we are in the process of -- we're going to meet with FDA this quarter to finalize -- fully aligned on the regulatory path in second-line ET, and we expect in the first half of the year to initiate the Phase III in second-line ET. So that's already moving forward in a way. In second-line MF, we're finalizing some of the data that we need for optimizing the dose in patients with second-line MF. We obviously present the data as well at ASH, which we thought was very impressive in terms of SVR35, TSS50 anemia and molecular responses, particularly when you think about the reduction of the size of malignant clone in the bone marrow and in peripheral blood. So with that data, as it continues to evolve, we will accelerate that in the second half of the year, and we expect to start a pivotal trial in second-line MF patients in the second half of 2026. So those two studies will start this year.

And when do they end?

Let's get them started, and then we'll give you more clarity on when. But -- and the reason -- I'm not -- regarding your question, but the reason -- one of the key questions for that is particularly in ET is whether we align with the FDA on the timing for the primary endpoint, which traditionally has been 52 weeks. We think we have a good argument based on the responses we've seen on normalization of platelets, which happened very fast with 989 to have an endpoint at 24 weeks, which we believe is more meaningful in terms of accelerating time to market. Once we have the full alignment with FDA, we'll talk a little bit more about the timelines for approval.

Jess, one thing I would add, and we're pretty modest about the accuracy of our future predictions. But if you look at the pipeline, G12D, CDK2, the additional indications for Niktimvo, which I think are important and 989, I'll just focus on those four, all have the potential to launch between 2027 and around [ 2023. ] Time is of the essence here. And obviously, 989 is one of the more appealing pipeline assets that we have. This is a giant execution test, but all of these Phase III studies are going to start in the next 6 to 9 months.

And what about your JAK2V617F inhibitor. You talked about like a new solid dispersion formulation to address previous exposure issues. So what's the status there?

So we have the formulation. It's been testing on healthy volunteers, and that's going to enter the clinic this quarter. So that's why our guidance at second half of this year, we'll have data -- clinical data from the small molecule V617F inhibitor. I think it's important to remind everyone where that program is at, we escalated the dose over the course of 2025. We realized that we would not hit the exposures that we needed, we would not hit [ IC-35, ] which is what we predicted we needed to have a clinical impact in these patients. So to be clear, the hypothesis that inhibit and cytokines of V617F, we believe it's intact that if you inhibit that target, you will have clinical efficacy in patients with MPN. So we expect to have that data to confirm the hypothesis in the second half of '26.

And assuming the kind of exposure challenge has been addressed, what's the kind of target product profile you're seeking for that product?

I think it's pretty traditional what we've done in other -- with other medicines in MF and PV in this case. This is an important component of potentially for patients with polycythemia vera, which is improvement in the classic end points. That's what we need to see. We need to see improvement in SVR35, TSS50, hematocrit increases in PV, was basically the same thing. By blocking this target, we expect we're going to have, not only the impact on the clinical symptoms, but also impact the molecular endpoints like we saw with 989.

And Pablo just comment on the mutation frequency for 617 relative to CALR.

So the really important part there is, thank you for reminder, is in PV, 90% of the patients have V617 mutated. So that is a really, really large segment of the population. In MF, that segment is about 60% or so of the patients. So it's the majority of the patients have V617 mutations. Just to remind everyone, between 617F and CALR, you basically cover with one or the other, and they're mutually exclusive about 90% of all the patients with ET and MF and PV.

There is potentially a Gleevec moment with 989. Now we have a lot more work to do, and we have to convert Phase I information to Phase III. But if you think it took a decade for there to be appreciation in the hematology community that Gleevec was disease modifying. It was originally thought to be a glorified hydroxyurea that debt with blood counts. That's changed a lot. Now that's a fairly high bar, you got half to that concept, this is going to be a very meaningful product.

Okay. And then you talked about for Opzelura, the AD opportunity in Europe from like a volume perspective. What about price? How confident are you in the kind of being able to preserve price as you move into that space?

Yes, it's a good question. In -- most of our business for Opzelura in vitiligo is in France, Germany and Italy. And the prices there are 50% of what they are in the United States. In Germany, however, the price is much closer to the U.S. market, a big part of the growth of Opzelura in AD in Europe will come from Germany. And the way to think about is Opzelura becomes essentially a step ahead of Dupixent. There's -- that is a stopping point before going to an IL-13. I think the best benchmark is at current pricing with vitiligo, which is small. As a market in terms of prevalence, this business was $150 million just under. And so even it's 5x at a lower price, the ex U.S. business for Opzelura could be a $300 million incremental sales opportunity for Opzelura we think about the next five years.

So I guess when you talk about the core business, which are these kind of like approved non-Jakafi products, but not the kind of development stage products. Where do you think the -- there's the biggest disconnect between like where you see street numbers, and where you think those products are going?

Well, I think if you look at the historical rates on Opzelura, I mean, that business is growing at a 20%, 25% clip. I mean this year will be up over 30%. Niktimvo, obviously is in its first year, and new product launches are unpredictable. It had a very good first year, and there's still a lot of headroom there given the penetration of the third line plus market and as I mentioned, persistency. I think as we continue to progress into 2026. I think you probably see those numbers continue to be refined. And then Monjuvi, that's $200 million, $250 million product right now, I think that frontline DLBCL study, it's not about how it compares to Polivy. DLBCL is a heterogeneous cancer. R-CHOP is still standard of care, and we have solid data in terms of PFS and EFS, like I said, we'll go into the subgroup activity in the second half of the year. That's clearly not incorporated in any estimates for on Monjuvi. And you have a three-indication lymphoma treatment. There's value there.

Great. All right. So we're out of time. So thank you.

Thank you.

Okay. Good morning, everyone, and welcome. Welcome those of you here at -- in Orlando at ASH, and welcome those at the webcast. Apologies for the late start. We had to adhere to certain guidelines from ASH, and there was no way to schedule this. And 2 of our speakers were busy presenting actually scientific data at the meeting. So we were forced to start a little bit late. So thank you for your patience. I'm sure you had an opportunity to grab some lunch. We're going to spend the next 45 minutes or so reviewing data from our 989. We're going to call it 989 for short program with you. I think this data, some of it was presented in June of this year at AHA in patients with ET. And yesterday and today, you heard from 2 of our speakers today about the translational data and the data in MF. We think this is a really important moment for patients with MPNs and for Incyte. We think 989 not only has the potential to redefine the standard of care in patients with MPNs, but to really redefine the goal of therapy in these patients.

You're going to see a lot of data over the presentation about the ability of 989 to not just induce impressive clinical responses, but to really normalize hematopoiesis in some of these patients. And we believe that is, over time, going to show that the goal of therapy in these patients has changed. It's not just symptomatic improvement, but it's true potential for disease eradication. So we'll walk through that data. Forward-looking statements, our agenda here today, I'll be brief, and then I'll hand it over to Dr. Claire Harrison, who's going to talk about MF to again reset where we are with this disease today. John Mascarenhas, who just presented at ASH, will go over the data for the single-agent cohort in patients with myelofibrosis and the combination with ruxolitinib and Dr. Beth Psaila will talk about the translational data, which was presented yesterday. Our CMO, Steven Stein, will talk about the next steps and how are we advancing this new medicine into pivotal trials. We'll have plenty of time for Q&A.

Briefly introducing our speakers, Dr. Claire Harrison, I think many of you know her Deputy Chief Medical Officer at Guy's and Thomas' Hospital and Professor of Medicine at Guy's and Thomas' Hospital. John Mascarenhas, Director of the Center of Excellence for Blood Cancers and Myeloid Disorders and Professor of Medicine, the Icahn School of Medicine at Mount Sinai; and Bethan Psaila, Associate member of the Oxford Branch of the Ludwig Institute for Cancer Research and Professor of Hematology at the University of Oxford. Just to set things up for the next presentations, as you well know, almost all patients with myeloproliferative neoplasm have disease that is driven by 1 of 2 mutations that are mutually exclusive. That is a mutant CALR, a mutation that is about 25% of the patients with ET and 35% of mutant -- MF or a V617F mutation, which is the remaining of the ET/MF patients and almost all the patients with PV.

Our goal at Incyte is by the end of this decade to have a targeted therapy for every patient with the myeloproliferative neoplasm. So what you're going to see today with 989 is the first step in that journey, a journey that will continue with a T-cell engager for CD3 and CALR with the V617F inhibitor and other programs that we're working in discovery to address the needs of every patient with an MPN. To remind everyone, I think you heard probably a couple of times this over the last 2 days, so I won't spend a long time. 989 is a mutant CALR specific antibody. Mutant CALR protein binds in a mutated form with the TPOR receptor, travels to the surface of the cell and signals, and that is an oncogenic driver signal.

What the antibody does is disrupt that heterodimer, the complex is internalized and degraded. It is a specific targeted therapy for patients with mutant CALR myeloproliferative neoplasms. What you heard yesterday, today and you're going to hear tomorrow comes from these cohorts of studies. The monotherapy in patients with essential thrombocythemia will be presented tomorrow. We announced this morning that we received breakthrough designation for patients with essential thrombocythemia. We requested that from the FDA for patients with type 1 mutations. It's the data that we had at the time that was most compelling. We wanted to accelerate that approval. We received that. Now we're going to discuss with FDA the pivotal trials in patients with ET and Steven will talk more about that.

You heard from John, you're going to hear again today, monotherapy in MF and combination. And importantly, we are in the process of enrolling patients with naive MF, previously untreated disease to randomization of 989 versus 989 ruxolitinib. That data, which we'll have in 2026, will inform a potential first-line pivotal trial in patients with MF. These are the abstracts. I think you heard from the 2 on the right, the one on the left, it's going to be tomorrow, which is an update of the data that we presented on ET. I will now hand this over to Dr. Harrison so we can get with the kind of the agenda, and I look forward to seeing you in a few minutes for the Q&A. Claire?

Thank you very much. So it's my job to give you a whistle-stop reminder of myelofibrosis. I think the pictures kind of say it all really. This is a disease that all 3 of the clinicians at the podium struggle with and our patients have a constant battle with. You're aware of the key characteristics, clonal driver mutations, myofibrosis, splenomegaly and symptoms. Among the MPNs, because we are also talking about ET to some extent, of course, this is the disease with the worst prognosis for patients. Anemia is a key feature of this disease, and it becomes increasingly prevalent over time. So 35% of patients at diagnosis and then by 1 year, more prevalent. What you see on the right-hand side is survival of patients stratified by the presence of anemia of different degrees.

And you can see that severe anemia clearly has -- is a marker of a patient with the worst type of prognosis, 2.1 years. What we also know and have learned in recent times is that improvement of anemia is linked to survival benefit for our patients. So our management goals are controlling splenomegaly, alleviating anemia, improving symptoms, but primarily as clinicians, we want something that also is going to improve survival for our patients. The RNA isn't lost on me that in 2011, I was in a room like this with Incyte in search for stat sig offset presenting the data from the COMFORT study, which led to the approval of ruxolitinib, which is still the standard of care.

At that time, I said I thought 70% to 80% of patients with myelofibrosis would get that drug. And indeed, that's true today. It's a very good drug. It prolongs survival and improves quality of life for our patients. But when they fail that drug, there are very few other options for them. And what we see is often patients are cycling through other JAK inhibitors, which have the same target and the same or indeed, definitely in the second line, less benefit for patients. Once we move from our first-line JAK inhibitor, outcomes for these patients are poor. So this is my conclusion slide. I really don't think you as an audience need an introduction to the disease, but just to set you where we are today and where we hope to be in the future. Thank you very much. So John, I think I'm handing over to you.

Okay, Claire. Thanks for setting the stage. Now I'll get into the preliminary efficacy and safety results. This is from 2 Phase I dose escalation trials involving 989. This is the myelofibrosis data that we literally just presented and I'll just remind the group that the CALR mutation is present in at least 1/3 of the patients with myelofibrosis. There is a link between the higher VAF and worse outcome, including more advanced disease, anemia and increasing circulating blasts. And the treatments that we have right now are mainly JAK inhibitors. They're not mutant targeted. And the reality is we have very ineffective agents for reducing VAF as a surrogate for better outcomes. So there's a lot of rationale for why treating our MF patients that are mutant CALR expressing would make sense with an antibody. And this is the MF portion of this study, which also includes an ET cohort, and we're going to be discussing the results of patients, both monotherapy and combination who get 989 with mutant CALR positive disease.

Of course, it's a Phase I study, so it's DLT and treatment-emergent adverse events that are going to be characterized. We're also looking at secondary endpoints outcome measures. So what I'm going to do is focus first on the monotherapy cohort. This was 52 patients. You can see the baseline characteristics and demographics of these patients. I'll draw your attention to the distribution of types of CALR mutations that were present. The median VAF was 36%. And it was supposed to be a relapsed/refractory group of patients, although you could -- the investigator could deem a patient ineligible for a JAK inhibitor. So there were 10 patients that got on that had not seen a JAK inhibitor previously and I'll highlight that as well. And these are the baseline counts. The baseline spleen volume is 1,300, the symptom score 21. And you can see the various doses from 24 milligrams, which we started in the U.S., all the way to 2,500 milligrams ex U.S.

It is -- as I said, it is a super well-tolerated therapy. I've done in our Phase I studies that this is probably the best tolerated therapy I've seen in this setting. And you can see the treatment-related adverse events were 57%, Grade 3, 4, 30% and serious were 5. I'll just mention the one serious just in case it comes up as a question, was a patient who had monoclonal B-cell lymphocytosis, which is not uncommon, and these diseases do progress. In this case, mantle cell lymphoma with the intestinal obstruction that I don't think is related to the study drug but could happen naturally in patients with myelofibrosis. There really were infrequent dose reductions and interruptions of the infusion. I should mention if it's not obvious, this is an infusion every 2 weeks. And there were no dose-limiting toxicities in this study.

And therefore, there was no maximally tolerated dose noted and 86.5% of patients remain on study, which is also, I think, quite remarkable, considering this is a relapsed/refractory population, and this is an unmet need with a very well-tolerated therapy. So it speaks to the fact that patients were coming every 2 weeks to get this therapy, and they were obviously seeing some sort of benefit not having toxicity that would keep that retention rate that. There were some AST elevations in 11 patients, 9 out of the 11 resolved, 1 grade -- 2 Grade 1s were ongoing at the time of the data cutoff. And what we saw was that patients who had Grade 1 elevations at baseline, which is very common because of extramedullary hematopoiesis were more likely to have this transient up and down effect of their LFTs that wasn't clinically significant or meaningful. And this didn't really lead to dose delays or discontinuations. So there was no -- importantly, there was no treatment-emergent adverse event profile that was dose related.

On the right, you can see the -- irrespective of attribution, the common adverse events of 15% or greater, very minimal Grade 3/4 toxicity and the things that you would normally expect in patients with advanced myelofibrosis including anemia and thrombocytopenia, are there at low frequency. So very well tolerated, very easy to give. We did see meaningful spleen responses with monotherapy 989 in this relapsed/refractory setting. What we've done is grouped the doses by low dose, 240 to 250 and then 400 to 2,500, which is in the darker blue columns and the asterisks note the patients who are type -- non-type 1 CALR mutant. So we saw at week 24, 42% of patients achieved an SVR25. That's a regulatory endpoint in the relapsed/refractory setting. 33% achieved an SVR35. If you look at best SVR, 48% and 31% achieved, respectively, at SVR 25 and 35. And most patients baseline assessments were performed prior to JAK inhibitor washout. So there's always that phenomenon that occurs.

If you look down below at week 24 data, it's pulled out by whether patients had a prior JAK inhibitor and in this evaluable population, the denominator is 7. So the responses, not surprisingly, are higher in terms of SVR in the JAK inhibitor naive group with SVR35 of 57% and 27.6% in the relapsed/refractory setting. We also saw symptom improvement, and I can attest to this both not just the study, but the patients that I personally treated. We also saw symptom improvement that was very reproducible. 93% of patients had experienced improvement in their symptoms, 60% achieved the regulatory endpoint of TSS50. And at week 24, 39% of patients had a TSS50. And again, the asterisks show us the non-type 1 patients. And if you look at week 24, the TSS50 response of 39% for all comers is not as high as the 60% in the non -- no prior JAK inhibitor therapy, which is, again, not surprising. I think really importantly, beyond the spleen and symptom benefit, we saw anemia benefit here. This is divided by the baseline anemia.

So in blue are the patients that would be deemed by IWG criteria to have anemia, less than 10 in a men and less than 11 grams per deciliter in a woman. Both green and blue curves improve pretty quickly, but I think it's quite notable that the anemic patients really have an improvement in their hemoglobin. We saw that in patients that were receiving transfusions and have a lady who's been out of the transfusion suite for over a year, and it's quite remarkable. So if you look at it from ELN-IWG 2024 response criteria, the response rate is 56%, and that includes 10 major responses and 4 minor responses. But all these responses are clinically meaningful to patients who are with myelofibrosis who are anemic. We did see VAF reduction as well. Again, it's color coded by dose range. I think what's complicated in looking in -- early in a Phase I study in a dose escalation study is that there was intra-patient dose escalation. So I don't know that we get the full picture here.

But nevertheless, 90% of patients had at least 1 post-baseline VAF assessment and 10% of those patients had achieved a 25% or greater reduction in their VAF. This is the combination. So that was all monotherapy data. So this was the 20 patients who came on. They were already on ruxolitinib and then 989 was added because they were deemed suboptimal responders. So you can see the baseline characteristics here. Again, 60% type 1, meaning CALR VAF is 39%. The median -- the mean daily dose of ruxolitinib was 35. So they weren't underdosed with ruxolitinib for the most part. And you could see the baseline counts, the TSS score is 15, spleen volume is quite large, 23, 51 and then the doses that were used in this dose ramp-up. Again, very well tolerated, tolerated as monotherapy, tolerated in combination with ruxolitinib, 55% Grade 3/4 treatment-emergent adverse events, 5 that were serious. There was a patient here who developed non-Hodgkin's lymphoma.

I would still argue that this is what we see in these patients with advanced disease very frequently. And there was very infrequent dose reductions, infusion interruptions or really dose delays. There were no DLTs and again, no MTD in combination with ruxolitinib. And the profile looks, I would say, rather similar to what we saw with monotherapy, what you would see with RUX treatment, maybe slightly more anemia, but only 10% thrombocytopenia Grade 3/4. Most patients did enjoy some spleen and symptom benefit, spleen is on the left and symptom is on the right. Again, color coded by dose. Best SVR at 65% achieved an SVR25 and 47% achieved an SVR35. At week 24, 50% and 25% hit those SVR25 and 35. In terms of symptoms, 81% of patients experienced a symptom improvement, 33% achieved a TSS50 at week 24. And there was -- on the right, you can see a stability in the hemoglobin curve.

There was one patient who was non-transfusion dependent who did have a major anemia response by IWG criteria, but we didn't see worsening anemia at all. So in conclusion, I feel very confident in saying 989, very well tolerated monotherapy and in combination with ruxolitinib in patients who have a suboptimal response. And there was no dose-limiting toxicities, and we did not even hit an MTD with this dose escalation. 87% of the patients remain on monotherapy, 85% remain on combination therapy. That's I still think quite remarkable. And we did see rapid and robust spleen and anemia response as well as symptom improvements.

And we saw at higher doses, which I didn't totally pull out here, at higher doses, we saw improvements in symptoms anemia even in the non-type 1 and type 2. So in my opinion, in my experience with some of these patients that at higher doses, you overcome what might look to be less responsiveness in these non-type 1 patients. And we did see reductions in mutant CALR VAF. What I didn't show here Beth is going to go over is some of the correlatives, which I really think speak to the this is really a potentially disease-modifying drug. So with that clear and robust proof of concept, I'm excited for Incyte to move forward with a pivotal registration study in the near future. So thank you.

Hi. So I'm going to go now over in a little bit more detail the molecular characterization of patients with myelofibrosis and ET who were treated with INCA033989. So you heard a little bit of background about the disease already from Claire and from Pablo, but just really to go over that in some detail again. So all MPNs arrive following the acquisition of a gene mutation in a blood stem cell that basically results in cytokine independent receptor signaling. In 1/3 of patients, that affects the gene encoding calreticulin. This actually came as a surprise when it was first discovered, reported actually in a pen session in 2013 at ASH because calreticulin is well known as a chaperone protein within the ER but hadn't been implicated in the context of blood malignancies before. So all known pathogenic mutations result in the same mutant-specific C-terminus on the protein, and that has 2 critical consequences.

One is it changes the charge on that C-terminus, which forms an aberrant complex with a thrombopoietin receptor. And the second is that protein then loses the signal that retains it within the ER and the complex travels up to the cell surface where it induces signaling and also presents a really excellent opportunity for targeted therapies. So you've heard already that INCA033989 is a first-in-class antagonist antibody being tested in the context of ET and myelofibrosis in 2 first-in-human clinical trials in previously treated patients. And it's been shown to inhibit oncogenic signaling and proliferation of cells. So Claire was going over some of the physiology of the disease, but just to recap in a little bit on that and give you a little bit more detail. So mutant CALR MPNs result in a significant burden of morbidity and mortality. So most patients present with a condition called ET or essential thrombocythemia.

Here, the mutation drives an increased number of megakaryocytes and platelets, and this causes significant symptoms that can have impacts on life and work productivity and also an increased incidence of bleeding events and thrombosis. Then 1/3 of patients will progress to a much more sinister cancer called myelofibrosis. So here, you get fibrotic remodeling of the bone marrow microenvironment and you get bone marrow failure, leading to cytopenias, in particular, anemia. And then extramedullary hematopoiesis occurs affecting the spleen primarily and patients get very painful splenomegaly and Claire showed a beautiful photo there in her image of a patient with a very large spleen. From this stage, 1 in 5 patients will progress further to a secondary leukemia that unfortunately is refractory to all leukemic therapies that we have. And patients at that stage have an incredibly poor prognosis, surviving usually 12 months after the diagnosis despite best available care.

This progression occurs slowly over years or even decades and is associated with a gradual expansion of that mutant clone and evidencing this, you can see that the CALR burden at baseline, the so-called VAF or variant allele frequency is higher in the MF patients than the ET patients at baseline. So one thing to note about -- when we talk about VAF is that most patients with mutant CALR MPNs actually have a heterozygous mutation. So the VAF is measuring the number of alleles, and it's telling you the percentage of alleles, which are mutant versus wild type. So when we talk about a 40% VAF, that actually means that 90% of all hematopoietic cells are mutant positive. And if we talk about a 5% reduction in VAF, that's actually a 10% reduction in the CALR mutant cells. So it's important to bear those in mind when we're looking at VAF changes is that they're actually half of the percentage change in cells overall mutant cells overall.

A second thing to highlight is that there are differences in terms of the bone marrow microenvironment and what's going on with the wild-type stem cells between patients with ET and patients with myelofibrosis. So in patients with ET, they have a lower level of VAF usually, and they also have -- they have a more normal bone marrow microenvironment. So they still have some ongoing wild-type hematopoiesis. And we're showing this here depicted as 2 taps, obviously, wild-type hematopoiesis and mutant hematopoiesis. With this therapy, you turn off the tap of the mutant clone, but the tap, which is running out the healthy cells, keeps going. Now in myelofibrosis, that tap is the wild-type tap is turned off more. And then when you turn off the mutant clone, the wild-type cells are going to take longer to recover for 2 reasons. One is because they were lower actually at baseline. And secondly, because this is happening in quite a perturbed microenvironment. The fibrosis that Claire showed is really quite profound.

So it's going to take longer for that to recover because the healthy cells, they need a healthy microenvironment. So that's how we're depicting that in this image, which I quite like actually, yes? Okay. So patients with myelofibrosis, we know they have greater clonal complexity at baseline and also -- progression is also associated with the development and the acquisition of additional mutations in addition to that first primary driver. And you can see that in this cohort. So basically, in the cohort tested in these studies, 1/3 of patients with ET and almost 80% of patients with myelofibrosis had an additional co-occurring mutation. And those are shown on this plot here. And you can see that many of those mutations are in high-risk genes, so ASXL1, EZH2 and TP53, just to call out a few, and these are gene mutations associated with progression to leukemia. So this slide shows the ET efficacy data or highlights of that, that was presented or will be presented tomorrow.

And what you're looking at here is the effect on the platelet count. So you can see the median platelet count here is around 1,000. That's significantly high. But within -- by cycle 2, so after only 2 infusions of antibody therapy, you can see it's normalized. It's reached the normal range. So that's after only 2 infusions. So a very rapid decline here, rapid efficacy and normalization of the platelet count. And that response then is maintained over the course of the study. And you're looking here -- the results are shown here over the first 6 months. You can also see that there are more consistent decreases in platelet counts in patients receiving these higher dosing cohorts. But looking on the right, so this is now showing that those hematological responses are actually correlating with decreases in mutant CALR VAF in the mutant clone burden, again, split by low dose and high dose. And the lines here represent individual patients.

What you can see in the ET cohort is that there are these rapid decreases in mutant CALR VAF occurring by around cycle 4 and then being maintained over the first 12 months here on study. And that's more consistently seen in patients on the higher doses and correlates to see more consistently in patients who are achieving durable hematological responses. Patients with myelofibrosis. So John very nicely presented the impressive impact on spleen reductions. And here, I'm correlating again those responses with VAF reduction. So you can see again an association between clinical responses and molecular responses. So in this part, again, you're looking at individual patients in the columns and the columns are colored according to the best change in mutant CALR VAF. So the deep blues and greens are patients who've had deeper changes in their mutant CALR VAF. Again, you can see that 48% of patients achieved an SVR25 and 31% of patients achieved an SVR 35%.

These are impressive responses considering this is a second-line setting. So the majority of these patients have already received ruxolitinib therapy. And again, these lines are now showing the changes in the mutant CALR VAF over time, low dose, high dose. And what you can see here is that, again, changes to the mutant CALR VAF correlate with SVR and/or anemia response. And the dynamics of this change are slightly different. You can see here that they're continuing to decrease even by -- after 10 or 12 cycles on therapy. So to dive in a little bit then in more detail. So I mentioned that the mutant CALR protein is only expressed on the cell surface of cells, which also bear the TPO receptor. Now fortunately, in the setting of MPNs, this is actually 2 different cell types. Firstly, it's the stem cells. These, of course, are the cancer initiating and maintaining cells, the ones which is really crucial to hit.

And then the second cell type, which expresses the thromboprotein receptor are cells of the megakaryocyte lineage. So these are the cells which are implicated as the key drivers of fibrosis and inflammation in the bone marrow. So these 2 cell types are the direct targets of antibody therapy. Now all the other cells, are more downstream progenitors, myeloid cells, lymphoid cells, they're so-called silent mutant CALR carriers. They're mutant positive, but they don't express the protein on the cell surface, and therefore, they're not direct target of therapy, but they are major contributors to the VAF when it's measured in whole blood. And I'll go into that in a bit more detail. To drill into this then, we performed single-cell multiomic testing on single cells isolated from the peripheral blood of the subset of patients with ET and myelofibrosis. And these cells were analyzed using a platform that enables targeted immunophenotyping in parallel with genotyping.

And that data is represented on these UMAP plots. So in these plots, each dot represents a single cell. The cells are then clustered and annotated according to their expression of cell surface markers that identify them as these different cell types. And then the dots are then colored according to whether they're wild-type in gray or mutant in red. And to pick out just 2 features, you can see that in the myelofibrosis patients, there are expanded populations of stem cells and these erythroid progenitor cells here. So when we -- as hematologists, when we look at the blood form of these patients, these are changes that we classically see. You see mobilization of stem cells to the peripheral blood and then you see these very aberrant nucleated red cells that aren't normally present in the peripheral blood. So those are features that represent this transition to myelofibrosis. The second thing to note then is the so-called silent carriers are really in very high abundance.

So high numbers of mutant monocytes, NK cells, B cells, which is very interesting. And also actually some T cells are also mutant, yes, seen on these plots. So first, focusing then on these stem cells. These, of course, are the most important cells to hit because of the cancer initiating and maintaining cells. On the right, you can see rapid decreases with therapy in the percentage of mutant CD34-positive stem and progenitor cells over time. And you can see that the lower levels of mutant CALR HSPCs in patients with ET also decreased with therapy. So in contrast, when we look at those silent carrier cells, we see much more minimal reductions at these early time points. This is Cycle 1, Cycle 4, just 4 months on therapy, and there really are much more minimal changes in these cell types. This is what we would expect. And the important thing to note is that these cells are terminally differentiated and don't have any long-term repopulating ability.

So these cells will be expected to decline with time if we're getting true targeting of the stem cells as they won't be replenished. Instead you'll be replenishing wild-type downstream cells. So then we also need to assess the burden of mutant megakaryocytes, and this is depicted really beautifully in these slides. So to do that, you can perform immunohistochemistry on bone marrow biopsy sections, and we're fortunate to have an antibody that works really specifically and only identifies only stains mutant CALR, doesn't stain wild-type CALR. So this is an exemplar image from a patient with ET. You can see these abnormal clusters, too many megakaryocytes in the bone marrow, and they're all staining positive for mutant CALR. Cycle 7, you can see a significant reduction in the mutant megakaryocytes. And these changes here are quantified across the cohort of patients, and you can see quite dramatic reductions in total megakaryocytes and mutant megakaryocytes and a really nice increase here in the percentage of megakaryocytes that are wild-type, so non-staining for mutant CALR.

And that correlates very nicely with improvements in fibrosis. And of course, changes to fibrosis will take time and actually is quite a difficult thing to assess. So it's graded in these big buckets. So what about anemia? John also mentioned a very nice benefit in terms of anemia responses in the patients with myelofibrosis. So 56% of patients achieved either a major or minor anemia response. So correlating that with what's going on with disease pathophysiology, the first thing we were able to show is that these anemia responses correlated with the clearance of these atypical circulating mutant CALR-positive Erythroid Progenitors that I mentioned. So they decrease. And then interestingly, we saw an increase looking in the bone marrow at CD71 positive cells, reflecting Erythroid Progenitor. So what this is reflecting is we're getting a renormalization of bone marrow hematopoiesis and recovery of healthy hematopoiesis occurring within that bone marrow microenvironment.

Finally, then perhaps most importantly, we also saw nice responses in patients who have not only the primary mutant CALR driver, but also these co-occurring mutations. So if we look at the patients with myelofibrosis who had a co-occurring mutation, 40% of those patients benefited from either a spleen volume or an anemia response. And then 2 patients here who have very high clonal complexity are shown, for example. So these are what we call fish plots. In these plots, the blue area represents the healthy wild-type hematopoiesis and then the colored areas, the mutant CALR clone is shown in orange and then the additional mutations in EZH2, SF3B1 and KRAS for patient 1, ASXL1 and EZH2 for patient 2 are shown in other colors. And you can see with treatment, this reduction in all clones and recovery of the wild-type hematopoiesis.

So then to conclude, INCA033989 treatment results in rapid normalization of platelets in ET, splenomegaly symptoms and anemia in myelofibrosis. These clinical responses are associated with rapid reductions in the mutant CALR clone burden. And this is really demonstrating a speed and depth of response that hasn't previously been seen with other therapies tested in this setting. And importantly, is highlighting the VAF as a relevant and measurable endpoint. The clinical responses were also observed in patients who have co-occurring high-risk mutations, including those associated with increased risk of progression to AML and the improvements in the bone marrow really reflecting recovery of the bone marrow hematopoiesis. And this really supports the potential of INCA033989 therapy to modify the disease of patients with mutant CALR MPNs. Thank you. With that, I'll hand the podium back to Pablo for the Q&A, and thank you for your attention.

Given the extremely encouraging data you just saw presented by the prior speakers, Bill and Pablo get to invite me to talk about next steps. And using the words extremely encouraging here may be classic British understatement given the robustness of the proof of concept you just saw. So the mutation landscape here defines the opportunity for the development in myelofibrosis. In the United States, there are approximately 25,000 people living with myelofibrosis. CALR, as shown to you is the second most common mutation after JAK2 in myelofibrosis and occurs in approximately 35% of these patients. If you use SVR35 as a surrogate for response, only about approximately 1/3 of patients currently benefit with available therapies, thus defining the unmet need in this population. And the unmet need may be best addressed by innovative approaches targeting underlying molecular drivers like the mutant CALR mutation.

Our program will focus across the board in all types of mutations, but just to point out that if you look at type 1 or type 1 like in myelofibrosis, that constitutes about 76% of the population as illustrated on the top right for you. The data shown today, and I think John defined a new term on the podium this morning, super well tolerated. I think in our world, when we say generally well tolerated, it could be like 90% febrile neutropenia, but super well tolerated, I think, really reflects the incredibly well-tolerated drug this is and then indirectly reflected by 85% plus of patients remaining on therapy in both cohorts. Just to be clear, no dose-limiting toxicities were seen and no maximum tolerated dose was defined as is common case with targeted therapies. As prior speakers just showed you, rapid and robust reductions in spleen volume in both the monotherapy and combination cohorts. The week 24 data is pointed out because that is a typical regulatory endpoint.

But this was, as John pointed out, an ongoing dose escalation and expansion study, and there is some expectation that people who are given the correct dose for the right length of time may actually have increased rates of response here. But in this study, 42% of patients achieved an SVR25 and 33% of patients and SVR35 at week 24, respectively. Symptom improvement was seen in the vast majority of patients in monotherapy, 93% and the combination cohorts, 81%. And then specifically looking at the binary validated endpoint that we used, TSS50 at week 24 monotherapy in an ongoing escalation study, 39% with monotherapy and 33% with combination therapy achieved TSS50 with the caveat that this is not randomized data, obviously.

Again, as shown by John, the trifecta, if you will, after spleen and symptoms seen in an unprecedented way, I would add, anemia improvements as well, with 56% of the evaluable patients by the definition, achieving an anemia response and in fact, 40%, a major response by the Tefferi criteria. At the higher doses, reductions in spleen volume, symptom improvement and anemia response was seen in both type 1 and non-type 1 patients. And then as Bethan just showed you, the potential for disease-modifying activity, very elegantly demonstrated by her by the decreases in mutant CALR megakaryocytes seen and the increase in erythroid progenitor cells, which probably then translated to the anemia improvements that we saw in the actual data. So where will we go? Next year, we will begin based on the breakthrough designation that we announced this morning, a Phase III trial, hopefully by the middle of the year in second-line ET.

Because speed is of the essence here and not to wait for the subcu development to be ready, we will begin the study with an IV Q2 week of 989 first best available therapy. The actual doses, et cetera, will be determined after regulatory consultations, which are going on at the moment. The intent is also to begin a second-line myelofibrosis study based on the dose expansion you've seen going on now with dose selection being finalized over time and to begin that study in the second half of 2026. Currently, it is planned to begin with the IV therapy as well, again, given speed is of the essence, but there is some potential to use the subcu if that is ready in time.

And then based on the ongoing Phase I in the first-line setting, which includes monotherapy 989 plus the combination, when those results are delivered in the second half of 2026, the intent is that will inform a first-line pivotal trial design. The subcu development, you saw the announcement, the Enable agreement is signed. The EnFuse device is going into the clinic in early 2026 in a Phase I in both ET and MF. And we will -- if we use this IV in the registration studies, we'll do a bridging study to use those in those 2 settings. With that, I'll hand the podium back to Pablo for the Q&A, and thank you for your attention.

Thank you, Steven. We will now -- do we have microphones? Yes, we have microphones. We open the floor for Q&A, and then we'll go to the webcast as well.

Okay. Alex to start -- okay.

Brian Abrahams, RBC. First off, congrats on the data. I wanted to dig into those 7 patients who were JAK naive or ineligible just to gauge how representative they might be for a treatment-naive population, the treatment-naive population that you're studying. Just is there anything you can tell us about the characteristics of the responders there, whether they were type 1, what doses that they were on? And then maybe for the clinicians, is this the population, a JAK ineligible CALR mutant population where you could foresee using 989 as a monotherapy in the front line? And how large is that subgroup in your practice?

So let me touch first the definition of ineligible was determined by the investigators. Most of these patients were deemed ineligible because of anemia. In terms of the future, we intend to develop 989 in all patients in first line of treatment-naive MF, not just in this cohort. This cohort is included -- this was of patients was included in the study because of the Phase I study, and we didn't want to take RUX-eligible patients. In the long run, our vision is that this medicine is going to be used in first-line MF regardless of eligibility for Jakafi. I don't know, John, Claire or one of you wants to comment on that population.

No. I mean I can just agree that the major region -- major reason that the investigator deemed those patients ineligible was anemia, which we see with CALR mutation. So I think in those cases, the thought process was that maybe a JAK inhibitor wouldn't bring the same kind of benefit and the patient -- so I got to tell you, patients are interested in this therapy. That's the other thing that gets missed in this is that I didn't think we had so much CALR mutant patients until this antibody came out. And now there's all these CALR mutant patients that come out of the woodworks in the community practice, which is where most of MF is.

So my clinic is inundated with CALR mutant patients. And many of them don't understand why they would have to fail a JAK inhibitor. It doesn't make sense for them to have to wait to get it. Even though this is a first-in-human Phase I study, I mean, we had patients that were more than happy to go on. So if the patient had anemia and we weren't clear that the spleen and symptom burden was such that it would necessarily require a JAK inhibitor and the patient wanted to, and that was often the case, they could out.

Just one thing to add as well as anemia, the other risk reason can also be infection risk because, of course, JAK inhibitors do increase your risk of infections. So that's often patients are very aware of this. I work in Oxford and our patients tend to be very educated crowd. So they often come to you with the statistics about toxicities of treatment. So infection is another one. And just to echo the idea that actually our thoughts about this therapy probably eligibility for JAK inhibitor isn't necessarily how you would see eligibility for this drug because you use JAK inhibitors when you want to achieve spleen and symptom responses.

Here, we're looking at spleen and symptom anemia and, of course, then disease modification. So you may -- you have different criteria thinking about eligibility for agents like this.

And then finally, just to say, we use JAK inhibitors currently in patients with pretty advanced disease. We're testing this agent in ET, which is generally a precursor for myelofibrosis. I think generally, the community tends to wait quite late to treat myelofibrosis patients. I think we would be really looking to intervene early and halt the disease.

Steven?

Yes. And Brian, just to add, what -- I think what you're alluding to and what's potentially really encouraging about this data set, though imperfect, it may be a surrogate for first line because they're JAK ineligible, 5 of 7 get SVR35, 60% plus SVR35 rate with all the caveats. Obviously, our first-line study is ongoing, but if that carries through to first line, that's truly high activity there.

Next question. Where are we going? Great, I think it's...

Erik from Mizuho, Erik Lavington, sorry. So I'm just wondering what sort of time line you'd be looking for VAF reduction in the MF patients to get the majority of them over the 50% reduction?

Well, it's a good question. We're going to ask Beth to comment. We don't have a time line for that. I would take a step back and remember what we just saw, which is that 989 impacts every relevant clinical endpoint, SVR35 symptoms and the anemia data, which I would argue is completely unprecedented in this disease for single agent in this population, the 50-plus percent improvement in anemia, we thought it was remarkable. And importantly, it does all those things, not in a symptomatic way, but it does all those things because it's literally reducing the burden of the disease in these patients.

Measuring VAF, I believe, and Beth can confirm is a lagging indicator for what's going on in the bone marrow and what's going on with the cancer stem cells in peripheral blood. Over time, we're confident VAF will continue to go down. If you shut the faucet, as Beth showed, it's going to happen. We don't have a specific goal how long it should take and how low it should go. It's obviously good to see. But that -- so silent carriers will have to die out in the peripheral blood for the peripheral blood VAF to continue to go down. So I don't know, Beth, if you want to?

I might have called a tap rather than a facet, but that's okay.

The tap.

Just, yes. Yes. I think we're kind of in uncharted territory when it comes to knowing what the dynamics of the VAF changes should be and even in terms of how low you need to go and what happens when you stop therapies because actually, we don't have other therapies that reliably reduce the VAF in mutant CALR MPNs. So to relate it perhaps to interferon, which is probably the best drug we have in the context of JAK2 mutant MPNs, those reductions are incredibly slow. And often, we don't even bother measuring it until a year after someone's on therapy.

And of course, that then ends up being typically very clinically meaningful. So I think we need a lot more information to understand this. So slow reductions could be very meaningful. As you were just saying, it may underrepresent when we look in whole blood, what's happening in that important stem cell compartment. And then when it comes to thinking about the depth of response that's required, that again, is uncertain. But you could argue given that we know this is a disease that evolves over years or decades that a small reduction in VAF is very meaningful because it can push the disease back by years or decades. And that is an important goal for these patients.

Once again, to emphasize, the right things are happening. We're reducing cancer initiating cells. We're reducing malignant megakaryocytes. We're reducing malignant erythroid progenitors. All those things are happening, and they're happening pretty fast. VAF, will get there. Next?

It's Michael Schmidt with Guggenheim. Pablo. Nice data read. Congrats on the Phase I data. How are you thinking about dose selection in expansion cohorts and -- in Phase III? And are you considering different doses for ET and MF, for example? And then what about type 1 and type 2 patients? And could you comment -- I know there was intra-patient dose escalation. And what dose did the type 2 patients get up to in this study?

So let me separate the 2 scenarios here, the 2 diseases. In ET, as we announced this morning, we got breakthrough designation. We have initiated conversations with FDA already about the design of a Phase III trial and the dose selection. We're very close to the dose selection in ET. Our goal here is to develop 989 across the spectrum of mutations in both ET and MF, first of all. The dosing strategy, in order for me to give a definitive answer, I need a little bit of time. We are finalizing the dose selection for ET. We're almost there. We're very close.

Platelet normalization is such a rapid and simple PD marker, if you may. It's obviously a goal of therapy, but it's also a PD marker in ET that it makes the dose selection simpler. So that's -- we're very close. In MF, a little bit more data. Particularly important there is going to be the data in naive patients that we're generating as we speak in order to lead to dose selection. Will the dose in ET and MF will be different, I can't comment right now. What I can tell you is that the pivotal plans that we are working on will encompass all types of mutations and the dosing strategy may be slightly different in ET and MF.

[indiscernible] occurred really fast after 2 cycles, I think. So for example, could you consider a low-frequency maintenance dosing in that setting?

It's a good question. The antibody has a short half-life. We haven't dosed patients with less frequent administration. It is something we've discussed and it's something we're contemplating maybe as a maintenance therapy perhaps, but we're not there yet. It's a good question.

This is Srikripa from Truist. Congrats on the data today. So one on ET. The breakthrough designation is for a subset of ET patients. Can you remind us what percent of ET patients those are? And also, how does that read through to the whole program that you have? And then for the MF, maybe a follow-up question for Brian's question. In the monotherapy, you had no high-risk patients. You only had intermediate 1 and intermediate 2 risk patients, I think. In the combination, you did have high-risk patients. How do these high-risk patients perform? If you can give any color, that would be helpful.

Yes. It's a -- the latter is a good question. We're going to have to get back to you on that. I mean we're starting to slice these groups a little bit too much for me to have those numbers on top of my head. I think the difference is simply one is a combination with Jakafi, the other a single agent is a Phase I study. And as a first-in-human study, I think high-risk patients are a little bit more difficult to treat. To the first question you asked, so about 55%, 60% of ET patients are type 1. And I think, Steven, one thing that we start thinking about is Steven showed this in his slide, there's type 1, there's type 2 and then there's others. And in the other category, there's a type 1 like and type 2 like mutations. The picture is a little bit more complex. We still believe that based on the data and the data you're going to see an update tomorrow, 989 works across a range of mutations.

Maybe there's a difference in sensitivity in different mutations. But over time, responses are seen in patients with all kinds of mutations, particularly as you push the dose. The breakthrough designation was in type 1 patients because at the time when we had the submission, the data was more compelling in type 1, and we wanted to get that out of the way and engage with FDA. I see no reason why the trial will not be running all comers with all mutations. There's clear responses in patients with non-type 1 mutations across both ET and MF. And I think John showed some of that data today, and you're going to see some of that data tomorrow. In fact, if you look at the 10 patients with type 2 mutations in the waterfall that were treated with doses of 400 or higher, 3 of the 10 are SVR35.

So it's a response rate of 30%. So this medicine works across a range of mutations. Time and dose are 2 variables that we need to keep in mind. The other variable we need to keep in mind is washout. Remember, these patients were treated with no mandatory washout. And that's a very important point when you look at the benchmark data. So a lot of these patients rebounded between the assessment for the study and when therapy started. As we know, when you discontinue Jakafi, some of the patients have a rebound. So keep that in mind as you look at benchmarks in the literature that these patients had no mandatory washout. I see nodding from our panel. So hopefully, we -- go ahead.

Just to comment, we use momelotinib as we did in Simplify 2 with no washout, the spleen response rate was 7%, and they failed on the symptoms, so just as...