Regeneron Pharmaceuticals Aktie

Good afternoon, everyone. Thank you so much for joining us. Really pleased to have with us the Regeneron team. Next to me is Chris Fenimore, CFO; Andres Sirulnik, SVP, Clinical Development Unit Head of Hematology and Ryan Crowe, IR and strategic analysis. And Ryan, let me turn it over to you.

Just to get this out of the way. And Salveen, thank you very much for having us. Great to be back in Miami again to see a lot of familiar faces and excited to have this chat. But first, let me get through this forward-looking statement disclaimer.

I'd like to remind you that remarks made today may include forward-looking statements about Regeneron, and each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in such statements. A description of material risks and uncertainties can be found in Regeneron's SEC filings that are on our website. And with that, Salveen, let's jump in.

Great. Chris, to start here, Regeneron has been challenged recently on both the earnings front, driven by headwinds facing the EYLEA franchise. And on the pipeline, most recently for fianlimab Phase III failure. In that context, how do you see the company positioned from here for second half of the year and into the end of the decade? And maybe touch on the key priorities for the company at this point.

Thanks, Salveen, and I hope we have plenty of time for Andres because he's got a lot of exciting things to talk about. So if you look at the Regeneron business, it's fundamentally strong, resilient, coupled with a balance sheet that provides us with a tremendous amount of flexibility to allocate capital in a way that we think will drive the most long-term value for our shareholders. If you look at the first quarter alone, we had strong double-digit growth, both on the top and bottom line, driven by our core franchises.

So continued strong performance from Dupixent. We basically saw Libtayo, which I have to say, our commercial team has done a remarkable job of really driving and executing on Libtayo since we took that product back from Sanofi in the middle of 2022. And it really just goes to show you that when we, as a management team, sort of put the execution behind it and the focus, what you can do with the brand in our hands. And then lastly, continued strength and momentum that we're seeing in the EYLEA HD franchise following the approval of the enhancements to the label at the end of last year in both retinal vein occlusion and every 4-week dosing.

So a lot of the reasons to be excited about the current core business as well as what the future holds. You mentioned fianlimab. Fianlimab is one of basically 50 things in our pipeline. We historically and will continue to be very focused on driving what we think is a world-class pipeline. If you look at the perspective, it's always been multiple shots on goal, spreading those shots across multiple therapeutic areas and having opportunities where we think in the short, medium and long term, have significant commercial opportunities. So we're very excited about what the pipeline will be able to deliver over the next few cycles.

If you look at the balance of the year, there's a few catalysts that we're also very, very focused on delivery. Some of them are regulatory catalysts. So we've got the approval for the prefilled syringe. We've got an approval for cemdisiran in myasthenia gravis, and then we've got the approval for garetosmab in FOP.

Looking at clinical catalysts, and I'm sure Andres will talk about these. We've got data coming in our complement franchise in both PNH and geographic atrophy. So a lot of catalysts coming in the second half of this year.

We're also, at the same time, laser-focused on commercial execution. So I touched upon, obviously, our 3 growth drivers. We will continue in the remainder of the year to really stay focused on driving that commercial execution and doing it, obviously, in as efficient way as possible and continuing to drive growth. One thing not to forget about as well is the repayment of the Sanofi development balance, which will be repaid by the end of the second quarter, which will allow an inflection in our share of collaboration profits, basically in the second half of this year.

If you just think about other things that are there in the pipeline in terms of where we think we've got some exciting opportunities. I think Ryan and the IR team, coupled with members of management have done, I think, a very good job using the Regeneron Roundtable as an opportunity to highlight where we have exciting near-term opportunities with large commercial potential in areas like multiple myeloma, anticoagulation, complement mediated diseases and obesity. And those are just some of the nearer-term opportunities.

If you then turn and focus to a pipeline with 50 different sort of candidates in there, there are plenty of earlier stage opportunities that will eventually become mid- and late-stage opportunities as we continue to drive those forward in exciting areas like inflammatory and immunology, ophthalmology, cardiovascular, metabolic and even neuroscience. So there's a lot going on at Regeneron and a lot to be excited about.

Just touch on strategy here. It does seem like the company is increasingly open to larger M&A. Just speak to your view here regarding size of deal and modalities and therapeutic areas and stages of development. And you've also spoken to valuations in cases being prohibitive in the context of return on investment and acknowledge competitive dynamics amongst acquirers. How do you think about all these factors when you put it together?

Yes, it's a very good question, Salveen. I don't -- the way we view it, we're not limited by either the size of the transaction. As I said, we've got the balance sheet with an enormous amount of flexibility. We're not necessarily limited by therapeutic area. We really look at things and evaluate opportunities where we think the science really makes a lot of sense and that can translate into commercial opportunities where there's unmet medical need.

I think if you look historically, we've done more in the traditional collaboration sort of side of things and not necessarily traditional M&A. And those historically have been opportunities where they are complementary technologies or things that augment some of our capabilities as recently as in the past couple of months, we did a deal with Telix in radiopharmaceuticals. We did a deal with Parabilis, using their Helicon technology, coupled with our ability to conjugate them to antibodies to allow potentially targeting those Helicons in interesting ways. And we will continue to do those sorts of things.

We are also very active looking at larger-scale M&A or even smaller types of transactions. You alluded to the fact that we've talked about being involved in some competitive processes as we've evaluated them and kicked the tires. What ends up happening in some of those situations are you have companies that probably don't have necessarily the discipline or don't evaluate the opportunities the way we look at them that when you look at the value that was sort of where those deals actually transacted relative to what we saw as the opportunity on a risk-adjusted basis, we just couldn't get there. But that doesn't mean we won't get there in the future. It really depends on the opportunities that present themselves. We have the ability to basically in a disciplined fashion execute if something makes sense, and we'll continue to evaluate things going forward.

Great. Could we also touch on the Sanofi collaboration here from 2 standpoints, 1 from the IP, but also from the openness you've talked to about working with your partner to potentially add more assets into the collaboration. Where do these efforts stand? And to what extent are you looking externally for assets to bring in? And what characteristics are you looking for in terms of these assets? And if I could just add, how long will this process take?

Maybe I could start with the Dupixent loss of exclusivity question. Clearly, that's of importance to investors given the impressive scale of the product and its continued very strong growth trajectory. Dupixent has a very broad and layered intellectual property estate that has expiries beginning in the early 2030s, including its composition of matter patent in March of 2031, but additional patents that go into the mid-2040s. And these cover other facets of dupilumab, including its manufacturing, its formulation as well as its methods of treatment for various diseases, which really underscores the clinical work that's gone into this antibody that's now approved in 9 distinct diseases. So this -- it's not -- there is no date certainty at this point. I think it's important to consider all of these different patents when trying to figure out when eventually biosimilars could launch. So the most important for us is continuing to drive the growth along with Sanofi and then put up a vigorous defense of the patents that we do have and feel very strongly can extend the runway meaningfully beyond the composition of matter patent in 2031.

Updates will probably come as we approach that date. And as the patent challenges and litigation processes get underway. We're still a few years away from that really happening. So unfortunately, today, I can't tell you when biosimilars will launch, but I can assure you, we are going to mount a very vigorous defense of all of the intellectual property that we have to extend Dupixent's marketing exclusivity for as long as we can.

And just on the maybe 2 aspects. One, the ability to expand upon the collaboration with Sanofi, but also on the life cycle front, the extended IL-13, when could we expect to see data from this agent or the other agents? And when could they [indiscernible].

I'll take the collaboration aspects of it and I'll ask Ryan to IL-13. I think if you look at what we and Sanofi have built with the Dupixent franchise, there's a tremendous amount of value that's been built there. If you just look at relationships with the provider community, relationships with the payer community, even just patients themselves in terms of the trust and confidence that they have in Dupixent in terms of what it's been able to do for them, in terms of, in a lot of instances, changing their lives, in terms of the therapeutic efficacy there.

Being able to leverage that is extremely valuable and it makes a lot of sense if we can do that. With that being said, it's got to make, obviously, strategic and financial sense for both parties. I will tell you with Sanofi's new CEO joining, we've had some initial conversations along those lines. And we'll have to see where those conversations evolve. There are, I think you've alluded to it, a number of different opportunities that we basically have in the pipeline that we can bring as well as whatever Sanofi might be able to bring as well as external opportunities. But we've got the long-acting IL-13, which Ryan will talk about, a long-acting IL-4, basically a [ supi-dupi ] as we call it internally as well as a bispecific. So there's a lot of opportunities to really grow and develop what's there in terms of from an I&I perspective.

Thanks. So Chris, thanks for that. And I think the long-acting IL-13 antibody is the first in a wave of Dupixent, I'll call them next-generation opportunities for us. The long-acting IL-13 antibody went into its first patient earlier this -- last month or earlier this month, the last couple of weeks. And so that will begin a Phase I study in normal healthy volunteers initially. But then move into patients with varying degrees of atopic dermatitis where we hope to learn what the clinical activity looks like and what the durability profile is. We think that this fully human VelocImmune-derived antibody has an opportunity to meaningfully extend the dosing interval that Dupixent currently has without reducing its efficacy and have -- and maintain a similar safety profile.

So we're very excited to be in the clinic. We're moving in as quickly as we can. We believe we have the expertise, the experience, the relationships, all the capabilities to run this program very efficiently start to finish. And to Chris' earlier point on the collaboration, this is an opportunity that Regeneron wholly owns. And we intend to run this program to maximum effect and make sure we get it to the clinic or get it to patients commercially as quickly as possible and in a competitive time frame.

Just switch before we go to the pipeline, just switching over to EYLEA HD. For the [ prefilled syringe ], what are current expectations in the context of both sites?

We don't really have an update to provide, really no change from the information we provided on our Q1 earnings call. We have 2 pending applications with the FDA, 1 with Catalent and another with an alternative vial filler for the prefilled syringe. We continue to expect a decision on one or both of those applications before the end of the second quarter. But I'd say, importantly, the momentum for the product continues to be very strong in its current presentation. And the prefilled syringe is -- we're not dependent on a prefilled syringe to continue to drive growth for this franchise. It's becoming increasingly recognized as the best-in-class product.

The label enhancements that were added in November of last year only continue to add to the bolus of patients on therapy. So we're very excited about the revenue result in Q1 and then hope for a very strong 2026.

And what are the scenarios from here, just given the observations at Catalent, but also the PDUFA being passed for the other site?

So I'm sure Catalent is working very hard to resolve the observations that were noted during their April inspection, and we would expect them to continue to dialogue with the FDA in order to tick all the boxes required to get that facility back to VAI status.

In our alternate manufacturer, as you noted, the PDUFA date was in late April, the FDA opted not to act. There's been continued engagement between this manufacturer and the FDA, and hopefully, progress is being made, and they can approve that file at some point in the future.

And just looking back at the first quarter sales for EYLEA HD, there was impact from pricing and inventory and seasonality. Maybe speak to which factors are specific to 1Q and how to think about that read-through to 2Q from them and beyond?

So as you look at the performance in the first quarter, we talked about the underlying demand approaching basically 10% sequentially and as we talked about, obviously seeing continued momentum just based on the current product profile, as Ryan talked about. The biggest factor that we saw was definitely attributable to inventory. Wholesaler inventory is something that's totally at the discretion of the wholesalers. It was at an elevated level at the end of Q4. They drew down those levels in Q1, which impacted the net sales relative to the demand.

There is pricing headwinds out there. It's a very competitive category, and we obviously are -- have to operate in that environment and do what we feel is necessary to maintain our competitive position out there in the marketplace. So if you look at historical pricing and what you see in the class, we would expect similar competitive pricing pressure to continue going forward.

As we pivot over to the pipeline here, you do have a lot of programs that are reading out over the next 12 months and beyond. Where do you have the most conviction in terms of those programs translating to meaningful revenue?

I think a lot of them are actually being managed by Andres, and I can't wait to get into some of his programs. So certainly, C5, BCMA in myeloma are 3 and then obesity, which we can certainly talk about as not only about weight loss, but also about better managing kind of cardiovascular risk. So those are the 3 that I'm probably most -- 3 or 4 that I'm most excited about. And hopefully, we can have Andres dive into a few.

Perfect. Andres, I'll turn it over to you for any comments here, and we'll jump into some of the -- maybe we could start with the C5 pipeline here.

Great, Salveen. Thank you for having me and the opportunity to share what we are doing in hematology. Quite a lot going on, as was just said. So C5, we are very excited with the prospects of our C5 assets and the approach that we are taking in exploring how different degrees of C5 inhibition may translate in defined and clinical outcomes for patients. We span indications from in hematology, PNH, paroxysmal nocturnal hemoglobinuria, to myasthenia gravis and to geographic atrophy, diseases that are driven by complement dysregulation. And from the earlier on, we hypothesized that maximal C5 inhibition will be required and [ tested ] that question to benefit patients. And we have learned a lot throughout these programs.

I think the one that really the readout taught us a lot about how the degree of complement inhibition may translate or not in clinical benefit has been in myasthenia gravis. And maybe we can go a little bit into the results of our data in myasthenia gravis, which essentially is driving a launch at the end of the year in this disease. And this is where we tested either driving full complement inhibition by combining siRNA that inhibits the production of C5 with an antibody that inhibits the activation of whatever remaining C5 is in the circulation. And what we learned in myasthenia is that you don't need full complement inhibition to actually benefit patients.

Furthermore, the study -- the NIMBLE study demonstrated that single-agent siRNA benefits the vast majority of the patients in the trial. And this was done with what we call a potentially sweet spot. We observed a 70% inhibition of complement while in PNH, we know that we want to drive 100% inhibition of complement to decrease hemolysis. Here, we learned that in this disease that was not necessary. And we are very excited with the results of the clinical trial. We think that we have the potential for the best-in-class in terms of the C5 inhibition. We're looking across different studies where we observed a sustained benefit and improvement in symptomatology to patients. This was -- and when I say sustained, why is this important? Because we observed the benefit throughout the dosing period from beginning to the next dose where patients sustained their symptomatic relief.

And doing so with an administration that is very convenient to patients every 3 months, given subcutaneously, which we think will drive a lot of the future market opportunity for cemdisiran in this disease. Importantly, also, when we look at the study, the safety was very manageable. And when we look at serious -- we have no serious adverse events in single-agent cemdisiran. We had no discontinuations throughout the study period and when we reported at 24-week outcomes, which we think is very favorable within the class. So we think that there is a tremendous potential for cemdisiran there.

Where do you see it being positioned versus the FcRns or Amgen's UPLIZNA?

So that's a great question. So let's start first with why it's different and what is the differentiation. One of the critical, I think, differentiation is, [indiscernible], a very efficacious drug, yes. We have comparable, if not better, to C5 inhibitors in terms of symptomatic improvement. When we look at the duration of that improvement vis-a-vis FcRn is sustained, it's not cyclical. And even in C5 inhibition, it has been observed that you may see worsening of the symptoms as you get closer to the end of the dosing period.

So sustained inhibition and then convenience, of course. We are looking at subcutaneous administration 4 doses a year, which I think, again, will be critical in terms of driving the success of this drug. But I think that one aspect that sometimes goes unrecognized, and we should pay a lot of attention is about safety. We are hypothesizing and based on the data that we observed with minimal adverse events or not minimal, but with no cases of meningitis, with no SAEs throughout the treatment is the fact that potentially the sweet spot that we found where you don't necessarily need to drive full inhibition of complement allows for some remaining complement activity that may potentially help in fighting infections. So we have to generate more data to demonstrate this point. But I think the data from the clinical trial already suggests based on infections, SAEs and so forth that there might be an advantage of cemdisiran.

When you look at where FcRns are depleting all immunoglobulins with other potential for infections, viral infections and so forth, which you don't see with complement inhibition. And when you look at the CD19 inhibitor targeting plasma cells, again, we think that the complement inhibition may be associated with less infections and so forth.

And lastly, I want to highlight the rapid onset of benefit that we observe. We looked at symptomatic relief when we assessed this was at 2 weeks. And in fact, the vast majority of patients already start experiencing symptomatic relief within 14 days of initiation of therapy. CD19s can take months. In fact, it takes half a year to get to that steady state of improvement. And as we know, FcRns and other C5s potentially delay a little bit vis-a-vis what we observed here, but with the problem of this losing of benefit towards the end of dosing.

And in geographic atrophy, you're going to disclose 26-week data. Could you just discuss the desired clinical profile here and the differentiation that you need to see to support further development and the likelihood of this given it's systemically delivered?

Absolutely. And this is an excellent question. So what are we going to learn from the first 225 patients really? The first one is C5, systemic C5 inhibition have an effect on the slope of progression of the growth of the lesions in the eye. That's the first thing that we're going to learn. Also, we're going to learn whether monotherapy or double inhibition with the antibody and siRNA is necessary in this disease. We learn in myasthenia, it's not. We know and we strongly believe that in PNH that's necessary, but we don't know yet in the eye.

Those are the first 2 things that we're going to learn, but I think that the data that is going to emerge also is going to help us further refine the ongoing clinical program in GA.

Now moving to what is that we are looking for. So we're looking at the slope of growth of the lesion. But importantly, in this study, prospectively, we are going to be looking at [Audio Gap] as you know, that has not been done prospectively in any of the clinical trials with injected C5 or C3 inhibitors.

So I want to point out, however, we are looking at 24 weeks. It's a bit early. As you know, most of the benefits are observed longer term, but we're looking at the slope of 24 weeks, and we may get a hint on a potential benefit in terms of visual acuity. Those are the 2 important aspects that we're going to learn towards the end of the year, and we're going to be sharing with all of you as the data becomes available. Of course, we're going to learn about safety, which is always very important. But we think that we will learn more towards the end of the year.

Perfect. Ryan, you touched on obesity being a key focus for the team and we'll see some data by year-end. Maybe help us understand what proof of concept could play out with that data set and then the overall strategy for the obesity portfolio.

Yes. I mean I think for the strategy, it's really about more than just weight loss. I think that's patient -- that has largely been solved, right? I think we're going to focus on other elements, including improving tolerability as well as addressing comorbid conditions and starting with cardiovascular disease. So Hansoh, the company that we in-licensed olatorepatide from, disclosed earlier this year top-line data in their Chinese patients with obesity with weight loss on par with leading agents. But with the GI tolerability profile that was much more favorable than [ like-run ] studies in China were. So we're very encouraged by that, and we're in the process of enrolling a small Phase II study in the U.S. to see if that GI tolerability profile can be replicated. And should it be replicated, I think we will have an impressive competing agent within a category that has room for many, many therapies.

Beyond just the monotherapy opportunity in obesity and type 2 diabetes, we're also in the process of co-formulating olatorepatide with our PCSK9 antibody, Praluent. Of all the miracles that GIPs and GLPs have produced, one that it has not is lowering LDL in the pivotal studies for those agents, something like a placebo-adjusted decline in LDLs was only in the mid-single-digit percentile. So not really having much of an effect on lipids. However, we think that about half of these patients actually have elevated LDL levels and could benefit from being on a PCSK9 inhibitor like Praluent.

So our approach is going to combine these into the same weekly injection that many patients are already used to. And in addition to lowering their weight, we would also expect their LDL to lower on par with what we saw in the Praluent monotherapy studies, which were in the range of 50% to 60% at 6 months. So this is a way for us to enter the market, a large and growing market in a differentiated way. We have other potential combinations to address other comorbidities of obesity that we will talk about at a later time. But certainly, we feel this could be a differentiated opportunity and make a nice -- take a nice part of a large market.

And you announced collaborations on radiopharmaceutical therapies with your agreement with Telix and Antibody-Helicon Conjugates by your agreement with Parabilis. Can you discuss your interest in these technologies and how you envision integrating them into your platform?

Yes. I think this is, as Chris was talking about, opportunities that really complement Regeneron's core strength, which is antibody development as well as genetics, but in this case, primarily focused on antibodies. We're going to use these antibodies that we make with our platform to better direct these radioligands and these Helicons that Parabilis makes in an effort to, in the case of Parabilis, address intracellular pathways that antibody simply can't address. So this is a way of kind of enhancing a core strength that Regeneron already has, but take us to places that we couldn't go with antibodies alone.

So we're very excited to get started with both a lot of work to do, but this could be a very important expansion of our capability set to address some of these different types of opportunities.

Great. With that, thank you so much.

Thank you, Salveen.

Thank you, Salveen.

Thanks, Salveen.

Thank you for joining us. Welcome back to the Bank of America Healthcare Conference. It's my pleasure to have with me our next presenting company, Regeneron Pharmaceuticals. Up here on stage with me are two members that we'll be talking to you for the next 30 minutes. Marion McCourt, who is, of course, Executive Vice President of Commercial, as well as Ryan Crowe, who is Senior Vice President, Investor Relations. Guys, thanks for making the trip over from the East Coast...

[Audio Gap] In exchange, we are not going to be subject to future government pricing mandates, and we'll also have tariff relief through at least January of 2029. So all in all, a very similar construct to the previous deals that were announced. Perhaps one detail that we've included in some of our disclosures is that this includes products that are wholly owned by Regeneron in the United States. So that excludes certain of our alliance products from this agreement.

Are those exclusions inclusive of EYLEA and DUPIXENT?

So we have never made any comments about specific products and because of the confidentiality around these agreements, I can't name specific products, but what I will say is we wholly own EYLEA and EYLEA HD in the U.S., but we do not wholly own DUPIXENT in the U.S.

Okay. So you talked about this $27 billion plan to invest in R&D and manufacturing in the U.S. Can you talk to us over what time frame and how that's going to be invested?

Yes, there's a little bit of mixing and matching of time frames and numbers and exactly what is what. But maybe I can just do a quick summary of that. So we've committed to approximately $9 billion of capital investment through at least the end of the decade, probably 2030, 2031. We expect that to all have been completed. That includes R&D facilities in our Tarrytown headquarters expanding our R&D footprint in Upstate New York as well as with some contract manufacturers we're working with in the United States.

On top of that, so that's around 1/3 of it. The other 2/3 are related to expenses for R&D that will be incurred in the U.S. as well as for manufacturing expenses that will be incurred in the U.S. through approximately the end of the decade as well. So there's a bit of mixing and matching in terms of investment versus what we're going to spend. But all in all, I think very supportive of the U.S. economy, which was one of the objectives of this deal.

Okay. So let's move on to DUPIXENT. Can you just talk about the evolution of the different indications? Rightly or wrongly focus remains on AD. What's your penetration in that indication? And how should we be thinking about uptake. We do our own survey work. We do a lot of checks with physicians. One thing that we've noted is a particular level of excitement, for example, around COPD. So we'd like to hear, maybe Marion and your thoughts on where you are and where you think it's going to go from here.

Sure. Very happy to talk about DUPIXENT. I also thought really briefly just to share with you. Ryan talked about Otarmeni, the product that we're giving for free to patients in the U.S. marketplace. It has been launched. It's a small population of patients babies that have this in young children, this profound hearing loss. Some of you may have seen in the report from the Oval Office as Len and George we're talking about our MFN plan, but also sharing the story of young Travis who is there with his mom and for the first time, hearing her words as she was able to share things like I love you to her son.

So I mentioned Otarmeni, fortunately, it's a very small number of patients and families, but incredibly important that we can make a difference for them.

Over to DUPIXENT, which helps so many patients. So there are 1.4 million patients on therapy right now worldwide. We have nine indications in the U.S. marketplace. I'll give you kind of a brief tour of a product that's at a run rate of about $20 billion a year right now. It's been an amazing journey. My time at Regeneron has been spent with all of our portfolio, but certainly launching DUPIXENT across indications, atopic dermatitis was the first blockbuster indication. Today, we have four because in addition to atopic dermatitis, we also have asthma, nasal polyps, eosinophilic esophagitis. And then more recently, we've launched five more indications I'll talk about the original launches in every indication, we lead the market in new-to-brand prescriptions, total prescriptions.

In some cases, like asthma, we launched it to a very competitive market and quickly the physician experience and the patient experience with DUPIXENT was so remarkable that it became the leading product in category. Atopic dermatitis, I come to you weeks off being at the American Academy of Dermatology and pretty much every KOL I met with didn't -- well, they didn't always use the exact same words, but everyone had the same message is that DUPIXENT is first and best in category. Unlike so many other categories in our industry, sometimes follow-on products give improvements. In the case of DUPIXENT is seen as the standard of care, the gold standard and has helped so many patients with atopic dermatitis.

Children as young as 6 months are being helped by the product in atopic dermatitis and children as young as a year of age eosinophilic esophagitis. So whether it's one of our established, more blockbuster -- all the indications are growing or newer launches, to your point in COPD or bullous pemphigoid, prurigo nodularis, CSU, in all these indications, it's so important that there's a product that's been so well experienced. DUPIXENT, I'm pleased to share with you is the leading biologic for allergists, pulmonologists, respiratory therapists and also for physicians who are treating eosinophilic esophagitis for that particular indication.

But the product, in addition to helping the indication, which has brought the patient to see their physician, it also helps across type 2 allergic conditions. And it's not uncommon for example, that a patient that is suffering with asthma also has nasal polyps or the atopic dermatitis patient who also has some other type of type 2 illness. So I hope I've gotten to answer all your questions.

Maybe just one more moment on COPD. The launch is going very, very well there. Obviously, first biologic to launch four COPD patients and we continue to see great reports from physicians, their patients and continue to help those patients.

So one question I'll throw in there since you mentioned COPD, and it's in line with what we're hearing from physicians is that -- what do you think is the undermet need there? What are the therapies that are approved, not addressing the patients? And what's particularly appealing that you're hearing from your field force on why docs want to try it.

Sure. and directly from physicians as well. I would say the first element for COPD is the unmet need in patients who are on triple therapies but not getting the level of relief, the exacerbations, the difficulty of many patients having to be on oxygen therapy, which is really, really difficult for patient, family and their caregivers. We hear stories of patients coming back in to see their physicians after being on DUPIXENT for COPD and coming off their oxygen therapy, feeling better than they have in years in terms of dealing with their condition. And all the while a product that is convenient to use and is safe to use, so it's made a remarkable difference in these patients.

If I could just add, the competing biologic in the market for COPD has never demonstrated any lung function improvement, whereas DUPIXENT and its pivotal studies demonstrated on approximately 80 ml improvement in FEV1, which is the gold standard for measuring lung function.

So these patients are not only exacerbating less, but they're feeling better. And I think that's probably what they noticed the most. As Maria mentioned, a lot of patients are able to either discontinue or significantly reduce their reliance on oxygen.

So you've been picking up a lot of real estate with all the different indications that you've launched on for DUPIXENT over the last several years. And so naturally, I think people are thinking two things. Number one, your partner Sanofi and extending the IP, which seems like it's largely in their court. But also you as a company have talked about next generation, so what we affectionately call supi-dupi. So maybe you can quickly tell us what you think would be an attractive profile for a next-generation drug.

Yes, sure. I can probably start with that. I think we believe that DUPIXENT as Marion mentioned, is first and best-in-class. But these next-generation opportunities that we've developed in our preclinical pipeline are looking to at least improve on the dosing interval that DUPIXENT currently has, which is every 2 weeks in most indications. So our goal is to extend on that.

And supi-dupi happens to hit the exact same receptor that DUPIXENT does. The issue was trying to put more drug and just trying to get a longer dosing interval simply by adding more drug is a receptor-mediated clearance is something that happens with the IL-4 receptor, which means that you can put more drug into it, but it's unlikely to meaningfully extend the dosing interval.

So we've come up with a new approach using a new antibody that seeks to avoid or at least mitigate this target mediated clearance issue that the IL-4 receptor presents. We haven't discussed exactly how that approach works publicly yet, but I'm sure we'll get into that once we reach the clinic. And we do expect that antibody to be clinic ready by year-end or perhaps in early 2027.

Perhaps in the backing up in terms of what's in the collaboration with Sanofi versus what is not, that supi-dupi , the IL-4 receptor next-generation opportunity is covered by this collaboration because it is the exact same target as dupilumab does today. Other opportunities like the long-acting IL-13, which is about to enter the clinic is not part of the collaboration. So we certainly are working collaboratively with Sanofi in certain areas, but then independently in others. So we look forward to continuing with that.

Would you want to do parallel development of both mechanisms at the same time?

Yes, I think that's -- I think it's in both companies' best interest to maximize all the commercial infrastructure we built, all the commercial leverage that DUPIXENT has established. So -- and I'm sure there's discussions that have taken place and will take place about expanding the collaboration. But I think it's premature to get into exactly what form that takes.

Okay. Now I think partly -- well, definitely because of the success of DUPIXENT, lots of other companies have tried to make tweaks, if you will, and make adjustments to this drug, whether it be an oral version or, let's say, or an oral compound or less frequently dosed. So as you think about the evolution of this market opportunity, knowing what you just said about moving into clinic in the nearer term, does it change the level of differentiation you think you need to achieve just because there might be other options coming around in the beginning part of the 2030s?

So let me start, and I'm sure Ryan has some comments to and you had asked this before, when it comes to penetration in the market for atopic dermatitis, there's only about high teens percentage penetration for patients who could and probably would benefit their lives if they were treated with DUPIXENT.

So what we found is more products have come into the marketplace it actually helps grow the market, educate the market, bring more patients into the treatment continuum.

Obviously, today, DUPIXENT is incredibly highly held by physicians and patients if we're able to bring additional enhancements to product profile in the future, with Sanofi, as Regeneron, that will be incredibly important to the market as well. And I think we're in a good position to do that. We obviously understand the market very well. We have a really experience...

[Audio Gap] differentiation on efficacy, at least in a meaningful way because when you think about the biologic cascade, it really starts at IL-4. So even STAT6 inhibition or degrading is further down the cascade. So perhaps an oral option will be desirable for some patients. But to think it's likely to outperform on skin clearance or itch seems unlikely to us biologically.

So yes, there's going to be perhaps improvements on certain convenience properties or the convenience profile for some of these. But we believe that DUPIXENT, as Marion said, is kind of the top of the cascade and it's going to be very difficult to beat if you're in the space.

Marion, maybe I wanted to ask you, what is the latest that you've heard about patients that are needle phobic, let's say, for AD?

So it's interesting. The evolution of DUPIXENT across indications has demonstrated that for better efficacy for safety and for what is a very easy self-administration for most patients themselves or for family members with children, it has not been a barrier to care as you can see evidence in DUPIXENT performance. It's interesting in the world as well. I think injectables have become more a mainstay across so many different disease areas.

Having said that, if in the future, Regeneron is able to keep everything great about DUPIXENT and give other options for use. Some patients actually now prefer injectables because it's not something they have to remember daily others potentially might be more drawn towards an oral therapy or the -- I think the number of pure needle phobic is probably not what it was in years past. But certainly, we want to be on the cutting edge of that delivery options for patients and doing the right thing.

Is that something that you'd be willing to try to acquire if you thought you found a good asset?

I don't think anything is off the table for us in terms of M&A. I don't want to speak to specific therapeutic areas or targets, but we certainly cast a broad net, look at everything that's going on out there and what we think is interesting scientifically and can be complementary to what Regeneron has, we'd certainly take a look.

Okay. Maybe let's do a couple of questions on EYLEA before we go on to LAG-3, which I get a couple of questions on here and there now. So the HD launch, I think going back a year ago, I think people were still of the view that with the biosimilar for 2mg EYLEA, it was unclear how that franchise in general would survive biosimilar launch. But it does look like from our work, and I'd love to hear your thoughts from your feedback from the field that HD is something that's very appealing to physicians and patients. So maybe can you give us a little bit of color on that?

Without question, certainly, EYLEA HD has the profile of product to be standard of care as EYLEA has been in category. Together, they are the overall innovative branded franchise leaders I'm pleased to report that EYLEA HD is almost half of that in terms of net sales now. The product grew nicely in the last quarter based on demand increases that we shared with you. And certainly, the approval towards the end of November of having Q4 weekly dosing in the label, the RVO indication and also dosing durability out to 20 weeks is really, really important to physicians in choosing the product that is best for their patients.

So we see good performance there, very solid performance and certainly look forward to potentially bringing prefilled syringe into the market as well.

But in spite of that, we still guided and I guided to you on the most recent earnings call that we expect to see in the coming quarter demand growth in the range of about that 10% as we produced prior quarter.

Similarly, we also guided that we would expect to see continued decline -- demand decline in EYLEA, the 2-milligram product in the range of the mid- to high teens.

Okay. And as you think about the market moving forward, what do you think is the most attractive about the HD or even from your competitor, Vabysmo? Is it that it's more efficacious or is it the convenience of less frequent dosing?

So I'd say with EYLEA HD and EYLEA long now the standard of care. Physicians really like the profile of EYLEA HD. They trust the safety. They like the clinical efficacy in indications like RVO. EYLEA had always been the standard of care. There was never wavering of that and it was based on performance. We also see EYLEA HD referred to as the product that's got the greatest durability for patients who can have the extension of dosing. That coupled back to safety and efficacy are the ingredients that the retina community is most looking at.

What on average is the dosing frequency are you hearing right now? It's early.

It really varies by patient, but I can share with you that, when we look at data, looking at durability, EYLEA HD is the product that can achieve the greatest durability for patients when you look at totality of care.

I like very much that we have the Q4 weekly dosing available now because physicians can't always determine after three loading doses on EYLEA HD. They can't always determine which patients can get out to a 7-week dosing interval which is required in most instances for payer coverage. They just didn't know. Now having this assuredness is really helpful. Additionally, having the indication for RVO, where they really wanted to use have been using EYLEA really wanted to use EYLEA HD. That certainly now is something that is available to them as well.

So at EYLEA HD, if you look in totality, has the broadest label, greatest dosing flexibility of any product in the category.

And based on what you said, you do think that when the PFS does come online, that would be meaningful improvement in terms of how doctors see it for patients.

We do think it's important. Physicians as you can see, want to use EYLEA HD, but we do think that flexibility of having the prefilled syringe will be important a reference point for you within EYLEA, about 95% of the use is with prefilled syringe opposite vials. I think what is also remarkable and very, very important is that EYLEA HD is highly held in the minds of physicians. So even though we've had the vial only delivery physicians are using the product, they're having a great experience for patients. And you can imagine for blinding eye disease, efficacy, safety and durability are key ingredients.

Okay. Perfect. So now let's move on to fianlimab to the LAG-3 study. Maybe, Ryan, can you level set for us metastatic melanoma? What do you think is the rough total addressable market opportunity here? And how does that compare to the products that we just talked about, EYLEA, DUPIXENT for Regeneron?

We believe the global metastatic melanoma market opportunity is somewhere in the range of $2 billion to $3 billion. Obviously, there's standards of care, including PD-1 monotherapy, PD-1 plus CTLA-4 and the incumbent PD-1 LAG-3 product that's out there. With fianlimab, Libtayo, we believe that we have a potentially differentiated efficacy profile relative to that incumbent LAG-3 PD-1 product and we expect to get our data very near term. We certainly were encouraged by the promising Phase I data that we generated across three independent cohorts that when pooled, generated a median PFS of about 24 months and a complete response rate of 25%. And those compare very favorably to the incumbent LAG 3 product that had around 10 months of median PFS and around 12% or 13% complete response.

And the differentiator against the CTLA-4 PD-1 combination, I think, is going to hopefully be efficacy as well. But certainly, on the safety side, we see a lot of toxicity with that combination. But at 11.7 months, the median PFS has set the highest bar for efficacy in this setting. So we're very encouraged. We are looking forward to getting this data and hopefully sharing with you guys shortly thereafter.

And what level of top line information should we expect?

That's TBD, but I think Regeneron typically errors on the side of providing more detail in our top line press releases than most other companies. I think it's safe to assume we'll say more than positive study and see a medical conference in 6 months. I would think providing the medians across all arms would be an appropriate level of disclosure and perhaps more depending on the interim overall survival readout and the objective response rates. So we'll see exactly what we get from the DMC when the data reads out and put together a fulsome disclosure, I'm sure.

Okay. After that, I think all eyes will move on to the adjuvant setting. So I think we've all talked about this, but love to hear your updated thoughts on what do you think the read-through is going to be from the metastatic study onto the adjuvant study. And again, as a reminder, you are going to be taking interim looks -- another interim look before year-end?

The adjuvant setting is quite different. I mean with Opdualag, the incumbent LAG-3 PD-1 combination product, the Bristol markets, obviously, they had a positive readout in advanced melanoma but an adjuvant generated a hazard ratio of 1.01 compared to nivolumab monotherapy. So literally, no efficacy whatsoever.

And the biologic rationale that their investigators came up with was that by resecting the tumor, you've essentially removed a lot of the T cells that you're looking to activate with LAG-3 blockade. So that biologically makes some sense to us, but we think that perhaps since we're able to dose much higher than relatlimab can be dosed in an Opdualag maybe there will be residual T cells that we can block that will enable us to generate a positive readout in adjuvant.

I do think it's much higher risk than the advanced melanoma setting. We don't have any Phase I data to support this. But it did enroll very quickly, and we will have a second interim analysis early in the second half of this year, and if necessary, a final analysis before the end of 2026 for this adjuvant melanoma opportunity.

I'll just add, as Ryan was talking about future product. Just a quick reminder to everyone. We obviously have a very experienced oncology team in the marketplace today with Libtayo across our non-melanoma skin indications of basal cell carcinoma, cutaneous squamous cell carcinoma Libtayo has been a really important product to Regeneron into the oncology community and patients.

There, we did recently secure the adjuvant CSCC indication, which has been launched has been incredibly well received. And obviously, we've made a lot of progress in IO therapy in lung. Second most frequently used product today with oncologists. So we look forward to future launches and certainly, potentially, we'll be ready if we have the clinical readout we hope for and an approval to follow.

Okay. And maybe we will wrap it up with this last question, which I think you might have gotten a couple of times in the last week or so. You did make that recent change to the statistical analysis plan. So that's going to now include all patients with at least 6 months of follow-up.

Len and George talked about this a little bit, but maybe can you just reiterate what the genesis of that was when it started? When the idea came and why you think it's important to have it be the case as you go into the readout that this change was made?

Yes. Thanks, Tazeen, for the question. I think there's certainly been some confusion out there about what actually happened, what the time lines for the decisions were. So let me kind of start from the beginning.

We ran this study with originally with two cohorts, a PFS cohort, which was to include the first 1,175 patients or so across four arms, and that was going to be the population that contributed to the primary analysis of progression-free survival.

Upon the 1,176 patient, we were going to begin enrolling a 360 patient cohort that was only going to contribute to the overall survival, secondary endpoint. And that enrollment ran from essentially January through late summer of 2025.

As we move through 2025, we saw a very slow accumulation of PFS events in the PFS cohort, which went for several consecutive months into the second half of 2025. And we were beginning to get concerned about when exactly the readout would occur.

So what we decided to do, and this was in the fall of 2025 was to add the patients that were originally only going to contribute to the overall survival, secondary endpoint to the primary analysis, without changing the number of events required to trigger the readout.

We also added the requirement that every patient would have the opportunity for at least 6 months of follow-up. And we did that because we didn't want to drop in those patients from the old OS cohort and then immediately read out the data when some of those patients would have just begun treatment.

So all patients will have at least 6 months of treatment. We need to reach 399 events in high-dose fianlimab plus Libtayo plus pembro. That analysis and then the low-dose fianlimab versus pembrolizumab. Each of those need to equal 399 and the last patient first dose needs to be at least 6 months beyond that first -- that last patient first dose in order for us to lock the database and read it out.

So it was done because of slow event rates, we made the protocol amendment towards the end of last year. I believe we submitted it to all the global regulatory authorities in November, December time frame. We had to wait until it was signed off by all of them before we began talking about it. And the EU member states that are involved in the study only approved this protocol amendment at the beginning -- towards the beginning of April, so only about a month ago. which is why it only became public then.

So we're now locked and loaded. As I mentioned, we're fast approaching this readout. We're really looking forward to it, certainly have high hopes for this data set and look forward to sharing it with you as soon as we can.

Okay. With that, we're out of time. So thank you, guys, for making the trip over again, and thanks, everybody, for listening. Thank you.

Thank you.

Welcome to the Regeneron Pharmaceuticals First Quarter 2026 Earnings Conference Call. My name is Kevin, and I'll be your operator for today's call. [Operator Instructions] Please note this conference is being recorded.

I will now turn the call over to Ryan Crowe, Senior Vice President, Investor Relations. You may begin.

Thank you, Kevin. Good morning, good afternoon and good evening to everyone listening around the world. Thank you for your interest in Regeneron and welcome to our first quarter 2026 earnings conference call. An archived and transcript of this call will be available on the Regeneron Investor Relations website shortly after our call concludes.

Joining me on today's call are Dr. Leonard Schleifer, Board Co-Chair, Co-Founder, President and Chief Executive Officer; Dr. George Yancopoulos, Board Co-Chair, Co-Founder, President and Chief Scientific Officer; Marion McCourt, Executive Vice President of Commercial; and Chris Fenimore, Executive Vice President and Chief Financial Officer.

After our prepared remarks, the remaining time will be available for Q&A. I would like to remind you that remarks made on today's call may include forward-looking statements about Regeneron. Such statements may include, but are not limited to, those related to Regeneron and its products and business, financial forecast and guidance, development programs and related anticipated milestones, collaborations, finances, regulatory matters, payer coverage and reimbursement changes to drug pricing regulations and requirements and our drug pricing strategy, intellectual property, pending litigation and other proceedings and competition.

Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in that statement. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission, including its Form 10-Q for the quarter ended March 31, 2026, which was filed with the SEC this morning. Regeneron does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

In addition, please note that GAAP and non-GAAP financial measures will be discussed on today's call. Information regarding our use of non-GAAP financial measures and a reconciliation of those measures to GAAP is available on our quarterly results press release and corporate presentation, both of which can be found on the Regeneron Investor Relations website. Once our call concludes, the IR team will be available to answer any further questions.

With that, let me turn the call over to our President and Chief Executive Officer, Dr. Leonard Schleifer. Len?

Thanks, Ryan. Thanks to everyone for joining today's call. We were pleased with Regeneron's performance to start 2026, highlighted by strong commercial execution across our key growth products, continued pipeline progress, a disciplined approach to capital allocation and our agreement with the U.S. government to lower drug prices for American patients while preserving innovation.

Starting with the financials. We delivered double-digit growth across both revenues and earnings. Total revenues increased 19% compared to the first quarter of 2025 and non-GAAP earnings per share increased 15% demonstrating our ability to deliver strong operating performance while continuing to invest in our science and long-term growth opportunities.

Global DUPIXENT net sales increased 31% on a constant currency basis to $4.9 billion in the quarter. Growth was broad-based and driven by continued strong demand across multiple approved indications and geographies, reinforcing DUPIXENT's position as the foundation of our immunology franchise. We also continue to advance our efforts with next-generation therapeutic approaches to strengthen our leadership position in inflammation and immunology.

EYLEA HD U.S. net product sales increased 52% year-over-year to $468 million. We continue to see encouraging physician adoption of EYLEA HD, reflecting confidence in its clinical profile and dosing flexibility. We resubmitted an application seeking FDA approval for filing -- for filling of the EYLEA HD prefilled syringe at Catalent Indiana, where the FDA has recently conducted a site reinspection. In addition, the FDA did not act by the April 2026 PDUFA date for the company's regulatory application for a second contract manufacturer for the PFS. Therefore, this application remains pending. Regeneron and both third-party filling manufacturers are working closely with the FDA to resolve all outstanding issues and we anticipate a regulatory decision on one or both applications during this quarter.

In oncology, global Libtayo product sales grew 54% to $438 million, driven by continued uptake in advanced cutaneous squamous cell carcinoma and advanced non-small cell lung cancer as well as early contributions from the adjuvant CSCC indication, which received FDA approval in the fourth quarter of 2025.

Turning briefly to our pipeline before George provides more details in his remarks, we've continued to make meaningful progress across multiple therapeutic areas so far in 2026. Last week, we received FDA approval of Otarmeni for genetic hearing loss, marking an important milestone for patients with this ultra-rare condition, and we have committed to offering this product for free. While this may seem like an unconventional decision, we believe it's the right one for Regeneron, and it reflects the ethos that we live by, pushing the boundaries of science to benefit humanity.

Moving to other advances in our pipeline. We presented positive Phase III data for cemdisiran, our investigational siRNA that targets C5 in generalized myasthenia gravis, which demonstrated a differentiated efficacy, safety and convenience profile relative to approved myasthenia gravis therapies. We submitted a new application utilizing a priority review voucher and anticipate an FDA decision in the fourth quarter.

In metabolic disease, we enhance or announced positive Phase III data in China for olatorepatide, our in-licensed GLP/GIP receptor agonist with full data expected to be presented by Hansoh later this year.

DUPIXENT achieved multiple regulatory milestones, expanding the eligible patient population to younger age groups and to new diseases. In addition, the FDA accepted our biologics license application for garetosmab and granted priority review with the decision in August, representing another important step forward for our rare disease portfolio.

Briefly on capital allocation. We continue to take an approach that balances internal investment which we believe offers the greatest long-term return for shareholders with direct return of capital through share repurchases and dividends as well as business development. In support of that approach our Board authorized a new $3 billion share repurchase program, reflecting confidence in our business and financial position.

We also recently entered into strategic collaborations with Telix and TriNetX. Finally, last week, we entered into a Most Favored Nation pricing agreement with the United States government, achieving our shared goals of ensuring timely and affordable access to groundbreaking medical advancements for [ Medicare ] patients, maintaining the United States leadership in biotechnology, innovation and manufacturing and addressing the imbalance in the distribution of cost for medical innovation, which we have long argued has placed a disproportionate burden on American patients.

In closing, we've made so far in -- the progress we've made so far in 2026 reflects the strength of our science and execution and sets a solid foundation for an exciting remainder of the year.

With that, I'll turn the call over to George to discuss our R&D progress in more detail.

Thanks, Len. I'll start with our differentiated approach to treating complement-mediated diseases, which was highlighted last week at our latest Regeneron roundtable investor event. Our core strategy is to deploy customized approaches using an siRNA, an antibody or a combination approach, depending on the level and durability of complement inhibition required for each disease. For example, it appears that in generalized myasthenia gravis or GMG, the partial blockade with the C5 siRNA alone delivers optimal efficacy, safety and convenience. While in PNH, complete blockade requiring a combination of the siRNA with our C5 antibody is required to optimize efficacy.

For myasthenia gravis, we presented results from the Phase III NIMBLE trial at the American Academy of Neurology Conference, which were also simultaneously published in The Lancet. Cemdisiran, our investigational C5 siRNA as monotherapy -- as monotherapy, met the primary and all key secondary endpoints with subcutaneous delivery every 12 weeks delivering a 2.3 point placebo-adjusted improvement in the MG-ADL endpoint at week 24.

In registrational clinical trials for the leading approved C5 inhibitors, which are administered as large volume intravenous infusions dosed every 2 weeks or every 8 weeks, placebo adjusted improvements in the same MG-ADL endpoints have ranged from 1.6 to 1.9 points at similar time points.

For cemdisiran, clinically meaningful efficacy was demonstrated by week 2. Moreover, these improvements deepened over time and were sustained through week 24 with no indication of waning efficacy between doses. The totality of the data, including mostly mild to moderate adverse events support a compelling profile for cemdisiran as a stand-alone quarterly therapy for this disease. These data have been submitted to the FDA, and we expect a regulatory decision in the fourth quarter of this year.

In PNH, our Phase III lead-in results reinforce the requirement for the combination of cemdisiran plus pozelimab, our C5 antibody, to deliver complete and sustained disease control, lead-in results suggest that our combination will provide best-in-class control based on LDH measures, and that patients who are uncontrolled on ravulizumab can largely be controlled when switched to our combination. Enrollment in the registrational enabling cohort of the Phase III study is now complete and results are expected late in the fourth quarter of this year.

Additionally, in PNH and as part of our ongoing complement strategy, we recently initiated a first-in-human study evaluating siRNA that targets complement factor B. This approach is initially intended for the 20% to 30% of patients who, despite optimal C5 therapy remain anemic due to extravascular hemolysis but also has the potential to expand to a broader PNH population. If successful, siRNA targeting of CFB could overcome the limitations associated with current CFB inhibitors, which require daily dosing and carry the risk of catastrophic hemolysis if doses are missed.

In ophthalmology, our C5 approach in Geographic Atrophy is on track to deliver interim data from the exploratory cohort of our Phase III study in the fourth quarter of this year, which will help inform our pivotal strategy. As a reminder, we are evaluating cemdisiran with or without pozelimab administered systemically with the goal of slowing the growth rate of GA lesions while avoiding ocular safety issues that have been observed with certain approved intravitreal therapies. However, to ensure that we have optionality depending on what we learned clinically, we have also recently begun clinical development of an intravitreal formulation of pozelimab, and we'll also follow up with a co-formulation of pozelimab with aflibercept since some of the patients also developed wet AMD while being treated for their GA.

Now turning to immunology and inflammation and starting with DUPIXENT. In the United States, DUPIXENT was recently approved as the first and only medicine for allergic fungal rhinosinusitis, or AFRS in adults and children 6 years and older. AFRS is a specific type of chronic rhinosinusitis with nasal polyps that more often require surgery and is associated with higher rates of postoperative recurrence. DUPIXENT was also approved in the United States and Europe as the first targeted medicine for children 2 to 11 years of age with chronic spontaneous urticaria, expanding the eligible patient population beyond adolescents and adults. This approval reinforces the expanding role of DUPIXENT across diseases driven in large part by type 2 inflammation and across a broad range of ages.

Regarding our efforts to develop next-generation approaches to DUPIXENT pathway, we have previously disclosed that we have developed innovative VelocImmune derived fully human, long-acting antibodies and bispecifics that target the IL-4 receptor itself as does DUPI as well as the IL-13 and IL-4 cytokines that act through this receptor. We are on track to initiate a first-in-human trial for our IL-13 antibody by the middle of this year, both in healthy volunteers and in patients with atopic dermatitis, with plans to execute an expedited path to regulatory approvals.

Beyond DUPIXENT life cycle opportunities, we continue to advance our next wave of immunology and inflammation programs. Our goal is to keep exploring genetically validated targets that have the potential to become future pipeline and product opportunities. We're initiating a first-in-human study of an antibody to a target identified by the Regeneron Genetic Center as being genetically linked to several diseases such as lupus, Sjogren and primary biliary cholangitis.

We're also continuing to evaluate the best path forward across respiratory and sinonasal diseases for Itepekimab, our interleukin-33 antibody. In chronic rhinosinusitis with nasal polyp, our Phase III studies are ongoing with the results expected in 2027. Regarding COPD, we, Sanofi and global regulators continue to discuss a potential third Phase III study, though no decision has been made on whether to move forward.

Turning to oncology. On fianlimab, our LAG-3 antibody in combination with Libtayo. Our Phase III study in metastatic melanoma remains on track with results expected later in the second quarter of this year. The primary analysis of progression-free survival will now consider all patients enrolled in the study with a minimum follow-up of 6 months. In adjuvant melanoma, the study continues following the first interim analysis, with the second interim analysis and if necessary, a final analysis, both expected in the second half of this year.

We also continue to advance pivotal studies for Lynozyfic in multiple myeloma and premalignant conditions and expect to have results by early 2027 from our study in multiple myeloma patients that have received at least one prior line of therapy as well as MRD negativity results in 2028 from our study in first-line myeloma patients who are ineligible for stem cell transplant. Our first-line study for odronextamab in first-line follicular lymphoma is fully enrolled. This is the only study exploring a bispecific as monotherapy versus the current standard of care, which is RCHOP, across this bispecific arena.

Moving to anti-coagulation. We initiated additional factor XI registrational studies in stroke prevention in patients with atrial fibrillation who are not candidates for direct oral anticoagulants as well as cancer-associated venous thromboembolism. Additional studies in peripheral arterial disease, peripherally inserted central catheter-associated thrombosis, secondary stroke prevention as well as [indiscernible] in DOAC eligible patients are all expected to commence this year. Initial registrational studies from studies in venous thromboembolism prevention following new replacement surgery are expected in the first quarter of 2027.

Turning to obesity. In March, Hansoh reported positive Phase II results for olatorepatide, or in-licensed GLP/GIP agonist in Chinese patients with obesity, which compared favorably cross-trial to a previous Chinese study of tirzepatide for obesity. In this is randomized double-blind placebo-controlled trials of 604 adults across 33 sites, olatorepatide met its co-primary endpoints and delivered up to 19% mean body weight loss at week 48. We are also encouraged by the safety results, in particular, the gastrointestinal tolerability profile. Hansoh is planning on presenting these promising results at a medical meeting later this year.

Building on this momentum, our olatorepatide Phase II study in obesity is enrolling rapidly and later this year, we expect to initiate 2 global Phase III programs, one in patients with obesity and in other patients with obesity, type 2 diabetes. In parallel, our work on the olatorepatide Praluent combination continues with our first clinical study of weekly Praluent initiating shortly.

In rare diseases, Len already mentioned the FDA approval of Otarmeni formerly known as DB-OTO. This was an incredibly meaningful moment for the company as is not only our first gene therapy approval but one of the most striking successes with gene therapy in history, restoring for this first time a sensory function in humans. As published in the New England Journal of Medicine, nearly half the children who are born profoundly deaf were able to regain hearing at normal levels within one year of treatment. The mother of one of these children recently told the President of the United States, a heartwarming story, of how her son is now able to hear her say that she loved him.

We decided to make Otarmeni free in the United States because we believe it was the right thing to do for these families. We hope this highlights and reminds the world that it is the biopharma industry, which is frequently viewed so negatively that is often responsible for delivering such medical miracles to humanity. Regeneron is a different type of company that attracts the best and the brightest to join our fight against disease because we have a heart and a soul as well as a mission and a willingness to play the long game.

Another rare disease that we have been studying for many years is Fibrodysplasia Ossificans Progressiva, or FOP, a devastating condition in which muscle and soft tissues are progressively invaded and replaced by abnormal bone formation. The FDA has accepted for priority review the BLA for garetosmab or [ active-NAD ] blocking antibody with a PDUFA date in August of 2026. If approved, garetosmab will become the first and only available treatment shown to prevent abnormal bone formation in FOP patients.

In genetic medicines, our first-in-human trials testing siRNAs targeting Superoxide Dismutase or SOD1 in amyotrophic lateral sclerosis, alpha-synuclein for Parkinson's disease and [ MAPT ] Tau for Alzheimer's disease, enrolling patients and our initial NASH siRNA program readings targeting [indiscernible] PNPLA3 and HSD17B13 are expected by the end of this year. Concluding with recent early-stage research updates, the Regeneron Genetics Center recently announced a collaboration with TriNetX to access de-identified electronic health record data from a global network representing 300 million patients, creating an opportunity to connect large-scale genomic and proteomic cohorts to real-world clinical data in ways that can accelerate drug discovery, translation, development as well as providing new ways of addressing digital health issues.

Regeneron also announced a strategic collaboration with Telix to codevelop and commercialize next-generation radiopharmaceutical therapies combining Regeneron's antibody discovery and oncology capabilities with Telix' radiopharmaceutical development and manufacturing expertise. In summary, we remain focused on advancing our late-stage, mid-stage and early-stage programs as well as innovative research, which we firmly believe has the potential to continue to change the practice of medicine.

With that, let me turn it over to Marion.

Thanks, George. Our first quarter results represent a strong start to 2026. Our market-leading brands, EYLEA HD, DUPIXENT and Libtayo, delivered ongoing growth based on their clinical profile and our ability to execute effectively in competitive markets. We begin 2026 well positioned to advance our portfolio and are excited by upcoming opportunities to change the lives of even more patients.

Starting with EYLEA HD and EYLEA, which delivered combined U.S. net sales of $942 million in the first quarter. EYLEA HD net sales were $468 million, representing 52% year-over-year growth. During the quarter, physician demand for EYLEA HD increased sequentially by 10% despite typical first quarter seasonality. Additionally, in the first quarter, wholesaler inventory levels were reduced to the normal range. EYLEA HD now has the broadest label and greatest dosing flexibility of any anti-VEGF medicine following recent label enhancements to include retinal vein occlusion and additional dosing options that range from every 4 weeks through every 20 weeks.

We are encouraged by physician adoption following these label enhancements. Importantly, we also look forward to the upcoming FDA decision for the EYLEA HD prefilled syringe, which if approved, would bring what we believe is a best-in-class device to retina specialists and help drive continued uptake for EYLEA HD.

In the first quarter, EYLEA's U.S. net sales were $473 million, representing a 36% year-over-year decline. This reflects ongoing conversion to EYLEA HD, competitive pressures and patient affordability issues Additionally, during the first quarter, there was only a modest reduction in EYLEA inventory and continued inventory absorption is expected to negatively impact net product sales in the second quarter by approximately $20 million. Looking ahead to the second quarter, we expect to achieve sequential unit demand growth for EYLEA HD that is consistent with the 10% sequential demand growth in the first quarter. Conversely, for EYLEA, we anticipate the demand will decline in the mid- to high teens in the second quarter ahead of the potential launch of additional biosimilars in the second half of the year, coupled with the factors that I highlighted earlier.

Together, EYLEA HD and EYLEA lead the innovative branded anti-VEGF category with more than 100 million injections by EYLEA HD and EYLEA administered worldwide since launch. Additionally, in the U.S., EYLEA HD now contributes half of net sales for our retina franchise.

Turning to DUPIXENT, which continues to transform the lives of more than 1.4 million patients worldwide with type 2 inflammatory diseases that are currently on treatment. In the first quarter, DUPIXENT net sales were $4.9 billion, representing 31% year-over-year growth on a constant currency basis. U.S. net sales grew 35% year-over-year to $5.6 billion sic [ $3.6 billion]. We continue to see growth across all line indications, including recent launches, making DUPIXENT the #1 biologic medicine prescribed by dermatologists, pulmonologists, allergists and ENTs, across the blockbuster indications of atopic dermatitis, asthma nasal polyps and [indiscernible], DUPIXENT continues to drive strong growth based on its differentiated clinical efficacy, safety profile and physicians strong preference for this brand.

Uptake is also strong across more recent launches, including chronic obstructive pulmonary disease, chronic spontaneous urticaria, polyps [indiscernible] and allergic fungal rhinosinusitis. These launches across a growing range of age groups provide a runway for even more patients to benefit from DUPIXENT. With annualized global net sales of nearly $20 billion and significant room for further market penetration across indications, DUPIXENT is well positioned for sustained growth over the near and long term.

Turning to Libtayo, which delivered $438 million in global net sales in the first quarter. In the U.S., net sales were $286 million as Libtayo continues its strong trajectory as the leading immunotherapy for advanced non-melanoma skin cancers. The recent launch of Libtayo in adjuvant CSCC is also an emerging growth driver with encouraging uptake and positive feedback on this paradigm-changing treatment. Libtayo is the only NCCN Category 1 preferred immunotherapy open for eligible adjuvant CSC patients. In non-small cell lung cancer, Libtayo is established as the second most prescribed first-line immunotherapy treatment in the U.S., and we expect continued growth through 2026 as we gain incremental share in lung cancer and drive uptake in adjuvant CSCC.

On to linvoseltamab, which is in its second full quarter on the market, early launch momentum has been driven by positive physician experience, a differentiated clinical profile, lower hospitalization requirements and convenient dosing schedule. We expect continual continued gradual uptake as we work to advance our clinical program in earlier lines of therapy.

I also wanted to spend a moment highlighting our expanding rare disease portfolio. Evkeeza is now in its fifth year on market in the U.S. and delivered net sales of $46 million for the quarter, representing 48% growth year-over-year. Evkeeza is well established as a leading treatment for homozygous familial hypercholesterolemia with more than half of all diagnosed U.S. patients currently on Evkeeza or in the process of starting of Evkeeza.

As highlighted by Len, we are also launching Otarmeni, which is the first and only gene therapy for children born with genetic hearing loss. In addition, we look forward to the anticipated FDA decision on garetosmab in August. Garetosmab is our potential treatment for FOP and has been shown to prevent 99% of abnormal bone formation, influencing our strong first quarter results demonstrate growth potential across our portfolio.

We continue to advance our in-line brands while also preparing for multiple potential indications and new product launches including for cemdisiran for generalized myasthenia gravis, where there is significant commercial opportunity in this large and growing market. We remain well positioned to deliver meaningful benefit to patients worldwide across a growing number of diseases.

And with that, I'll turn the call over to Chris.

Thank you, Marion. My comments today on Regeneron's financial results and outlook will be on a non-GAAP basis unless otherwise noted. Regeneron performed well in the first quarter, highlighted by double-digit growth on both the top and bottom line. First quarter 2026 total revenues grew 19% from the prior year to $3.6 billion, driven by higher Sanofi collaboration revenue as well as strong growth in net sales of EYLEA HD in the U.S. and Libtayo globally. First quarter diluted net income per share grew 15% to $9.47 on net income of $1 billion.

Beginning with the Sanofi collaboration, first quarter total Sanofi collaboration revenues were $1.6 billion, of which $1.5 billion related to our share of collaboration profits. Regeneron's share of profits grew 42% versus the prior year driven by DUPIXENT sales growth and improving collaboration margins. We now expect the Sanofi development balance to be fully repaid by the end of the second quarter. As a result, we expect Sanofi collaboration revenue to step up to reflect our full share of collaboration profits starting in the third quarter.

Moving to Bayer. First quarter net sales of EYLEA and EYLEA 8 mg outside the U.S. were $729 million, inclusive of $333 million of EYLEA 8 mg sales. Total Bayer collaboration revenue was $287 million of which $240 million related to our share of net profits outside the U.S. Other revenue grew 109% in the first quarter to $171 million. This included $101 million related to our share of profits from ARCALYST and royalty income from Ilaris.

Now to our operating expenses. R&D expense was $1.4 billion in the first quarter reflecting continued investments to support Regeneron's innovative pipeline, including pivotal programs across late-stage opportunities in hematology/oncology, complement-mediated diseases at anticoagulation. First quarter SG&A was $560 million, reflecting investments to support the launch of Libtayo and adjuvant CSCC and to drive continued growth of our EYLEA HD. First quarter matching contribution to good days and independent nonprofit patient assistance foundation were de minimis. We remain committed to matching up to $200 million in 2026 to support patient access and affordability.

Non-GAAP gross margin on net product sales was 86% in the first quarter. Our GAAP gross margin was 76%, which was negatively impacted by costs incurred due to a temporary interruption in bulk manufacturing at our Limerick Ireland site. We have now resumed initial production in the facility and expect to resume full production by the end of the second quarter. As a result, we anticipate our GAAP gross margin will continue to be negatively impacted in the second quarter as production returns to normal levels. This interruption has not impacted and is not expected to impact the availability of any products.

Regeneron generated $848 million of free cash flow in the first quarter of 2026 and ended the quarter with cash and marketable securities less debt of $15.8 billion. We repurchased $800 million of our shares in the first quarter and announced this morning that the Board of Directors has authorized a new $3 billion share repurchase program. With this new authorization, we have approximately $3.4 billion available for share repurchases as of today, and we remain opportunistic buyers of our shares.

We have made some minor changes to our 2026 financial guidance including updating our GAAP gross margin guidance to be in the range of 77% to 78%. This reflects actual and expected costs incurred as a result of the aforementioned temporary manufacturing interruption. A full summary of our guidance can be found in our earnings press release published earlier this morning.

In conclusion, Regeneron is off to a strong start in 2026 with financial results that position us well to continue investing in our pipeline delivering breakthroughs for patients and driving long-term value for shareholders.

With that, I'll pass the call back to Ryan.

Thank you, Chris. This concludes our prepared remarks. We will now open the call for Q&A. To ensure we are able to address as many questions as possible, we will answer one question from each caller before moving to the next.

Kevin, can we go to the first question, please?

[Operator Instructions] Our first question comes from Tyler Van Buren with TD Cowen.

So DUPIXENT continues to be a monster delivering strong performance this quarter after quarter after quarter. And it now looks like it will well exceed $30 billion of global sales. So given that we get a lot of questions from investors, not just on life cycle expansion but the Sanofi collaboration, so can you discuss your willingness to work on life cycle expansion efforts within the Sanofi collaboration or come to an agreement on commercializing these assets together in order to take advantage of the DUPIXENT rebate wall and the status of that as opposed to moving life cycle expansion candidates for yourself and potentially further building out the commercial infrastructure?

Tyler, it's Len. Thanks for that very pointed question. Maybe to give me an opportunity to publicly thank Paul Hudson for all the work he did on DUPIXENT since 2019. Thank you, Paul. We wish you good luck in your next chapter. Also as of today, Sanofi's new CEO, Belen Garijo is officially, I think, the CEO today. So we want to welcome Belen and wish her luck, and we look forward to working with her and the rest of her team.

Tyler, you're right, DUPIXENT is a remarkable product. As Marion detailed and George outlined, it's helping so many different people with some -- millions of people with different diseases and is a financial juggernaut for the company. We are always open-minded to transactions certainly leveraging what we've built in terms of both development capabilities as well as commercial capabilities has merit to it. We can do these things ourselves. We've had interest for many different places to sort of take on some of the next opportunities with us. But we're open-minded, and I look forward to talking with Belen and her team in the coming weeks and months, et cetera.

Our next question comes from Terence Flynn with Morgan Stanley.

Great. This is Chris on for Terence. We have a question about fianlimab in metastatic melanoma. Is the PFS differentiation enough to capture majority share? Or do you think you need OS as well?

Well, it obviously depends on the results. it depends on exactly what the PFS results are. But the study is also designed so that -- if we have a substantial OS benefit, we will see that as well. And so the hope, of course, is that the study will show both the PFS and an OS benefit. But the results remain to be seen.

Our next question comes from Chris Raymond with Raymond James. .

This is Sam Lee on for Chris Raymond. Just one on the EYLEA prefilled syringe. So any commentary on why FDA missed the April PDUFA and was that a request for more information or a backlog issue? And then you noted there was a reinspection at Catalent, Indiana, and you've resubmitted. Can we read in between the lines and assume that means the site inspection was positive? And what's kind of your overall guidance on timing for either of these applications?

Yes. So thanks for the question. I think we've told you what we know. We don't -- if the inspection turns out to be positive, then I think they will approve the drug. So we await and both applications are pending. And the only thing I can say is that based on our conversations and how hard everybody is working at this and the FDA, I think, desire to get these sites up to the standards they want as well as get the products out there that are waiting that we anticipate action on one or both of these during this quarter.

Our next question comes from Cory Kasimov with Evercore ISI.

I wanted to ask about Lynozyfic and kind of the outlook in the multiple myeloma space. When we talk with docs, there's obviously excitement about the potential of BCMA bispecifics, the main pushback on [indiscernible] spread adoption is the infection risk they carry, especially in earlier-stage patients. So curious what you make of the debate and how you're trying to mitigate this in your trials going forward?

So the debate of their use compared to what?

Existing standards of care like [indiscernible], et cetera?

So obviously, all of these approaches carry significant infectious risks. As we've shown in our study, the disease itself carries substantial infectious risk. And if you actually look at our detailed data and publications on the matter, it actually turns out that the longer you treat these patients, the more you control your disease, the more functional their bone marrow becomes actually infectious risk goes down over time, which is actually quite stunned. So I think that the profile, if you really look at it, of the bispecifics in general and our bispecific in particular, are very, very promising not only in terms of their impressive efficacy. But in terms of their overall side effect and tolerability profile, including, of course, the infectious risk. So we think that this is going to become the dominant class for the treatment of this disease as well as its precursors. And we believe that if you look at the data that our agent is certainly competitive, if not indeed best-in-class across all parameters here.

Our next question comes from Tazeen Ahmad with Bank of America.

As you think about next-gen DUPI, how are you thinking about the importance of having a late-stage program clearly defined before the U.S. IP for DUPIXENT goes away whenever that might be? Just given the increasing number of potential long-acting injectables and other oral agents that might come online.

Yes. Look, we don't know how long the patent life will be for DUPI because we have lots and lots of intellectual property out there, lots of different types of patents, used patents, formulation patents, in addition, obviously, to the composition patent. In terms of how we think about this, to us, we want to leverage our knowledge and immunology. We don't necessarily think about having to exactly replace or work on. We have nearly 50 things in the pipeline and we're looking forward to bringing as many important ones forward as we can. But we do have a number of these that George, I think, talked about the extended interval DUPIXENT going after long-acting IL-13, IL-4, other diseases that we haven't even covered with DUPI such as allergic diseases, in general food allergies and so forth. So I think there's a lot of opportunity and one shouldn't just focus on a simple replacement or what have you and one shouldn't assume when the patent for DUPI will actually expire.

Our next question comes from Carter Gould with Cantor.

Maybe change it up a bit. For George, as you spoke about the co-injection of C5 with aflibercept, should we think about that as more of a convenience play sort of with the co-administration or potentially more of, I guess, a label expansion as you think about potentially preventing wet AMD, I guess, forming for lack of a better term?

I think those are both interesting possibilities. It could be used to actually prevent the development of the wet AMD and/or to treat the patients who develop it. And very importantly, as you probably know, there's a lot of evidence and suggestions about the causes of the occlusive retinal vasculitis that is seen with the other agents that are, for example, totally different kinds of molecules [indiscernible] and so forth. And these -- some of the characteristics of those molecules are associated with this occlusive retinal vasculatis.

We hope and we believe based on our experience with biologics, with EYLEA and with this particular antibody that we may not only have these convenience benefits. But perhaps most importantly, we may also avoid the very tragic, very horrific side effects that are seen with the existing agents, which would allow them to be much more broadly used. Moreover, we would think, once again, as our experience indicates the history with EYLEA that we can have much longer-acting versions. And moreover, depending on how the data looks with the systemic as well as the local, one could imagine even combined to allow for a very long-acting injections [indiscernible]. So there's a lot of possibilities that could address better safety profile as well as convenience as well as potential even efficacy.

Our next question comes from Evan Seigerman with BMO Capital Markets.

I'd love for you to walk me through the commercial considerations for developing your combo GLP-1/GIP plus Praluent. And how can you accelerate the development to remain competitive in this rapidly evolving market?

Well, the way we look at it, and I think Len came up with this terminology, imagine if you invented a GLP that was as good as the currently best-in-class agent, let's say, tirzepatide, and acted very much the same, but also lowered your bad cholesterol by more than 50% and was shown to decrease your risk of cardiovascular outcomes like heart attacks and death, that GLP would become the preferred GLP on the planet, especially if you priced it at a very similar price.

Why would anybody take any other GLP. We are very by the data that we see coming from our collaborators in China, where the cross trial comparisons show that as we predicted based on our due diligence of the molecule, that it behaves if anything as well as tirzepatide. And of course, our folks in the lab have been busy working developing coformulated forms of this GLP together with our [indiscernible], which we believe we can be delivering by a very similar convenient autoinjector approach using the same approach as the are delivered as well.

And we believe that we can price it very competitively to the GLPs. And we would think that, honestly, any physician prescribing it or any patient thinking about it would say that why would they ever take a GLP, especially since we know of the profound co-morbidities associated with cardiovascular risk and hyperlipidemia in the same population. Why would they ever take a GLP if they had an option of taking a GLP that also lowered their lipids and also decrease the risk of bad cardiovascular outcomes.

To us, honestly, it sort of seems like a no-brainer. Obviously, there will be competition, but we believe we have potentially a best-in-class and a best-in-class PCSK9 and the convenience for many people of these auto injectors is now becoming so pervasive that we think a large segment of the population, we'll offer them. Now this is, of course, not even presuming that the side effect profile that we see in China more broadly pertains in our upcoming global studies. So we think this is a very, very exciting and a very, very large opportunity.

George, could you just correct the misunderstanding about weight loss, not lowering lipids?

Yes. So -- it's -- thank you, Len. It's a great point. As many people obviously know, weight loss and the GLPs can provide cardiovascular outcome benefits. But they do this by creating benefits across a wide variety of different risk factors, and they only lower your bad cholesterol by a few points in contrast to the 50% to 60% lowering that we see with the PCSK9 blockers. So this will be a real add-on in terms of the cardiovascular benefit and the lipid benefit compared to just GLP loans, which, by themselves, though they benefit outcomes, they do very little in terms of your lipid profile. So many patients are obviously left with still high risk based on their lipid profile if they're either obese or especially obese with type 2 diabetes where dyslipidemia there is a very serious and common comorbidity concern.

Finally, the use of cost of lowering drugs is now finally catching up, I think, to the science, where the recommendations are to start earlier and longer. So I think that you've indicated population to lower cholesterol and lose weight is going to be even broader. So as George said, this is a really significant opportunity.

Well, and very importantly, from the public health perspective, though recommendations are all about how focus on your lipids, much earlier, widespread use of lipid-lowering medications. They are dramatically underutilized in the world. Unfortunately, this caused us incredible morbidity and death, heart disease is still the leading cause of death in the United States, in part because of the underutilization of these incredible weapons we have, we think in a Trojan horse sort of way, this will provide incredible public health benefit by having [indiscernible] people who are really so worried about their weight loss also get the lipid benefit, which will have this dramatic benefit, which is unfortunately underutilized and underappreciated.

Our next question comes from Alexandria Hammond with Wolfe.

Can you share a little bit more on your clinical strategy to exhibit that development of your next-gen I&I assets, particularly [ Supi-dupi ]? How do you expect to be able to kind of leverage the changes within FDA to further speed this development up? And has there been an ongoing dialogue with the regulators?

Well, we've obviously -- we're world leaders in this field. We created the field. We did the first studies in atopic dermatitis in the field. And we are well positioned, we believe, to expedite and accelerate the programs as rapidly as possible, and we feel very good about our position and our plans here.

Next question comes from Salveen Richter with Goldman Sachs.

Just regards to the life cycle strategy for DUPIXENT, which is broad and multipronged, where do you feel you have the most line of sight? And how are you optimizing the IL-4 agent or [ Supi-dupi ]?

Yes. I think what George said is that we have a lot of experience here. We don't need to give out all of our details to help any competition that might be out there. But the team knows what they're doing. [ Supi-dupi ] is one that Sanofi and Regeneron have mutual agreement can add to the collaboration. We have the knowledge, the capabilities and the desire to do this as efficiently as possible.

Next question comes from Christopher Schott with JPMorgan.

This is Taylor Hanley on for Chris Schott. We were just wondering on Libtayo. Can you provide any color on the drivers of performance this quarter? Was there anything onetime in there? How much of this was driven by the new indication, CSCC? And is this a good baseline to think about growing off of going forward?

So sure, very happy to take the question. And I think the Libtayo performance certainly is strong. I would characterize the strength based on certainly the advances that we've seen in our our skin indications. Now with adjuvant CSCC, very exciting to help this group of patients with Libtayo. There's been a lot of enthusiasm. And certainly, the clinical profile of Libtayo in this indication is highly distinguishing. We also see performance in our lung cancer indication, U.S. and international performance are strong. I would characterize the quarter though by comparison to a year-over-year comparison in a quarter that had some movement in inventory. We can certainly go back and share more of the details with you on that. But it's a very strong quarter, but there is some comparison [indiscernible] this quarter.

Next question comes from David Risinger with Leerink Partners.

Len and George, my question is for you. So Regeneron spends aggressively on R&D, but the investment community lacks confidence that the company's candidates will move the needle commercially in particular versus established competitors. So could you please highlight the pipeline candidates in late-stage development that we'll have cards turning over in the near term or relative near term, i.e., in the next, I don't know, 18 months or so that you have the greatest confidence in that can generate multibillion-dollar peak sales that investors will be able to see more clearly in the next 18 months or so.

That's perhaps the most penetrating -- in the 160-odd conference calls have done, penetrating in detailed question. But unfortunately, David, probably take several hours to answer. We have a robust pipeline. We do have, obviously, highlighting the C5 franchise, where we'll have more data and an approval action. We will have 11, I think, Phase III trials ongoing in anticoagulation program. which is a massive opportunity. We have our Lynozyfic and our ogenextomab, our bispecifics in myeloma, in lymphoma are ongoing. I think George just talked about our [ ola plus and ola plus ally ] as the near term. And obviously, even in this quarter, we have fianlimab plus Libtayo with metastatic melanoma. So we -- maybe that I'll leave that for openers, but we -- and we have more and more things. But we've got some exciting data coming out that we haven't even talked about, and I didn't just mention. So lots going on when you have 48 exciting things in development.

Can I just say, I mean I want to comment that past performance should be the strongest indicator of future performance. There's only one company in recent history that of its own labs produced two $10 billion plus blockbusters. And let me remind you that I think you and probably a lot of other investors never saw those coming or ignored what we were saying about them. So I think that Investor confidence, I think, should in large part be reflecting historical performance and the recognition that where blockbusters come from sometimes for the investor community can't be directly anticipated

And the best way of producing very important big drugs is by having very exciting molecules across all stages of development that have enormous opportunity. And if you just look at our oncology programs, whether it's the [indiscernible], whether you look at Lynozyfic, whether you also look at odronextamab in follicular lymphoma. These are all potential blockbusters. The C5 franchise is a pipeline in a franchise, multiple blockbuster opportunities there are factor XI customized approaches are looking more and more exciting, especially based on competitive data using, we think, inferior and less convenient approaches. And we just covered the obesity opportunity, which arguably to become the preferred obesity approach that not only addresses obesity, but more aggressively addresses cardiovascular morbidity. So I know it's hard to think of a more exciting pipeline in the entire industry.

We have time for 2 more questions, Kevin.

Our next question comes from Geoff Meacham with Citi.

On fianlimab and lung, I just wanted to see if you guys can give us a bit more context for not moving to Phase III, maybe what was observed in the data? And from a tolerability perspective, is there any read-through to melanoma or broader solid tumor in terms of strategy?

Yes. I think that we've been talking about this for a long time. I mean we never indicated that we were excited about this opportunity. Our data from earlier-stage studies was always pointing us to the melanoma opportunity. Once we see that data, it will certainly guide our thinking forward and in terms of going into additional cancer settings as well. But as we've been saying for a while, we never had any reason to really believe that this was going to be a game changer in the lung cancer space.

And Geoff, there's no negative read-through from any new side effects or anything unanticipated.

Last question, please, Kevin.

Our last question comes from Brian Abrahams with RBC Capital Markets.

We were intrigued with the inclusion of milder patients in your long-acting IL-13 study versus contemporary AD trials. So I was wondering if you could talk about the potential untapped opportunity for systemic biologics here and the degree to which you can broaden the market even beyond where DUPI is used now?

Just certainly in patients with mild disease, there's a lot of unmet need. So this is a potential area for greater understanding in advance for treatment. I think we'll have to wait and take a look at clinical profile and opportunities and determine from there, but it is a large population. And when the patient or the parent of the child with mild disease, it really isn't mild, it's aggravating, it's difficult. And certainly, there's a lot of unmet need and potential.

And I have to say there was certainly in the early days of bias by investigators and the agency against using a powerful biologic. It could be immunosuppressive. Remember, we did find it to be immunosuppressive. In fact, in the moderate to severe cases of atopic dermatitis, we actually saw less infections in patients who had skin lesion healing. It is not immunosuppressive on the side of the immune axis, which deals with the kind of infections that people are used to with biologics or might be with some of the orals that suppress both arms of the immune system, as George has talked many times, the type 2 immunity is not something we rely on to keep us healthy from infections, might play some role in parasitic infections. But you've got so many people having been treated now and now thinking about going earlier makes some sense.

All right. That's all the time we have for today. Thanks to everyone who dialed in for your interest in Regeneron. We apologize to those folks remaining in the Q&A queue, who did not have a chance to hear from today. As always, the Investor Relations team at Regeneron is available to answer any remaining questions you may have. Thank you once again, and have a great day.

Thank you. Ladies and gentlemen, this does conclude today's presentation. We thank you for your participation. You may now disconnect, and have a wonderful day.

Welcome to Regeneron's conference call to discuss its C5 Complement Development Program. My name is Shannon, and I will be your operator for today's call. [Operator Instructions] Please note that this conference call is being recorded.

I will now turn the call over to Ryan Crowe, Senior Vice President, Investor Relations. You may begin.

Thank you, Shannon. Good morning, and welcome to our Regeneron Roundtable investor event, a series of presentations spotlighting key opportunities across Regeneron's pipeline. Today, we will focus on our C5 Complement Development Program built around cemdisiran, an siRNA that targets C5, and pozelimab, an antibody that also targets C5.

Before we begin, I would like to remind you that remarks made today may include forward-looking statements about Regeneron, and each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in such statements. A description of material risks and uncertainties can be found in Regeneron's SEC filings. Regeneron does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

Now let's begin. Regeneron has 5 key late-stage programs that are poised to deliver meaningful advances over the near, medium and long-term across diverse therapeutic areas, including solid tumor oncology, myeloma, complement-mediated diseases, anticoagulation and obesity. Additionally, our early-stage pipeline includes opportunity spanning inflammation and immunology, ophthalmology, cardiovascular and metabolic disease and neurology. We anticipate featuring many of these programs in Regeneron Roundtables in the months and years ahead, reflecting the excitement we have for this next wave of innovation.

We have used the Regeneron Roundtable series to provide focused program level deep dives on some of our most important late-stage development programs rather than trying to cover the entire pipeline in a single event. Today's C5 Roundtable follows the November 2025 Roundtable on the Factor XI development program for anticoagulation disorders and the December 2025 Roundtable on the Lynozyfic development program in multiple myeloma and premalignant conditions. We believe these late-stage programs are all poised to deliver meaningful advances over the next few years, bringing value to both patients and shareholders.

Today's roundtable will cover our C5 development program and in particular, how cemdisiran and pozelimab can be utilized to treat multiple complement-mediated diseases by matching the right therapeutic approach to disease biology with the goal of optimizing efficacy while mitigating safety events. And paroxysmal nocturnal hemoglobinuria or PNH, the combination of cemdisiran and pozelimab is designed to deliver rapid, complete and uninterrupted C5 inhibition addressing persistent hemolysis associated with current standards of care. Registrational data in PNH is expected in late 2026.

In generalized myasthenia gravis, or gMG, the disease biology supports only partial C5 inhibition that can be achieved with some cemdisiran monotherapy. We recently submitted an NDA taking approval from the FDA using a priority review voucher and expect a decision in the fourth quarter. And in geographic atrophy, we're exploring both monotherapy and combination approaches with initial Phase III lead-in data anticipated late this year. Taken together, this program highlights the flexibility of our siRNA antibody approach and positions our C5 franchise for multiple meaningful near-term clinical and regulatory catalysts.

Now let me introduce our speakers and the topics they will discuss during today's roundtable. This cross functional speaker panel consists of leaders across Regeneron's research, clinical development and commercial areas. First, Dr. George Yancopoulos, Regeneron's Board Co-Chair, President and Chief Scientific Officer, will provide a strategic overview of the C5 program including our siRNA with or without an antibody approach and how we believe it offers different levels of complement inhibition for different diseases. Next, Dr. Andres Sirulnik, Senior Vice President and Clinical Development Unit Head for Hematology will discuss the ongoing PNH and geographic atrophy development programs, which are both in late-stage clinical development. Following Andres will be Dr. Umesh Chaudhari, Vice President and Global Program Head of our C5 program, who will discuss generalized myasthenia gravis, where cemdisiran monotherapy has demonstrated robust efficacy with quarterly dosing, supporting a differentiated clinical and convenience profile.

This follows yesterday's publication of results in the Lancet and data presentation at the American Academy of Neurology for positive Phase III NIMBLE results were presented for the first time. And finally, Soma Gupta, Vice President, Commercial New Products, will lead the discussion on the commercial strategy and outlook focusing primarily on the upcoming potential of cemdisiran launch in gMG. We will then use the remaining time for Q&A.

With that, let me now turn the call over to George.

Thank you, Ryan. Our pioneering C5 program is the first time an antibody and an siRNA that target a single pathway have been combined, in this case, to inhibit complement. Pozelimab, a fully human antibody, which was derived using our VelocImmune technology was FDA approved in 2023 for the treatment of CHAPLE disease, an ultrarare indication. Cemdisiran is an sRNA designed and initially developed with our collaborator, Alnylam. Regeneron has licensed cemdisiran for use as both a monotherapy and in combination with pozelimab. Each of these reagents serves a different role in inhibiting complement. Cemdisiran reduces C5 production in the liver, where the majority of C5 is synthesized while pozelimab neutralizes any residual C5 protein in the circulation that was not already blocked by cemdisiran. This combination completely blocks the C5 pathway. There are several advantages to this dual approach compared to other complement inhibiting therapies.

First, having the 2 reagents gives us the flexibility to treat different diseases that require different levels of target inhibition to maximize efficacy. We also have data suggest that the combination approach will provide complete rapid and durable C5 inhibition that is not achievable with other therapies even at higher doses. Additionally, our antibody plus sRNA combination may enable lower antibody dosing in a highly convenient subcutaneous formulation. We believe these advantages will be critical across these distinct diseases.

Our C5 program's flexibility is reflected in the range of therapeutic areas and indications that we are pursuing. Because complement-mediated diseases require different levels of C5 inhibition, we can tailor the dose and the modality, siRNA alone, antibody alone or combination based on the disease biology and clinical need. CHAPLE disease is an ultra-rare, life-threatening pediatric disease caused by CD55 deficiency, where pozelimab monotherapy at high doses has demonstrated clear clinical benefit. In PNH, we believe the disease biology requires near complete uninterrupted C5 inhibition to prevent breakthrough hemolysis. The combination of the cemdisiran sRNA and the pozelimab antibody enabled deeper and more durable control of C5 than ravulizumab, a leading C5 antibody on its own, supporting our dual mechanism approach.

In generalized myasthenia gravis, we have now demonstrated that robust and sustained efficacy can be achieved with only partial complement inhibition using cemdisiran monotherapy, which delivered strong clinical benefit in this disease, while preserving residual complement activity, supporting a potential best-in-class efficacy and safety balance with quarterly subcutaneous dosing. In geographic atrophy, the biology and optimum level of complement suppression is still being explored. Thus, we are evaluating both cemdisiran monotherapy and the cemdisiran/pozelimab combination to identify the right balance of efficacy and safety in a large heterogeneous population. The key takeaway is that this is not a one-size-fit-all C5 program. We believe the flexibility of having an sRNA and an antibody allows us to match the treatment intensity to disease biology, creating a pipeline and a product opportunity across multiple disease settings.

Slide 10 illustrates the difference in C5 inhibition between cemdisiran monotherapy and the cemdisiran/pozelimab combination as well as why different complement-mediated diseases may require different levels of C5 inhibition to achieve optimal clinical benefit. The CH50 graph on the left was presented yesterday at AAN from the cemdisiran Phase III NIMBLE trial in generalized myasthenia gravis. Cemdisiran monotherapy delivered rapid and durable complement inhibition, which reached 77% by week 24, but was sufficient to drive robust clinical efficacy in generalized myasthenia gravis. The combination of cemdisiran and pozelimab achieved near complete C5 inhibition as early as week 12. That's important in diseases like PNH that require near complete uninterrupted C5 inhibition, which is where the siRNA and antibody combination becomes critical.

In contrast, efficacy in generalized myasthenia gravis was achieved without full complement inhibition, supporting the concept of preserving residual complement activity may be both effective and potentially favorable from a safety perspective. This precision-based approach underpins our strategy, match the right level of C5 suppression to the biology of each disease rather than forcing a one-size-fit-all solution.

Now I will turn it over to Andres to discuss PNH and geographic atrophy.

Thank you, George. Paroxysmal nocturnal hemoglobinuria or PNH is an acquired life-threatening hematologic disorder driven by uncontrolled C5 activation due to loss of CD55, CD59 on red blood cells, resulting in chronic intravascular hemolysis, thrombosis and substantial morbidity. Current standard of care therapies improved survival, but often fail to fully normalize ADH or prevent breakthrough hemolysis and patients with extravascular hemolysis remain inadequately served by existing C5 inhibitors or require complex multidrug regimens. The PNH landscape now spans multiple mechanisms, including inhibitors for complement Factor V, Factor III, Factor B and Factor D, yet no current approach consistently delivers complete sustained terminal complement inhibition with convenient dosing highlighting an opportunity for differentiation.

The cemdisiran/pozelimab combination is designed to address these gaps by reducing C5 production in the liver with cemdisiran and blocking residual circulating C5 with pozelimab, thereby enabling continuous durable C5 separation with subcutaneous dosing. The Phase III leading data, which I will review shortly, suggests this dual mechanism approach is needed to achieve potentially best-in-class disease control and improve on current standards of care.

Slide 13 is the trial design for the ongoing Phase III ACCESS-1 trial in PNH patients. This head-to-head study directly compares cemdisiran plus pozelimab against ravulizumab in cohort A and eculizumab in the registrational cohort B, enabling a rigorous assessment of disease control versus established C5 inhibitors that are considered today's standard of care for PNH. We are announcing today that enrollment in cohort B is complete, positioning the program for a registration-enabling data readout by the end of this year.

Taken together, the Phase III design, comparator choice and endpoint selection are intended to demonstrate that cemdisiran plus pozelimab can deliver more complete and consistent disease control than current standards of care, supporting best-in-class potential in PNH.

As a reminder, the exploratory cohort A from the registrational PNH trial readout in late 2024, supporting the combination's potential in this setting.

Now let's take a look at the results of cohort A. Slide 15 showcases the 26-week data generated from this exploratory cohort. Patients treated with our C5 combination achieved greater disease control compared to the current standard of care, ravulizumab and nearly all patients on the cemdisiran plus pozelimab combination were able to achieve normal LDH levels. Through week 26, cemdisiran plus pozelimab combo leads to average LDH levels of 0.8x below the upper limit of normal with 96% of patients maintaining adequate control of hemolysis. This compares favorably to ravulizumab with average LDH levels of 1.2x the upper limit of normal at week 26, with 80% of patients maintaining adequate control of hemolysis. Patients on ravulizumab were then switched to the cemdisiran/pozelimab combination in the extension study. At the start of the extension study, 13 out of 19 patients treated with ravulizumab had adequate control of LDH. After switching to the combo, all but 1 patient achieved LDH control, including 4 of 5 patients who had failed to achieve LDH control while on ravulizumab.

Our novel C5 combo approach enable complete rapid and interrupted and durable inhibition of terminal complement.

And as I mentioned before, enrollment in cohort B is complete, and we now anticipate reporting data from this registration cohort in the fourth quarter of this year. And Regeneron is still pursuing additional agents for PNH patients given the high unmet need. We recently initiated a first-in-human study of our siRNA targeting complement Factor V initially intended for 20% to 30% of patients who remain anemic despite optimal C5 therapy due to extravascular hemolysis with the potential to expand to a broader PNH population. We hope to share data from this ongoing program in the near future.

And now to geographic atrophy, starting on Slide 19. Geographic atrophy is a late-stage irreversible form of dry age-related macular degeneration that leads to progressive vision loss and has a meaningful impact on daily functioning, including reading, driving and recognizing faces. A substantial body of evidence implicates the complement system in GA pathogenesis, including genetic associations, histopathology and preclinical studies validated further by the fact that both approved GA therapies locally inhibit complement. However, despite 2 approved products, there remains significant unmet need in geographic atrophy as these approved therapies have slow lesion growth, but have not prospectively demonstrated preservation or improvement of visual function.

Also, current intravitreal therapies require frequent intravitreal injections and carry meaningful ocular safety risks. Cemdisiran plus pozelimab is being evaluated as a differentiated systemic approach with the goal of delivering meaningful disease modification while potentially avoiding the ocular safety issues associated with the intravitreal administration.

Slide 20 depicts the trial design of the ongoing Phase III SIENNA trial, which is a global randomized, double-mask placebo-controlled study in patients with GA secondary to AMD that will evaluate whether systemic C5 inhibition can deliver a meaningful disease-modifying effect while potentially avoiding ocular safety issues seen with intravitreal approaches. For this study, there will be a total of approximately 975 patients in the trial, which is designed as a seamless 2-cohort program similar to how we structure the Phase III PNH program. While Regeneron has not previously generated clinical data in this indication, we have decided to go straight to a Phase III program given our deep understanding of disease biology and data generated in other complement mediated diseases.

As we have previously stated, cohort A is fully enrolled, and we expect interim data in the fourth quarter of 2026. These results from approximately 225 patient cohorts will guide with a systemic C5 inhibition demonstrates sufficient therapeutic effect in GA, whether monotherapy, is sufficient or combination therapy is required and will inform future trial design parameters. Note, the cohort A is not powered for statistical significance and is not a regulatory readout, but rather it serves as a decision enabling checkpoint.

Systemic C5 inhibition offers a fundamentally different treatment paradigm compared to today's treatment options. Regeneron's approach moves beyond intravitreal only therapy by enabling systemic administration, which may allow treatment of bilateral disease without separate injections in each eye, addressing a key burden of current GA care. Approved GA agents will require every month or every other month intravitreal injections often in both eyes, a systemic subcutaneous option with meaningfully reduced procedural burden for patients and retina specialists, especially for those patients who may be co-treated with anti-VEGF therapies.

In terms of safety, current intravitreal therapies have reported ocular safety events, including occlusive retinal vasculitis, which has caused catastrophic blindness in some patients. A systemic approach is anticipated to reduce localized ocular risk, representing a potentially important safety advantage.

We also have an opportunity to go beyond slowing of lesions growth and prospectively demonstrate a functional benefit. Regeneron's program aims to show greater reduction in GA lesion growth alongside preservation of visual function, raising the bar on meaningful clinical outcomes. Further, today's therapies require frequent in-office administration by retinal specialists. Regeneron's approach introduces the potential for self-administration via subcutaneous dosing, reducing clinic visits and improving patients' quality of life. The C5 program leverages with Regeneron's deep experience with complement inhibition and established ophthalmology presence, positioning us to pursue a differentiated scalable opportunity in a large and growing GA market.

In parallel, Regeneron has also initiated development of an intravitreal pozelimab formulation aimed at longer durability, potential safety advantage from a non-pegylated reagent and potential to coformulate with anti-VEGF therapy, providing strategic flexibility across patient segments.

Now I will turn it over to Umesh, our Global Clinical Head of C5, who will discuss general myasthenia gravis.

Thanks, Andres. First, let me give a bit of background on generalized myasthenia gravis, starting on Slide 23. gMG is a rare chronic autoimmune disease where pathogenic autoantibodies, most commonly against the acetylcholine receptor activate the complement cascade, leading to a formation of the membrane attack complex at the neuromuscular junction. This complement mediate injury disrupts the neuromuscular transmission, damages postsynaptic membrane and ultimately drives the muscle weakness and fatigue that characterize this disease. Importantly, this is not simply an antibody-mediated signaling issue. It is a complement-driven structural injury, which is why inhibiting C5 has proven clinically effective.

Despite advances in treatment, there remains a clear unmet need. Many patients experience incomplete, fluctuating responses waning between doses, safety trade-offs and high treatment burden, particularly with chronic IV or frequent dosing regimens. Our goal with cemdisiran is to address this by delivering sustained targeted C5 inhibition that aligns with gMG biology, providing rapid efficacy, durable disease control and meaningfully reduce treatment burden.

Slide 24 outlines the Phase III NIMBLE trial, which was designed to evaluate cemdisiran and cemdisiran plus pozelimab combination in patients with symptomatic generalized myasthenia gravis. NIMBLE is a randomized, double-blind, placebo-controlled study, enrolling acetylcholine receptor positive patients on stable background therapy who have initiated meningococcal vaccination reflecting real-world clinical practice. This study includes a 24-week placebo-controlled double-blind period, which is the basis for the primary and key secondary efficacy analysis, followed by a 28-week double blind extension and open-label treatment period and then long-term post-treatment follow-up. The primary endpoint is the change from baseline in myasthenia gravis activities of daily living, or MG-ADL total score at week 24 with a key secondary endpoint of change in quantitative myasthenia gravis or QMG total score at week 24. During the 24-week double-blind treatment period, all patients -- all treatments were administered subcutaneously with cemdisiran dosed every 12 weeks, highlighting the convenience of a quarterly regimen.

As shown in the efficacy data presented subsequently, cemdisiran monotherapy met the primary and all key secondary endpoints, demonstrating rapid, deep and durable clinical benefit without weaning across the dosing interval.

Now let's describe the results from this registrational study. With this -- with quarterly subcutaneous dosing, cemdisiran met the primary endpoint delivering a 2.3 point placebo-adjusted improvement in the MG-ADL total score at week 24, which is clinically meaningful and statistically significant. The magnitude of benefit compares favorably to historical C5 inhibitor data, which have generally shown 1.6 to 2.1 placebo-adjusted MG-ADL improvements in their respective pivotal studies at similar time points.

Importantly, efficacy emerge rapidly with clinically meaningful improvements seen as early as week 2 continued to deepen over time and was sustained without any evidence of waning across the full dosing interval. The key secondary endpoint, QMG, was also met with a 2.8 placebo-adjusted improvement, reinforcing the consistency between patient-reported and physician-assessed outcomes. While the combination arm also met the primary and key secondary endpoints, it did not provide additional benefit over cemdisiran monotherapy in gMG, demonstrating that complete complement blockade is not required to achieve robust clinical benefit in gMG.

Taken together, these data suggest that cemdisiran delivers rapid, deep and durable efficacy with markedly reduced treatment burden, positioning it as a best in -- potentially best-in-class C5 targeted therapy for patients with gMG.

Safety also appears to be a differentiating factor for cemdisiran in this indication. Overall, safety profile was favorable and consistent with expectations for the C5 class with no new or unexpected safety signals observed across treatment arms. Cemdisiran monotherapy was generally well tolerated with no serious infections, no meningococcal infections and no treatment discontinuations during the 24-week double-blind period. Rates of adverse events, serious adverse events and severe adverse events were numerically lower with cemdisiran versus placebo and combination therapy, supporting the safety of partial C5 inhibition in gMG.

It is also worth noting that only 1% of patients in the cemdisiran cohort experienced the adverse event of myasthenia gravis compared to 17% of patients randomized to placebo, further reiterating the treatment of effect of cemdisiran in this setting.

Taken together, these data support a differentiated benefit risk profile, pairing strong efficacy with a generally manageable safety profile suitable for chronic use.

Slide 27 summarizes what we believe is a clearly differentiated clinical profile for cemdisiran in generalized myasthenia gravis. From an efficacy standpoint, cemdisiran delivered clinically meaningful improvements within the first 2 weeks with depth of response that compares favorably within the C5 class and remains durable across the full dosing interval. Importantly, that efficacy is sustained without waning, supporting a quarterly dosing regimen that meaningfully reduces treatment burden for patients managing a chronic disease.

From a patient experience perspective, subcutaneous administration and infrequent dosing differentiates cemdisiran from both IV-based C5 inhibitors and more frequent cyclic daily or weekly options.

On safety, through 24 weeks, cemdisiran demonstrated a generally manageable profile with no treatment discontinuations, no serious infections and lower rates of severe adverse events relative to placebo. Taken together, these attributes position cemdisiran as a differentiated potential advanced therapy option, balancing strong clinical performance with convenience that is highly relevant in a real-world gMG management.

This slide highlights how cemdisiran differentiates within the C5 class, specifically, compared cross-trial to Ultomiris, an infused C5 inhibitor. Cemdisiran achieved rapid, deep 2.3-point placebo-adjusted MG-ADL improvement with only 2 subcutaneous injections over a 24-week treatment period. Ultomiris requires 4 infusions over a 26-week treatment period and demonstrated a 1.6-point placebo adjusted MG-ADL improvement. We believe cemdisiran has the potential to offer a best-in-class profile, combining strong sustained efficacy with a substantially reduced treatment burden through convenient, quarterly subcutaneous dosing.

Now compared cross-trial to Vyvgart, the leading FcRn inhibitor, which have grown the advanced therapy market for gMG. We believe cemdisiran can offer a differentiated clinical profile. A key distinction is durability as cemdisiran maintains efficacy throughout the dosing interval without the cyclic waning of efficacy that can be seen with Vyvgart and the other SCR-based approaches.

Unlike Vyvgart, which is dosed cyclically, cemdisiran provides deep and continuous improvement in MG-ADL scores with only 2 injections over 24 weeks. That durability enables quarterly subcutaneous dosing, which meaningfully reduces treatment burden compared with frequent cyclic administration schedules. This is particularly relevant in a chronic disease like gMG where patients require sustained symptom control rather than episodic relief.

And finally, Slide 31 highlights how cemdisiran differentiates relative to the newly approved B-cell depleting agent, particularly in speed of response and durability. From an efficacy standpoint, cemdisiran delivers rapid placebo-adjusted improvements in MG-ADL, with clinically meaningful benefit observed within weeks rather than months. Also, the mechanism matters. By directly targeting complement-mediated damage at the neuromuscular junction, cemdisiran provides symptom control without relying on broad immune cell depletion.

While B-cell depleters may offer a potentially longer dosing interval, that does come with prolonged IV infusions that require premedication and post-infusion monitoring requirements.

In summary, the gMG market is very competitive, and we believe cemdisiran has the potential to offer a differentiated alternative to currently approved advanced therapies with strong efficacy, generally manageable safety and quarterly subcutaneous dosing.

With that, let me turn the call over to Soma, who will now discuss the commercial opportunity.

Thanks, Umesh. We believe our C5 program represents a late-stage multi-indication, multibillion-dollar opportunity, spanning gMG, PNH and GA. Today, these markets combined generate about $9 billion in annual globalized sales and continues to grow rapidly, supported by strong underlying prevalence dynamics. gMG represents the first and largest near-term opportunity with an FDA decision and potential product launch in the fourth quarter of 2026. As Umesh has highlighted, we believe cemdisiran's clinical profile, including quarterly subcutaneous dosing and strong efficacy, has the potential to position it competitively in the rapidly expanding advanced therapy market. PNH represents another potential large commercial opportunity with current annual worldwide sales of around $3 billion.

The cemdisiran and pozelimab combination targets patients who require complete and uninterrupted C5 inhibition, offering a differentiated option versus entrenched standards of care. And then rounding it out, geographic atrophy provides the largest population with over 1 million diagnosed patients in the U.S. alone. Currently approved agents have started to build this space, delivering just over $1 billion in annual worldwide sales today, reflecting the early stages of disease modifying agent adoption.

A systemic approach could differentiate meaningfully here versus chronic intravitreal injections if efficacy can be demonstrated. Two important commercial considerations for our C5 commercial strategy I'd like to highlight. First, Regeneron are solely responsible for development, manufacturing and commercialization for both cemdisiran monotherapy as well as for the combination and pay modest royalties on net sales to Alnylam. Secondly, our commercialization strategy is highly indication-specific, allowing us to optimize value and access [indiscernible]. This allows us to align pricing and access to the underlying disease biology, market size and competitive dynamics.

We believe this C5 franchise presents a long-term growth opportunity for Regeneron given this derisk program, multiple shots on goal and staggered launches.

Now let me focus on the near-term gMG commercial launch and strategy. The gMG market is undergoing a structural shift driven by rapid adoption of advanced therapies as treatment goals move beyond symptom control towards durable disease modification. Advanced therapy penetration is relatively low today at just 15%, but is expected to grow materially closer to 40% over time, creating a multiyear growth category. Both FcRn inhibitors and C5 targeting agents are expected to account for the majority of incremental sales as patients cycle through earlier lines of therapy more quickly.

Despite increasing competition, the market is expanding faster with total U.S. gMG net sales expected to more than double over the next several years to over $12 billion in annual net sales by 2032, supported by newly approved agents, higher treatment rates and longer durations of use. Cemdisiran is expected to enter this market at an inflection point as the first siRNA in gMG offering a differentiated mechanism, quarterly dosing and a profile well aligned with physician and patient preferences for durability and convenience. Importantly, this expansion in the use of advanced therapies broadens the treated population, potentially allowing differentiated agents to succeed without having to displace incumbents.

Our objective with cemdisiran in gMG is very clear. We plan to position cemdisiran as a differentiated and convenient targeted therapy for gMG patients. Cemdisiran represents a first-in-class siRNA approach targeting C5. This will require education to ensure stakeholders understand how this differs mechanistically from antibodies, FcRn inhibitors and B cell depleters. To establish cemdisiran in this market, we look to drive adoption by leading with cemdisiran's potential best-in-class clinical profile highlighted by its efficacy, safety as well as dosing convenience. The Phase III data show rapid, durable symptom improvement with no waning between doses, which clearly differentiates cemdisiran for cyclic or infusion-based therapies.

Just as importantly, quarterly subcutaneous dosing meaningfully reduces treatment burden with potential to improve predictability and adherence for patients living with a chronic neurological disease.

As we move into launch optimization, the focus shifts to maximizing long-term adoption and value. We are actively working to evolve from HCP administered vials to patient self administration, further reducing treatment burden and improving persistence. We also plan to expand beyond the U.S. into key international markets where the combination of strong efficacy and quarterly subcutaneous dosing is also viewed as highly differentiated there. As the use of advanced therapies for gMG expands, self-administration options are introduced, and we expand into additional geographies, cemdisiran is poised for sustained growth.

Now I will turn it back to George for closing comments.

Thanks, Soma. Let me briefly summarize this roundtable discussion. C5 program is not a single asset story, it's a differentiated pipeline and a product opportunity with blockbuster potential. Cemdisiran used either alone or in combination with pozelimab enables different levels of C5 inhibition, depending on how much complement suppression each disease requires. We've shown that partial C5 inhibition is sufficient and optimal in generalized myasthenia gravis while complete uninterrupted blockade is required in diseases like PNH. That flexibility is the core advantage of our siRNA and antibody approach.

Moreover, while our C5 program has achieved clinical validation in its 2 leading indications, we expect to generate proof-of-concept data later this year in geographic atrophy, potentially derisking yet another significant commercial opportunity for complement mediated disease with significant unmet need.

In summary, with near-term pivotal data and planned upcoming launches, we believe the C5 program represents an under-appreciated opportunity for long-term growth, not currently reflected in Regeneron's valuations.

And with that, let me turn it back to Ryan.

Thanks, George. This concludes our prepared remarks. Thank you for your attention. We will now open the call for Q&A. [Operator Instructions] Shannon, can we please go to the first question?

[Operator Instructions] Our first question comes from the line of Evan Seigerman with BMO Capital Markets.

Really appreciate you doing this. So regarding the geographic atrophy opportunity, can you walk me through some of the rationale why you think your approach will be better than the currently available assets? I know that there's limitations and most physicians are not thrilled with those. I'd love to know how you think you can improve on those given that this is a pretty tough indication?

Well, in one case, in terms of being better, our studies are powered to pick up a potential functional benefit, which the other studies did not actually pick up. But our major advantage is going to lie in the setting of both convenience and safety, as we outlined. Right now, patients often suffer from bilateral disease. And as you probably know, treatment often triggers a requirement for anti-VEGF therapy as the patients progress from dry AMD to wet AMD. So the treatment burden is very substantial for many of these patients with bilateral injections targeting complement as well as additional injections for their wet AMD.

What we hope to be doing here is using a subcutaneous systemic treatment approach that will dramatically decrease the treatment burden. It will allow simultaneous bilateral treatment from the systemic approach. And if the patients then require anti-VEGF therapies, those will be the only intravitreal injections they'll need. They won't need to also be continuing their C5 injections.

We also mentioned, of course, that we do have a follow-on intravitreal approach where we're developing a co-formulated form of what we hope to be a long-acting antibody combined with our long-acting anti-VEGF agent, which would be a completely independent way of addressing the profound treatment burden that these patients suffer from, the need to have these simultaneous treatment approaches going. And so these will be 2 important separate distinct opportunities that could dramatically address the biggest problem that these patients suffer from, which is the treatment burden and also obviously, the safety consideration with the occlusive vasculitis that unfortunately is seen with the current intravitreally administered agents, we would expect not to see that obviously, either with our systemic approach or with our dual antibody EYLEA approach.

Our next question comes from the line of Alexandria Hammond with Wolfe Research.

So what does the path forward look like for moving from the subcu administration in the clinic all the way to that self-administration option, such as I'm assuming with an auto-injector -- on-body injector at home without the need of a health care professional?

Soma, would you like to take that?

Sure. Happy to take it. So we believe that the auto-injector will be an important -- self-administration option will be important for patients. However, as we start, we actually think that the currently C5s are given as infusion therapies. And this is going to be a subcu in the office every 3-month administration, which aligns with those schedules that patients visit anyway. Many patients visit anyway. So we've heard that this is not going to be a barrier out of the gate. But ultimately, this was really a launch sequence that was designed to avoid delaying entry while still enabling a convenience step-up post launch.

I'd just add that the timing for the self-administration option is going to be largely dependent on upcoming regulatory interactions, and we'll certainly keep you informed as those evolve over time.

But certainly, having a subcutaneous treatment regimen every 3 months, which as Soma said, is aligned with patients visits to their physicians is a substantial difference compared to the much more regular large volume infusions having to visit often infusion centers and so forth that these patients have or even the weekly infusions that some patients have with some of these therapies. So obviously, we think it's a very differentiated approach that offers, of course, 2 important features. One is dramatic decrease in the treatment burden. Two is potentially best efficacy in class, but also an efficacy that is very rapid and durable and sustained without cyclical variations. So we believe that it offers a very advantageous profile for patients and physicians to consider from the convenience but also from the treatment benefit side.

Our next question comes from the line of Chris Raymond with Raymond James.

Just a question maybe from Slide 10, kind of intriguing the phenomenon you're seeing that the different diseases may require different amounts of complement inhibition. I think that's pretty interesting. Do you have any plans to maybe more systematically study the biology behind this phenomenon? Or do you think you'll maybe just gradually learn what amount of complement inhibition is needed as you run these trials?

We agree. This is a fascinating scientific question. We are honestly interested in trying to understand it. But as you said, the very first step is to just define how much inhibition you need in the various diseases. We have to admit that although we did the study, as shown on this slide, that showed partial inhibition compared to complete inhibition, that partial inhibition was, if anything, at least as good, if not better, was very surprising to us and I think to the entire field. It really opens up a whole new set of questions, which you're highlighting, and I think it's going to be something that we're all going to be very interested in studying. But the implications obviously are huge from the safety perspective.

Obviously, in a disease where patients have risk of breakthrough hemolysis, thrombosis and death and so forth, such as in PNH, you really want to do what's best to prevent those really bad outcomes in those patients. And there, we believe you do need the complete C5 inhibition that the combination affords. But in myasthenia gravis, the opportunity to be actually seeing, if anything, better efficacy with less complete blockade really raises the possibility that these patients will have a much more favorable infectious risk profile. Now we did see it that in the small study when you compare the adverse events, but we're going to do additional follow-up studies to follow up and see whether that really can hold up to further scrutiny. But that would be a huge advance for the field and for patients.

All the other therapies are much more substantially immunosuppressive. We've seen now even with the FcRn therapies that they can be associated with serious reactivation and even fatal infections from EBV. We all know about complete inhibition with C5 leading to meningococcal infections and so forth. So this offers a very important different opportunity from the potential safety perspective. But as you said, it's a fascinating scientific question. We did not predict this -- and it certainly is a question of that we and I think the whole field is now going to be very interested in following up.

Our next question comes from the line of Mohit Bansal with Wells Fargo.

Sorry about that. And I want to double click on the geographic atrophy strategy a little bit. So I mean that systemic administration and whether or not it does cross the blood retina barrier. And then the C5 that goes in, would it have similar or more benefit than the intravitreal C5. So how do you see that? Do you see C5 -- the intravitreal C5 as the bar? Or do you think a benefit in visual acuity would also be -- will also be need to be seen here for you to move forward here?

We're really sorry the reception on your call was not very good, so we couldn't get the whole question. But certainly, it seems as if, by blocking C5 where it is made, there is very little actually almost no evidence that C5 is made anywhere other than the liver. It does not appear to be made in the eye. So blocking it at its site of production, if anything likely be more effective than trying to block it at the very last point in the eye. That said, we think that our major advantage will not necessarily be in further slowing down the progression of the disease. But because we have larger studies planned and ongoing that we will actually be able to show a functional benefit that was not shown in the other programs. But the first hope in our first study is merely to show a very similar rate of slowing of geographic atrophy with the differentiated and potentially better and potentially safer certainly from the local injection safety perspective of the systemic approach. And that should offer, assuming it's a well-tolerated and safe systemic approach, a huge benefit to patients.

Many of these patients are not taking this treatment. There's -- even though there's over 1 million patients in the United States who could be eligible for this treatment, there is very slight penetration into this market probably on the order of 1% or so. Most patients are not taking these therapies, why because they require injections directly into the eye, multiple injections, you then trigger anti-VEGF injections on top of that and the injections themselves can actually cause catastrophic immediate blindness in rare cases because they cause occlusive vasculitis. So the problem is there is a treatment approach that can help these patients. It's just not widely used because of the treatment burden and the safety risk of the intravascular injections. We hope to open up this entire field and all these patients for a much more convenient treatment approach and allow many more of them to undergo an approach that could slow or prevent progression of their geographic atrophy disease.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

This is Elizabeth on for Salveen. We wanted to get your thoughts on targeting C5 specifically in GA and why inhibition at C5 is optimal within the complement cascade for this disease versus going upstream or potentially downstream?

Well, so far, approaches targeting either C3 or C5 have been shown to be similarly effective. There's no evidence to suggest that going higher up would be more effective. Of course, going higher up blocks more of the pathway and has higher risks in terms of infections and so forth associated with it. And so we thought that the C5 approach had the opportunity to have as good efficacy and potentially better safety once again.

Once again, we have in our pipeline other programs to both address other targets, both in the complement pathway, but elsewhere in this entire pathway as well in the upcoming years that we may be able to bring forth as well. But right now, we thought that C5 was the best known and available target from the safety and efficacy perspective and that we had this differentiated approach that could make the treatment much more convenient and hopefully safer for the patients.

Our next question comes from the line of Geoff Meacham with Citi.

This is Nishant on for Geoff. On gMG, given the competitive treatment landscape, at launch, do you expect uptake to be driven more by switching from existing C5 or by new starts that might otherwise have gone to FcRn? How should we think about that mix evolving over time?

Yes. So we're very -- we're excited about what we think this differentiated profile can do and potential best-in-class efficacy, dosing convenience, we think it will position as a very differentiated advanced therapy in the space. But the launch is really expected to capture a mix of switch and new patient starts. And the plan is really to compete for both because we think that there's certainly people who are on certain things, whether they're on infusions, whether they're on these cyclical based therapies and we think they are perfect candidates for switch. But also, there's so many patients coming into this advanced therapy filter that are going to look for new agents that we think there's also a really good opportunity for new patient starts. So we think it's going to be a little bit of both, but not to underestimate the competition, it's a competitive space. It will take time. And so we do expect that as well.

Thanks, Soma. Shannon, we have time for 2 more questions, please.

Our next question comes from the line of William Pickering with Bernstein.

In geographic atrophy, what read-through do you see from the failed Soliris trial, given that it's also a C5 inhibitor? And could you comment on why you initiated the intravitreal pozelimab trial?

This is Andres. So when you look at the complete study, I think it's important to understand that this was an investigator-initiated study relatively small study. I mean this is 30 patients randomized 2:1. And there are a few, I think, points that are important. One is eculizumab, which was used in that particular study was dosed at 900 milligrams, which compared with our approach does not provide full suppression of terminal complement activity. I think that, that is an important point that we should bear in mind. And also the way the study was designed with a very small number of patients looking at a large magnitude of an effect. Now we have a better understanding of what to look for.

And when we are looking at our particular study with a larger number of patients, and I want to remind you that we are planning to do an interim analysis with approximately 250 patients, we are looking for a 20% treatment effect, which is commensurate with what we have observed with IVT infusions. So I think that there were early days when the complete study was performed. And I'm not sure that had the best and enough power to really detect a significant improvement at that point.

Yes. I mean let's just emphasize what Andres said. We are not expecting to get a bigger slowing than the intravitreal agents. We're just expecting to do it in a much more convenient and safer manner. That slowing is about 20%. A 30-patient study was -- had an 80% power to pick up a 75% slowing. So obviously, with 30 patients, you would not have seen a 20% signal. So you have to just ignore that study if like it was not done, plus it was done with an inferior agent. So of course, we would not be taking a study that has no informative value at all into account into our thinking because it literally taught us or the world nothing except maybe it misinformed some people who weren't paying very close attention.

And you asked a question about the IVT formulation. Why are we doing that? I think that one important component is the fact that we recognize that maybe potentially one may need reduction of C5 or complement activity locally. So we understand that, that might be necessary. But I think what is important is our approach. And the approach that we are taking is a co-formulation with anti-VEGF because as you probably know, the -- when you treat with complement, you may actually worsen the situations with the wet AMD and so forth. So that is one important approach. The other is that our antibody will not be pegylated, which has been potentially associated or speculated that pegylation is what induces the complications, the ocular complications with intravitreal administration. So we recognize that we have multiple shots on goal.

Our last question comes from the line of Tyler Van Buren with TD Cowen.

This is Sam on for Tyler from TD Cowen. These roundtables are very helpful. So just 1 question from us on the Phase III PNH pivotal data later this year. What are your expectations for the performance of the control arm? And what does poze-cemdi need to achieve to reach statistical significance on percent change in LDH? And then maybe what does it need to show to be viewed as having best-in-class efficacy?

I think that the data that give us confidence on the outcomes of the study is what we presented during the roundtable. And that is that when you compare with ravulizumab, which is another standard of care -- a considerable standard of care today in the treatment of PNH, a larger proportion of patients that were treated with the combination of pozelimab plus cemdisiran achieved LDH control. Furthermore, a significant larger population of the patients have a normalization of LDH, which we think really represents the level of ongoing intravascular hemolysis. So we feel very comfortable.

Furthermore, when we looked at patients that were not well controlled or never achieved control with ravulizumab in that cohort, okay? There were 5 patients that never achieved control. When they were switched to the combination, our combination, 4 out of those 5 patients were able to achieve control of their LDH. So we feel confident that we have a more profound, sustained uninterrupted inhibition of C5 activity that will lead to better control of intravascular hemolysis.

So I think that, that is the data that encourages us and make us believe that we have a positive study.

And we won't have to wait much longer to get that data, should be coming in the fourth quarter. Thank you, Andres. And thanks to everyone who joined the call today. Unfortunately, that's all the time we've got. Thank you for your interest in Regeneron and our C5 Development Program. Everyone, have a great day, and we can now disconnect.

This concludes today's conference. Thank you for your participation. You may now disconnect.

So we'll kick it off here. Thanks for your patience. So I'm Dave Risinger. It's very much my pleasure to welcome members of the Regeneron management team. So with us is Marion McCourt, who's Executive Vice President of Commercial; and Ryan Crowe, Senior Vice President of Investor Relations and Strategy. So thanks again for being here with us. I thought that maybe I'd turn it over to you to provide some just opening comments about the prospects for the business this year.

Maybe I'll start, and we really truly appreciate the opportunity to be here, Dave. Leerink conference is always something we plan to attend every year and excited to be back. And today, we think we have a thoughtful discussion around the commercial momentum we have in our business as well as the deep, diverse and diversified pipeline and how we're executing all across that as well as kind of our disciplined approach to capital allocation. But before we get to all those topics and before Marion gives kind of an overview, I need to read this forward-looking statement.

So I would like to remind you that remarks made today may include forward-looking statements about Regeneron, and each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in such statements. A description of material risks and uncertainties can be found in Regeneron's SEC filings. Regeneron does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Marion?

That was double speed that was impressive.

I got out of practice doing it.

I think you've read that before.

Just a few times.

And I'll go a little bit more slowly, but good morning to everybody. And just to give a little bit of an introduction to the year, I'll give that in context of our fourth quarter performance and obviously wanting to continue the strength of our commercialization and the depth of our portfolio. But in fourth quarter, we shared with you our results on EYLEA HD. Certainly strong numbers with $506 million in the quarter. That was 66% year-over-year growth for EYLEA HD. And certainly, in the end of the year, in the November, mid- late November time frame, we had the enhancements to the EYLEA HD label, which were long awaited, but very important for Q4 weekly dosing and also the RVO indication.

Dupixent also a very strong performance, pleased to say through the year and in the fourth quarter, we had in the fourth quarter, specifically $4.9 billion in sales for Dupixent, and that was obviously in our relationship, the alliance with Sanofi, but very strong performance across all indications with Dupixent. And that also was a significant growth in the fourth quarter number, which was up about 32% versus prior year.

And then also over to Libtayo, strong performance, $525 million. That was a year-over-year increase of about 13%, strength not only in our skin indications, but also performance in lung cancer, and we had also recently launched into the adjuvant cutaneous squamous cell carcinoma setting. Other products certainly in our portfolio, but those would be the highlights and certainly the major brands that I'm sure you're interested in, in in-line commercialization as we go into the year.

Excellent. And so for this year, -- could you just talk about the pushes and pulls and what we should be focused on?

Sure. So I absolutely would continue to focus on -- I'll start with our largest brand in Dupixent. Certainly, we have major established indications in the marketplace. But the exciting thing is even our first indication launch with atopic dermatitis is very much underpenetrated in the marketplace. So the category is growing. Competition is coming in, but Dupixent remains the leading product as the KOL community frequently reminds me first and best product in the category.

We continue to lead in asthma as well in new-to-brand scripts and total scripts, also in nasal polyps, Eosinophilic Esophagitis, all major indications for Dupixent performing really well. on an international basis. And then more recently, we've had the launches of COPD for Dupixent performing quite well. CSU has been really important. chronic spontaneous urticaria, I'll remind is a patient population of about 300,000 patients as well in terms of potential. And then more recently to the label enhancement, we've also had the allergic fungal Rhinosinusitis, which is really important for patients with a really significant condition of allergic fungal infection, often resulting in surgeries, but then having to repeat surgeries because, frankly, it's not an effective means of treating that disease, which is chronic in nature.

So great things happening with Dupixent and certainly a lot of excitement for -- I mentioned Libtayo performance and the indications, but we recently also last year, in the last months of the year, launched Lynozyfic -- and that has been an exciting launch, certainly for later line patients in terms of treatment, but early days seeing a lot of very positive uptake in both academic and community setting based on the clinical profile of efficacy, safety profile, lesser hospitalization, which is so important to those patients and their physicians and also the ability to extend their dosing treatment interval more rapidly, also really important for patients being treated with multiple myeloma.

Excellent, excellent. And EYLEA.

So for EYLEA, certainly, the focus of my attention is now the expansion of EYLEA HD. We have some label expansion, hopefully, more to come with prefilled syringe, but certainly strong performance in the last several quarters in terms of being actually the leading product in the anti-VEGF category for innovative brands in terms of growth and certainly a lot more potential for the product EYLEA, I did mention in our most recent earnings call that we obviously had seen a double-digit decline on sequential quarters in EYLEA.

We expect to continue to see that as we go into the first quarter. At the same time, we commented on seeing growth in EYLEA HD. We talked about high single digits in terms of the EYLEA HD unit growth as we go into the first quarter. So again, declines in EYLEA, not only because of growth of EYLEA HD, but also because of obvious biosimilar competition that we have in market. And I'll remind everybody in the second half of the year, our expectation would be to see additional biosimilar competition to EYLEA 2 milligram.

Excellent. And so you mentioned high single-digit unit growth for HD in the first quarter sequentially. But how should we think about net price sequentially?

Well, I think you have to think a little bit more carefully on that because we did share with you that we had some inventory build in the fourth quarter of last year. That's not unusual. We had a similar inventory build on EYLEA HD and EYLEA in the prior year. I think it has to do with patterns of buying at the wholesale level. But certainly, we continue to see robust demand with EYLEA HD, and there has been very positive response to the enhancements of the label of the Q4 weekly dosing. It gives physicians confidence and flexibility prescribing as they want to use the drug. Even though they see with EYLEA HD great durability, there are occasionally patients, and they don't always know which ones that when they see them when they treat the patient, they want to use the shorter dosing interval for at least one or maybe a couple of more treatments.

And then how important is the prefilled syringe commercially meaning is adoption by physicians really constrained by the lack of a prefilled syringe?

So it's important. I would say that from our demonstrated performance, EYLEA HD has been in market now for over 2 years. We launched in August of 2023. We've been -- we're a blockbuster brand. So I'm very proud of the team and what they've been able to accomplish. It's really all about the science and the profile of the brand that allows that. But I'll share, even though we've done well with EYLEA HD, if I look at EYLEA as an example, 95% of use is with the prefilled syringe. So it's important to practices. It hasn't constrained use. It certainly will open use, though in some practices where they may have been more hesitant.

Great. And since we just talked about your commercial presence across different therapeutic areas, -- could you just talk a little bit about -- and maybe this is more of a question for Ryan, but both of you can comment maybe the opportunity to leverage Regeneron's infrastructure through M&A, meaning obviously, the company wants to invest aggressively in R&D going forward. But I would think there's an opportunity to roll in products that leverage where you're already operating in specific therapeutic categories to drive even better financial returns to support that R&D growth in the future.

I'm happy to start, and then I'm sure Ryan will have comments as well. So absolutely, when we built the commercial organization over many years now, starting in ophthalmology and then broadening into immunology, oncology, hematology, rare disease, and having the infrastructure to allow for increment to the portfolio, we did so always with the future of mind of being specialized in therapeutic areas, but being able to expand. I'll give you a quick example of something that already is a byproduct of partnership.

We have cemdisiran coming into the marketplace, fingers crossed with an approval, if not end of the year, early next year for generalized myasthenia gravis. We already are working towards the footprint and the build of a neurology business unit for a product that we brought into the organization. Similarly, as we look to the future of our own science and potentially partnered or M&A, as you asked, types of opportunities, we have the infrastructure in place to be able to do that.

Yes. I think Marion has it right. We certainly have the core infrastructure of the commercial team that can support a number of products. And as you know, Dave, we have a very broad pipeline across many, many therapeutic areas. And as those advance into pivotal stages, the commercial team begins to get built around that. I'd say in terms of bringing in outside opportunities, commercial synergies are unlikely to be the primary motivation there. We have done historically earlier-stage M&A and platform-focused M&A. I think that's probably going to remain how we view the opportunities outside, but not ruling out something bigger and more late stage for sure. I just -- I don't think it would ever be commercial synergy-driven M&A.

Got it. So regarding the Sanofi alliance, can you talk a little bit about the strategic decision-making framework within Regeneron, specifically, whether it makes sense to try to extend the duration of the alliance or not? Any high-level comments would be helpful.

Sure. So as a start, I think that the alliance with Sanofi has been very important for Regeneron, and we're incredibly proud of what we've created. And specifically with Dupixent today, we have 1.4 million patients on Dupixent worldwide. It's been an amazing product, helps so many patients and been obviously really important to both organizations. As we have opportunities to look at strategic endeavors that make sense for both companies, absolutely, that's the right thing to do. I think, Ryan, perhaps you have some more detail on some of the elements of consideration.

Yes. I think Dupixent would not be the product that is today without both Regeneron and Sanofi. And I think it's in the best interest of both companies to maximize all of the progress that we've made together beyond maybe Dupixent. And we have plenty of next wave opportunities within our own pipeline, Sanofi as well and trying to leverage Dupixent to the max, I think, is in both sides' best interest. There are certain assets that we've identified in our preclinical portfolio that also hit the IL-4 receptor alpha.

They're already kind of by default in the collaboration, but there are others that do not and are not currently in the collaboration. Whether that can change is a matter for us and Sanofi to figure out whether, a, it makes sense for both sides; and b, at what terms. So we're certainly interested in pursuing that. We've been great partners over the years, of course, with some disagreements along the way. But overall, a highly successful partnership that I think we should continue to try and maximize.

Excellent. And just remind us about what you had updated the Street on in early January about which candidates are in the alliance, which candidates are out of the alliance. I think there was that one specific slide where you had some of those details.

Yes, that's right, Dave. So it's not really that complicated. In fact, if it hits -- if an antibody or some other drug hits the IL-4 receptor alpha, which is the target of dupilumab, it's in the collaboration. That's a very bright line in the agreement. If it hits really any other target, it is not. So for some of the next-generation assets that we are working on preclinically at the moment, including our long-acting IL-13 antibody, our long-acting IL-4 antibody, our long-acting IL-4 by IL-13 bispecific antibody, none of those are in the Sanofi collaboration. So we are independently working on them.

We have, I'd say, bespoke development plans around each of those assets. IL-13 long-acting will be the first of those opportunities to enter the clinic. We've said that, that would occur in the first half of this year, and that remains on track. So we're looking forward to putting that into a human very soon. And the first indication that we'll be pursuing is in atopic dermatitis. So initially in healthy volunteers, and then we plan to follow an expedited development program to hopefully allow for registration and launch ahead of Dupixent's composition of matter patent expiry, which would be the earliest potential launch of a biosimilar. I think there's some opportunity to maybe extend that exclusivity runway beyond that date, though.

So is that what George referred to as supi-dupi? Or is that a different one?

Supi-dupi, I think George was talking about the long-acting fully human IL-4 receptor alpha antibody. So literally another version of Dupixent that can be dosed at longer intervals. So that is the supi-dupi. And then these other opportunities are kind of adjacent to that, all within the IL-4, IL-13 axis, which we think is truly the underlying driver of all these atopic inflammatory diseases.

Got it. Okay. That's great. And turning back to EYLEA. Could you just talk about sort of the commercial dynamics when a number of additional biosimilars launch later this year? Just how you manage this year ahead of that and next year after that? Obviously, I'm sure you want to convert as many patients as possible to HD. But it'd be just helpful to have you describe sort of your commercial positioning as you're operating it today?

Sure. So I think it's important to understand that when you look at the market today, even for years, there's always been a low-cost alternative with Avastin in the anti-VEGF category. So that's one fact that remains. And certainly, as more biosimilars come into the marketplace, you would expect to see more price competition, things of that sort, where today, the biosimilar use aflibercept 2 milligram has been limited to select practices as opposed to a widespread use in the marketplace. Having said that, your point was spot on, we're very fortunate to have EYLEA HD next-generation product. Retina specialists are a very sophisticated audience, both scientifically and from a business standpoint.

And I think for them, it's really important to be using state-of-the-art care for their patients. The durability of EYLEA HD is very exciting in the market. We know the label enhancements have been important. So the timing is really nice that we're bringing forward EYLEA HD to be all that it can be, hopefully very quickly so that we're in a really strong position to be the product in the marketplace and the innovative branded product in the marketplace that physicians see all the attributes of what's most important to them for the retina patients.

And then you would expect with more biosimilars, potentially more elements of pricing actions and also physicians potentially always having the thought in retina because we inject into the eye, there's always the consideration as new products come into the marketplace, wanting to see them in the real-world setting. It's not possible always to know, and this is true of all products, not just biosimilars, but even branded products, we've seen some products before the market experience fail because of safety, but we've seen others that we thought were going to be highly effective in the marketplace, not succeed because of issues related to safety. So that, too, is something that always will be really important in this category.

Sorry. So thinking about that commercial infrastructure that you have for EYLEA. So could you just talk about leveraging that longer term and maybe also comment on pipeline candidates as well that could fit in?

Yes. So very happy to. And there is a lot, obviously, in our various programs that potentially feed into the ophthalmology business unit for commercialization. So just to maybe mention a few that I've been incredibly impressed with is we have a program for uveitis. We have a glaucoma program. We have a geographic atrophy program. There may be others that we haven't commented on yet that Ryan, you can add to my comment, but really exciting and Regeneron is a long respected company in the retina and ophthalmology community. So we're really excited. And to your point of building out business units, that is an example. And I'll also share with you, I'm never hesitant to build a new business unit as we did for oncology or hematology or as I mentioned, neurology as our science feeds in. But in this particular case, it's a therapeutic area where we have a footprint.

Yes I would just add, we also have an opportunity in thyroid eye disease using a novel target. So a few of these are going to be first-in-human targets that we're excited about. And I think they -- as they move along in clinical development, the commercial team will be preparing.

Excellent. That's great. So maybe we could turn to a couple of other pipeline questions. So could you just talk about fianlimab, -- if you could provide an update. Obviously, the trial has been delayed. We're still awaiting the results. And I know that you've commented before. Obviously, there have been some investor concerns that maybe the pembro arm is performing dramatically better than anticipated. But would love to hear the latest please.

Sure. Certainly been a lot of scrutiny around this study and the readout has been delayed a couple of times, and we're now still on track for a first half readout as we await these final PFS events to come in. We don't believe we've enrolled a population that would result in an outsized pembrolizumab benefit of above and beyond its historical analogs of, call it, 4 to 5 months. Some of the inclusion criteria in some of the trials that have been recently conducted, I think, are slightly different than what we enrolled. And as a result, pembrolizumab perhaps did better in those trials than we would expect it to do here. We don't know how pembrolizumab is doing in our study.

We are totally blinded to the events and where they're occurring. We only know the total number and how they are accruing at the rate in which they're accruing. So we will see. I think you can look at it from 2 different ways. On the negative side, pembrolizumab is doing something miraculous and amazing and it's going to have a much higher-than-anticipated median PFS or you could look at it and say, well, the active arms are actually doing quite well and are approaching the activity that we saw in the early human studies where pooled median PFS across 3 independent cohorts was 24 months.

I'd add that we feel that we've conservatively powered this study and actually have assumed pembrolizumab performs at a median PFS of 7 months, which is roughly 50% better than it has in first-line metastatic melanoma in past studies. And so based on that assumption and our assumption of at least Relatlimab/nivolumab [indiscernible] activity from our combination, we feel comfortable with the powering of the study even if pembro were to outperform its historical analogs.

That's very helpful. And can you talk about with respect to that enrollment, the mix of patients by PD-L1 status?

Sure. We haven't stratified by PD-L1 status. There's no floor. There's no cap in enrollment. We are pursuing patients that are in the real world. So we would expect to enroll a roughly even split between expressers and non-expressers of PD-L1, but those baseline characteristics have not yet been disclosed.

Okay. Very helpful. So you have a new launch to prepare for in [ MG ]. Could you talk a little bit about that and whether there's any possibility of launching earlier than the schedule for the first quarter of '27?

Yes. Well, based on the filing and submission, we had been speaking about early portion of next year, January. There are scenarios where potentially you could move it late this year. We certainly will be launch ready, and we look forward to participating in this marketplace. The product profile is exciting from the standpoint of efficacy, safety, convenience of dosing. There's still a lot of unmet need in myasthenia gravis marketplace. It's about a $5 billion marketplace today. By 2030, it could be up to about $10 billion. A lot of potential, a lot of unmet need, obviously, a highly competitive marketplace as well, but one we're excited in being able to participate in with an approved product.

And I would just add, we do plan to present the full data from the NIMBL study next month at [ AAN ]. So we'll show what the curves on MG-ADL look like. And I think what you'll see is rapid improvements in the activities of daily living and sustained across 6 months with every 3-month dosing, which is very differentiated from the medicines that are approved today for myasthenia gravis.

Yes. And just given the evolution of the MG commercial market, could you just shine some light on exactly where you see the product being positioned and taking share?

I would say that we're looking at a variety of scenarios now based on the profile I mentioned related to efficacy, safety, dosing convenience and then the unmet need of patient population. I think it's early to give you specifics on the strategy because I'd like to have the final label, and there are a number of different opportunities, all very exciting. So I just would request a little patience, stay tuned. And then as with all of our other launches, we've always held back on specific strategy of launch until the timeliness, but delighted to share as we move along and the decisions being made.

Excellent.

I will share that as we've built a number of business units at Regeneron. It's always really been exciting the level of talent that we've had from -- in the industry wanting to join Regeneron. And I can share with you that early days in our build-out of the neurology business unit, we're seeing that again.

Excellent. And so could you talk a little bit about label scenarios?

I think it's early, candidly, Ryan, I'll always defer to you and the IR team of what you've been sharing or what you'd like to share. I would only comment that it relates to the notion of the mechanism of the product, the degree of inhibition, the level of efficacy you see, the -- as Brian was mentioning, the patient experience in terms of their activities of daily living, really important. dosing frequency is always an element of convenience that is important to patients with a chronic disease like this, which is truly debilitating.

As you know, for women, it's usually an earlier age diagnosis, bimodal disease. Men, the diagnosis tends to be a little bit later, more often patients in their 60, 65 and up age range. But all these patient groups having similarities of need in terms of relief of symptoms, products that are convenient to use, safe and allow them to go about their lives. But the specifics, I'm going to wait until we get the label. I appreciate the question, though.

All right. Why don't we pivot to the GA readout that you have ahead? That's clearly a very exciting opportunity, very substantial. Could you just remind us about that and discuss the efficacy bar for success?

Sure. So this is an exciting one for us. And of course, we're doing this a little differently than the currently approved products for GA, where we're approaching this with a systemic administration with both a combination of cemdisiran plus pozelimab, our antibody to C5 as well as cemdisiran monotherapy against placebo. We believe while the actual cause of geographic atrophy is a little ambiguous, the key driver of the disease is complement-mediated inflammation of the correl capillaries along with some genetic and perhaps environmental factors.

And by completely blocking C5, which we've demonstrated in multiple studies with the combination of cemdisiran and pozelimab, we can eliminate circulating C5 with pozelimab and stop the liver from making more with cemdisiran. So in the PNH -- I'm sorry, the gMG study, we saw the combination reduce C5 levels in patients by 99%, at least 99%.

So if you believe that complement drives this disease and you eliminate complement, you should see improvement in lesion growth or deceleration in lesion growth, which is what our interim analysis is going to explore at the half year mark. So it's going to be an early look. It's going to be a subset of patients, but it should give us an indication about whether or not the systemic approach for either the combination or the monotherapy is differentiated from a placebo. So we're looking forward to that. It's going to be towards the end of 2026. And that will inform our future plans for a second study in GA.

Excellent. Well, we're actually out of time. Thanks so much for joining us.

Okay. I think we can get started. Good morning, everyone, and welcome to Miami. Very happy to have Regeneron here with us today to kick off the morning here at the Barclays Global Healthcare Conference.

I'm Ellie Merle, one of the biotech analysts here at Barclays. Very happy to have Marion McCourt here with us, the Head of Commercial; as well as Ryan Crowe, the Head of Investor Relations. Thank you both so much for joining us.

Before we jump into questions, Ryan, I'll pass it to you for some opening remarks.

Thank you, Ellie, and thanks for having us, and welcome to the sell-side coverage of Regeneron. I wanted to start today kind of highlighting your initiation report from last week, which I thought hit on a lot of themes that we'll cover in our chat today. And really underpinning your buy rating was your argument that the stock is fundamentally mispriced on the durable cash flows.

And when you consider our valuation today really only reflecting the cash flows from DUPIXENT, the EYLEA franchise and our cash on hand, if anything in our pipeline works, I would argue we are undervalued. And if a lot of things work in our pipeline, we are significantly undervalued. So I'm sure we'll get to a lot of the themes I'm about to highlight in our chat. I just wanted to go through a couple of areas to frame the discussion.

DUPIXENT momentum, really as a pipeline and a product, is well positioned to continue with growth anticipated across all 9 of its FDA-approved indications, including more recently, the launches of chronic spontaneous urticaria as well as COPD. It has a long runway and a lot of growth to come.

EYLEA HD, now approaching half of the revenues from the EYLEA franchise, and market share is poised to continue to expand with the label enhancements that were put on the FDA label late in 2025 and the hopeful approval next month for the prefilled syringe, which will really round out the profile.

And then you specifically highlighted in your report, LYNOZYFIC, which I think is a very underappreciated asset that's now approved in late-line myeloma, but with a significant commercial opportunity in earlier lines of myeloma as well as in precursor conditions, all of which are currently being evaluated in various clinical studies.

And finally, there's a lot of near-term catalysts that I think we'll talk about today, including Fianlimab plus LIBTAYO in metastatic melanoma, which has a near-term readout sometime in the first half of this year.

And then we have some interesting data coming from our Geographic Atrophy program likely in the second half of this year as well as a pivotal readout in paroxysmal nocturnal hemoglobinuria or PNH from the C5 combination of pozelimab and cemdisiran late this year.

So before we go any further though, I need to read this forward-looking statement disclosure, and we can jump straight into the questions. I'll do this as quickly as I can.

I'd like to remind you that remarks made today may include forward-looking statements about Regeneron, and each forward-looking statements are subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in such statements. A description of material risks and uncertainties can be found in Regeneron's SEC filings. Regeneron does not undertake any obligation to update any forward-looking statements whether as a result of new information, future events or otherwise.

New record time.

That was very fast.

Anyway, I think -- I hope I framed the conversation well. Let's get into your questions.

Awesome. Well, starting off with DUPIXENT, what are your expectations for some of the newer launches this year?

Yes. Ellie, I'll jump in, and good morning to everybody. Very nice to be here. So certainly, DUPIXENT has been amazing as we reported to you most recently in our earnings call, last year's sales $17.8 billion, up 32% year-over-year. We have the established indications that are still growing based on patient unmet need like atopic dermatitis, like asthma, certainly been really excited by the recent launches as well.

COPD has been remarkable for patients who had such limited therapeutic choices previously. And then additionally, as Ryan was mentioning, as I go to some of the newer launches, with so many indications, I'll try to give you a quick comment on some of them, but I don't want to miss anybody either.

But certainly CSU, chronic spontaneous urticaria is off to a really strong start. A lot of unmet need for these patients where antihistamine therapy alone just didn't give them the relief from the hives and the itching and the concerns that they had.

Bullous pemphigoid for older patients, an amazing launch in that arena, smaller group of patients, but previously tremendous unmet need. Really the only therapy that was used was chronic steroids, which isn't good for that age group of patients. Worse still, it did not work.

And certainly across all the indications, most recently, we launched for allergic fungal rhinosinusitis, very difficult disease, often results in immune allergic fungal responses requiring surgery, but now with DUPIXENT, a tremendous opportunity for patients. So across geographies, indications, age groups, we continue to see growth and tremendous progress with DUPIXENT.

Great. And COPD as well, I mean, I know it's approved a little bit earlier, but massive indication. Can you talk a little bit about some of the trends that you're seeing there and how we could think about that as contributing to the top line this year?

Sure. So very exciting indication, as I mentioned, tremendous unmet need. But now with some time in the market with COPD, often, it's an older age group of patients. We've made tremendous progress in making sure that pathways are established where necessary eosinophilic levels, biomarkers [Audio Gap], payer coverage is robust.

So there's a lot of enthusiasm with pulmonologists as we brought COPD into the marketplace. Of course, they'd had experience often or their institutions had with DUPIXENT in asthma, so rounding out into COPD patients where there's so much unmet need, has really been amazing.

Each phase of launch has gone on track. Our DUPIXENT organization, I think Regeneron overall, we're a bit of a launch machine, but certainly, each stage of launch has important parameters, goals, execution, delivery performance metrics that we look at, and COPD certainly has been living up to the opportunity it presents for patients and their prescribing physicians.

We've heard stories of patients coming back in for routine visits who had been on oxygen therapy. For anyone who's ever had a loved one on oxygen therapy, you know how incredibly difficult it is even for transport, the patients coming back into the office, being able to be ambulatory, engaging not only in their physician visit, but life generally just makes such a tremendous difference in their care.

Okay. Great. And turning to the atopic dermatitis side of things. There's a lot of compounds in development for atopic dermatitis. Obviously, DUPIXENT was the first. How are you thinking about life cycle management here, what you have in development and sort of the sustainability of the DUPIXENT revenues in light of some of this emerging competition?

Sure. So I'll take it as a 2-step. Maybe I'll cover the market currently, and then Ryan will cover a little bit of the future for us. But one of the things that I hear most frequently at the KOL visits or major meetings like the upcoming American Academy of Dermatology meeting later this month, the KOL community so often repeats one simple phrase to me is that is DUPIXENT is first and best in atopic dermatitis.

And the data, the clinical data, the market experience, the patient experience really does seem to at every turn, establish that dynamic. Other categories that many of us have worked in across our careers, the later compounds sometimes show improvement in differentiation. It's the opposite with DUPIXENT, and it's better that they describe it to me and I repeat it to you, but it's the dual mode of action that you see with DUPIXENT, it's the tremendous market experience, it's the efficacy, it's the relief the patients feel.

So other products coming into the marketplace have actually been important from the standpoint of getting more education to the market, more consumer education, more physician education, and this actually is benefiting DUPIXENT as the product, the patients and their physicians know now and reach for first.

So we'll keep a close eye on competition. Competition always makes you better. But in the case of DUPIXENT, all the aspects of our dosing convenience, mode of action, the fact that we have so many indications and truly is the product that gets at comorbidities across the type 2 cascade is highly differentiating.

It also really matters to physicians and patients that across any of the age groups and indications, you can say that DUPIXENT is approved for children as young as 6 months in atopic dermatitis, 1 year in eosinophilic esophagitis, which is a major indication that I didn't even talk about today. But these characteristics, this market experience, efficacy of the product and safety really make it the first product that physicians and patients turn to.

Yes. So the bar that Dupi has set in the marketplace and in its clinical studies is very high, and we've seen many competitors try and reach that bar and fail to reach it. We have been thinking about life cycle management for DUPIXENT for a number of years, and I think we've built a robust approach to ultimately succeeding DUPIXENT with even better products.

I would highlight a few that we've talked about in recent months that should be entering the clinic either later this year or into 2027, all of which have custom development plans, and we plan to expedite based on our experience, not only in the marketplace, but also in conducting these studies.

So I'll start with the supi-dupi as our Chief Scientific Officer, George Yancopoulos, termed on our last earnings call. This is a long-acting fully human IL-4 receptor alpha antibody that is the exact same target that DUPIXENT currently hits and would have that same dual mechanism of action that Marion mentioned.

That one is part of the Sanofi collaboration by default as it targets the same receptor that's in our agreement, and we are looking forward to hopefully partnering with Sanofi on developing it once it is clinic-ready.

Beyond that, outside of the Sanofi collaboration, I would highlight the lead candidate being a long-acting fully human IL-13 antibody that we'll be entering the clinic within the next couple of months, we've said first half of this year. And we will be looking at the IL-13 antibody in atopic dermatitis initially.

We believe we can reach at minimum every 3-month dosing with this antibody and would hope for even longer intervals with comparable efficacy to DUPIXENT. We think longer intervals are obviously more convenient for patients and would be well received in the marketplace.

Beyond that, we have other long-acting antibodies, including one for the IL-4 ligand, which would be outside of the Sanofi collaboration, as well as a bispecific that would target both IL-4 and IL-13. So a life cycle strategy that is certainly centrally focused on the IL-4/13 axis as we believe that is the fundamental underlying driver of all these atopic diseases, and we look forward to keeping you updated on our progress across this important part of our pipeline.

Great. A lot of exciting programs. So for EYLEA HD, the prefilled syringe approval is expected soon. I guess, what's been the feedback from the retina clinics on the importance of prefilled syringe and operating their workflows? And I guess, how should we think about a potential inflection in the demand curve for EYLEA HD once the prefilled syringe is approved?

Sure. Thanks, Ellie. So I'll reflect a little bit on the recent experience with label enhancements. As you know, it's towards the end of November, where we were able to secure FDA approval for Q4 weekly dosing for EYLEA HD and also the RVO indication.

Also just as a quick reminder, in the last quarter, we reported sales of $506 million, up 66% year-over-year for EYLEA HD. So certainly progress being made. I was really proud of our commercial and medical affairs team on the education and promotion in the marketplace, showing that EYLEA HD was actually the innovative branded product growing more than any other in the anti-VEGF category.

To the question of prefilled syringe, very much look forward to that approval. I do think it will be important. As a point of reference for you, with EYLEA, about 95% of our business is with prefilled syringe. But certainly, I believe we have a very strong profile with EYLEA HD that we're working with right now and working on steadily in the marketplace, and obviously, a very competitive anti-VEGF category.

But EYLEA HD is becoming known as the product with the broadest label in terms of dosing flexibility opportunities and the durability at every turn is bearing out. So the phrase there that I hear most often is EYLEA made better in EYLEA HD. So certainly a lot of work underway and a lot of progress to be made even before we have the prefilled syringe in the marketplace.

And I guess turning to sort of the implications for pricing, both for potentially EYLEA HD as well as EYLEA with the entrance of new biosimilars this year. How should we think about that in terms of the incentives of the practices to say, continue to stock both products and the implications for pricing?

So I think it's a number of factors. One is that the retina community and physicians like to choose the product that they're selecting for their patients. Many of them are highly academically oriented, have participated in clinical trials. And certainly, there are select practices, and it is select, it's not across the market, that have used biosimilars for financial reasons.

That's not the totality of the marketplace, it's something that we're well aware of. But I would think more broadly over time, consider that physicians want to make the selection of product that's best for their patients as they're treating blinding eye disease.

Having said that, we did want to be balanced, and I think I shared with everybody in the last earnings call, when you think of EYLEA, now I'm not talking about EYLEA HD, but EYLEA, we would expect to see declines quarter-over-quarter.

I referenced double-digit types of sequential decline. That in part is because of coming biosimilar or current biosimilar competition, but it's also because we deliberately are making conversions not only of EYLEA, but other patients coming into the anti-VEGF category, naive patients or switch patients over to EYLEA HD.

Great. Pivoting a little bit to the pipeline, you recently had some data in obesity. The question that we get from investors is obesity is a very crowded market. So where do you think Regeneron and your program fits into this?

That's a great question, and I'm pleased to share the information that was relayed via Hansoh, our -- the company from China that we've licensed our GLP/GIP receptor agonist from, a peptide called olatorepatide, which is a mouthful. But the first pivotal data in China was generated and showed that olatorepatide was able to generate 19% weight loss and over 95% of patients were able to achieve at least 5 months -- 5% of their weight reduction.

These are very similar to the in-market and market-leading GLP/GIP agonists that are out there. And I would add, perhaps differentiating about olatorepatide is its tolerability profile, particularly in GI tolerability, where Hansoh reported, on average, under 10% incidence of nausea and under 5% incidence of vomiting, both of which would be about 1/3 of the incidents reported by the market-leading GLP/GIP agonist.

So very excited about this encouraging data from China. Our plan for U.S. development and, I guess, ex-China development, which is where we have our rights in this license, is to begin our Phase III study later this year, initially enrolling patients outside the U.S., and by end of year or perhaps in early 2027, begin enrolling patients into these pivotal studies in the U.S.

In parallel, we are working on co-formulation of alirocumab or Praluent with olatorepatide, which we hope will eventually lead to a product that combines these 2 important products to one that can generate meaningful weight loss while also reducing LDL cholesterol, which is a need by about half of the market today that is currently not being served by in-market products, which only reduce LDLs by low to mid-single digits.

Praluent, on the other hand, has demonstrated in its clinical studies, at least 50% reduction in LDLs, which I think could be very important for many patients from hypercholesterolemia. So we're excited about the opportunity in obesity. We have other ideas around combining olatorepatide with other assets and pipeline opportunities in our pipeline. So look for more to come in terms of our approach in obesity.

Great. Well, turning to LAG-3, which is certainly of a lot of focus in the near term. Maybe for either the first-line metastatic melanoma trial, how are you thinking about what success looks like here from a competitive perspective? And what should we expect to see on OS?

Great questions and ones I wish I could answer today. But unfortunately, the data is still maturing. So we've been running a study in first-line advanced melanoma. We're looking at 2 different doses of Fianlimab, our LAG-3 antibody, in combination with LIBTAYO, our approved PD-1 inhibitor, compared to pembrolizumab or KEYTRUDA.

So we -- the primary endpoint of the study is progression-free survival. And once we reach a certain number of events in this study, we'll be able to read out the data. So we're waiting on events to continue to accrue. And once we reach that magic number, we will lock the database and read out the data.

I think for differentiation, we've seen in the PD-1 class kind of mid-single digit, maybe low single-digit median PFS. We see combinations from Bristol with ipilimumab and nivolumab, hitting around 11 months of median PFS and their LAG-3 -- Bristol's LAG-3 combination has generated around 10 months of median PFS.

So while the study is powered against pembrolizumab, I think cross trial comparisons will be made, and I think they'll be appropriate given the population we're enrolling is very similar to those in other pivotal studies.

For differentiation there, I think low to mid-teens median PFS would put us clearly at the top of the board there and potentially practice changing. In terms of OS, it's highly unlikely that, that data will be mature at the time of the final PFS readout. Hopefully, we'll be able to have some initial trends in overall survival, and there will be interim analysis.

I think there's 4 interim OS analyses built into this clinical protocol before a final OS analysis will be made. So there's opportunity to have a clinically significant or statistically significant, clinically meaningful benefit on OS, where Opdualag has failed to do so in theirs. So that would really be another differentiator that we're hopeful for from this study.

Great. Just in the interest of time, turning to LYNOZYFIC. Maybe starting first with sort of the first line plus opportunity. Marion, I guess, how are you thinking about the size of this opportunity?

Sure. so very exciting launch in hematology with LYNOZYFIC this year, both U.S. and select international markets. Early progress and early read on use has been that the differentiating characteristics of efficacy, potential for less hospitalization for patient on initiation of therapy, getting to extended dosing intervals more quickly, all has been really important. Early use has been positive.

I will just comment, it is a refractory patient population, fourth line plus. So patient population in the U.S. about 3,000 to 4,000 patients. But certainly, we're making a lot of progress with pathways at the institutional level going through the REMS process of education and payer coverage.

So early days, really exciting, and perhaps most important of all, this early experience in later line certainly suggests that with clinical trial readout in earlier lines of therapy, we'll be able to participate more broadly in this $30 billion market, which is really significant and a potential to help a lot more patients.

But we're starting in the late line setting, and certainly we'll work hard there and then be ready to go into earlier line settings with the clinical data readout and approvals.

And yes, I guess how should we think about the cadence of the launch over the course of this year? And then as we pivot to thinking longer term, I mean, can you sort of help quantify a little bit how we should think about the size of the opportunity as you potentially move into the second line plus setting?

As you start moving earlier, and Ryan maybe can help me with some of the specific numbers, I know that the patient population, for example, in the U.S., about doubles as you go from fourth line plus the third line plus. As you go up into second line plus, it's a much bigger patient population.

So we have aspirations to go into the earlier settings as quickly as we have the data readouts and the product profile is suggestive that we really will be able to make a difference for these patients. Ryan may wish to add more.

Yes. I mean I think we've demonstrated best-in-class activity in the late line settings. And as we are generating earlier line data, we're also seeing best-in-class activity in second line and in first line myeloma with very limited combinations.

So we're very excited about LYNOZYFIC as a differentiated BCMA by CD3 antibody. I think we can compete very effectively. And oftentimes in oncology, the data will sell your product, and we're in the process, we think, of generating a very compelling data set for patients.

Great. Well, you guys have a very rich pipeline. Maybe in the last minute or so that we have, Ryan, can you sort of walk us through maybe what you think are the key catalysts for the pipeline over the next 12 to 18 months? And any programs that you think people should be paying more attention to?

Sure. I can walk through a few. We've already talked about LAG-3. That's clearly front of mind for many. I think in the second half of the year, we should have an interim readout for the C5 opportunity in Geographic Atrophy, which is a very meaningful opportunity and then in PNH towards the end of this year.

We also have Factor XI in the process of enrolling patients. And I think even by sometime in the first half of next year, get a readout in the VTE study following post knee replacement. So beginning to read out some pivotal data from Factor XI as early next year. So we're certainly excited about that. That program is huge and has a lot of opportunity.

I think there's also going to be read-throughs that we can make from competitive readouts that should be occurring in the second half of this year. So we'll be looking at those. Additionally, I think the obesity study start will be important for us as a milestone. And then I guess, ultimately, we're going to be looking for those LYNOZYFIC readouts beginning sometime in 2027.

Great. Well, thank you both so much for joining us, and thank you for everyone for joining us in Miami.

Thanks, Ellie. Thanks, everyone.

Thanks, Ellie.

Good morning, everyone. Tyler Van Buren here, senior biotech analyst at TD Cowen. Thank you very much for joining TD Cowen's 46th Annual Healthcare Conference.

For next session or first session of the day, actually, very excited to be hosting a fireside chat with Regeneron. And it's my pleasure to introduce Chris Fenimore, Executive Vice President of Finance and Chief Financial Officer; and Ryan Crowe, Senior Vice President, IR and Strategic Analysis for Regeneron.

Chris and Ryan, it's a privilege to have you here. Thank you very much for joining me.

Thanks, Tyler. I think my shoes have finally dried out from the trudge in through the snow last night, but it's always great to be here at the TD Cowen Conference and looks like a great attendance. So thanks, everyone, for coming.

Chris and I have a very compelling story to tell you today, I think, when you look at Regeneron and all the things we're going to talk about over the next 30 minutes, most of it's besides maybe Dupixent and EYLEA, not reflected in evaluation. We've got clinical programs that we're working very hard on to bring to patients, none of which is really being appreciated, I think. So I'd ask that you listen to the story here today.

And before we get to it, though, I got to read this forward-looking statement. So I'll do that very quickly. I remind you that remarks made today may include forward-looking statements about Regeneron. And each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in such statements. A description of material risks and uncertainties can be found in Regeneron's SEC filings. Regeneron does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

Tyler, back to you.

Wonderful. So at a high level, I wanted to kick off just with the earnings growth story over the next 2 to 3 years, it's undeniable if you spend enough time in the model, it's pretty objective just modeling the underlying business and things like the Sanofi development balance payoff that's now occurring midyear.

Some are saying could even get to $70, $80 of earnings and 2 to 3 years from now. And if you guys trade at a discount to your historical multiple of 20 times, you're going to get to well over $1,000 per share regardless of the pipeline, which we'll get to.

So maybe you guys could talk about some of the key growth drivers to earnings over the next few years on the top line? And maybe just the details of the Sanofi development balance payoff and the magnitude of that? And then also on the bottom line with respect to your update on earnings margins, expenses and then tax as well.

Sure. Again, thanks for having us, Tyler. So as we look at the top line, there are a number of different levers that will drive the top line going forward. We are obviously with our commercial team laser-focused on converting EYLEA 2 mg over to EYLEA HD as rapidly as possible.

We had our approvals at the end of last year for every 4-week dosing and RVO. If you think about RVO, it's upwards of close to 20% of the market opportunities, so something that we were unable to tap before. It really presents a sizable opportunity for EYLEA HD and for every 4-week dosing, it was something that was very important for reimbursement confidence for the physician community. So getting those 2 behind us is very encouraging for EYLEA HD and then obviously with the prefilled syringe coming next month. That is also something that we'll be reinforcing for the EYLEA and ophthalmology franchise.

As we turn to Dupixent. Dupixent continues to do exceedingly well. If you just look at the fourth quarter and annualize the revenue that was just under $5 billion, obviously, doing very, very well, continue to do well, supported by recent launches and obviously, additional expansions going forward. As you think about the base of the revenue as it continues to grow, we would -- while obviously continuing to support the brand and invest in the brand, expect some sort of margin enhancements as the higher revenue would drop to the bottom line.

And then as you touched on, Tyler, the repayment of the development balance. So we've guided that we expect that to be repaid by the middle of this year. We ended 2025 with approximately $600 million. So just doing it on a run rate basis, on an annualized basis, that's approaching $1.2 billion. So we'll get the benefit of that in the second half of this year and then obviously a benefit in '27 and beyond on a full year basis.

And then beyond Dupixent, we have our oncology franchise and hem/onc franchise, where Libtayo recently with a launch in adjuvant CSCC, which we believe is sort of a blockbuster status onto itself, at least on a global basis. And then Lynozyfic, which is approved in late lines in multiple myeloma, it will be its first full year, so we'll see some growth there as well.

Turning to other things in the pipeline, and I know we'll touch more on that a little bit later, but a filing for myasthenia gravis and then a potential launch potentially as early later this year will be another inflection point. And that's just one of the many things that are in the pipeline that we expect to evolve over the next couple of years. On the expense side, I will say that the way Regeneron manages the business is we make sure we resource our capital allocation priorities.

So first and foremost, that's investment in our internal R&D capabilities. We guided at the midpoint of the range to roughly $6 billion on a non-GAAP basis in R&D expense in 2026. Just a reminder that we have several late-stage Phase III programs that are fairly large. So we will continue to ensure that those are properly resourced and properly funded. With that being said, we're very mindful and cost-conscious in terms of managing our expenses. We recently hired a Chief Digital and Technology Officer as well as a Chief AI officer. So trying to run the operation, obviously, as efficiently as possible and leveraging technology in AI as much as we can as trying to get as much leverage on the expense side.

We gave guidance on the tax rate and also COGS. I think on the tax rate, it's consistent with what we've described in the past, which is from a mid to long term to be kind of in the mid-teens range. What drives that to go lower historically has been stock-based compensation, and that just depends on the timing of when employees exercise their options.

And on the cost of goods sold front, we view that as transient in terms of some investments that we're making in terms of the impact on margins. It will be a multiyear journey as we're investing in various aspects of our manufacturing network in both manufacturing as well as fill/finish capabilities.

Awesome. That was a lot. But we'll try to knock off some commercial questions and then we'll get to the pipeline. And I'll do my best to be efficient. So forgive me for the multipart questions.

But -- so EYLEA HD, a real nice reacceleration and growth last year entering '26 with some momentum. Can you just talk about if you've seen kind of increased uptake following the RVO and every 4-week dosing label expansions, so far, if you're seeing that already? And just, I guess, PFS were high level of confidence we're getting that in Q2 and the latest on charity funding as well.

Sure. So there's a lot in that question. So as you look at the enhancement and we talk about them. It's -- we used to get asked a lot which one is the most important in our response was always they're all important. So what we hear from the physician community is obviously very receptive to having RVO because as you think about it, when they keep product in their refrigerators, in those physician offices, if one of the products doesn't have one of the indications, it's just the way we described it, it was almost a handicap in terms of our commercial team's ability to execute in that area.

So obviously, important, as I said earlier, reimbursement confidence also important and very important to the physician community. In terms of the prefilled syringe, as I said, we're expecting that next month. And people always ask how important is the prefilled syringe. It's very important. I mean there are going to be some practices that just basically don't want to use it just because of the administration that's required in their practices and the overhead involved in that. There are going to be others that it really doesn't matter. But at the end of the day, we know based on our own data that EYLEA 2 mg is upwards of, I think, 95% of utilization is a prefilled syringe. So it's clearly important to the physician community to have the flexibility of having a prefilled syringe.

On the charitable funding side, we announced basically that there was a contribution at the end of last year and the fourth quarter of $60 million. We matched that accordingly based on our matching program. So there was funding available around the beginning of the year of around $120 million. We know historically based on what the need is out there in the community that that's not enough to satisfy all the need that is out there.

We obviously want to see that patients get access to the therapies that their physicians recommend for them that they think is most appropriate, which is why we, again, announced that we are prepared to match in 2026. Up to another $200 million. But we also recognize the reason we put that matching program in place and then reinforce it for 2026 as we can't do it alone, and we need others to participate. From an impact of what we saw in 2025, the data that we see is the number of injections in terms of on the branded side, decreased about 12% year-over-year.

And the number of Avastin injections increased year-over-year. The data that was recently told to me, about 1 million injections increased from '24 to '25. So it clearly has an impact on the ability for patients to get the therapies that they think are and their physicians think are important. So it's meaningful, and we're prepared to obviously fund assuming that others are as well.

Sounds like the potential for a pretty significant reversal if others get their act together. But have you seen anything year-to-date to match? Is there any updates on that front with respect to charitable contributions?

I think it's too early to tell just based on where we are in the year.

Okay. All right. So Dupixent, I mean, a beast of a franchise continues to beat almost every single quarter. The CSU launch has been very impressive as well in addition to [ COPD ], many indications for that product. But maybe I could just touch on maybe IP first, right? That's been a recent topic. What your expectations are for IP and also the ability to extend the Dupixent IP beyond current expectations.

Yes, it's a great question and certainly an amazing commercial story, but we'll start with IP. We have a composition of matter patent for dupilumab that expires in the U.S. in March of 2031. And in Europe March of 2033 and then in Japan in 2034.

So that's sort of your earliest potential timing for biosimilar competition for Dupixent. But that's just one patent of many dozens, in fact, many of which cover the dosing paradigms for each of these indications as well as the formulation, the manufacturing processes that are used to make dupilumab efficiently, all protected into the mid- to late 2030s, and even some patents going into the early 2040s.

And of course, us and Sanofi, our partner on this product are going to be asserting and defending this intellectual property to the greatest extent we can, and hopefully extend beyond that composition of matter date, expiry date. So we have a strategy there, and we're -- but in the background, also working on next-generation products that offer, we hope, a longer dosing paradigm with similar or even better efficacy than Dupixent can offer today. And the first of those efforts is going to be entering the clinic in the first half of this year. So we can probably talk more about that later, but that's sort of the high-level IP view here, and we'll see what -- how this plays out over the coming years.

Yes. It'd actually be great if you just expanded on the life cycle management plans and updates that you provided earlier this year as well as touch on the Sanofi relationship and the ability to potentially leverage that very significant commercial infrastructure with life cycle management programs in the future.

Sure. yes. So I was just beginning to hit on that. The long-acting IL-13 opportunity is hopefully going to be entering the clinic very soon. The first indication will be exploring there is going to be atopic dermatitis and we're certainly looking for a minimum quarterly dosing, if not longer, with this fully human antibody.

Beyond that, we also have a long-acting IL-4 blocker, which would be outside of the Sanofi collaboration as with the IL-13 long-acting antibody. In addition, we have a long-acting antibody that hits the IL-4 receptor alpha that would be part of the Sanofi collaboration should they decide to codevelop it with us.

And then lastly, we have an IL-13 by IL-4 long-acting bispecific that we are going to be hopefully bringing to the clinic next year. So we have several antibodies, all of which are fully human come from the same platform that Dupixent did. We are going to be exploring, I think, kind of custom and expedited development plans for each of these where we see IL-13 long-acting as a good opportunity, perhaps in atopic dermatitis.

It might not be the right opportunity for another indication, such as asthma or any of the others that DUPIXENT is approved for. So we have to thought this through. We have a plan. We're looking forward to executing that plan on an expedited fashion. And to the extent that Sanofi would like to work with us, and leverage the commercial infrastructure we have jointly built and had amazing success around for Dupixent. And I think we would be open to that, but of course, there need to be some terms that are agreeable to both sides on how that would change the collaboration. So we're certainly open to it. But at this point, no decisions have been made there.

Understood. Itepekimab, obviously, great results with AERIFY-1. The first half of AERIFY-2 looked great and then something happened. A lot of focus on approvals with one pivotal trials -- one pivotal trial nowadays. So just give us the latest on the path forward there and when we could get an update.

Yes. So we are obviously -- we're excited to see the results of AERIFY-1 and a lot less excited about seeing the results of AERIFY-2 and we certainly have been staring at that study and what happened there and trying to figure out how a pretty dramatic reduction in annualized exacerbation rates could be observed through 26 weeks only to see that effect attenuate over the subsequent 26 weeks.

We don't have an answer there. There's no magic bullet about aha, that's it. I haven't been able to figure that out. And at this point, we kind of have to work with what we've got. It's a safe drug. We obviously have AERIFY-1, which is a very supportive data set that demonstrated a 27% reduction in annualized exacerbation rate but it's unclear if that single study will be sufficient for registration in the United States.

But the FDA has changed in how they're looking at application and potentially using one randomized well-controlled study as the basis for an approval. We're certainly going to ask the question. And we have a meeting with them very soon, where I think that will probably be covered as the top of the agenda. I think we'll see what the results of that conversation and I think that's going to inform whether or not, a, they can review it and potentially approve it based on AERIFY-1 alone or whether we need to run a third pivotal study to enable registration.

And if we are going to need a third registration-enabling study, whether or not Sanofi and Regeneron decided to do that, I think, would be another discussion. So we have a lot to answer for. I think we'll get that answer in the fairly near term, and hopefully, we'll be able to share that with you guys very soon.

Great. Let's move to Libtayo, a sneaky strong contributor to the P&L. What have you seen so far with the adjuvant cutaneous squamous cell carcinoma launch. What are your expectations for that launch moving forward and the ultimate opportunity?

The data that we see in terms of the size of the opportunities, it's roughly 10,000 patients in the U.S. and another 10,000 patients outside of the U.S. So we view it as a fairly sizable opportunity, which is what I said earlier. Our team is obviously out there spreading the word and the messaging and working with payers, working with physician providers, getting on formulary, getting in pathways and things like that.

So we're very encouraged about the progress we've made so far, and we'll see how that product performs going forward, but we think it's an exciting opportunity.

Great. Maybe a good segue to the pipeline. So Libtayo, fianlimab, LAG-3, frontline melanoma combo data coming by the end of the first half. Maybe you could just discuss expectations there, what we could see from the top line? And again, the delay, is it the active or the control arm outperforming or both your latest thoughts?

So I'll start with we are totally blinded to the data. We don't know what it is. The data is not mature yet. We continue to launch events accrue. And once we get to the magic number that's defined in the clinical trial protocol, we'll lock the database, analyze the data and then rate it out.

We obviously have high hopes for this opportunity. We saw very compelling results across 3 independent cohorts in Phase I, where on a pooled basis across approximately 100 patients we demonstrated a 57% objective response rate and a 24-month median PFS, which compares very favorably to the approved agents for disease. If we're able to even approach replicating those results, I think we'll have the opportunity to really change the standard of care in advanced melanoma. Why the events have slowed, that's a really big question. We don't know the answer to yet. We hope that similar to the Phase I results, there was a high level of response, and those response are very durable. And therefore, they're not seeing an accrual of events once these patients respond because they're not progressing.

Of course, there is an outside chance that pembrolizumab is outperforming its historical analogs, which has been something in the order of 4 to 5 months in the population that we enrolled. So that could happen as well. It's unclear at this time. We think we have got 2 differentiated antibodies we've designed the study with statistical powering that we're very confident. We'll demonstrate this result and our overall survival, an endpoint that the incumbent LAG-3 therapy failed to achieve, we've actually powered it even further with additional patients. So there's a real opportunity to differentiate not only on response rate in PFS at this initial region, but eventually on overall survival as well.

And then further on LAG-3, we also have an interim analysis to be performed in the adjuvant setting for melanoma. I think the base case for that should be that the trial continues as uninterrupted adjuvant melanoma is a much harder bar, I would say, and we have no data in Phase I to support it. But we're going to see what we have here at the interim analysis in the near term as well.

Great. Let's move to C5. You mentioned cemdi earlier in your remarks, Chris, in the beginning. So can you tell us the status of that filing in MG? Could a priority review voucher have been applied? And how do you think about the overall opportunity, not just in MG, but also GA with data coming later this year and PNH data coming next year.

Great questions. We love the C5 program. We've been working on it for years, and I think we've got a couple of different angles here with cemdisiran monotherapy generating a 2.3 point improvement in the myasthenia gravis activities of daily living scale, which puts it at the top of the heap in terms of the placebo-adjusted benefit among C5 agents better approved for myasthenia gravis. And not only do you get the best efficacy potentially with this product, but you're only going to be dosed 4 times a year on the subcutaneous injection.

We'll initially launch in physician-administered vials, but within a year or maybe 18 months, we expect to have an at-home prefilled syringe and/or auto-injector for this product. So better efficacy, fewer injections and a safety profile, we think once fully disclosed, we'll show that it also has a very strong benefit risk opportunity.

So myasthenia gravis, we're very excited about. Could we have used a priority review voucher? That's not something we would disclose until the applications accepted and when and if it is be happy to let you know that. In terms of PNH, we are targeting either at year-end or perhaps early 2027 readout for the pivotal study in PNH. This will evaluate the combination of cemdisiran plus pozelimab in a monthly subcutaneous injection. We've seen here already in a lead-in cohort that 96% of patients that were dosed with this combination reached normal levels of LDH, which is the surrogate for breakthrough hemolysis, our primary endpoint in pivotal study versus something like 80% for ravulizumab, which is the current standard of care antibody.

So we've shown differentiation there. And then took it one step further and said, for those that didn't get to normalized levels of LDH on ravulizumab, we switched them to pozelimab, cemdisiran and so all but one of those patients achieved normalization of LDH levels. So we feel that complete blockade of C5 is necessary to prevent breakthrough hemolysis. We saw in the data from the myasthenia gravis study, which evaluated the combination as well as the monotherapy that in the combination arm, C5 was blocked by over 99% in those patients.

So we think this will ultimately become another opportunity for the C5 franchise. Lastly on geographic atrophy. We do have an interim analysis planned for the first Phase III study there for the second half of this year. It's going to be at an earlier time point than the primary analysis. It's going to be done at 26 weeks the primary analysis, which will be done at 52. But it should give us an indication about, a, whether or not systemic blockade of C5 can slow lesion growth; and b, whether the combination of pozelimab cemdisiran is necessary or perhaps again cemdisiran alone with a very extended dosing intervals could be adequate to control this disease. So we'll learn a lot in the second half with this interim analysis. We're looking forward to it. But I think first up is the submission and hopeful approval of gMG and getting that to market.

Great. Now let's move to obesity. Your strategy there continues to evolve the OLA co-formulation with Praluent announcement was intriguing and highly rational. But maybe you could just discuss steps forward there and overall, your focus in obesity and your strategy moving forward.

Sure. So as I talked earlier, Tyler, about late Phase III programs and resourcing those programs. This is one of those programs that we expect to invest and really bring it forward. So the part of the program is obviously bringing forward in monotherapy because we need to get the program approved in monotherapy obesity. And then using that and the label of alirocumab being able to co-formulate and be able to bring to physicians as well as patients, the ability that if you want to lose weight, and you're also having problems with controlling your LDL. Why not get that in one convenient dose and want injection. So the other aspect of this is pricing.

So we're planning on pricing this reasonably close at parity with existing therapies that don't have the ability to offer LDL lowering. So we view it as an opportunity to really differentiate ourselves and obviously go after one of the comorbidities in terms of cardiovascular disease and the number of patients that are unfortunately impacted every year by cardiac events.

Great. We have a couple of minutes left, but Factor XI, obviously, a very broad effort there to interestingly differentiated antibodies with encouraging early data. So maybe you could just elaborate on those 2 programs a little bit, how you're prioritizing them and what folks should pay attention to in terms of data readouts in the next year or 2?

So the vision for our Factor XI program is really to cover the entire beachhead of anticoagulation disorders and really serve as a tailored approach for each patient. We have one antibody that blocks the catalytic domain, which we see in preclinical assays has extremely strong anti-clotting activity.

And completely blocks thrombo very, very quickly, which is an important part of the anticoagulation cycle. We have a second antibody that blocks a different domain on Factor XI A2 essentially blocking Factor XII in the cascade from there. This has more modest but yet competitive anti-clotting activity in our preclinical assays. But we think we'll serve and be extremely safe and perhaps have 0 increased bleeding risk. That's the vision for both of the antibodies.

And we're going to be creating programs we're working on launching programs across about a half dozen diseases or conditions that require antithrombotics. Leading is the post knee replacement surgery study where we're going to give an IV administration of our catalytic domain antibody shortly after a procedure. And hopefully, that basically stops all clots. We'll be running that 2 studies in that setting. We're, of course, going to be running studies in atrial fibrillation in an all-comers population as well as in patients who are ineligible for DOACs. And this is probably the untapped opportunity we're excited about where many patients who should be anticoagulated will not or cannot tolerate the incremental bleeding risk from Factor X As.

And this is where we believe perhaps the A2 domain antibody could play an important role. So in addition to that, we are also looking at peripheral artery disease and peripherally -- I'm sorry, the catheter associated thrombosis indications. And these are -- I think in total, we'll have 8 pivotal studies -- expect to have 8 pivotal studies up and running before the end of this year and at the start of the year, we had 2, and I think we've already launched a third in this noncandidate study in Afib. So we're excited about all of the opportunities in Factor XI and the data should start to mature beginning in 2027 with this post knee replacement surgery that I mentioned.

Great. There's the earlier stage bispecific programs, allergy, otoferlin gene therapy, FOP, others. Unfortunately, we're not going to have time to get to. But Chris, just wanted to ask you about the mountain of cash that you guys have that continues to grow. What do you plan to do with that? Should we expect it to continue to grow or do you plan to put that to use? And maybe on that topic, also touch on your focus on business development.

Sure. So our capital allocation priorities have not changed. First and foremost, as I said earlier, we want to invest in our internal R&D capabilities. We also have a very active business development group that is out meeting with many biotechnology companies out there as well as some of our peers that are larger. And historically, our BD approach has been to do earlier stage, either acquisitions or partnering types of opportunities. If you look at our pipeline today versus a couple of years ago -- a couple of years ago, it was primarily antibodies. If you look at the pipeline today, we clearly have diversified that with gene editing as well as RNAi with our partners at our collaborators at Alnylam. And we'll continue to move forward and bring in either complementary technologies or assets that make sense that we think will complement the portfolio.

With that being said, we are actively looking at acquisition opportunities. We just haven't found the right one of size. The challenge that we find out there tends to be valuation. It's our CEO Len Schleifer has been known to say he doesn't want to spend $9 billion or $10 billion on a single asset and turn that into $1 billion or potentially 0. And that's the discipline that we have as we evaluate opportunities. We're really trying to find those that we think make sense and where we see things that others don't necessarily see because if you look at some of the later-stage assets, they're extremely competitive. And if it's something in late sort of Phase III or just getting Phase II proof-of-concept data, it's extremely competitive in terms of the number of participants that are out there looking at these assets and bidding them up.

But we have the flexibility with around $19 billion in cash to execute a transaction or multiple transactions if we found the right one, we just haven't found the right one. In terms of the third prong of our capital allocation strategy is obviously returning capital to shareholders. We've -- obviously, in 2025, we're outlying our shares. We continue to buy our shares. We tend to refresh our share repurchase program on a 12- to 18-month sort of time horizon.

I would expect that we'd continue to do that going forward. And then our dividend in terms of allocating dollars in 2025. It was $0.88 per share. We were targeting roughly $400 million of capital with a primary purpose of really broadening the investor base. We increased that to $0.94 per share in 2026, primarily to target that $400 million number. So in terms of expectations on dividend increases or anything like that. Our goal is not to necessarily strive to increase the dividend. It's just really having a modest dividend out there to make the stock attractive to those funds that have a dividend mandate.

Great. We're out of time. But to wrap up the conversation, Chris and Ryan, maybe I'll ask you both what you believe is the most underappreciated aspect of the Regeneron story by investors right now?

I'm curious to hear Ryan's perspective on this. I mean the pipeline, obviously, with roughly 45 different assets in the pipeline is something that everybody here can spend a lot of time. But I think one of the true things that differentiates us is the investment that we've been making in the Regeneron Genetics Center. And with 3 million exomes sequenced linked to electronic medical records, that data allows us to translate that into many of the assets that are in the pipeline today, several that will be forthcoming in the ensuing months and years, and we will continue to add to that database because we think we've got a competitive advantage in terms of being able to mine that data.

Absolutely. Genetics kind of grounds everything and every decision we make at Regeneron. And I'm personally excited about many things in the pipeline, I think we're beginning to launch the early ophthalmology opportunities that we've been talking about. We have a CD3 for noninfectious uveitis that's entering the clinic now. We have an opportunity with a novel target in glaucoma that we hope to have in eyeballs later this year and then another one for Grave's disease also likely later this year.

And then I guess I'll close on the metabolic pipeline where we've been working on several opportunities on for MASH that we have provided very little data on, but we are seeing some pretty provocative early data across that portfolio as well, and we're looking forward to sharing that with you later this year.

Wonderful. Chris and Ryan, thank you for your time.

Thank you.

Thank you.

Welcome to the Regeneron Pharmaceuticals Fourth Quarter 2025 Earnings Conference Call. My name is Shannon, and I will be your operator for today's call. [Operator Instructions]. Please note that this conference call is being recorded. I will now turn the call over to Ryan Crowe, Senior Vice President, Investor Relations. You may begin.

Thank you, Shannon. Good morning, good afternoon and good evening to everyone listening around the world. Thank you for your interest in Regeneron and welcome to our fourth quarter 2025 earnings conference call. An archive and transcript of this call will be available on the Regeneron Investor Relations website shortly after our call concludes.

Joining me on today's call are Dr. Leonard Schleifer, Board, Co-Chair, Co-Founder, President and Chief Executive Officer; Dr. George Yancopoulos, Board Co-Chair, Co-Founder, President and Chief Scientific Officer; Marion McCourt, Executive Vice President of Commercial; and Chris Fenimore, Executive Vice President and Chief Financial Officer.

After our prepared remarks, the remaining time will be available for your Q&A. I would like to remind you that remarks made on today's call may include forward-looking statements about Regeneron. Such statements may include, but are not limited to those related to Regeneron and its products and business, financial forecast and guidance, development programs and related anticipated milestones, collaborations, finances, regulatory matters, payer coverage and reimbursement, intellectual property, pending litigation and other proceedings and competition.

Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in that statement. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission, including its Form 10-K for the year ended December 31, 2025, which we plan to file with the SEC next week.

Regeneron does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. In addition, please note that GAAP and non-GAAP financial measures will be discussed on today's call. Information regarding our use of non-GAAP financial measures and a reconciliation of those measures to GAAP is available in our quarterly results press release and our [indiscernible] presentation, both of which can be found on the Regeneron Investor Relations website. Once our call concludes, the IR team will be available to answer any further questions. With that, let me turn the call over to our President and Chief Executive Officer, Dr. Leonard Schleifer. Len, take it away.

Thanks, Ryan, and thanks to everyone for joining today's call. Regeneron capped 2025 was another solid quarter of commercial execution with fourth quarter total revenue up 3% year-over-year driven by double-digit net sales growth for 3 of our leading products. Compared to the fourth quarter of last year, global net product sales for Dupixent as reported by Sanofi, increased by 32% and Libtayo by 13% at constant exchange rates, while EYLEA HD in the United States grew by 66%.

Global Dupixent net sales were $4.9 billion in the fourth quarter and $17.8 billion for the full year 2025. Dupixent is currently the most widely used innovative brand antibody medicine with more than 1.4 million patients on therapy globally. Now approved in 8 indications, most of which remain significantly underpenetrated, Dupixent is well positioned for future growth.

Global Libtayo net product sales were $425 million in the fourth quarter and $1.45 billion for the full year 2025. In the U.S., Libtayo continues to be the market-leading immunotherapy for advanced non-melanoma skin cancers. Following FDA and EC approvals of Libtayo for adjuvant CSCC in the fourth quarter, we are making great progress launching this potential blockbuster opportunity, with this indication expected to be a significant growth driver for Libtayo in 2026 and beyond.

Libtayo also continues to build share in advanced non-small cell lung cancer, where in the U.S., it is now the second most prescribed immunotherapy in the first-line setting with new patient market share in this setting greater than Opdivo, Tecentriq and [ Imfinzi ] combined. EYLEA HD net product sales in the United States were $506 million in the fourth quarter up 66% and $1.6 billion for the full year 2025 of 36% despite continued patient co-pay affordability issues that have dampened branded anti-VEGF category growth.

In November, the FDA approved LHD for macular edema following retinal vein occlusion or RVO, and monthly dosing across all approved indications, further strengthening the EYLEA HD compelled profile. Our FDA submission seeking approval of the EYLEA HD prefilled syringe using a new manufacturer has been accepted for [indiscernible], a standard pre-license inspection has been scheduled and the decision on our filing is expected in late April.

In addition, as a backup, [ Catalent Indiana], continues to work with the FDA to resolve findings from a previous inspection. We continue to believe that all 3 of these product enhancements are key to fully unlocking EYLEA's HD commercial potential. While we anticipate continued growth in EYLEA HC this year, [ ILEAD 2 ] milligrams will continue to be under competitive pressure, which is expected to intensify in the second half of 2026 as multiple biosimilar products are launched in the United States.

Regarding patient affordability, we are pleased that we matched a $60 million donation to the good days retinal vascular and neovascular disease fund in the fourth quarter. Today, we reiterated our commitment to helping patients afford their medicines by extending our matching program through the end of this year up to $200 million.

Turning now to our negotiations with the United States government regarding efforts to reduce drug costs for American patients. We are actively engaging in constructive discussions with the [ Centro ] Medicare and Medicaid services and other federal agencies, and we anticipate reaching agreement in alliance with the framework previously established by other companies. We remain optimistic about striking a deal with the administration to achieve our shared goals ensuring timely and affordable access to groundmaking medical advancements for American patients, maintaining the United States, the leadership in biotechnology, innovation and manufacturing and addressing the long-standing imbalance in the distribution of costs for medical innovation, which has historically placed a disproportionate burden on American patients.

Finally, looking ahead to the next 12 months, Regeneron has several key objectives that I'd like to share. First, we anticipate at least 4 FDA approvals, including 3 for new molecular [indiscernible] across 3 distinct modalities plus approval for the EYLEA HD prefilled syringe as well as several additional regulatory submissions.

We expect registration-enabling data for multiple programs, including [ fianlimab], our LAG-3 antibody in combination with Libtayo in advanced melanoma and as well as a combination of [ sivisian ] and [ pozelimab ] in PNH. In addition to the online pivotal study for areas such as myeloma, anticoagulation and complement [ media ] diseases, 2026 will be an important clinical development execution year as we anticipate initiating 18 additional Phase III studies with cumulative target enrollment of approximately 35,000 patients over multiple years, setting the foundation for Regeneron's next wave of potential blockbuster products.

We also plan to begin clinical development of at least 3 first-in-class antibodies that address novel targets, of which 2 were discovered and validated by the [ general genetic ] center as well as our long-acting IL-13 antibody in atopic dermatitis. We expect strong commercial execution to continue maximizing the potential of our leading brands across key therapeutic areas.

And finally, we plan to continue to prudently deploy capital through share repurchases, dividends and complementary business development, all with the goal of driving long-term shareholder value. Obviously, a busy, and a fast and ambitious year ahead, one that I'm particularly energized and excited to evolve. We look forward to reporting our progress on these goals as we move to [indiscernible]. With that, I'll turn the call over to George.

Thanks, Len. Earlier this month at the JPMorgan conference, we highlighted the breadth and depth of our pipeline, which is expected to generate clinical data over the next few years spanning oncology, hematology, complement mediated diseases, anticoagulation and obesity as well as in other areas.

In 2026, we plan to build on our established leadership in ophthalmology as well as immunology information while advancing key late-stage programs. Starting with ophthalmology. EYLEA HD was recently approved by the FDA for monthly dosing and for the treatment of RVO, further strengthening its clinical profile. Data supporting these approvals will be presented at the upcoming angiogenesis meeting further highlighting efficacy, safety and durability of EYLEA HD along with dosing flexibility designed to support more personalized patient care.

In terms of our ophthalmology pipeline, for our [ C5 ] program for geographic atrophy, we expect interim data from our Phase III study in the second half of 2026. We are currently evaluating our C5 sRNA [ cemdisiran ] as monotherapy and also with [ posasalimab], our potentially best-in-class C5 antibody, with the goal of providing a system systemic treatment that avoids safety issues from repeated [ intravitreal ] injections associated with currently approved GA therapies.

In case intravitreal delivery is required to [indiscernible], we've also begun clinical development of an intraventional formulation of [ flagelmab ] to evaluate local C5 inhibition for appropriate patients. Beyond GA and ophthalmology, we have initiated a study of a novel in traditional in delivered T-cell receptor blocking antibody for noninfectious [ uveitis], a disease generally driven by autoimmune T cells. This advance was made possible for our unique and vital capabilities as we are not aware of any other company that's been able to generate such an antibody.

This year, we also plan to initiate clinical development for a long-acting antibodies targeting a novel genetically validated target for [ glaucoma ], along with the long-acting antibodies that aims to treat terrain eye disease and grades disease.

Moving to immunology and inflammation. We are committed to strengthening our leadership by advancing several next-generation therapeutic approaches. A reverse [indiscernible] of the JPMorgan conference, in addition to exploring longer dosing integrals for Dupixent, we are progressing velostophy-derived fully in the long-acting antibodies with enhanced branding process that targets the IL-4 receptor alpha, the same target as Dupixent as well as antibodies targeting IL-13, IL-4 and a bispecific antibody targeting both IL-4 and IL-13.

All of these approaches are designed to enable extended dosing. Our long-acting IL-13 antibody is expected to enter the clinic in the coming months, embarking on an expedited development plan in atopic dermatitis that we believe will enable us to remain competitive as other industry players that are pursuing related approaches. Our other long-acting antibodies are expected to enter the clinic by 2027, each with a custom development plan. At the same time, our Regeneron Genetics Center has utilized its large-scale genetics approaches to identify several exciting new immunology and inflammation targets.

Similar to Dupixent, we believe these may represent future pipeline and product opportunities. The first of these analyses is expected to enter clinical development in the first half of this year. After initially evaluating healthy volunteers, we plan to rapidly advance this candidate to establish proof of concept in several genetically linked cases such as lupus, [indiscernible] and primary billing [indiscernible].

Turning now to [indiscernible]. Our initial cat and birch Phase III study demonstrated that [ allogen ] specific monoclonal antibody cocktail can meaningfully address ocular endpoints adding to earlier data that showed significant reductions in nasal respiratory and skin endpoints. The Phase III data from the cat inverse programs will be presented at the upcoming [ Quad ai ] conference. We anticipate initiating the confirmatory Phase III secular [ catalog ] in the first half of the year, both confirmatory Phase III such for [indiscernible] is already underway.

We are also advancing an innovative strategy with the goal of eliminating all IgE-mediated allergies. Our initial clinical effort is in patients suffering from severe food allergies, involving transient [ litfin ] treatment followed by long-term Dupixent maintenance. This approach demonstrated proof of principle with the first 4 treated patients, all achieving over 90% sustained IT reductions. These results validate our approach of first removing [ IG ] producing plasma cell and then preventing their return.

Building on this, we are developing next-generation agents specifically targeting [ IT ] producing cells with the first expected to enter clinical development over the next year for potentially more rapid and broader allergy applications.

On to oncology at the analysts, our last antibiotic combination with [ total]. Our pivotal study in first-line metastatic melanoma remains on track to read out in the first half of this year. Early clinical data from our first-in-human study across multiple advanced melanoma cohorts suggested a potentially differentiated best-in-class profile. Also in the first half of this year, we're expecting an interim analysis for our study in adjuvant melanoma as well as Phase II data in advanced non-small cell lung cancer, a more speculative setting and with clinical validation has not yet been established for LAG-3 and PD-1 combinations.

Moving to hemo. [indiscernible], our [ BCMA ] by [indiscernible] is establishing a new benchmark in multiple myeloma in late long disease and with the caveat cross-trial comparisons, Lynozyfic has demonstrated nearly double the complete response rate compared to other [ besy3-bispecifics ] as similar follow-up. With lower rates of cytokine release syndrome, shorter hospitalization requirements and more convenient dosing is.

Building on its remarkable monotherapy activity across multiple lines of therapy, we are undertaking an ambitious development plan to simplify the existing myeloma treatment paradigm, which currently relies on highly complex and burdens of triple and quad drug combinations by exploring Lynozyfic monotherapy as well as in simple combinations in early sets.

In our Phase II study in newly diagnosed multiple myeloma, all no evaluable patients treated with Lynozyfic monotherapy at the planned Phase III dose achieved MRT negativity, at endpoint, the FDA recently endorsed as a registrational enabling for this malignant disease. Even more compelling are the early signals in myeloma precursor and related [indiscernible]. For example, in evaluable patients with high-risk smoldering myeloma, Lynozyfic once again achieved 100% MRT negative in all 12 of [ balance ] patients whereas the standard of care [indiscernible] achieved less than 10% complete response.

Similarly, in second-line patients with like chain amyloidosis, Lynozyfic monotherapy normalized abnormal lighting levels in approximately 2 weeks, whereas in a separate study, a [indiscernible] containing quad combo regimens took approximately 5 months to approach these levels in first-line patients.

Both of these promising results could help market advances through existing standard of care, which to involve complex and toxic multidrug combinations. With 4 pivotal studies underway and 4 more initiating by this year, we are rapidly advancing our Lynozyfic development program with the hopes of transforming the myeloma treatment para and ultimate intervening progression to malignant disease.

On to complement-mediated diseases. Our C5 program consists of customized approaches to treat different diseases, which require different levels of target inhibition to maximize efficacy. For each condition, I previously summarized both our G5 efforts in geographic atrophy. Our pivotal study for generalized [ myasthenia ] [indiscernible], we show that condition alone achieve differentiated efficacy and convenience with every 3-month subcutaneous dosing delivering a potentially best-in-class profile with the placebo-adjusted improvement in the myasthenia [indiscernible] activities of daily [ livid ] score of 2.3 endpoints of 24 weeks.

The primary endpoint of the study and the best result among C5 inhibitors to take based on cross-trial comparisons. We remain on track to submit our U.S. regulatory application in the first quarter with potential approval anticipated later this year or early next year. [indiscernible] nocturnal hemoglobinuria, or PNH, where our Phase III lead-in data showed the combination of [ cemdisiran pozelimab ] was necessary to achieve potentially best-in-class disease control with 96% of patients controlled in the pivotal trial leading cohort.

And with the ability to rescue patients [ prelentreated ] with [ ravulizumab ] who had not been well controlled, these results once again have the potential to deliver a best-in-class profile with pivotal data expected late this year or early next year, positioning this combination of C5 complement inhibitors as a new standard of care for [ PNH ].

Moving to anticoagulation. Plot prevention remains a critical unmet need, has less than half of eligible patients received anticoagulant therapy primarily due to concerns about their bleeding risk. To address this, we are developing 2 complementary [ Factor XI ] antibodies, one optimized for maximum anti-robotic activity and the other designed to further reduce bleeding risk, enabling a tailored approach based on individual patients benefit risk profile.

The usual clinical data support this strategy showing impressive efficacy and a favorable [indiscernible] profile compared to current standards of care. [indiscernible] studies are already underway in prevention of postsurgical [ venous thrombo], or VTE with pivotal data in cancer-associated team prevention, [indiscernible] associated thrombose, stroke prevention in patients with atrial [indiscernible] and peripheral [indiscernible] disease, all expected to initiate this year.

Moving to [indiscernible]. We continue to pursue a differentiated strategy that includes [indiscernible], our in-licensed GLP GIP agonist entering pivotal monotherapy studies in 2026, as well as a co-formulation of [ aldorepatide ] with Praluent or antibody to [ PCSK9]. Since current GLP ages do not meaningfully lower LDL cholesterol, this come combination is designed to treat the large population of people living with obesity who also suffer from hyperlipidemia.

With a single, convenient and similarly affordable once-weekly subcutaneous injection analogous to the currently approved GLPs. Moreover, imagine someone had invented a new GLP gap in addition to delivering profound weight loss but also a lower bit cholesterol by 50% to 60%. It would create an important and differentiated opportunity for the many of these patients simultaneously suffering from [ maleic olipidemia ] with elevated cardiovascular risk. Our clinical program for this novel combination that we believe can deliver these same dual benefits is expected to begin later this year.

Before I turn the call over to Marion, I would like to quickly address a couple of additional developments in our pipeline. In rare diseases, our DB auto gene therapy continues to produce transformative outputs with meaningful hearing gains in 11 of the 12 treated children born with profound genetic [ et]. This program was selected as the first new molecular entity to receive the FDA Commissioner's National Priority Voucher designation, and we are awaiting a regulatory decision in the first half of this year.

In [ viral dysplasia oxytane progress ] or [ FOP], a debilitating disease in which the soft tissues of the body are progressively replaced with admiral bone or [ theartosimab ] program demonstrated more than 9% reduction in [ admirable gold ] formation at 56 weeks, an unprecedented results, and we are waiting on regulatory decisions in the U.S. and EU in the second half of this year.

Our commitment and dedication to these types of rare diseases, particularly those that affect children not only speak to the heart and soul of Regeneron, but have also proven to pave the way for broader opportunities in the future, as we would hope would be the case here.

In summary, our scientific and clinical momentum continues to accelerate across the R&D enterprise with multiple pivotal readouts, regulatory milestones and first-in-class programs advancing in 2026, I have never been more excited about the breadth, depth and potential impact of our pipeline. With that, let me turn it over to Marion.

Thank you, George. The fourth quarter delivered a strong finish 2025, completing a successful year across our commercial portfolio, our market-leading brands, EYLEA HD, Dupixent and Libtayo continue to deliver sustainable growth based on their clinical profile as well as our ability to execute effectively in competitive markets.

In 2025, we expanded use of our existing brands and successfully launched new medicines and indications across multiple therapeutic areas and geographies. We begin 2026 well positioned to advance our portfolio and are excited by upcoming opportunities to change the lives of even more patients.

Starting with our retinal franchise EYLEA HD and EYLEA, which delivered combined U.S. net sales of $1.1 billion. In the fourth quarter, EYLEA HD net sales reached $506 million, representing 18% sequential growth. Performance was driven by a 10% increase in physician demand compared to the third quarter, highlighting EYLEA HD's strong clinical profile and commercial momentum despite a 7% sequential decline in the overall anti-VEGF category.

This fourth quarter dynamic is typical for the anti-VEGF category for full year 2025, the category maintained approximately 5% growth versus 2024, while the innovative branded segment, which excludes Avastin and biosimilars declined by approximately 12%. Importantly, EYLEA HD represents a growing proportion of Regeneron's total anti-VEGF franchise now contributing nearly half of total net sales.

Following recent label enhancements to include monthly doses and retinal vein occlusion, EYLEA HD now has the broadest label and greatest dosing flexibility of any anti-VEGF medicine. Physicians were eagerly awaiting both label enhancements, and we are seeing positive early launch signals in our efforts to get this important medicine to even more patients. The combination of this new dosing flexibility with EYLEA HD's demonstrated durability further strengthens its position in the anti-VEGF retinal category.

New real-world market data shows that on average, patients with ongoing anti-VEGF therapy who switched to EYLEA HD, we're able to extend their treatment duration by almost 4 weeks. This underscores EYLEA HD's durability profile in addition to its well-established efficacy and safety. We look forward to the potential FDA approval of our prefilled syringe, which if approved, will provide additional convenience for retina specialists and further enhance EYLEA HD's profile.

While EYLEA HD grew EYLEA 2 milligrams fourth quarter U.S. net sales declined 15% sequentially to $577 million. Together, EYLEA HD and EYLEA continued to lead the innovative branded anti-VEGF category. Looking ahead, we remind you of 2 separate factors that will impact early 2026. The first quarter is typically impacted by patient reauthorizations. And as we disclosed earlier this month, wholesaler inventory levels were elevated by approximately $30 million at the end of the fourth quarter for EYLEA HD as well as EYLEA.

We expect first quarter net sales will be negatively impacted as the inventory is absorbed. For EYLEA HD, we anticipate high single-digit sequential demand growth in the first quarter, while EYLEA demand is expected to decline at a double-digit rate based on competition and importantly, ongoing conversion to EYLEA HD.

Turning now to Dupixent, which delivered $4.9 billion in the fourth quarter global net sales, representing 32% year-over-year growth on a constant currency basis. U.S. net sales grew 36% year-over-year to $3.7 billion based on broad demand growth and strong performance across several ongoing launches. Dupixent is now approved in 8 Type 2 inflammatory diseases and is the #1 prescribed biologic among dermatologists, pulmonologists, allergists, [indiscernible] interest specialists based on the combination of its differentiated efficacy, safety and treatment experience.

Across Dupixent's established indications, including atopic dermatitis, asthma, nasal polyps eosinophilic esophagitis, Dupixent continues to deliver robust demand growth supported by strong physician preference in each of these indications. We've also seen remarkable uptake in our more recent launches, including COPD, chronic spontaneous urticaria, bolus [indiscernible] and with physicians regularly sharing their experiences and how Dupixent has changed the lives of their patients and many of who previously had no approved treatment options. With many indications still significantly underpenetrated, Dupixent continues to be well positioned to deliver near, medium and long-term growth.

Turning to oncology and hematology. Libtayo reported $425 million in global net sales in the fourth quarter, up 13% year-over-year on a constant currency basis. In the U.S., net sales grew 14% year-over-year to $285 million based on strong demand growth across all approved indications. [ Motivas], leading immunotherapy for advanced non-melanoma skin cancers our recent launch in adjuvant CSCC is off to a great start, including the recent addition of Libtayo in the NCCN guidelines as the only Category 1 preferred immunotherapy in this setting.

In advanced non-small cell lung cancer, Libtayo is now the second most commonly prescribed treatment for patients receiving their first immunotherapy. Physicians increasingly recognize Libtayo as a preferred treatment option based on clinical experience, versatility as a monotherapy in combination with chemotherapy, supported by an increasing body of robust clinical data including recently reported 5-year survival results.

Briefly turning to Lynozyfic, our new treatment for relapsed refractory multiple myeloma. We are encouraged by the launch progress to date. With physicians appreciating Lynozyfic's differentiated clinical profile, less burdensome hospitalization requirements and convenience dosing regimen we expect adoption to continue to steadily build over time in this late-line setting with the larger commercial opportunities in earlier lines of therapy.

In summary, in the fourth quarter, we delivered strong growth across EYLEA HD, Dupixent and Libtayo, and we continue to progress several launches, including Lynozyfic. In 2026, our commercial portfolio is well positioned to capitalize on many near-term growth opportunities, enabling us to deliver more treatments to patients. With that, I will turn the call to Chris.

Thank you, Marion. My comments today on Regeneron's financial results and outlook will be on a non-GAAP basis unless otherwise noted.

Fourth quarter 2025 total revenues of $3.9 billion grew 3% compared to the prior year, reflecting higher collaboration revenue driven by strong global Dupixent sales growth, continued growth in net sales of EYLEA HD and Libtayo as well as higher other revenue, partially offset by lower net sales of EYLEA 2 milligrams.

Fourth quarter diluted net income per share was $11.44 on net income of $1.2 billion. Beginning with the Sanofi collaboration, fourth quarter total Sanofi collaboration revenues were approximately $1.6 billion, of which $1.5 billion related to our share of collaboration profits. Regeneron's share of profits grew 42% versus the prior year primarily driven by Dupixent and improving collaboration margins.

The Sanofi development balance was just below $600 million at the end of the year reflecting a reduction of approximately $300 million since the end of the third quarter and over $1 billion in full year 2025. Dupixent's continued strength enabled a rapid reimbursement of the development balance in 2025, which we now expect to be fully reimbursed by mid-2026. Once fully reimbursed, Sanofi collaboration revenues will reflect our full share of global profits for Dupixent and Kevzara.

Moving to Bayer. Fourth quarter net sales of EYLEA and EYLEA 8 milligrams outside the U.S. were $817 million, inclusive of $312 million of EYLEA 8-milligram sales. Total Bayer collaboration revenue was $319 million, of which $270 million related to our share of net profits outside the United States. Other revenue, which includes profit share and royalties associated with license agreements as well as amounts earned for contract manufacturing grew 33% in the fourth quarter to $239 million.

This included $179 million related to royalty income from Alaris plus our share of profits from ARCALYST. Alaris net sales exceeded $1.5 billion in 2025 and achieving the top royalty tier of 15% for the first time. Per our agreement with Novartis, escalating royalty tiers, which range from 4% to 15% are applied to cumulative net sales from the start of each calendar year. This leads to the step-ups and royalty income each quarter as higher royalty tiers are applied to cumulative net sales.

Now to our operating expenses. R&D expense was $1.3 billion in the fourth quarter, reflecting continued investments to support Regeneron's innovative pipeline, including multiple late-stage opportunities.

Fourth quarter SG&A was $691 million, inclusive of a matching contribution to the good days vascular and neovascular retinal disease fund of approximately $60 million. Our effective tax rate in the fourth quarter was 17%. The increase in our tax rate from the prior year primarily reflects a lower tax benefit from stock-based compensation. Regeneron generated $4.1 billion in free cash flow in 2025 and ended the quarter with cash and marketable securities less debt of $16.2 billion.

We returned $3.8 billion to shareholders in 2025, primarily through $3.4 billion in share repurchases. We continue to be opportunistic buyers of our shares, with $1.5 billion remaining authorized for repurchases as of December 31.

We also initiated a quarterly dividend last year, providing us with additional flexibility to return capital to shareholders. In 2025, we paid nearly $400 million in cash dividends and announced this morning that our Board of Directors has authorized a quarterly dividend of $0.94 per share payable in March equivalent to $3.76 on an annual basis. We continue to view our dividend as a way to expand the pool of potential Regeneron's shareholders to include funds with a dividend mandate while share repurchases will remain the primary means of returning capital to our shareholders.

I will conclude with our financial guidance for 2026. Consistent with what was provided at the JPMorgan conference a few weeks ago, we expect 2026 R&D spend to be in the range of $5.9 billion to $6.1 billion. The increase versus 2025 is driven by cost to support our expanding late-stage pipeline including new Phase III studies in oncology and hem/onc are Factor XI antibodies and our obesity program.

In addition, as you heard from George, we plan on advancing several new molecules into the clinic across a number of different therapeutic areas, including ophthalmology and [ I&I]. We expect 2026 SG&A to be in the range of $2.5 million to $2.65 billion, reflecting investments to support the ongoing launches of Libtayo and adjuvant CSCC and Lynozyfic and late-line multiple myeloma, as well as other potential launches, including [ sandisirin and gMG].

We expect our gross margin and net product sales to be in the range of 83% to 84%. This guidance reflects a change in product mix as well as cost to support expanding our bulk manufacturing capacity and fill-finish capabilities. We also expect 2026 capital expenditures to be in the range of $1.1 billion to $1.3 billion, primarily related to the ongoing expansion of the R&D facilities at our [ Tarrytown ] headquarters and investments in our manufacturing network to support our growing commercial portfolio and pipeline.

Finally, we expect our 2026 effective tax rate to be in the range of 13% to 15%. It is important to note that our 2025 effective tax rate benefited from a favorable tax audit settlement, which reduced our 2025 ETR by 1.2 percentage points. A full summary of our guidance can be found in our earnings press release published earlier this morning.

In conclusion, Regeneron's strong performance in 2025 positions us well to continue investing in our differentiated pipeline to deliver significant advances for patients and deploying capital to drive long-term value for shareholders. With that, I'll pass the call back to Ryan.

Thank you, Chris. This concludes our prepared remarks. We will now open the call for Q&A. [Operator Instructions]. Shannon, can we please move to the first question.

[Operator Instructions] Our first question comes from the line of Alexandria Hammond of Wolfe Research.

So clearly, there's a ton of interest in the upcoming as for Libtayo film. So in metastatic [indiscernible], any update on when we could receive this data beyond first half? Should we expect to get an adjuvant interim update with the metastatic? And I guess as a follow-up, [indiscernible] other several interims for the adjuvant. So if we don't get an update on the adjuvant with the metastatic readout, when could we expect that next interim?

Thanks, Alex. We don't really have any additional clarity right now on the timing for the advanced melanoma readout. First half is the best estimate at this time.

In terms of the adjuvant timing, that's also in the first half. They may coincide. They may not. Once we have the data, we will read it out shortly thereafter.

Our next question comes from the line of Chris Raymond with Raymond James.

Just a question on Dupixent IP. I'm sure you're aware of Sanofi's commentary yesterday about taking potential for taking the runway out well beyond the current thinking, and I think their commentary took things out maybe to the [ 2040 ] or beyond range. I know you don't want to get too much detail here, Len, but maybe any commentary you can provide in light of those comments yesterday.

No. No additional comments. I thought Sanofi did a good job laying out what the realm possibilities are.

I think we should highlight the fact that we have also a lot of exciting follow-on opportunities in this space, particularly with our collection of what we hope will prove to be the best-in-class long-acting IL-13, IL-4 and IL 413 bispecifics as well as what we call a new [indiscernible] molecule that is a new version of Dupixent that was naturally selective that might have even more improved properties.

I think it's worth just highlighting again because a lot of people don't realize how special Dupixent is. In terms of -- not only its remarkable efficacy, how I mean, it delivers -- it doesn't just help a little. It really dramatically benefits patients across these 8 now approved diseases. But the thing that I think is underappreciated is its incredible safety profile.

And I think that -- we've all seen now so many people are trying all sorts of other approaches to go after some of the same disease like atopic dermatitis. We're seeing data, let's say, with [ OX40 ] and [ OX40 ligand ] which I think most people now realize they're somewhat [ porting ] not only from the efficacy side, but perhaps even most importantly, from the safety side. What people, I think, don't appreciate and understand is when we discovered Dupixent in this whole -- understood this whole pathway, we realized that this was a specific pathway that was driving only allergic disease and it was a [ vestigial ] -- largely a [indiscernible] part of the immune system that was no longer required to fight most pathogens.

That's why unlike most other immunomodulators, it doesn't suppress overall immunity. When you suppress overall immunity with things like [ JAK ] inhibitors or things like [ Oppligand], you suppress everything and then you raise concerns and fears the possibility that the general immunosuppression will now subject the patients to more infections, which is generally actually what we see. And [indiscernible], with Dupixent, you don't see these sorts of things.

So you don't see general line increases in infections. We don't have black box warnings on sections because we're not generally suppressing the immune system. We're only suppressing the part of the immune system, which is largely [ vestigial ] and is largely activated in our modern world for reasons we have theories about the [indiscernible] now that drive allergic inflammation. So it's a very special approach and you don't have to worry about, for example, getting [indiscernible] sarcoma or things like that with treatment with.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

Just a follow-up here on the frontline metastatic melanoma data in the first half. Is there any way you could frame for us how to think about the bar on hazard ratio here? And just any commentary about the PD-L1 expression levels of these patients as we look to this first interim read?

I think as we've discussed before, this study is largely powered to get an effect in terms of the primary endpoint, which is the PFS analogous to the current combination standard of care. I hope -- of course, we hope that we might actually achieve better. We have 2 dose groups in the study and so forth. But we're also powered that if we were to hit at that level as the current standard of care. We would also hope to demonstrate a benefit in the study is appropriately powered to pick up an overall survival benefit. That is the minimum hopeful expectations, and we might we might see better than that as well.

And regarding PD-L1 status of the enrollment, we are not -- we are screening patients, but we are not using it as an inclusion or exclusion criteria. There's no forward cap meaning the patients with high expression or low expression. So this population, we expect would represent a true first-line advanced melanoma population. And we look forward to the results.

Our next question comes from the line of Tyler Van Buren with TD Cowen.

I wanted to ask about broader R&D strategy. In your presentation, you have the slide where you divide your pipeline among the 6 therapeutic areas and [ I&I ] has expanded significantly as of late as well as ophthalmology, which is not terribly surprising, and I would argue is necessary given the history of the company. So would you say that these 2 areas in addition to oncology, will remain a bigger focus than the 3 others? Or are you committed to remaining relatively balanced across all 6 areas over the next few years?

Well, Tyler, thanks for bringing that up. First of all, I do want to point out that we are somewhat disappointed with the industry in that we invent a great leading drug like EYLEA and then you get literally dozens and dozens of companies just trying to come up with a me-too and take a little bit of that business or the same thing with DUPIXENT. They're just trying to come up and try to mimic Dupixent and maybe try to make a little incremental improvement.

What our goal is to really do what I think this industry should be doing, which is taking advantage of the most innovative approaches to come up with new drugs for new indications. And what we do is we take an agnostic approach that is generally guided by genetics, which has proven to be so successful in our history.

This is perhaps one of the first, if not the first company that its entire future on the power of genetics versus [indiscernible]. So we make our choices based on the most powerful available data and technology that can guide decision-making, which is large-scale human genetics, which allows us to use AI in ways that other people can't. And that allows us to pick targets.

So many of the targets that we've now described, for example, in ophthalmology and in immunology and inflammation, but across other areas of wealth are driven by the same kind of genetic that allows us to know whether Dupixent will work in an indication enough. That is the genetic says that if you're missing that genetic pathway, you're likely going to help your disease and if you have increases in that genetic, you're going to get more of that disease. And that has proven very powerful for us to make a decision.

That's how we find indication. We are therapeutic agnostic, but obviously, we have capabilities broadly across all these areas, but we are very excited about these new programs because like our previous success, they are driven by human genetics, telling us that these targets if we can make, and we believe we have the most powerful technologies to address these targets, whether it be antibodies bispecifics, genetic method.

If we properly can target these genetically validated, we can create new opportunities, new drugs for new indications, not just also protecting our existing franchisees by making sure that we always have the best anti-VEGF approach and portfolio. We have the best [ antiology ] portfolio and so forth. When we want to break new ground, we're doing it across all these therapeutic areas, we're very excited about.

Our next question comes from the line of Dave Risinger with Leerink Partners.

So my question is for George. George, could you talk a little bit more about the souped-up version of Dupixent that's in development, including the event path ahead?

Yes. Obviously, Dupixent is a very unusual antibody. I don't know if everybody remembers the history of it, but some of the biggest companies in the world try to make a molecule like Dupixent and sales in clinical trials, for example, Amgen using an inferior humanized mouse approach try to make a Dupixent that is starting the same receptor as we did and their body completely failed in all their clinical trials.

So Dupixent was apparently a special molecule. What we continue to do is use our best technologies, our best antibody generating technology, starting with our best-in-class human immune system in a mouse generating millions and millions of versions over the last many, many years and testing them in comparing.

And we think that we have one that might actually be in some ways, even better than Dupixent. It looks like it may be longer acting and they have some other advantages as well. So we're going to be moving it forward in the clinic as we announced and we'll be testing it, and we'll see whether indeed. We have been able to come up with an even better Dupi or [indiscernible] as we call it.

And just to remind everybody that while not formally in the alliance with Sanofi, it is covered by the alliance, meaning that if it goes into full development that we'll be doing this with Sanofi.

Our next question comes from the line of Tazeen Ahmad with Bank of America.

I wanted to spend a minute on geographic atrophy. You guys have a cohort, I believe, reading out in the second half of this year on your GA program. I think there was a lot of promise a few years back just given the number of patients with GA, but the 2 approved drugs have proven not to be able to get a ton of market share. So what do you think is differentiated in your program? Do you think that you'll need to show a visual acuity benefit? Or is it going to be in your mind, it's just as good to show slowing of vision loss, given that you expect to have a better safety profile than both those drugs.

Well, let me just remind you that the first drug in the [ wet AMD ] space was [ Macugen], which was an [ aptamer]. And if you compare the benefits that it provided compared to something like EYLEA, yes, it had a benefit but it was just barely slowing down wet AMD disease as opposed to what we were able to do with EYLEA where we could actually reverse and improve vision even and maintain or maintain the restored vision for years thereafter.

So obviously, the approaches that we have at our disposal, things like our antibodies and our sRNAs have historically proven to be much more powerful at blocking pathways, then technologies approaches such as active [ pegylated ] does and [ pegylated ] peptides and so forth. So one possibility and opportunity, of course, is that by providing more profound blockade, one might actually see better benefit.

Another, of course, important aspect of our program is we are trying both systemic blockade as well as local blocking. So one of the problems with the existing therapies and why they're not so widely used, they're largely [ preventages], but they come with very dangerous side effects in that they can cause essentially problems that might resolve intermediate blindness like retinal vasculitis with occlusive vasculitis disease.

So imagine you're taking something to prevent the line that can actually cause [indiscernible]. So the systemic approach, now of course, they may have its own problems, there's always risk. So they come with its own problems in terms of systemic infection, but it should be free from causing these local potential blinding risks in the eye. So you may end up either with better efficacy or the same efficacy but with a better safety profile in terms of avoiding these blinding risks.

And also, in the case of right now, the current treatments, most patients actually have bilateral disease. So you have to inject both eyes. And many of them also suffer now. And in fact, the [indiscernible] can actually, in some cases, cause wet AMD, progression [ wet AMD ], they need the injections in both eyes, and they also need injections with anti-VEGF.

So obviously, a systemic approach will avoid all these complications, you would have to give 2 sets of injections to both sets of eyes and so forth. So we're very excited because there's many, many opportunities here.

And I also remind you that we are testing both the monotherapy in terms of [indiscernible] alone, which works so spectacularly in myasthenia grabs as well as the combination of some distrain with the antibody, which worked so beautifully and was required to optimally work in PNH.

We don't know because we collectively society, the medical system does not understand why in one case, you need complete blockade. In the other case, you need this sort of [ segesterone ] type of effect. We're exploring both. So there's many, many, many ways to provide improved benefit for these patients who really need an improved way of treating their disease.

It could be something that really addresses the tremendous bird that's inflicted by palatal disease, layered with anti-VEGF requirements and so forth. It could be better efficacy, it could be better safety. And it could also be for example, a systemic approach that does not completely inhibit the complement system. So many, many, many ways to imagine delivering a better outlook for patients who really need it here, especially if more of them will choose to undertake this preventative approach.

Just to add one point, which George fully emphasizes VEGF is made locally. And so you give a local drug to a local problem. The C5 is made systemically primarily in the liver. So it may require systemic blockade as opposed to individual. But we have all the tools to dissect what the best approach is.

And final note on this to Tazeen. The primary endpoint of our initial pivotal study is the growth rate in GA lesion area, but I would note that we do have a prospective secondary endpoint that will measure 15-letter loss of visual acuity. So we will have an endpoint that looks at visual acuity at year 1 and year 2 of this study, unlike incumbent therapies, we looked at this on a post-op basis.

Our next question comes from the line of Geoff Meacham with Citi.

Thanks, for the question. I just want to talk about EYLEA HD for a sec. Maybe just talk about the trends for growth for this year. I wanted to get maybe your perspective as you kind of exit '25 and going to '26, sources of growth with regard to new patients, switches versus competition? And then on the prefilled syringe related, do you characterize that as kind of a tipping point? Are there ophthalmologists? Are there practices that are sort of waiting for that? I want to get a sense for how much of a gating factor that is to ultimate demand.

And I'm going to start with the last portion on EYLEA HD and the prefilled syringe potential approval that we talked about today. And as you know from the numbers that we shared, we're making good progress with EYLEA HD in the marketplace, the recent label enhancements with Q4 weekly dosing in RVO have been very well received. And of course, prefilled syringe, as I mentioned, will be a convenience factor for offices.

So some that find that to be incredibly important. Obviously, we'll have a new opportunity to use EYLEA HD, but obviously, we have a lot of users today. It will only get better when we get and potentially have the prefilled syringe approval.

Our next question comes from the line of Akash Tewari with Jefferies.

On your [indiscernible] GIP combo, can you talk about the co-formulation here? How are you able to deliver both drugs in a single auto-injector versus something that came to an on-body infusion? And what are the chances you partner this asset out to share the development cost? Can you characterize any of those discussions so far?

We don't comment on the status of discussions. We're always open minded to deal with and enhance our shareholder value.

But as you touched on it, that's the magic, and that's the secret of our capabilities best-in-class formulations group that delivered unprecedented formulation capability with EYLEA and EYLEA HD. It's the same people doing the same things that have figured out how to magically be able to get into an auto injector of very similar injected is just for GLP, similar sort of volume, both the antibody and a peptide.

And so we're very excited because [indiscernible] put it this way. Imagine inventing a GLP, that in addition to doing what -- the leading GLP do is also just lowers cholesterol, or [indiscernible] by 50% to 60%. We wouldn't everybody want to take that because we understand that so many people who suffer from obesity also suffer from cardiovascular risk. And while losing weight helps your cardiovascular is, it also was dramatically driven by the bad cholesterol, which weight loss doesn't appreciably impact.

So it's a very, very exciting opportunity. We're very excited that our [indiscernible]. We're able to figure out how to make this magic happen, and we think it's going to offer patients a really differentiated way of not only having their desirable weight loss, but also dramatically improving their [ hypolipidemia ] associated cardiovascular risk as well. So we're very, very excited to be able to offer this opportunity and move forward with our clinical program to see if it's a reality.

Okay. We have time for 2 more questions, Shannon.

Our next question comes from the line of Terence Flynn with Morgan Stanley.

Bayer is going to be presenting some Phase III data for their oral Factor X inhibitor [indiscernible] next week. Just wondering anything you'll be focused on in that data set as it pertains to your Factor XI antibody program in terms of development, et cetera.

Yes. I mean it is very hard to compare these [indiscernible] molecules with antibodies. As we know, historically, and if the case here, small molecules suffer from both lack of specificity that we know they inhibit multiple [ proteases ] including the target of interest here. And they also have [indiscernible] target effect as well.

And so the hope here is by having an antibody, which we think is very, very different than a small molecule, the specificity as well as the efficacy may allow you have a very different profile where you will actually have better anticoagulation, but also, hopefully, better safety, less bleeding, which we think what it's all about. And so there will be some read-through, there will be some usefulness to following that.

On the other hand, we believe our antibody has a very substantial differentiated and potentially advantageous profile. And so the key thing is if our antibodies really can deliver what we believe they can with dramatic decreases in the overall bleeding risk, then they should allow somebody to essentially get an occasional shop once after a procedure, let's say, or once a month attention, things like that, that won't require these patients to be either having worried about making sure they stay on their meds or borrowing and so forth.

So very different opportunity. Of course, there's some read through, but we think our antibiotic is going to be very different.

Shannon, let's go to the last question, please.

Our last question comes from the line of Evan Seigerman with BMO Capital Markets.

I'd love you to talk a little bit about the confidence that gives you to move your GLP-1 GIP to Phase III clinical trials globally, just given how rapidly this market is evolving. Put it another way, what's differentiated about this asset from currently available standard of care and other advanced assets in development?

So I think if you go back and listen carefully to what George is saying that the biggest advance here from our perspective is the ability to combine this with our [ PCSK9 ] [ antibody ], there are only 2 approved PCSK9 antibodies and the ability to combine this antibody with these peptides in the same syringe at the same dosing interval, I think that's highly differentiated for the 15% -- the 50% or more people who are obese and have high cholesterol.

We know several hundred thousand people already take both a [indiscernible] and [ PCSK9 ] inhibitor. And that's without the convenience of having to put that together in a single shot and without really focusing any marketing on the obese group. So I think, Evan, that's what the core of the differentiation could be.

Obviously, we're considering putting it together with other assets in our pipeline, other combinations we can't imagine directly competing, but I do think we should have favored that's competitive to the best-in-class. But the commercial strategy is not directly compete with that combination. George, do you want to add something?

Yes. So remember, one of the reasons we have confidence is there has already been extensively studied in China. And it's designed to be and the clinical data suggests it is very [ prozepetide-like in its efficacy and safety profile when compared to the same population. And it is already in advanced Phase III trials in China.

That's why we think we have very much a tozepatide line or a best-in-class type agent. But as Len said, we don't necessarily want to just compete just for the weight loss. A lot of people are just so focused on the weight loss load and they're trying to say, "Oh, let me get a little bit more weight loss. A little less nauseousness, a little less vomiting."

They're all competing around the weight loss. They're all fighting in that space. We want to take this to a whole other place where we're adding of completely new benefit, a completely different benefit to the weight loss. So let everybody else fight for an extra 1% or 2% of weight loss, we're going to give you 50% to 60% [ LDL ] lowering with the associated expected cardiovascular benefit.

That's highly differentiated. So we didn't get this to compete just by itself in the obesity space, though we think we have an agent here that is very similar to the best-in-class type of reagent. It's all about the combinations.

And the first combination that we're rolling out we think is this very, very exciting one. And frankly, honestly, every obese patients should take okay, regardless of their lipid stats because lower lipids is better. And that would be better. It would, frankly, be better for the entire population.

Why do we know? Because cardiovascular disease driven by [ hypolipidemia ] still the #1 killer in America and people are not taking it. So it may be almost a Trojan horse. Imagine, they just -- they want to lose their weight and they're not even going to realize that they're going to be helping their hearts, they can decrease the overall rate of cardiovascular disease and death in this country. A Trojan horse to really make an impact for society.

This is what we're trying to do. Everybody, frankly, in America should be on a [ PCSK9]. This is a way to actually do it and do it in a way that people will actually want to take. And we think we have a variety of other ways not to compete on the weight loss side, but to give another important benefit on top of the weight loss.

Thank you, George, and thanks to everyone who dialed in today for your interest in Regeneron. We apologize for those remaining in the Q&A queue. We do not have a chance to hear from today. As always, the IR team is available to answer any remaining questions that you may have. Once again, have a great day and a nice weekend.

This concludes today's conference. Thank you for your participation. You may now disconnect.

Good afternoon, everybody. I'm Chris Schott at JPMorgan, and it's my pleasure to be introducing Regeneron today. From the company, we have Regeneron's Co-Founders and Co-Chairs President and CEO, Len Schleifer; and President and CSO, George Yancopoulos. Between the core portfolio and an increasingly broad pipeline, I'm very much looking forward to the presentation today. So with that, over to Len, and we'll go to some Q&A after that.

Thanks, Chris. It's great to be here. We're going to try and do maybe 20 minutes of presentation and then leave it to you for questions. It's great to be back in San Francisco for the 44th I guess JPMorgan Conference. .

We think it's a very interesting conference. It mainly got interesting 37 years ago when we started presenting. We have been in every room at the conference. And in every single room many times the most common phrase that we have heard, so it shows how consistent the place is, is promising data.

Okay. We -- that went over well. That's my team said, don't do it Len. Anyway, I'm Len Schleifer, CEO of Regeneron. I'm joined on stage by my longtime partner Regeneron, Dr. George Yancopoulos, Regeneron's Chief Scientific Officer and Co-Founder. During our presentation, we will be referring to slides, which may be found on our website.

This is one of my -- this one is one of my favorite slides. It contains our forward-looking statements. There's 44 lines in there. We've added one line each year. And you should read them carefully and understand there are a lot of risks of what we say and refer to our SEC filings for more detail. With that underway, let's get started.

Let me start by providing a brief overview of Regeneron, a company that has proven itself to be truly unique, I think, in the biopharmaceutical industry. Our strategy is deeply rooted in following the science. It's a phase that many people use, but it's one that we truly live by. And we harness the power of science and Big Data to consistently deliver transformative therapies to patients.

Over the past 10 years, George and the team have created a powerful tool kit of proprietary turnkey technology platforms such as VelocImmune, Veloci-bi and the Regeneron Genetic Center that provide Regeneron's secret sauce. These platforms enable rapid and efficient drug discovery and development, enabling us to screen thousands, if not millions of antibodies, significantly increasing our likelihood of identifying the optimal candidate.

Regeneron is also -- is also recognized as a pioneer in bispecifics, genetic medicines as well as a leader in genomics and proteomics based Big Data in the health care space. While we did not invent genomic sequencing or proteomics, we have pioneered the high throughput aspect of that, creating affordable technologies which allow us to apply these game-changing approaches to millions and millions of people.

And while AI approaches can be powerful, they are very limited by the amount of -- they are very limited by the amount of genomics and proteomics data available for health care discovery and management. We believe in this area, we stand alone on our Big Data assets. Driven by this science first and Big Data approach, our pipeline now includes 45 clinical candidates across 6 major therapeutic areas.

This breadth reflects our dedication to tackling a wide spectrum of unmet medical needs and establishes a strong foundation for continued success. With 14 internally discovered therapies that have been approved over the past 15 years or so, Regeneron has averaged roughly one new approval per year and has demonstrated the ability to repeatedly deliver important therapeutic breakthroughs.

Regeneron's commitment to innovation has resulted in a portfolio of brands that continue to deliver sustainable growth. In the fourth quarter of 2025, our Retina franchise reported combined U.S. net sales of $1.1 billion for EYLEA HD and EYLEA. Fourth quarter 2025 EYLEA HD net sales in the U.S. were $506 million, up 66% versus the fourth quarter of 2024 and up 18% sequentially versus third quarter of 2025 driven by a 10% increase in physician demand.

EYLEA's HD label was expanded in late November to include every 4-week dosing and the addition of macular edema following retinal vein occlusion, further enhancing its commercial potential. The mix of our franchise net sales has been steadily shifting towards EYLEA HD since launch with EYLEA HD now comprising nearly half of net sales.

Importantly, we submitted an application for a new filler for the EYLEA HD prefilled syringe with an FDA decision anticipated in the second quarter of 2026 this year, and the FDA also recently approved an alternate vial filler for EYLEA HD. Turning to DUPIXENT, a drug we commercialize with Sanofi. DUPIXENT has become the world's most widely used branded antibody with over 1.3 million patients actively treated worldwide.

As we first predicted here at the JPMorgan conference about a decade ago, DUPIXENT is delivering on its pipeline in a product promise. DUPIXENT is now approved for 8 different diseases driven by type 2 inflammation and leads in new-to-brand prescription share and total prescription share in 7 of these indications. With annualized global net sales exceeding $19 billion based on third quarter net sales, which grew 27% year-over-year, DUPIXENT is positioned for sustained growth. And in our most recent blockbuster LIBTAYO continues its strong growth as the leading immunotherapy for advanced non-melanoma skin cancers.

LIBTAYO is now the only approved IO treatment for adjuvant CSCC an indication with 10,000 addressable patients in the U.S. alone, which we believe could be a blockbuster commercial opportunity in and of itself. LIBTAYO also continues to make significant inroads in lung cancer and is now the second most prescribed I-O treatment in first-line advanced lung cancer in the U.S.

Our capital allocation strategy prioritizes robust investment in internal research capabilities, which we believe offer the highest potential return for our shareholders. We expect to invest approximately $6 billion in R&D this year as well as over $7 billion of capital investments in the U.S. in the coming years to support our R&D and manufacturing capabilities.

Regarding external innovation, we are constantly evaluating opportunities with a particular focus on platforms and technologies that enhance our core strengths or accelerate our existing development strategies. Our business development efforts have delivered meaningful results. For example, our collaboration with Alnylam, including the in-licensing of cemdisiran which has enabled us to independently pursue development in generalized myasthenia gravis as well as other complement-mediated diseases.

More recently, we in-licensed Olatorepatide, a GLP receptor agonist from Hansoh to accelerate our strategy in obesity and entered into multiple gene editing collaborations with Intellia, Mammoth and Tessera. After investing in R&D and business development opportunities, we return excess cash to shareholders. We view opportunistic share buybacks as an efficient use of capital and initiated a modest dividend in 2025.

Altogether, we returned $3.8 billion to shareholders in 2025 alone through buybacks and dividends. I'd like to say a few words on why our mix of R&D spend is more focused on internal investment than our peers. While other companies on average dedicated almost half of their R&D investment to external business development, we have historically concentrated about 95% of our resources on internal initiatives. We do this for 2 reasons. First, we have the benefit of an extraordinarily productive R&D organization.

Second, our internal analysis shows that the overall return on external business development throughout the industry has been modest, with only a small percentage of deals leading to successful approvals and even fewer still to commercial success.

Large M&A deals, in particular, have often resulted in value destruction. These data underscore the importance of investing in our sustainable innovation engine -- by focusing on internal R&D, we avoid the inevitable pit force of becoming overly reliant on external deals to replenish pipelines and in most cases, dramatically overpaying.

Instead, we have built and continue to invest in a robust, sustainable pipeline that we believe can deliver long-term shareholder value. Let me briefly move on to our pipeline. We are investing in large categories across multiple therapeutic areas that collectively address a global market opportunity of over $200 billion. With that, I'd like to turn it over to George for a deeper dive into our pipeline, and that will be followed by questions and answers. George?

Thanks, Len. I'll dive right in and to expand on Len's last slide. This showcases several of our key clinical programs from our broad pipeline, expected to generate clinical data over the next few years. With each representing a significant opportunity to advance care and address medical need in various unmet need areas.

Our pipeline features antibodies bispecifics, siRNAs, AAV gene therapies, CAR-T, and other cell therapies, peptides and gene editing approaches as well as novel combination across these modalities. While time doesn't permit a deep dive into every program, I'll use the next few slides to spotlight those with exciting near-term impact.

And let me start by highlighting several initiatives with our immunology and inflammation franchise aimed at maintaining our leadership in this field. Our multifaceted strategy includes exploring longer dosing intervals for DUPIXENT and developing innovative Veloclmmune-derived fully human, long-acting IL-4 alpha, IL-13 and IL-4 antibodies with enhanced binding properties for these drivers of type 2 inflammatory conditions.

Notably, we are pursuing an expedited clinical development plan for our interleukin-13 antibody, which will enter the clinic shortly ensuring we remain competitive in terms of timing with other industry players that are pursuing similar approaches.

Going beyond the DUPIXENT related opportunities and following similar strategies that we pursued with DUPIXENT our Regeneron Genetics Center has identified multiple additional genetically defined I&I targets, each with the potential to become our next pipeline and a product. We will soon be bringing the first of these candidates into clinical development. We are also advancing opportunities to treat or cure allergies following 2 distinct approaches. One that is allergen-specific where we have Phase III programs underway to treat cat and birch allergies and another approach that seeks to eliminate all immunoglobin E or IgE-driven allergies.

We have previously discussed our novel approach of reversing severe food allergies by transiently treating with Lynozyfic, our BCMA by CD3 bispecific, so as to rapidly eliminate the allergy-causing IgE-producing plasma cells, followed by long-term DUPIXENT treatment to prevent their return. We have now achieved proof of principle with this approach. With all 4 of our first patients treated achieving greater than 90% sustained reductions in their IG levels.

We also plan to advance to the clinic novel therapeutic candidates designed to more specifically eliminate the IG producing cells as a follow-up approach that may prove more rapid and with broader allergy applications. Together, these efforts position us to maintain our I&I leadership and unlock new growth opportunities.

Let's now shift our focus to 5 key late-stage programs that are poised to deliver meaningful advances over the next few years across multiple therapeutic areas, including solid tumor oncology, myeloma, complement-mediated diseases, anticoagulation and obesity. These registrational studies are already ongoing or will commence shortly.

We expect a steady stream of critical data readouts from these studies starting the first half of this year. Let's start with our checkpoint inhibitor program involving our LAG-3 antibody, Fianlimab in combination with LIBTAYO, where our proof-of-concept clinical data showed that this combo may be very much differentiated when compared to the standard of care in first-line metastatic melanoma. We're excited for the upcoming readout of our pivotal trial, which is investigating this combination versus pembrolizumab monotherapy with data anticipated in the first half of this year.

Moving to Lynozyfic-- our BCMA by C3 antibody, which was approved in the United States last year in late line multiple myeloma based on best-in-class data as a monotherapy in this late-line setting, with nearly double -- let me repeat that, nearly double the complete response rates of other BCMA by CD3 bispecifics with similar follow-up.

Because of this rather remarkable monotherapy activity, we are undertaking an ambitious development program to drastically simplify the existing treatment paradigms, exploring monotherapy as well as simple combinations in early line settings, which currently are dominated by highly complex, intense and burdensome triple and quad drug combinations.

As we detailed at our Regeneron roundtable last month, we have already generated compelling initial data with these monotherapy approaches in earlier line settings in leading portions of our pivotal Phase III trials. In fact, in all evaluable patients in the first-line setting treated with monotherapy at the planned Phase III dose, 100% achieved MRD negativity.

Beyond malignant myeloma, we have a differentiated strategy in precursive conditions to myeloma, where we are generating exciting early data that support our ambition to treat patients early and potentially prevent progression to the malignant disease through early intervention. Once again, in the precursor smoldering setting 100% of evaluable patients treated with Lynozyfic monotherapy achieved MRD negativity. With 4 registrational studies now underway and 4 more initiating this year, we continue to advance our differentiated approach of pursuing monotherapy or simplified combinations across many and early settings.

Another exciting program in our pipeline is for complement inhibition. This program includes both an siRNA and an antibody, both targeting the complement component C5. The siRNA cemdisiran lower C5 target burden while the antibody, pozelimab, blocks circulating C5, enabling together near complete inhibition.

We're using a customized and tailored approach to treat different diseases that require different levels of target inhibition so as to maximize efficacy. For example, in paroxysmal nocturnal hemoglobinuria or PNH, where the current standard of care do not achieve optimal emission, we have shared results from the lead-in portion of our pivotal Phase III trial, which compared our siRNA antibody combination against the current standard the antibody ravulizumab.

Remarkably, only 4% of patients treated with our C5 combination did not achieve LDH control. In contrast and consistent with historical data, about 1/3 of patients treated with the standard of care did not achieve LDL control. Even more impressively, after switching those uncontrolled subjects on standard of care to our siRNA combination -- antibody combination, almost all were able to rapidly and durably achieve LDH control, giving us a lot of confidence that this combination could become the new standard care for PNH with pivotal data expected late this year or early next.

In generalized myasthenia gravis, we reported last year that cemdisiran monotherapy alone delivered positive Phase III results, showing potentially once again best-in-class efficacy and safety with a highly differentiated every 3-month subcutaneous dosing regimen. In the pivotal NIMBLE study cemdisiran achieved a 2.3 point placebo-adjusted improvement in the MG-ADL score at week 24, the best result among C5 inhibitors to date. We are on track to submit our U.S. regulatory application to the FDA in the first quarter of 2026, with potential approval anticipated later this year or by early next year.

Finally, we anticipate completing enrollment for the leading cohort of our initial Phase III geographic atrophy study, exploring these C5 blocking agents in the first quarter of this year with preliminary results expected in the second half of the year. Building on our hematology efforts. Factor XI antibodies represent the next wave of innovation and anticoagulation with the potential to expand into large underpenetrated markets.

We all have to understand that COG prevention remains a critical unmet need. And one reason is that less than half of eligible patients receive therapy, primarily due to bleeding risk concerns. Our goal with our Factor XI antibodies is to develop safer anticoagulants, reducing the bleeding risk while maintaining efficacy and allowing much broader utilization. Our 2 mechanistically distinct antibodies enable a tailored approach. One antibody is designed to optimize anticoagulation activity, while the other is designed to further minimize bleeding risk.

And our initial clinical data support our customized approach with impressive efficacy while suggesting a favorable bleeding profile when compared to current standards of care. Our data support development in multiple indications from postsurgical VT prevention to stroke prevention atrial fibrillation with multiple additional Phase III trials set to initiate in 2026.

Lastly, just as we're redefining anticoagulation, we're also pursuing transformative opportunities in obesity, a therapeutic area with enormous unmet need and significant commercial potential. While we are excited about our monotherapy capabilities with our in-licensed GLP agonist oletorepatide, or OLA, we are fast-tracking programs combining OLA with our proprietary antibodies addressing obesity-related comorbid conditions.

For example, about half of obese patients also suffer from hyperlipidemia and the associated cardiovascular risk and GLP agonist do not adequately address this as they only lower LDL-cholesterol by less than 10%. Therefore, we plan to more thoroughly address this unmet need by combining OLA with Praluent, our PCSK9 antibody, which has demonstrated more than 50% LDL lowering with cardiovascular disease prevention as demonstrated in large cardiovascular outcome studies.

Our plan is to provide patients with a co-formulation of OLA and Praluent that can be administered with a similarly convenient and affordable once-weekly injection as the current GLPs, but now adding on the important benefit for the large unmet need for those obese patients with hyperlipidemia.

Regeneron is uniquely positioned for this opportunity with clinical studies expected to begin later this year. Before I hand it over to Chris for some Q&A, I'd like to point out that we've only had time to touch on a small part of our pipeline. I'd like to highlight 2 more programs that have the potential to benefit children suffering from serious health challenges.

And while these programs may not have enormous commercial potential, they help remind us what our business is really all about. First, our innovative gene therapy approach, DB-OTO, which miraculously restored hearing to children born genetically deaf and which the FDA has recognized with its commissioner national voucher program, allowing potentially accelerated approval this year.

Second, our therapeutic antibody, garetosmab which has demonstrated an ability to stop in its tracks, a progressive and debilitating disease in which the soft tissues of the body are replaced by bone, so-called Stone man disease leaving people unable to move their muscles and even to breathe.

And this approach can also be potentially approved later this year. So as I said, while these may not have huge commercial impact for us at Regeneron, it really inspires us to keep doing what we're doing, which is trying to bring innovative new approaches to the biggest opportunities, but also to those with the greatest need. So with that, I'd like to thank everyone for their attention and hand it over to Chris for some Q&A.

Great. I appreciate all the comments there. Maybe start with the discussion, I want to touch on I&I and appreciate some of the updates we had there. Maybe first, can you just clarify these incremental opportunities you're talking about? Are these generally going to be part of the Sanofi collaboration? Or it seems like some of these are going to be developed by Regeneron on a stand-alone basis? Can you just talk through the -- how you thought about going forward with these.

Sure, Chris. So obviously, the total unique programs have nothing to do with Sanofi. Some of the things that George referred to as exciting new targets that have nothing to do. But closely related to DUPIXENT, some one in and others not. The long-acting DUPIXENT because it targets the IL-4 alpha, that's covered by the collaboration. The IL-13, the IL-4, the bispecific for IL-13, IL-4, those are not part of the collaboration. That doesn't mean they can't be part of the collaboration in the future, but right now, they're not.

And can you just elaborate a little bit more on those novel agents, what you're hoping to achieve in terms of profile relative to a fairly high bar that you have with...

Yes. You hit the nail on the head. It is very, very difficult to improve upon DUPIXENT. It is the most broadly used antibody in the world, 1.3 million people take it. It has a remarkable track record of safety and efficacy driven by the genomics that George referred to, developed in collaboration with Sanofi.

So it is hard to beat that. When you have such great efficacy, 8 for 8 in clinical trials more coming and a wonderful really remarkable safety profile. But nevertheless, there may be some settings where you would like to have be able to give a longer acting [indiscernible] as an example, maybe instead having to give it every couple of weeks, you could get every couple of months or every quarter or longer, and that you may be able to get there without some of our long-acting agents. It is hard to imagine that one can actually improve upon the safety and efficacy, but we could improve upon some of the convenience factors.

And maybe just last one, the time lines around this, I think you're going pretty aggressively forward. It sounds like how quickly can you move this through programs?

We know a lot about how to develop this drug, having done the initial development in atopic dermatitis. We know what kind of patients you should enroll. We -- the FDA is familiar with George's platform. We put more antibodies from a consistent platform, I think, than anybody else in the world. .

So we know how to get this through. We know how to move it quickly. We know how to identify the right patients, and we're expediting the first one, the IL-13 move very quickly.

We certainly expect to be competitive with anybody else in the field. And we think that because of our platforms and technologies. These are the best reagents. I mean we've compared them -- they're fully human, they derive, as Len says, from an established platform and they have incredible biophysical properties. I don't think there's better antibodies in the world than the ones that we deliver. .

Excellent. Maybe just a couple on EYLEA quickly. Now you have RVO and the 4-week label enhancements, Talk about what that means for the HD franchise going forward and how we should think about uptake from here? .

So what Chris is referring to, we've got, I would say, 2 of the 3 enhancements we've liked that is we've got be able to use the drug monthly, if necessary, that's on label as well as the approval for about 10% to 20% of the market. which is RVO, retinal vein occlusion. Those are very important. The third leg of that enhancement tool will be, we hope, approved in -- early in the second quarter or sometime in the second quarter, which will be the prefilled syringe.

All of those put together, we have made great progress in getting people to accept that the drug of choice is EYLEA HD. I think it's the only branded product that's actually growing, at least based on last quarter's data. I think that the team is very excited. We went from about a year ago, 1/4 of our franchise sales were in HD to now we're somewhere around 50% and we expect that to keep growing.

Obviously, with competition, biosimilar competition coming for 2 milligrams -- so there's some out there already, but more coming later in the year. We're trying to get as much HD traction as we can, and it seems to be going quite well. We have tried to deal with the foundation issue. This past quarter, we had put up a big match. Nobody had sort of were willing to go for it. But now in this last quarter, there was a $60 million contribution, which we matched. So that's also going to contribute.

I think the monthly dosing regimen is actually going to make a big difference because since payers weren't covering monthly dosing, even though only about 5% of patients because EYLEA HD is so long acting. A very small number of patients need to go to monthly, but physicians were hesitant to start them on something and then have to switch and get approval for a different product. So they weren't starting many patients on EYLEA HD. I think now that they don't have to worry about that, many more will choose what the data says is the best and longest-acting product for most patients. .

Great. And maybe just one last follow-up on the foundation front. Do we have funding in place at this point to start to reverse some of the similar Avastin dynamics that were playing out last year. .

Well, as I said, finally, in the fourth quarter, there was a $60 million contribution, which is a large contribution, which we matched that puts $120 million in there, and hopefully, that will continue.

Excellent. Pivoting over to LIBTAYO. You had your Phase III results in adjuvant CSCC were pretty impressive. It seems like KEYTRUDA had some struggles in the same indication. Just what do you think contributed to that difference between what we saw with KEYTRUDA versus what we saw with your drug?

Well, it gets back to the point that I was making about our antibodies for longer-acting IL-13 or 4 or even our next-generation dupi. A lot of people have a mistaken belief that it's easy to make antibodies and all antibodies are created the same. I think what the data, if you look at it, as Len said, more fully human antibodies have been approved from our platform than any other platform, 10% to 20% of all approved antibodies come from our platform.

And we repeatedly are producing the best agents with the least number of problems such as ADA, antidrug antibodies and so forth. And so when you have 2 antibodies against the same target, they're not necessarily the same. And across many programs. Remember, other people have tried to make DUPIXENT like antibodies that all failed, including Amgen. So it's not that easy to always make the best antibodies. Our platform and our people have perfected that ability. And that's why our antibodies seem to work in places where other antibodies against the same targets don't work.

So on that commercial opportunity, how big of an opportunity is that incremental indications.

Yes, I think that could be a blockbuster opportunity in and of itself, probably at least 10,000 people would qualify and label there.

Yes. Excellent. Talking about novel programs year LAG-3, one of the big updates we're waiting for this year. Can you just discuss your confidence in a program here that's going to show differentiation from existing standard of care? I guess I just -- given the extended time lines here, are you feeling increasingly confident you have a profile that can really separate from uptake?

Well, our confidence comes from our previous trials that had showed substantial numbers of patients treated, where it looked like the combination cross study looked better than previous standards of care. Delays in the program have just been because event rates were slower in this trial than we planned or anticipated. That could either be good or bad. We won't know until we unblind the data. But we remain very excited, because of the previous trial experience we have with these agents.

George, where we powered for survival there or other or not? .

Yes. So that's another important point. So in the initial analysis, we'll do our first interim for overall survival, but we are, we believe, adequately or more adequately powered to pick up a survival advantage, even if it was on the order of magnitude of what was seen with the previous LAG-3 combination. .

And that would, from a market standpoint, really .

That will make a difference, since they do not have a survival benefit.

And just as we frame out this opportunity, can you talk through the size of the opportunity that you would see here in melanoma?

Yes, it's difficult to quantify, but it is a big -- it is a blockbuster opportunity for sure. We also have the the adjuvant melanoma trial, which I guess comes a little bit later. But if you put it all together, our unique data in skin cancer, we were the first with the market leader. Our data in adjuvant in CSCC, where KEYTRUDA was -- it wasn't like KEYTRUDA was close. KEYTRUDA was at 0, and we were 68% reductions with [indiscernible] or whatever it was. So we really, I think, have a big halo effect now going on in the skin cancer, skin oncologist framework. Hopefully, we get some good data out of these 2 upcoming trials.

Excellent. Let's come back to OS. Will we see that OS data with this initial update? Or is it independent .

Only if it's positive, but it's probably not powered in the first update be unlikely. .

Okay. The other one, I guess, in this indication, non-small cell, how do we think about the decisions go forward there? Is part of this wanting to see some of this melanoma data and how the profile go.

We want to see the melanoma data, but I think if we had time, we could tell you that, that's far more speculative and risky. And it's not something that we're counting on there.

Okay. adjuvant melanoma. How -- the risk spectrum? How do you see that? Is it...

More likely than the lung. So you agree with that, George?

Factor XI is going over there. Can you talk, maybe first of all, we're going to see some competitive readouts over the next 12 months. How much read-through should we be thinking about for your programs versus some of the oral data sets we're going to see?

Well, I think there's a big difference between the orals and the antibodies. We can achieve much more specific and complete blockade. They inhibit other proteases, other molecules, and it can't get as deep inhibition as we get. And when you're comparing antibodies, we specifically designed our antibodies.

So one of our antibodies looks biochemically and by all measures to be able to achieve most complete blockade. The other one is designed to get better efficacy by targeting a different aspect of the target. And so I think that having this balanced approach, I think there's actually room for both antibodies, because as I tried to explain, the reason people don't take anticoagulation is because they're afraid of bleeding.

For those people who are most concerned about anticoagulation, we think one of our antibodies may be able to provide them the best efficacy. For those who want anticoagulation, but maybe they want very little, maybe no bleeding risk based on the genetics or other antibody may be able to provide that. So we may be able to provide exactly what people want. They want to focus on Intellia. We'll give you that. If you're totally worried about bleeding, we may be able to offer you something that will significantly impact your clot risk, but may very much eliminate your fears about bleeding. So we think both of these could be blockbuster opportunities independently. And it's different segments of the population.

It's worth going back to looking at this slide when you have a chance because on that slide, there's evidence that there's less bleeding in a standard aspirin-induced bleeding with a factor X drugs cause increased bleeding and doesn't. And there's evidence to better anticoagulation in 2 settings as well.

So we have the preliminary proof-of-concept data. I think it's going to be exciting to see we probably have a half a dozen Phase III plan.

I think that's an important point. A lot of people are very much focused on stroke prevention and atrial fibrillation. We think if you have safer anticoagulants, they can be used much more broadly. So we think, in fact, the other opportunities outside so-called staff may end up dwarfing the staff opportunity. Everybody is focused on where the puck is now, but with safer anticoagulation, we imagine that the puck may be able to help many, many more people in the future.

Excellent. Last few minutes here on me switch over to the C5 program. First, can you talk about MG and just your thoughts of how you see your asset fitting into the broader MG landscape?

Well, I think the thing that's remarkable as we briefly went over -- but it seems like in different diseases, you need different degrees of blockade to optimize efficacy, which also allow you to get perhaps even a safer agent out there. So we showed is that in PNH, you need complete blockade. And there, you need the double combo. What we actually showed that, if anything, something that achieved about in certain assays, about 70% to 75% blockade was the best agent side by side to complete blockade, but also cross study to every other C5 agent that's been tried out there.

And that might -- it takes a long time to prove it, that might actually come with better safety, which could be an incredible profile. But to remind you, not only do we have the best data compared to C5. But when you look at the other class, the FcRn class of antibodies, those are given in 2 ways. If you an optimized safety, they're given for a short period of time and then patients are giving a drug holiday. So you get a U-shaped dose response curve. Essentially, the patients get back their normal level of disease before you retreatment.

I'm not sure if that's a a desirable profile where your disease is constantly waxing and waning or you can give lower levels of it for safety reasons, still in the extension studies of those programs, they did also see safety events. But when you give those levels, then you see much less improvement in this famous MG-ADL score. So we may have an agent that's not only best-in-class among the C5s. May, in the long term, we'll have to prove it to have a better safety profile, but may have better both safety and efficacy profiles compared to the other major competitive class in this area.

So I think it's a very exciting opportunity. And as I said, not only is it an independent opportunity in PNH given in a different way as a combo, but we're exploring it, as Len said, in a variety of ways in geographic atrophy as well. And there could be, once again, we'll see. We like tailored approaches. We like not just trying one thing and hoping it works trying a few different things and see which one works better.

Excellent -- on that GI program, just your confidence in the approach there and as we approach that data later this year? .

Well, the data will speak for itself. We're about 6 months or a little bit more away from that data. But I think the fact that we think we're going to do at least as well as the existing agents, but perhaps with a better safety profile, at least from the fact of calling occlusive vasculitis in the retina, I think there's reason to be excited about that. So we're very much looking forward to that data.

Excellent. Well, I appreciate the update on everything here and exciting year ahead for the company. So thanks again for joining us.

Thank you guys.

Welcome to the Regeneron conference call to discuss its Lynozyfic development program. My name is Shannon, and I will be your operator for today's call. [Operator Instructions] Please note that this conference call is being recorded.

I will now turn the call over to Ryan Crowe, Senior Vice President, Investor Relations. You may begin.

Thank you, Shannon. Good morning, and welcome to our Regeneron Roundtable Investor event, a series of presentations spotlighting key opportunities across our pipeline. Today, we will focus on our Lynozyfic development program in multiple myeloma and precursor conditions.

Today's roundtable features key leaders from Regeneron, including Dr. George Yancopoulos, Board Co-Chair, President and Chief Scientific Officer; Dr. Andres Sirulnik, Senior Vice President and Clinical Development Unit Head, Hematology; Dr. Karen Rodriguez-Lorenc, Vice President of Malignant Hematology Therapeutic Area Leader; and Justin Holko, Senior Vice President, Oncology and Hematology Commercial.

Before we begin, I would like to remind you that remarks made today may include forward-looking statements about Regeneron, and each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in such statements.

A description of risks and uncertainties can be found in Regeneron's SEC filings. Regeneron does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

With that, I will turn the call over to George.

Thank you, Ryan. I will begin with a brief introduction to Regeneron's broad and diversified Heme-Onc pipeline. We won't be focusing on hematology today. Andres, who leads both efforts, will then discuss the current multiple myeloma landscape and our strategy for revolutionizing myeloma treatment with Lynozyfic, our BCMAxCD3 bispecific antibody. Karen, who leads the malignant hematology clinical programs at Regeneron, will review our ambitious Lynozyfic development plan, including our best-in-class data and ongoing development in relapsed/refractory multiple myeloma, our differentiated development plans in earlier line settings and our visions for addressing myeloma precursor conditions.

Justin will then review the commercial opportunity for Lynozyfic, and Andres will conclude by summarizing our development strategy in linvoseltamab's value proposition. We will then open the call for Q&A. Through decades of research and investment, Regeneron has built a broad hematology pipeline spanning multiple areas, including the hematological malignancies, coagulation disorders, transplantation and immunomodulation, complement and other emerging areas with assets across early, mid- and late stages of development.

In our last roundtable, we took a deep dive into our emerging Factor XI program in anticoagulation settings, an exciting program that exemplifies the progress we are making in hematologic disorders using our differentiated technologies to drive innovative scientific breakthroughs. In heme-onc, our turnkey technology platforms have allowed us to be a leader in monoclonal antibodies and particularly in bispecific.

Recall that we were the first to advance a fully human bispecific antibody into the clinic and have continued to build on our knowledge and expertise over time. Today, we will focus on Lynozyfic, our cornerstone asset in multiple myeloma, which we believe has the potential to radically reshape myeloma treatment and potentially eliminate myeloma entirely for treatment of precursor conditions.

Our differentiated and ambitious development plan positions us well to deliver on our vision, which Andres will now out. Andres?

Thank you, George. I will begin with an overview of the existing multiple myeloma treatment paradigm and our strategy with linvoseltamab. Turning to Slide 8. Today's myeloma treatment landscape is highly complex with that complexity increasing as patients have progressive disease and move through lines of therapy.

Standard of care for transplant eligible patients in first-line multiple myeloma includes triplet or quadruplet combination regimens based on CD38 antibodies, followed by an autologous stem cell transplant and maintenance therapy until progression with monotherapy, doublet or triplet combinations.

Patients ineligible for transplant receive one of several toxic multidrug combinations until progression. As patients progress, the standard of care becomes increasingly unclear with patients receiving a range of intense complicated combination therapies in hopes of achieving a response. There is a clear unmet need for simplified, effective options for -- that provide patients with less intense regimens that reduce the treatment burden and deliver simpler treatment optionality for physicians, a need which we believe we will be able to meet as we progress our linvoseltamab development program.

As discussed, we have leveraged our unique scientific expertise to identify and develop a highly differentiated BCMAxCD3 bispecific antibody, which is the foundation for our strategy in multiple myeloma. As we lay out on Slide 9, our aim is to transform myeloma treatment with simplified regimens that deliver deep durable responses. With our recent approval, we are now establishing Lynozyfic in the late-line setting, where we plan to build market share and generate positive patient and physician experience.

We are advancing into early lines of therapy with a differentiated development plan and encouraging emerging data, which Karen will detail shortly. And in the long run, we believe we have a unique strategy to treat myeloma precursor conditions to prevent progression to malignant disease, potentially eliminating myeloma completely.

We believe this strategy supports our ambition to provide significant benefit to patients and establish linvoseltamab as the therapy of choice in the large and competitive multiple myeloma market. I will now pass the call to Karen to discuss our data and development plans in detail. Karen?

Thank you, Andres. I will begin our efforts in late-line multiple myeloma before moving to our development plan in early lines of therapy then to precursor conditions and amyloidosis. Noting that these are cross-trial comparison depicted on Slide 11, Lynozyfic has demonstrated a differentiated profile compared to other BCMA bispecifics in relapsed/refractory setting.

We have deep and durable responses with nearly double the complete response rate of other bispecifics a similar follow-up and in general manageable safety profile, including the lowest rate and severity of cytokine release syndrome or CRS. Lynozyfic has also offered patients shorter hospitalization requirements, a simplified step-up dosing schedule, a convenient IV administration with the opportunity to extend to monthly dosing for patients with a very good partial response or better, only 24 weeks and at least 17 full doses.

The strength of this late-line data from the LINKER-MM1 study in highly refractory patients give us confidence that linvoseltamab may be the best-in-class agent and that our approach can translate to profound efficacy in early line setting. Moving to the Slide 12. We have continued to follow patients in this study and at 20 months of median follow-up, the overall response rate reached 71% and the complete response rate reached 52%.

Patients respond quickly to Lynozyfic with a median time to response under 1 month. And those responses are durable with a median duration of response of 29 months. Importantly, we have seen responses in these patients deepened over time, a very well-known phenomenon in myeloma treatment. With an additional 10 months of follow-up, the complete response rate from linvoseltamab observed at 21 months was 52% versus 45% at 11 months of follow-up.

The tendency for response to deepen was also observed in Teclistamab, although its 46% complete response rate reported at 30 months was in line with the complete response rate observed for linvoseltamab after only 11 months of follow-up. Linvoseltamab profound efficacy and deepening of response over time in this setting give us further confidence in emerging data in early lines of therapy. We received accelerated approval for Lynozyfic in the United States in July 2025 based on the results of the LINKER-MM1 study, and our confirmatory Phase III LINKER-MM3 study is now fully enrolled.

This study includes approximately 410 patients comparing linvoseltamab monotherapy against standard of care elotuzumab, pomalidomide and dexamethasone combination or LOPD, which has historically shown an overall response rate of 50%, a complete response rate of approximately 8% and a progression-free survival of approximately 10 months in third-line patients. Importantly, because the study allows the inclusion of patients who were previously treated with anti-CD38 antibodies such as daratumumab, we have selected a comparator in this setting that does not include CD38 therapy.

Over 50% of patients enrolled in this study are considered refractory to daratumumab, meaning they progress while on therapy. we believe using the comparator helps to ensure linvoseltamab will be clearly able to address the many CD38 exposed and refractory patients in this setting. We look forward to the results of LINKER-MM3 study, which are anticipated in 2027. Moving to Slide 15 on our efforts in early lines of therapy.

Emerging data in the first-line and second-line setting has demonstrated profound responses rate for patients in Lynozyfic monotherapy or in simplified combinations even with limited follow-up. I will first detail second-line data for the differentiated linvoseltamab combination with carfilzomib, a proteasome inhibitor, which included patients who have progressed after at least 2 lines of therapy and were double class refractory or triple class exposed.

Which was reported early this year at the ASCO conference, along with our plans to advance into Phase III studies. I will then review the data we have generated in the first-line setting with linvoseltamab monotherapy, which was just presented at the ASH conference this past week and detail our differentiated development plan in first-line patients.

On Slide 16, you can see the encouraging early data we reported at the ASCO conference early this year for a differentiated combination of linvoseltamab with carfilzomib. The combination demonstrated an overall response of 90% and a complete response of 76% across all linvoseltamab doses with responses continue to deepen with additional follow-up. Notably, at 200-milligram dose, 3 of the 5 patients have already achieved a very good partial response or better with less than 6 months of median follow-up, which we expect will continue to improve over time.

We've also observed a strong early MRD negative results with 5 of the 7 patients evaluable achieving MRD negativity to the 10^-5 sensitivity. Patients respond quickly to these combinations with a minimum time of partial response or greater of less than 2 months. Responses has also been durable with 87% of the patients maintaining a response at 12 months.

Safety was generally consistent with expectations based on the known profiles of each of the drugs and no new safety signals have been observed. Cytokine release syndrome was the most common non-hematologic treatment-emergent adverse event and most cytokine release syndrome occurred prior to the patients starting carfilzomib. There was no Grade 3 or higher cytokine release syndrome observed. There was 1 patient with a Grade 4 thrombocytopenia at the 100-milligram dose during tumor lysis syndrome in a patient with a very elevated baseline serum free light chain.

This fully resolved and the treatment was resumed at the same dose. This exciting data is informing our Phase III LINKER-MM5 study with the plan to initiate at the beginning of 2026, comparing this combination to linvoseltamab monotherapy and physician choice standard of care. Pivotal data from this study are expected in 2028.

We believe this differentiated combination will provide patients and physicians with an important new treatment option in this setting that does not rely on an anti-CD38 antibody, making it valuable option for many second-line patients who are CD38 exposed or refractory. Moving now to first-line setting on Slide 17. We report exciting new data last week at ASH Annual Meeting for our LINKER-MM4 study in newly diagnosed multiple myeloma, the first study to evaluate a BCMA bispecific as monotherapy in this setting.

In the study, newly diagnosed patients with no prior multiple myeloma treatment who received linvoseltamab monotherapy at 200 milligrams achieved an overall response rate of 86% and a complete response rate of 43% with only 9 months of follow-up, with responses deepening over time as expected. Across all dose levels, over 70% of patients achieved a very good partial response or better despite limited follow-up.

Depth of the response is also confirmed by the encouraging MRD negativity with all 9 patients dosed at 200 milligrams with available samples who have a very good partial response or better achieving MRD negativity at the 10^-5 sensitivity. Across all dose groups, 95% of evaluable patients with VGPR or better achieved MRD negativity status. Similar to what was observed in both the second line and late-line setting, patients responded quickly to the treatment with a median time to partial response or better of just over 1 month. The safety profile of linvoseltamab remains generally manageable with no new safety signal identified. The incidence of adverse events were similar across dose levels, and there was no dose-limiting toxicity or Grade 5 treatment emergent adverse events.

Cytokine release syndrome was the most common non-hematologic treatment-emergent adverse event, of which most cases occurred during the step-up dosing and all were grade 1. These results support initiation of 3 Phase III trials in first-line setting, LINKER-MM6 in transplant ineligible patients, LINKER-MM7 and 8 in transplant eligible patients. Slide 18 depicted Phase III LINKER-MM6 study in transplant ineligible patients, which is sponsored by the European Myeloma Network and is now enrolling.

The study will evaluate linvoseltamab monotherapy after a short course of standard of care debulking therapy compared to CD38-based standard of care multiple combination data that is commonly used in this setting. Our goal is to simplify frontline therapy and provide patients and physicians with option for a less intense monotherapy regimen following a limited debulking treatment regimen that remains a strong efficacy while potentially improving upon safety.

Linvoseltamab is the first and only BCMA bispecific being evaluated as monotherapy for transplant ineligible patients rather than a combination approach, which is supported by the remarkable results in newly diagnosed patients reviewed previously. Pivotal data from this study is also expected in 2028.

Moving to Slide 19. We are also advancing a differentiated strategy from frontline patients transplant eligible patients, where standard of care consists of an intense CD38-based triplet or quadruple combination, followed by a burdensome autologous stem cell transplantation and maintenance therapy.

Our strategy in this setting aims to give physicians increased flexibility to provide patients with convenient, less intense regimen that do not compromise efficacy. In the LINKER-MM7 study, we are evaluating linvoseltamab monotherapy in the post-transplant maintenance setting with a differentiated approach to potentially enable a longer treatment-free period for patients, significantly reducing patient burden while maintaining the efficacy.

The LINKER-MM8 study will evaluate simplified and less intense linvoseltamab combination both with and with an alternative to transplant as compared to standard of care autologous stem cell transplantation treatment, including standard of care induction, consolidation and maintenance regimen. First, we will evaluate less intense linvoseltamab combination in conjunction with transplant using this combination in the induction, consolidation and maintenance setting.

We will also evaluate the potential for differentiated simplified linvoseltamab combination as an alternative to transplant, which may significantly reduce burden. Together, this regimen could enable significant improvement physicians optionality with less intense treatment, both with transplant as an alternative to the transplant. Both studies are expected to initiate in the first half of 2026 and if successful, have the potential to dramatically reshape the treatment paradigm in frontline setting.

Moving now to our development strategy in amyloidosis and precursor conditions. We are pioneering treatment of amyloid light chain amyloidosis and precursor conditions like high-risk smoldering multiple myeloma and monoclonal gammopathy of undetermined significance or MGUS. Early data that we have generated suggests significant potential for linvoseltamab in this setting, where there have been limited progress developing new treatments.

Our differentiated approach supports our long-term vision to potentially eliminate myeloma through early intervention, preventing progression to malignant disease. As shown in Slide 22, early data presented from the Phase II LINKER-SMM1 study in high-risk smolder in multiple myeloma show linvoseltamab has a profound efficacy effect with very limited follow-up.

With median follow-up of less than 4 months, linvoseltamab 200-milligram monotherapy demonstrated an overall response rate of 100% with a complete response rate already reaching nearly 40% -- this represents best-in-class potential compared to the approved daratumumab monotherapy, which achieved only 9% complete response rate in the same setting with a median follow-up of 60 months -- 65 months, sorry.

Through -- though there is currently lack of head-to-head data in this setting. Based on the strength of this data, we plan to initiate a pivotal LINKER-SMM2 study in the first half of 2026, comparing linvoseltamab monotherapy head-to-head with daratumumab monotherapy.

Positive data could establish linvoseltamab as the standard of care in this setting, potentially placing linvoseltamab ahead of other BCMA bispecifics in the treatment algorithm. We are also evaluating linvoseltamab monotherapy in monoclonal gammopathy of undetermined significance or MGUS, a common and often asymptomatic precursor condition to myeloma as well as in non-high-risk smalling multiple myeloma.

Initial proof-of-concept data is expected next year, and if successful, could represent a significant long-term opportunity for linvoseltamab as a prophylactic treatment to prevent progression to malignant myeloma. Moving now to amyloid light chain amyloidosis, a related condition where abnormal plasma cells produce an excess of misfolded light protein, creating amyloid, which deposit in the tissues and organs, leading to severe complications.

We have created compelling early data with linvoseltamab monotherapy in the second-line amyloidosis patients. a majority of whom previously received daratumumab containing combination, showing profound reduction in mean involved free light chain to normalized level in just 15 days. For comparison, daratumumab-based quadruple combination in the first-line amyloidosis patients took approximately 5 months to approach mean involved free light chain normalization.

The pivotal LINKER-ALA2 study is enrolling with that expected in 2029. If successful, this could allow linvosltamab to address a disease where significant unmet need remains and continue to reshape the treatment of myeloma and related conditions.

In summary, we have an ambitious differentiated development plan spanning across life of myeloma therapy and intraprecursor conditions, which we believe has the potential to establish linvoseltamab as the therapy of choice in the treatment of myeloma and related conditions.

I'll now pass on the call to Justin to discuss the commercial opportunity.

Thank you, Karen. Let's move to Slide 25. I'll begin with our recent launch of Lynozyfic in relapsed/refractory multiple myeloma, where we have seen strong early momentum. Enrollment in the REMS program has been strong with more than 300 institutions now certified. We've also secured early formulary wins at key institutions with Lynozyfic now added to over 35 formularies and in some cases, with preferred status.

Physician feedback and adoption in the late-line setting has been favorable, not only because of Lynozyfic's differentiated clinical profile, but also because of its patient-centric hospitalization requirements and dosing. However, the late-line setting is just the beginning for Lynozyfic. As you can see on Slide 26, there is significant opportunity in the estimated $30 billion multiple myeloma market, a market which we expect to continue to grow in the coming years.

While we are excited about the opportunity to provide profound benefit to late-line patients, the more significant opportunities will come as we advance into earlier lines of therapy. Today, the first-line and second-line settings represent the largest share of this opportunity with each setting representing an estimated market of over $10 billion.

Our strategy is to generate a firm foundation of positive physician and patient experience in the late-line setting and then advance with approvals in earlier lines where the market opportunity is significantly larger. We believe upcoming pivotal readouts from the first- and second-line trials detailed by Karen will be key catalysts for unlocking this value. We also believe our differentiated strategy in precursor and related conditions could add meaningful additional commercial opportunities for Lynozyfic.

Smoldering myeloma and ALA represent significant untapped commercial markets, and that early data suggests the potential for Lynozyfic to have a differentiated efficacy in these settings. We look forward to data readouts and potential launches in these settings in the coming years. Additionally, as Karen mentioned, successful proof-of-concept data in MGUS could open up another long-term commercial opportunity.

In summary, we are making encouraging progress with our launch in late-line myeloma and Lynozyfic's paradigm-changing potential represents a major commercial opportunity for Regeneron, both in early lines of multiple myeloma in ALA and in precursor conditions such as smoldering myeloma and MGUS.

I'll now turn the call back to Andres for some closing remarks.

Thank you, Justin. We previously reviewed the complex and confusing treatment algorithm in myeloma. but our vision is to significantly simplify this treatment landscape. We believe linvoseltamab provides a clear and differentiated value proposition in every line of therapy with the potential to provide better outcomes and convenience to patients and increase optionality to physicians.

As Karen reviewed, we have generated data across the treatment landscape, and we have been pleased with the consistently remarkable efficacy across lines of therapy. We have taken a bold approach in our development, moving to early lines and precursor conditions with monotherapy or simplified and less intense combinations.

The data we have generated has been remarkably consistent and profound with as high as 100% molecular remissions achieved very quickly across different lines of therapy as well as in high-risk smoldering myeloma and amyloidosis. The data generated to date supports our ambitions to establish linvoseltamab as the backbone therapy for treatment of myeloma as well as precursor and related conditions.

Finally, we continue to advance our comprehensive development plan with 8 registrational studies underway or anticipating to initiate in the next 6 months, spanning across lines of therapy and into precursor and related conditions.

We look forward to a steady cadence of data in the coming years, particularly as we leverage the surrogate endpoint of MRD negativity with the goal to pull forward time lines and provide these options to patients and physicians as quickly as possible.

I will now turn it back to Ryan.

Thank you, Andres. This concludes our prepared remarks, and we will now move to the Q&A session of the call. To ensure we are able to address as many questions as possible, we will answer one question before moving to the next. limit. Shannon, can we please move to the first question?

[Operator Instructions] Our first question comes from the line of Tyler Van Buren with TD Cowen.

This is Nick on for Tyler. For me, J&J presented the results from the MajesTEC-3 trial at ASH yesterday. However, 95% of patients were dara naive. What do you think your linvo plus dara data suggests about the potential efficacy in a more real-world dara-exposed patient population?

So thank you for the question. So your question is in reference to the data from MajesTEC-3 with more like naive patient population to anti-CD38 versus the data that we are currently generating. So it's difficult to compare because of the patient population from the 2 different studies are not exactly the same.

What we are trying to do in our clinical trials is to enroll patients are representing the patient populations that are going to be treated in the future with our monotherapy or combinations. And we are encouraged by the observations that we have on the efficacy and safety and some of those combinations are going to move forward to pivotal Phase III trials as the one that we previously discussed with [indiscernible].

Thank you, Karen. Next question please.

Our next question comes from the line of Alexandria Hammond with Wolfe Research.

So I think there's a lot of growth with many community centers still not using bispecifics. As you try to kind of expand into the community, what have you been hearing as the reason for reluctancy on their part to use this bispecific -- and how do you think Linvo will be able to kind of address those concerns? And just lastly, how difficult is it for these centers and their patients to adhere to the REMS program?

Thanks, Alex. Justin, maybe you want to take that one?

Sure. I would say the first thing is that we are seeing significant more utilization of bispecifics in community. Clearly, this class is being used in multiple myeloma, in lymphoma as well as in some solid tumors. And so it was a bit of an inevitability that more and more physicians would want to get their hands on these really important and powerful treatments.

What has typically held some of these groups back historically is that you have hospitalization requirements, in which case, there may not be appropriate monitoring in place -- and there's also just capacity constraints when considering those types of requirements. When you look at the profile of Lynozyfic, whether a patient is going through step-up dosing in an academic center or in community, what's clear is that having only those 2 days of hospitalization and monitoring is an advantage compared to some of the more laborious requirements for some of the other bispecifics.

So in the end of the day, we are seeing utilization grow within community, and it's through the help in part as a result of the -- again, the patient-centric dosing and the less hospitalization requirements that we have for our step-up dosing.

Thanks, Justin. Let's move to the next question, please.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

This is Shrunatra on for Salveen. So at ASH, we also saw some late-line disease data from AbbVie and AstraZeneca's assets, pretty limited, but also interesting. Just your thoughts on how that data compares against linvoseltamab's profile and how you think those assets might impact the late-line competitive landscape in the future if they're approved.

So your question is in reference to the other assets that were also presented in relapsed/refractory multiple myeloma. Can you please confirm?

Yes.

So we are very encouraged by the data that we have in late line therapy with our depth of response like 52% of the patients reaching CR and also the depth based on MRD negativity. So we understand that there are also other players that are coming, but also our data in initial lines of therapy with monotherapy are very encouraging with not only the efficacy, but also the safety that looks even better than the relapsed/refractory.

So for us, and there is room for getting into early lines of therapy coming with combinations that are less burdensome and providing this optionality for the treatment. I think that all in all, we are very happy with the linvoseltamab information that is generated because, again, it's not only the efficacy and the safety profile, but also the convenience, the shorter hospitalization and relapsed/refractory. So I think that all in all, it is providing a good option for physicians and for patients.

Let's move to the next question.

Our next question comes from the line of Cory Kasimov with Evercore ISI.

This is Josh on for Cory Kasimov. What has FDA feedback been like in regards to MRD negativity as an endpoint? And then I'll squeeze an extra one here. When can we see a subcu formulation for linvoseltamab?

So we are currently -- this is Andres. We are currently working on a subcu formulation. So eventually, we will be generating data. We are generating data, and we'll be presenting that data in due course. In terms of the feedback from MRD as an acceptable surrogate endpoint for an accelerated path for potential approvals, I think that at the moment, that has been the case and accepted following the ODAC that took place now almost a year ago.

And in many of our pivotal studies that we have described today, MRD is our primary endpoint for which we plan to potentially submit in the future.

Our next question comes from the line of Evan Seigerman with BMO Capital Markets.

This is Conor MacKay on for Evan. I guess following some of the LINKER-MM4 data you presented this week at ASH, can you maybe share a little bit on how you're thinking about the use of bispecifics in earlier lines of therapy? In the context of these data and also maybe how you're thinking about sequencing versus CAR-T.

So we consider that, as you know, currently, the treatment paradigm for patients in initial lines of therapy is quite cumbersome as we were discussing in the case of transplant, the patients are receiving triple or quadruple combinations, high-dose chemotherapy followed by autologous stem cell transplantation and then consolidation and maintenance.

So it's quite a heavy treatment. And what we see is that probably the bispecifics can contribute on decreasing the intensity on the therapy and providing even better efficacy and with a good safety profile. So I personally think that these patients are going to transition into early lines of therapy with a very good option for physicians and for patients. And in reference to the use of CAR-T or if there is any sequencing as what we know is that, yes, bispecifics are also working well in that setting.

So yes, I think that they are more like a momentarian for the treatment of these patients. But I think that we need to also highlight that the bispecifics are providing an off-the-shelf option for many more patients or for a broader group of patients. So I think that all in all, it's like a good optionality of tools for physicians in the future to treat these patients in early line setting.

Yes. I mean maybe we should just give a little bit of a bigger picture, and it's a little hard to probably take in all this data and put it into context and understand the opportunity, and we're just hearing it in the early line with or without transplant eligible, ineligible and so forth. I think the thing that's really stunning about the data, I mean, it starts with how differentiated this bispecific is.

I mean we got to all remember, I mean, this is the history of Regeneron. We have many programs where we create the best-in-class reagent, the best-in-class antibody because we have technologies. We don't just take any one antibody, any one bispecific and move forward. We've screened thousands and thousands based on our technologies, which nobody else has access to. So for example, dupilumab, which is one of the, if not the largest, most highly prescribed antibody in the world, it succeeded where other companies, including Amgen, failed against the same exact target.

Why? Because all the antibodies are not the same and bispecifics are even more complicated. I think the big picture here is it's cross-study comparisons, but these data stand up pretty much historically over time. In the last line setting, what these guys are telling you is they have double the complete response rates with similar times of follow-up. That says that this bispecific is perhaps very different.

Just like Dupi was very different than the failed molecules from other programs. This is perhaps very different bispecifics than all the other BCMAs. And what you're seeing in monotherapy, and it doesn't matter which setting that they're looking at. They're looking at it in the first-line setting, you're looking at in the premalignant setting. You're looking at it in the later line settings in the second-line setting. They're producing MRD negativity rates that have really never been seen before.

And now the challenge is figuring out how in this very complex landscape with all these different lines of therapy and all these so forth to take advantage of something that by itself, I mean, the data went by pretty quickly. But for example, by itself, in many of these settings, the data as a monotherapy delivering molecularly negative disease, MRD-negative disease exceeds that of complex triplet and quadruplet regimens. That is really stunning.

And this is why you see a very complex large development path because we're trying to take advantage of it in all these settings. In almost all these settings, what we're trying to do is simplify the regimen. The regimens are so complicated right now. People don't even know what to do. They do various triplets, quadruplets and so forth. If you could simplify these things with single agents or simple double combination that the data suggesting might have even higher rates of producing molecularly measured negative disease, it can really change the treatment paradigm.

And what we're also seeing is the earlier you go, this bispecific behaves even better. So not only are we talking about going into the first-line settings, but we're talking about going to the premalignant settings where, as you've seen, stunning results in 2 weeks, you're making disease disappear in light chain amyloidosis, whereas with other approaches, more complicated and so forth, it takes months to get even close to that level.

Same thing in smoldering, we believe it's going to be even better in MGUS, where we may have the opportunity, for example, to do prevention, eliminate a very prevalent pre-existing condition that people are constantly dreading, Oh, I have MGUS, when might it convert to myeloma. If you have a safe and effective treatment that can essentially eliminate the disease safely in a large percentage of the patients, you can potentially eliminate the threat of this disease.

So we got to understand, this is very complicated. We can look at each individual study and try to look at the data in particular and so forth. But the big picture message is when you look at the data in the last-line setting as a monotherapy, it looks impressively different than anything that's ever been tried before in terms of any other bispecifics. You go to earlier lines of therapy as a monotherapy, you're still outperforming much more complex regimens.

And the opportunities that we're now seeing with very simple doublets are also incredibly impressive. And so this offers enormous opportunity to simplify regimens and go earlier and early in the disease course and maybe even eliminate the threat of disease in the premalignant settings.

Thank you, George. Let's move on to the next question Shannon.

Our next question comes from the line of Brian Abrahams with RBC.

This is Joe on for Brian. I wanted to touch on the safety profile in the newly diagnosed patients. So just wanted to hear your view on the rates of rates and severity of CRS and ICANS you saw how manageable these would be for centers in earlier line and presymptomatic setting. As I imagine, there would be a much higher volume of patients versus later line and what this means for patients' duration of hospitalization, if any?

And I wanted to just quickly touch on dosing frequency as well in earlier lines in the presymptomatic patients, given most patients seem to be responding to the therapy.

So you're asking about the safety profile and then if that is going to be correlated with hospitalization requirements. So in the case of linvoseltamab in the LINKER-MM4 study, we tested the 2 patient populations, transplant eligible and transplant ineligible patients. And the results in safety are very encouraging. In reference to cytokine release syndrome, we observed very few cases and all of them were only grade 1, which means like only fever.

There were no patients with Grade 2, Grade 3 cytokine release syndrome. We have a single patient with ICANS that was also a grade 1 and all the events recovered and the patients continue with the therapy in the same dose that they were previously receiving. So we hope that this enables us to have monitoring in the future instead of hospitalization because of the better safety profile that we are observing in initial lines of therapy compared with our existing data in relapsed refractory.

So in reference to the regimen, the regimen is starting with the weekly doses then following for biweekly doses and then monthly doses. And what we are trying to do in the initial lines of therapy is also trying to see -- to evaluate fixed duration therapy.

So by the way, a lot of people are focused on CRS and so forth. But obviously, one of the biggest problems that these patients are suffering from are infections. And you guys now have some experience in the newly diagnosed setting treating with your BCMA bispecific where we know these patients are prone at baseline because their marrows are so compromised and so forth to severe infections.

So maybe you guys can describe what is your experience now while you're dosing as patients are responding, what remarkable things are you seeing in terms of safety and infection rates there?

Yes. It has been remarkable is when we look at relapsed/refractory multiple myeloma with our bispecific. One of the notable findings was that infections decreased over time. Everybody thought that as you continue treatment with bispecifics, infections were going to increase over time. But actually, we saw that after approximately 6 months, the rate of infections decreased.

So there are many ways of thinking why that will be possible, but one of them is you have reconstitution of the marrow, you have a healthy individual and a better immune system. As we move into early lines of therapy and the data that we just generated in newly diagnosed showed us that actually the rate of infections decreased even earlier. So now we went from a decrease in infections on the first 6 months in the last line of therapy to a decrease on the rate of infections after 3 months.

Again, showing that as you clear the disease, patients are better off and infections actually go down instead of going up. So I think that that's also speaking to the safety and how important it is to bring to patients potential therapies that are not bothersome, that are potentially less toxic and why we are taking the bold approach of thinking of monotherapy in first line or less toxic combinations that may afford a better risk-benefit profile without compromising efficacy.

And as you say, Andres, I mean, it probably is about taking a sick bone marrow, a bone marrow that's been infiltrated that doesn't have the capacity to create, for example, all the white cells that you need to respond, neutrophils and so forth by getting rid of the disease, you allow the bone marrow to recur.

And as you said, the evidence suggests in the later-line patients because it's been a more long-standing disease and the bone marrow sicker takes longer for the bone marrow recover, whereas you're seeing in the early-stage patients, much quicker apparent recovery of immune function as measured by the decreasing rates of infection. So that's a really, really important feature.

While everybody is focused on CRS, the fact that you're actually almost paradox, but actually makes sense now in retrospect, you're actually decreasing infections. I mean that is actually quite stunning and quite unlike the other therapies. And we got to remember, drugs like daratumumab, the CD38 targeted agents, they're actually compromising neutrophil function and they actually increase risks of infection on their own.

So these are very important differentiators and reasons why it's important to pursue these minimal regimens that are using a drug that might actually not be harming in general, the rest of the immune system while it is eliminating the myeloma cells.

Thank you for those comments. Next question please.

Our next question comes from the line of Simon Baker with Rothschild & Company Redburn.

Just wanted to dig a little bit deeper into early feedback on Lynozyfic use. If you could give us some idea of the characteristics of patients and prescribers at this stage, particularly the split between community and academic center prescription, that would be really helpful.

Justin, do you want to take that?

Yes, happy to take that. So as you would expect, the majority of use right now really across the class is happening in the academic centers. And it's a bit of a mix in terms of patients seeing all of their dosing taking place there. There are some instances where patients come from the community, they get their step-up dosing within the academic to the community. You do have, in some cases, some community sites that are equipped and doing step-up.

That's still probably the minority right now. The patients that we're getting are probably typical to what you would see across this fourth and fifth line plus. They've been through a lot. And thus far, the feedback that we have is actually quite strong. We certainly get a lot of feedback on the -- as I mentioned, the convenience of the dosing and the ability to go out longer with good responses, but we really see strong feedback on the safety and the efficacy as well. So early days, but a lot of our metrics that we're tracking are at or ahead of where our competition was at a similar point during launch.

Thanks, Justin. Shannon, we have time for 2 more questions.

Yes. Before we go on to the question, I was just -- a question came up before about late-line relapsed/refractory and the use of other bispecifics and combined bispecifics and people are excited about that data. And I didn't want to say anything because I just wanted to look up and remind myself of the numbers.

But everybody is very excited about this combination, for example, of a GPRC5D and a BCMA which together in the late-line setting with about 12 months of follow-up are giving you about 79% overall responses and 53% complete responses. And people are excited about because it's doubling the rate of the BCMA bispecific by itself or at least that BCMA bispecific by itself. So I just want to remind you again, if you're excited about that combination data, which comes with a lot more toxicity.

I mean, severe, much more toxicities there. Remember, the Regeneron bispecific, which, as I said, different technology, fundamentally different, is delivering pretty much those numbers at a similar follow-up as a monotherapy. So I think we have to understand why we should be excited and other people are excited about adding more stuff to the point that we are already. And I think this is, I think, a really big take-home message.

I mean this is behaving fundamentally different, and it's approaching the numbers that you see when you start mixing other things together and layering on toxicity. So the big picture here is impressive efficacy as a monotherapy or with very limited combinations and hopefully safer combinations. So I think that, that's an example. People are excited about that bispecific combo. Well, you should be more excited about a monotherapy bispecific that's delivering very similar results.

Okay. Shannon, 2 more questions for us, please.

Our next question comes from the line of Geoff Meacham with Citibank.

This is [ Nishant ] on for Geoff. So following up on the earlier question in terms of sequencing in myeloma, where some physicians would prefer CAR-T and then BCMA bispecifics. So would it make sense at some point to include a cohort of CAR-T relapsed patients in the study given CAR-Ts are moving into earlier lines?

Sorry. So your question is if we are exploring data with post CAR-T with -- yes, we are -- okay, so we are already including a cohort in one of our studies with Post CAR-T data. And yes, that is being generated and it will be released probably next year.

But once again, the big picture is, I think we have to start realizing or recognizing -- I'm sorry, CAR-T is largely yesterday's news. I mean it's a very -- once again, a complex therapies, it's also a combination therapy. You have to give chemotherapy before you can give the CAR-T. That probably explains the incrementally slightly improved numbers that they get with a very complicated therapy.

There is really little evidence to suggest that they're actually giving better results and long-term results than you can get with the best bispecifics here. So I don't think we're talking about a future world where CAR-Ts and all their toxicities and problems with kidney and so forth are going to be moving to the early lines of therapy, okay?

You're talking about where bispecifics and particularly the best bispecific is going to be moving to the early lines of therapy and to premalignant disease and probably make CAR-Ts either obsolete or for late-stage salvage patients if they still have activity in that setting. So I think eventually, the whole thing is going to be reversed.

CAR-Ts are going to become yesterday's news. They may have some late line salvage opportunity. But there is no way that they're going to actually be competitive in the early line settings and the premalignant settings.

All right. Shannon, one last question for us, please.

Our last question comes from the line of Mohit Bansal with Wells Fargo.

And I think my question is also a little bit big picture. So oftentimes, when we have seen in competitive markets, I mean, the drug could be better, but at the same time, I think the development strategy could be more important. And it does seem like that there is a lot of emphasis on early-stage myeloma here.

Can you talk a little bit about the strategy there? I mean, how do you think you are differentiating the key parts of differentiation versus the competitor from J&J and all other bispecifics, which are also trying to do the same. But how would you think that you could be differentiated on the development side of things?

I mean I think the team did a good job in a very complicated setting to try to communicate this. I mean the point is that other people are pretty much looking at adding their bispecifics on top of existing regimens and so forth, creating even more complications. And why are they doing it? Perhaps as we just showed you, in the last-line setting, you have to combine somebody else's BCMA with the GPRC5D to get to where our bispecific is by itself.

When our bispecific is so active, we're thinking that we can now be using that either as a monotherapy. We've already told you the incredible response rates and MRD negativities that we're seeing in the first-line setting. We think that we can be doing that either in a monotherapy or with very limited combinations. That's the great differentiator here. And the fact that we can also go with this monotherapy into the premalignant settings and essentially remove the threat of myeloma disease.

Okay. Thank you, George. Unfortunately, that's all the time we have for today. Thanks to everyone who dialed in for your interest in Regeneron and our Lynozyfic program. We look forward to seeing you at our next event. Thank you very much, and have a great day.

This concludes today's conference. Thank you for your participation. You may now disconnect.

[indiscernible] of Citi Global Healthcare Conference. My name is Geoff Meacham, I'm the senior biopharma analyst here. We're thrilled today to have Regeneron. And speaking on behalf of Regeneron, we have CFO, Chris Fenimore; and we also have Ryan Crowe from the IR team. So welcome, guys.

Thank you Geoff.

Ryan is going to do a forward-looking, and then we'll get right into it.

Yes. Thanks, Geoff. Great conference you're running down here, and we're really excited to do the fireside with you. I just need to read this forward-looking statement, and we'll jump right in.

I would like to remind you that remarks made today may include forward-looking statements about Regeneron, and each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in such statements. The description of material risks and uncertainties can be found in Regeneron's SEC filings. Regeneron does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. With that, let's jump in.

All right. Okay. So Chris, let's first focus on maybe on the policy and the macro. We've had a lot of announcements from some pharma companies on manufacturing and tariffs and that kind of stuff, give us kind of an update of where you guys are with respect to either -- I know you made some announcements on manufacturing, but on MFN, price negotiations, just kind of the state of the kind of the world as -- from a policy context.

Sure. And again, Geoff, thanks for having us. So just to recap in terms of our commitment to domestic manufacturing and fostering employment in the U.S. We announced earlier this year about a $7 billion commitment in terms of both expansion of our R&D capabilities as well as domestic manufacturing. So some of that is tied up with a relationship with Fuji Diosynth in terms of contract manufacturing arrangement. We're expanding our headquarters in Tarrytown, New York, which will enhance our own internal R&D capabilities. Most recently, the Governor's office in New York announced that we are expanding our manufacturing capabilities in Saratoga, New York as well to allow us to continue to fulfill our abilities to meet the demands of our growing pipeline. And in addition, we also have a fill/finish facility that we've been constructing for the past few years, that is also going to allow us to diversify in terms of risk on the supply chain and bring new capabilities to Regeneron in terms of doing fill/finish, which historically, we had an outsourced to third-party manufacturers.

On the MFN front, we were 1 of 17 recipients of the letter from the administration on them -- in terms of what they'd like to accomplish with drug pricing in the U.S. We're in active negotiations with the administration. I think if you look at the contents of those letters as well as some of the deals that have been publicly announced, the administration has a couple of goals in mind. Many of those goals are -- we're very much aligned with, and we've been vocal over the years in terms of what needs to happen in terms of fostering innovation in the United States, allowing companies to make investments and -- but at the same time, get rewarded for making those investments with innovation, but also seeing that countries in the rest of the world that can afford to pay for those medicines are paying their fair share. So we're very aligned with administration in terms of those goals and those -- in terms of what they're looking to accomplish. But the other thing that's very, very clear is they value the industry, they want to reward innovation. And we're very much focused on investing where we think is appropriate. And we see, as we look at our pipeline, a lot of opportunities to drive long-term shareholder value by investing in the pipeline, investing here in the U.S.

Okay. That's super helpful. I guess, Chris, to stick with more sort of financial questions at the onset. You guys have a very substantial cash balance and you've initiated a dividend, you've done some buybacks, but you historically haven't done a lot of M&A or BD deal sort of size. I guess -- and most companies that have done that have needed to do that to fill their pipeline. So I think that's a good sort of scorecard on like where you are from a pipeline perspective. But is that something that you're thinking about differently looking to, say, '26 or '27? Are there, say, tools or technologies or indications that maybe you could be more aggressive with the cash? I mean, I guess the question is, is it burning a hole in your pocket or is it not?

So in terms of our capital allocation priorities, first and foremost, Geoff, it's investing in our internal capabilities, and we will continue to do that. I think as you look at external opportunities, you saw on Monday, we announced a relationship with Tessera. We will continue to look at external opportunities where we think it makes sense. I think historically, our focus has been on more traditional collaboration type arrangements where we either think there's a complementary technology or a target of interest where it's complementary to things that we have ongoing. With that being said, we are very much open to looking at external opportunities from an M&A perspective. We've got a fairly active business development group that evaluates things that are out there that are available. The challenge is, companies are all looking for the same thing. They're looking for late-stage opportunities that are -- either have proof-of-concept data or in Phase III that have the ability to drive near-term revenue and multiples of billions of dollars. And the valuations of some of those opportunities can be fairly high. With that being said, if it's the right one, and we think it makes sense and the science makes sense and the commercial opportunity makes sense, we definitely have the balance sheet and the wherewithal to make the appropriate investment if we think it's the right opportunity. And we're not shy to do that.

And how would you sort of tier that? Would it be sort of unmet need, new verticals, new therapeutic areas? Or would it be just sort of stage? Like is there a way to think about kind of how you would prioritize something on the BD external front?

I think we evaluate internal and external opportunities the same. It's -- what does the science look like. Does -- do we think there's a reasonable probability of success that the opportunity will result in obviously an approval and a commercial opportunity? What do we think the commercial opportunity looks like? Do we necessarily have some complementary resources on the sales and marketing front where it would make sense? But at the end of the day, the lens that we evaluate those opportunities is really no different between whether it's an internal or an external opportunity. It's got the same rigorous process.

Okay. That makes sense. And then just a follow-up on the CapEx and the commercial investments you're making in the U.S., I guess, is the intermediate to long-term goal to manufacture products in the U.S. for the U.S. market and Europe for the European market. Is that kind of how you would think would ultimately end up steady state wise?

Managing supply chain is a fairly complex way of bringing products to market. Ideally, that would be sort of the framework in terms of the way it would work. With that being said, things don't always necessarily work out as cleanly as you're describing. And obviously, you have to match the capacity that you have with the demands of the products and sometimes don't necessarily match up the way you're describing. But we're firmly committed to basically for domestic manufacturing, doing all that we can to increase those skills and capabilities. And we will always have a need to satisfy the demands of markets outside the U.S., and we've got manufacturing capabilities out outside the U.S., that's very important, and we will continue to obviously manufacture outside the U.S. as well.

Okay. That's helpful. Well, let's switch to some of the commercial markets. So we'll start with EYLEA. In terms of EYLEA HD enhancements, just got approval of RVO in the Q4 dosing. Maybe talk about the -- when these could start to play out in the commercial setting? Is this maybe more of a '26 kind of inflection for EYLEA HD? How should we think about the kind of the timing of the impact of those?

So we were very excited to get those approvals just before Thanksgiving. Our commercial team immediately upon approval was getting trained, is out there, obviously, talking to practices to get the word out on both every 4-week dosing as well as RVO. As we talked about the enhancements to the profile of the product, that's 2 of the 3. So we're still waiting on the pre-filled syringe. In terms of the impact, because we're entering the holiday season and they're just getting the word out, it's really not a 2025 impact, but we are really encouraged about what it means for the brand starting in 2026.

Okay. Yes. And then on the third one on the pre-filled syringe, maybe help us with kind of what are approximate time lines? What's been the gating factor? And how should we think about that as being kind of the 1/3 of the approval to really see the -- a bit of a tipping point?

Yes, that's a great question and certainly would round out the profile for EYLEA HD, which I think is differentiated in all of its approved indications, but needs that pre-filled syringe to really, I think, set it apart from the other competitors. We are on track to submit a filing with the FDA to get the pre-filled syringe approved sometime in the second quarter. I think we've committed to a submission by January. This will be with an alternate pre-filled syringe filler that's not Catalent. So we are still on track for that and would anticipate that approval to come probably in the second quarter.

Okay. That's helpful. And guys, look at -- looking at the overall franchise, I know over this year, you've had some payer or foundation issues with regard to EYLEA, EYLEA HD. There's been a lot of nuances in the market. Would you say by middle part of next year, a lot of these things will normalize, assuming that you have the pre-filled syringe, do you expect maybe a return to sort of franchise growth for the combined EYLEA and EYLEA HD?

So I mean there's a few questions in there, Geoff. One is the affordability issue. It's obviously something that we follow very, very closely. We initiated a matching program in the middle of this year, where we recognize that the need is out there, and we want patients to get the therapy that their clinicians believe they should be prescribed, but we realized that we couldn't do it alone. So we initiated the program with the goal of matching dollar for dollar up to $200 million through the end of 2025. Unfortunately, we didn't have significant amount of participation, at least in the third quarter, and that was less than $1 million. So we're really looking for other participants out there to help us and patients for that matter in terms of addressing the patient affordability issues.

In terms of the franchise and the brand, our goal is obviously, especially now with these 2 enhancements to get out and convert as many EYLEA 2 mg patients to EYLEA HD. We believe EYLEA HD is really the best product for patients out there in terms of the clinical profile and the durability. And I assure you that our commercial team will be out there in full force trying to do that as rapidly as possible.

Okay. That's helpful. And when you think though, Chris or Ryan, about the competition. So maybe help us with the Regeneron response to have biosimilars been impactful thus far? I know it's fairly early days. And then help us with kind of how you're thinking about Vabysmo looking to next year as a competition? I'm just thinking at a high level like kind of price and volume strategies.

Yes. I mean biosimilars present a formidable challenge, especially for the 2 milligram, but I would say anyone who has converted to a biosimilar, still remain an excellent candidate to be switched to EYLEA HD, which we view to be the best product in the category with unprecedented durability across wet AMD, DME and RVO. The dosing flexibility issue has been addressed with the label update. And on RVO specifically, we are the only product in the category that's approved for every 8-week intervals, and we have an uncapped dosing period. So I think we've got a differentiated label in RVO. And I think the 2-year data that we presented really underscores how efficacious, safe and durable this product is. So we continue to compete. Of course, our competitors are out there doing the same. But we view the best product will win. And we're really looking forward to completing the profile with this pre-filled syringe approval in a few months.

Okay. And last one, just on the -- sort of on the policy front. I know we've seen some announcements on MFN and on at least for GLP-1s, new Medicare, Medicaid access. Are there any EYLEA specific policy kind of data points that we should focus on looking to say, '26 or new shifts, new emphasis on wet AMD markets, in particular, for example.

I guess we're still waiting to see what the first round of Part B IRA drug selections are. We would think that because EYLEA faces biosimilar competition, it would be excluded. But until we get that list from the CMS, we will continue to watch. So I don't envision there being any impact from a negotiated price. We do believe that the active moiety rule, meaning any drug with the same active moiety will be bundled for purposes of selection as well as exclusion would then exclude EYLEA HD from potential selection down the road. But we, again, want us to kind of where the CMS lands on its initial round of Part B drug selections. And that is due by February 1, 2026, so it could come any time from now between now and then.

Okay. That makes sense. EYLEA HD is outside of those conversations.

We -- so like I said, if you have a biosimilar for one, it should exclude the bundle based on the active moiety rule that's been defined in the guidance document that CMS has issued.

Okay. That makes sense. That's helpful. Well, Dupi still is -- I wouldn't ever call a drug on autopilot, but it's still growing up into the right pretty robustly in the core markets. In the case of AD and asthma are still growing as well. Maybe let's focus on just those 2 indications. So help us with kind of the growth drivers going forward. Biologics are still very low penetration in AD. Talk about kind of what activities you guys have done commercially to continue to invest in that as a brand?

Yes. I mean Dupi is an incredible product. It now is actively treating over 1.3 million patients globally. Its lead indication is atopic dermatitis was approved in the U.S. in 2017 and really has set the standard for atopic dermatitis treatment, in moderate to severe atopic dermatitis. So I think we continue to benefit from our own commercialization strategy that we collaborate with Sanofi on. We're obviously out in the field very actively detailing dermatologists. We have active DTC as well. Obviously, there's been some competition that have launched in the last couple of years. What we've seen is they've also invested in those launches and that has driven patients to dermatology practices, but it's been really market expanding. And as the market leader, I feel that Dupixent has been a disproportionate beneficiary of that market expansion, which is driving a lot of the growth there. That said, Atopic dermatitis is very underpenetrated, especially when you look across other dermatological diseases such as psoriasis. Dupixent and other biologics for atopic derm have only penetrated the adult market by 20%, 25%. When you look at an analog like psoriasis, biologic penetration something around 40%. So we still have quite a bit of runway in just atopic dermatitis.

In asthma, we continue to lead in both new-to-brand share as well as total prescription share, really underscoring the efficacy profile that we've demonstrated there. And obviously, with the COPD launch, we've been seeing a lot of pulmonologists more frequently and certainly underscoring the value proposition that ashtma brings to patients.

Talk a little bit about the COPD launch Ryan. When you think about eosinophil testing, I know initially that was thought to be an uncertainty with regard to patient identification and adoption, is that become a more normalized like commercial situation?

Yes, I think so. There -- we ran our studies, BOREAS and NOTUS in patients that had eosinophils greater than 300 cells per microliter. And that is essentially what our clinical data in the little says and what most payers have adopted as their prior authorization requirement. There is oftentimes a look-back period so that patients that have been tested for eosinophils, say, for 6 months ago or 3 months ago or a year ago, and they exceed 300 would be considered a high eosinophil patient and therefore, eligible for reimbursement with Dupixent. So we haven't really run into a lot of issues with patients getting the drug. And I think what we saw was around the 30%, 35% reduction in annualized exacerbation rate in our clinical data, which compared to the other approved biologic for COPD at around high teens, maybe up to 20% is just dramatically different, that's greater than 50% improvement on that, while not head-to-head, of course. So we think that the drug itself, it works better. It also has demonstrated in FEV1 improvement, lung function improvement, I should say, versus our competitor, which demonstrated actually a detriment in lung functional improvement. So patients feel better, they're exacerbating less. We hear anecdotes where patients that have been on oxygen therapy for years are all of a sudden able to walk up the stairs without a tank, really remarkable patient stories that we've heard in this launch, which is now only about 15 months in. So there's a lot of runway there in terms of its trajectory, it's the best-performing respiratory launch for Dupixent and second best overall trailing only atopic dermatitis in terms of new-to-brand share. So very excited about the momentum we have generated in COPD and really think there's a lot more work to do to get it to more patients.

Yes. And in terms of the future runway, so CSU, BP or new line extensions and you have AFRS as the next kind of lineup. So talk a little bit about how you think about this as a kind of commercial investment. Do you redeploy a lot of the sales professionals to new indications? Are you growing overall, the commercial effort? I just want to know, how do you maximize as you add more line extensions?

The beauty of all these new indications is that they kind of fall within the same spaces and practice specialty areas that the existing indications do, like for CSU, which is chronic spontaneous urticaria, spontaneous breaking out an itchy hives. This is obviously a skin condition. And dermatologists historically have referred a lot of CSU patients to allergists and allergists have been treating them with Xolair because it was the only approved product for this. Now when a patient presents at a dermatology clinic with chronic spontaneous urticaria, first option can be dupilumab after failure of antihistamines. So we have seen a lot of uptake in the derm community. They certainly want to retain those patients in their practice, and they're seeing great results with Dupixent. So while the sales reps are in their detailing on atopic dermatitis, they're also certainly going through the clinical data for CSU as well. Both [indiscernible] similarly at dermatological condition. This is a blistering, a very painful blistering of the skin often in elderly patients. And there was no approved therapy before Dupixent. And now there is, and these patients are seeing very dramatic results right out of the gate. So very complementary additional indications to where we are already entrenched with Dupixent. And with AFRS, we have a pending decision from the FDA. I believe it's in late February. This is a respiratory indication, almost a subset of chronic rhinosinusitis with nasal polyps. So I think that would, again, fit very nicely into the respiratory sales force's detail.

Okay. That's helpful. Well, let's switch gears to a pipeline. We can talk about Libtayo too, but for LAG-3, the -- maybe just remind us of the timing of when we could see that data? What was -- what does and -- you guys view kind of a win look like in terms of clinical differentiation and maybe just remind folks the assumptions of the study.

Sure. The -- we're conducting a Phase III study that combines fianlimab with Libtayo in first-line advanced melanoma, and we are using KEYTRUDA or pembrolizumab as our control arm. This study completed the PFS cohort enrollment in January, and we are awaiting enough events to read out the final endpoint or the primary endpoint, which is median PFS. We pushed out the timing of this readout to the first half of 2026 due to a slowing of event rates. So we continue to wait for events to accrue. And once we reach the number that has been dictated in our trial protocol, we'll complete the study. We have a lot of hope and confidence that fianlimab-plus Libtayo can generate a meaningful differentiation against current standards of care. We look at PD-1 monotherapies, median PFSs range sort of in the mid-single digits, 4 months or so for pembrolizumab, around 5 months for nivolumab. And clearly, this study powered against KEYTRUDA, you want to have a statistically significant result, first and foremost. But when we look at other competing first-line melanoma therapy such as Opdualag from Bristol-Myers, which is another LAG-3, PD-1 combination product. They were able to generate a 43% response rate and a 10-month median PFS with no benefit to overall survival. In our Phase I/II studies, where we studied fianlimab plus Libtayo in 3 independent cohorts on a pooled basis of about 100 patients, the response rate was 57%, and the median PFS was around 24 months. So should we be able to even approach replicating that result, I think we'd have a very meaningful advanced -- for first line advanced melanoma. So we're excited about the data and hope that we can read it out in the next few months.

I'd add beyond first line advanced melanoma, we're also studying this combination in advanced -- adjuvant melanoma and which is a study that we fully enrolled and would anticipate first interim analyses to perhaps be conducted next year, dependent, of course on event rate accrual. Beyond that and beyond skin cancer, we also are looking at this combination in lung cancer, where we will read out some Phase II results in an all-comers population as well as in a high-expressing PD-L1 high-expressing population sometime in the first half of next year as well. But I think it all comes down to this first-line melanoma study showing that we truly have a differentiated combination here, relative to not only pembrolizumab but other standards of care in the setting, and we look forward to the results.

And then I guess the follow-up would be in lung, maybe other indications, could you go right -- I'm assuming you have Phase II success in lung. Could you go right into a Phase III? Would you do more of a basket trial? Like what would you say would be the maybe the next steps outside of melanoma?

Yes. Obviously, the Phase II results are going to inform what we do in lung. We are running that study. As I mentioned, an all-comers population at 2 different doses of fianlimab 1,600 milligrams, which is the dose that we tested in Phase I/II as well as 400 milligrams to see if there's any differentiation on or have a dose response. And we're comparing it to cemiplimab every 3 weeks, it's approved indication. We combined in the all-comer study, all arms with chemotherapy. And in the high-expressing population, there is no chemotherapy component. So once we get that data, and we'll be looking at different histologies, different PD-L1 expression levels to perhaps inform how we may design our Phase III program. We need the data though to inform that, and we're looking especially at progression-free survival and potentially likely immature but all survival as well.

Okay. And when you think commercially in LAG-3 and melanoma what are lessons to be learned from Opdualag in this, adding a next-gen combo therapy on top of an already pretty well established market. Is there something you guys can take away that as an opportunity in melanoma?

I don't know if there's a lot of lessons learned. I think in oncology, data sells your product. We hope to come to market with a very differentiated combination potentially with a benefit in overall survival, which Opdualag lacks. And we think that will be the key to unlocking the European market, especially, but even really converting the PD-1 monotherapy holdouts that are continuing to use that as opposed to these as more advanced products would likely come if you're able to show that you can generate a statically significant overall survival benefit. So I think that's probably the biggest thing. But in general, I think really the data itself is the best way to market an oncology product.

And looking to the core Libtayo franchise, maybe give us a bit of an update in terms of the future growth drivers, obviously, not including LAG-3, but if you had the derm indications versus lung, like what's been the trend over the past couple of quarters and maybe what gives you perhaps optimism looking to '26.

I have a lot of optimism about Libtayo. It's doing over -- well over $1 billion and growing at almost 30%. And that's not -- we think that the momentum there is going to continue. We were approved in October for another potential blockbuster indication in adjuvant cutaneous squamous cell carcinoma, where Libtayo was previously approved in the metastatic setting for the non-melanoma skin cancer. So a lot of opportunity there. And I think the halo effect of this differentiated data set will only help us in the metastatic setting as well.

In lung cancer, we've made a lot of progress and are currently second in new-to-brand share in the U.S. in lung cancer. The data there stacks up quite well compared to the market leader, KEYTRUDA. When you look at the 5-year overall survival benefits that we presented at World Lung this year, very comparable to what has been generated by KEYTRUDA at the same time point. So continue to make a lot of progress with lung cancer as well, and I think we'll continue to see great growth out of Libtayo going forward.

Yes. I guess the bigger question is, how are you guys thinking about the KEYTRUDA and the OPDIVO LOE sort of an indirect effect. I know -- I don't know if you guys have really felt this effect, it's not happening with Dupi and maybe EYLEA just recently had sort of biosimiliar, but is this something that you guys can sort of manage going into that your competitors' LOEs. I know you have some differentiation, obviously, on the labels with respect of CSCC and basal cell.

Yes. I mean we're kind of the standard of care in cutaneous squamous cell carcinoma and KEYTRUDA is also approved in that indication, but I think our data is better, and that's why it's getting used more. And so a biosimilar for KEYTRUDA, I don't think it's going to impact the momentum we have in the non-melanoma skin space. In lung cancer, I think that remains to be seen. We'll see the impact of biosimilars in oncology. I think oftentimes, it's the brand that has the biosimilar itself that is the most impacted, but there's likely to be some ripple effects of that across the category, especially in highly competitive spaces.

Okay. Let's switch gear to Lynozyfic,