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Hello, and thank you for standing by. My name is Ian, and I will be your conference operator today. At this time, I would like to welcome everyone to the Alnylam Pharmaceuticals Q1 Earnings Conference Call. [Operator Instructions] I would now like to turn this call over to the company. Please go ahead.

Good morning. I'm Christine Akinc, Chief Corporate Communications Officer at Alnylam, with me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Research and Development Officer; and Jeff Poulton, Chief Financial Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events. During today's call as outlined in Slide 2, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Pushkal will review pipeline updates, clinical progress and upcoming milestones, and Jeff will review our financials and guidance before we open the call to your questions. I'd like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those in our most recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to Yvonne. Yvonne?

Thanks, Christine, and thank you, everyone, for joining the call today. The first quarter of 2026 demonstrated continued strength of the business and represents the type of execution that will drive continued growth at Alnylam. Our leadership in TTR amyloidosis was on display, having achieved over $900 million in total net revenues from AMVUTTRA and ONPATTRO combined. We also entered into exciting new collaborations that we expect to drive TTR disease awareness and diagnosis and improve overall care pathways for patients. On the R&D side, we continue to progress our deep pipeline of investigational medicines, including the presentation of impactful data for vutrisiran and zilebesiran at ACC. We also initiated a Phase I trial of ALN-2232, which is our first adipose-directed RNAi therapeutic and targets ACVR1C. And on the financial front, the more than $1 billion in combined net product revenues generated in Q1, marks Alnylam's first quarter, exceeding the threshold in our history, an important milestone. We're also reiterating our full year financial guidance, reflecting continued confidence in the AMVUTTRA CM launch and the strength of our overall portfolio. Alnylam stands apart in biotech with a differentiated model built on a proven durable innovation engine and strong commercial execution, positioning us for sustained long-term growth. As the leader in RNAi therapeutics, we have established a modular reproducible approach to drug development and a product engine that has consistently translated scientific innovation into successful medicines. This high-yielding platform, combined with our outsized historical probability of success relative to the industry will be key to driving future growth. That capability is reflected in a deep pipeline of more than 25 programs currently in clinical development with continued expansion into new indications and therapeutic areas along with evolving platform capabilities. Lastly, today, there are 6 Alnylam invented medicines that are collectively generating several billion dollars in annual revenues, reaching hundreds of thousands of patients around the world. My colleagues will outline for you the commercial, R&D and financial progress we made in the first quarter of 2026. All of this progress builds our momentum towards accelerating innovation and scaling our impact as we look to deliver on our recently announced 5-year vision, Alnylam 2030. These ambitions are anchored in 3 strategic pillars: the first is to establish global leadership in TTR while continuing to build a durable franchise; our second pillar focuses on growing through sustainable innovation where we aim to deliver therapies that not only slow the progression of disease, but prevent, halt or reverse it; and the third pillar is scaling with discipline and agility to enable durable profitable growth. Taken together, Alnylam 2030 represents our strategy to become the leading science-driven, fully-integrated global biopharmaceutical company and to maximize the potential of RNAi therapeutics for patients. With that, let me now turn the call over to Tolga for a review of our first quarter commercial performance. Tolga?

Thanks, Yvonne, and good morning. I'm pleased to share our continued progress in bringing Alnylam's therapies to patients globally. Q1 was another strong quarter of commercial execution and marked our first quarter exceeding $1 billion in product revenue. Specifically, we delivered $1.036 billion in combined net product revenues, up 121% year-over-year and 4% over Q4 2025. While our TTR franchise continues to be our primary growth engine, we continue to see consistently strong performance in our rare disease business. So let's start there. Our rare disease portfolio continues to deliver meaningful impact for patients and consistent performance for our business. We generated $126 million in rare disease net revenue up 15% year-over-year. Growth was driven by increased patient demand, partially offset by higher gross to net deductions across U.S. and international markets. Now turning to our TTR franchise. One year into the ATTR-CM launch, AMVUTTRA continues to show strong momentum. Global TTR net revenues reached $910 million in Q1, up 6% from Q4 and 153% year-over-year. In the U.S., TTR revenues grew 9% versus Q4 and more than 230% year-over-year, reflecting continued growth in patient demand. The $59 million in U.S. revenue growth over Q4 was achieved despite fewer Q1 shipping weeks and customary insurance reauthorization dynamics earlier in the year, anticipated headwinds that we shared with you on our February earnings call. Access remained broad, pull-through was strong and adherence exceeded 90%. Outside the U.S., revenues declined $7 million from Q4, primarily reflecting our previously announced updated pricing in Germany following the ATTR-CM launch, but grew 35% year-over-year. Importantly, international TTR revenue outperformed our Q1 expectations shared in February, primarily due to continued strength in Japan, where our CM launch execution remains on track with leading analogs as well as strength in PN performance across our international markets. This strength provided more balance to the quarter than anticipated as we did see the expected headwinds from the price adjustment in Germany. We remain confident in our 2026 TTR revenue guidance as we continue to expect more substantial quarter-over-quarter growth in TTR revenues, both in the U.S. and across the world over the balance of the year. As we move into the next phase of U.S. ATTR-CM launch, our focus is grounded in the strong foundation established in 2025. First, physician preference and utilization. AMVUTTRA's clinical profile has driven a strong and compelling first-line positioning with strong preference demonstrated by physicians who have experience using it. Second, access and affordability. Our access has improved versus 2025 and continues to be durable with over 90% patients covered with first-line access and most facing 0 in out-of-pocket costs. Third, site of care infrastructure. We built a robust provider network designed to deliver a seamless patient experience. These fundamentals enabled a highly differentiated launch with rapid uptake and strong utilization across lines of therapy. Importantly, our initial success has shown that physician experience with AMVUTTRA leads to deeper and sustained use over time. As highlighted during our TTR investor event, moving forward, we're focused on the following 3 indicators of continued launch success. First, prescriber base expansion. We've already built a large and expanding base with more than 1,200 unique new U.S. prescribers since last March. When we look at prescribing trends on an individual healthcare professional basis, we generally see that initial utilization of AMVUTTRA by a new prescriber is relatively balanced between first and second lines of therapy. Second line use is being driven primarily by moving that prescriber's existing base of patients progressing on stabilizer onto AMVUTTRA, either a switch or combo therapy. Over time, as the existing base of stabilizer patients is transitioned, we generally see that prescriber's new second-line scripts reduced to a normalized level. Importantly, healthcare professionals' experience with AMVUTTRA breeds a greater number and proportion of new scripts in the first-line setting. So our experience with AMVUTTRA has translated into a durable preference, and we also see significant opportunity coming from expanding the number of prescribers. We will do this by increasing engagement with physicians who don't yet have experience with AMVUTTRA, reinforcing the role of AMVUTTRA across the full patient journey and maintaining seamless patient access. Second, sustained category growth. ATTR-CM remains significantly underdiagnosed and undertreated with an estimated 200,000 patients in the U.S. and more than 80% still untreated. We are addressing this gap directly as part of our TTR leadership agenda, advancing practical, AI-enabled partnerships to facilitate earlier diagnosis and treatment. Collaborations with Viz.ai and others as well as support for an initiative with American Heart Association are embedding AI diagnostics into real-world care pathways, expanding patient identification, and accelerating access to therapy. Third, adherence and persistence supported by quarterly dosing and actual patient adherence. Pushkal will share some more color in a moment, but recently presented real-world data demonstrate greater than 90% adherence to vutrisiran over more than a 2-year period. This profile translates into sustained benefit for patients and by extension into sustained revenue, which is central to any long-term growth outlook. Alnylam's global footprint is enabling strong execution on international market access for AMVUTTRA, reflected in a series of positive reimbursement milestones across key markets. In Europe, we're seeing favorable health technology assessment outcomes and reimbursement momentum, including recent launches in Austria, the U.K., Switzerland and Italy, supporting broader patient eligibility and more streamlined treatment pathways. Taken together, these developments reinforce the growing global recognition of the value of AMVUTTRA and positions us well to expand patient reach around the world. With that, I'll turn things over to Pushkal.

Thank you, Tolga, and good morning, everyone. Alnylam undoubtedly has one of the most robust pipelines in biotech with over 25 clinical programs, spanning multiple therapeutic areas across rare, specialty and prevalent indications, representing a tremendous opportunity to improve patient health and create value in the years ahead. Over the next few moments, I'll double-click on some of these programs to highlight some key near-term value drivers in the pipeline. In support of our ongoing efforts to demonstrate AMVUTTRA's unique profile that we believe supports first-line use, we shared new data on the drug's impact on patients with ATTR-CM at the recent American College of Cardiology Annual Meeting. As Tolga briefly mentioned, a retrospective cohort study of approximately 4 years of real-world data in patients with transthyretin-mediated amyloidosis indicated high adherence and persistence to vutrisiran treatment. Over the treatment period, greater than 93% of patients were adherent to vutrisiran, defined as 80% or more days covered by vutrisiran and over 85% remained on therapy for more than a year. These data stand in contrast to the low adherence and persistence we've seen with many oral therapies and support the potential for vutrisiran's clinical trial benefits to translate into a real-world setting. In another analysis, we looked at diastolic dysfunction, which is known to be prognostic of poor outcomes in patients with ATTR-CM. A post-hoc analysis of HELIOS-B assessed outcomes at month 30 in patients who had evaluable diastolic dysfunction grades, DDG, at baseline. There were 3 key findings: first, higher DDG at baseline corresponded with adverse outcomes in ATTR-CM in the HELIOS-B study; second, vutrisiran was associated with a lower risk of worsening DDG compared to patients receiving placebo; and finally, vutrisiran reduced the risk of all-cause mortality and cardiovascular events during the double-blind period, irrespective of patients' baseline DDG. Together, these data continue to underscore the differentiated and substantial impact of vutrisiran in ATTR cardiomyopathy. We also continue to advance our next-generation TTR silencer, nucresiran, in the TRITON Phase III program. As a reminder, interim Phase I results with nucresiran demonstrated greater than 95% mean TTR knockdown and were supportive of a twice-yearly dosing regimen. TRITON-CM is a randomized double-blind, events-driven outcome study of nucresiran versus placebo. We initiated the study last year and are encouraged by the very strong interest we've seen from both investigators and patients who wish to participate. As a result, enrollment is proceeding faster than expected. In addition, and as anticipated, the patients enrolling in this study have somewhat milder disease on average than those enrolled in HELIOS-B due to greater disease awareness and earlier diagnosis around the world. Our study already includes a built-in safeguard against potentially low event rates in that it is event-driven. In other words, we will continue the study until we have enough endpoint events to ensure sufficient study power. Today, we are announcing that we will take advantage of the fast pace of enrollment to utilize a prespecified option in our protocol to expand enrollment by approximately 500 patients or from 1,250 to about 1,750 in total. This increase further mitigates the risk of low event rates while maintaining or potentially even accelerating time lines for this important study. Given the rapid pace of enrollment and the anticipated accrual of endpoint events, we still project a launch by 2030, assuming positive data and regulatory approval. In addition, the TRITON-PN Phase III trial in hereditary ATTR polyneuropathy is also ongoing, and if successful, has the potential to support approval in this indication by 2028. As we look ahead to the next period of R&D evolution at Alnylam, we're guided by our new Alnylam 2030 set of 5-year goals, specifically the pillar of growth through sustainable innovation. As a reminder, we've committed to delivering at least 2 new transformative medicines beyond TTR with blockbuster potential. We also anticipate achieving RNAi delivery to at least 10 tissue types with over 40 programs in the clinic by the end of 2030. And lastly, we aim to invest approximately 30% of revenues in non-GAAP R&D through this period to support our next wave of medicines. We're on our way to achieving these goals and look forward to many clinical readouts in the coming quarters and years to unlock these transformative programs, which will propel Alnylam into its next phases of growth. As for 2026, we plan to share updates from across the pipeline as outlined here. In the first half of the year, we expect to complete enrollment in the cAPPricorn-1 Phase II trial of mivelsiran in cerebral amyloid angiopathy and to initiate a Phase II trial of mivelsiran in Alzheimer's disease. We're also on track to initiate a Phase II trial of ALN-6400 in a second bleeding disorder. In addition to these study milestones, we also look forward to several clinical readouts from 3 different programs in the second half of the year. For ALN-6400 in bleeding disorders, we plan to share Phase I data from healthy volunteers and Phase II results in patients with hereditary hemorrhagic telangiectasia. We also plan to share Phase I data for ALN-HTT02 in patients with Huntington's disease and ALN-2232 in development for obesity and weight management. Within our robust pipeline are several programs, each with multibillion-dollar potential that we believe represents the next wave of transformative medicines. ALN-6400, which we believe has potential application across a wide range of bleeding disorders; zilebesiran, which has the potential to reduce the risk of cardiovascular events by providing continuous control of blood pressure; and ALN-HTT02, which we are studying to treat Huntington's disease are among the many opportunities in our pipeline that may improve human health and accelerate growth in the years to come. Given these are novel therapeutics that have the potential to change the practice of medicine, I'm excited to announce that we will be discussing each of these programs in greater detail during upcoming webinars starting this summer. Those of you who have followed Alnylam for a while may recall our RNAi Roundtable series in which we spotlight key pipeline programs of interest and discuss disease areas, treatment landscapes, unmet needs and the differentiated impact possible with RNAi therapeutics. We'll be using a similar format to deep dive into each of these programs and outline the opportunities this summer. Stay tuned for more details in the coming weeks. With that, let me now turn it over to Jeff to review our financial results and 2026 guidance. Jeff?

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's first quarter 2026 financial results and discussing our full year guidance. Let's begin with a summary of our P&L results for Q1 2026. Total global net product revenues for the first quarter were more than $1 billion or 121% growth versus Q1 last year, driven by the continued uptake of AMVUTTRA and ATTR cardiomyopathy. We achieved $910 million of TTR revenue in the first quarter, $52 million increase versus Q4, consistent with the Q1 phasing expectations we discussed on our year-end earnings call in February. For the first quarter, collaboration revenue was $82 million or a 17% decrease compared with the same period last year. The decrease was primarily driven by a $30 million milestone payment received from Vir in Q1 2025. Royalty revenue for the first quarter was $49 million, representing an 85% increase compared to the first quarter of 2025, driven by higher global LEQVIO sales. Gross margin on product sales was 80% for the first quarter, representing a 5% decrease compared with Q1 last year. The decrease in margin was primarily driven by increased royalties on AMVUTTRA as higher revenues in 2026 resulted in an increase in the average royalty rate payable to Sanofi compared with the same period last year. Additionally, a quick reminder that the royalty rate we pay Sanofi on sales of AMVUTTRA resets each calendar year. As a result, as AMVUTTRA sales increase over the course of the year, we anticipate that the average royalty rate on sales of AMVUTTRA paid to Sanofi will increase, resulting in a decrease in quarterly gross margin on product sales over the course of the year. Our non-GAAP R&D expenses of $335 million increased 39% compared to last year, primarily driven by the costs associated with our ongoing 3 Phase III clinical studies, including the

Thank you, Jeff. Operator, we will now open the call for questions. [Operator Instructions].

[Operator Instructions] Our first question comes from the line of Ritu Baral with TD Cowen.

So Tolga, I wanted to ask you a little more about your comments around first-line use and second-line use. You said that they were balanced, and I believe you mentioned that use improves with experience. And then you said something about second-line use reducing to normal levels. What is that sort of experience that you're seeing? Is it that doctors are starting with second line and then with increased exposure and experience willing to start patients on first line? Or are they starting on first line? And how much does your detailing -- sort of detailing contribute to it or combination therapy contribute to it as well?

Thanks, Ritu. There's quite a lot in that question, and we'll try to plan to unpack it as we go. But just before I turn it over to Tolga, I mean, just to kind of reiterate our confidence really in the fundamentals of the AMVUTTRA launch. And we're really pleased with the progress that we've made as we march towards achieving our goal of TTR leadership by revenues through this next period. But Tolga, let's dive a little bit into Ritu's question.

Sure. No, I think it's an important dynamic and happy to expand more on that. So what we're really describing is the natural evolution of second-line dynamics as the launch progresses. As new prescribers begin using AMVUTTRA, essentially initial utilization is typically balanced between first and second line. Early second-line use is obviously driven by physicians treating patients progressing on stabilizers. They had these patients that were already progressing in the last 5, 6 years, and they were waiting for a product with essentially an orthogonal mechanism of action. So over time, as those patients have transitioned, second-line volume normalizes. At the same time, what we're really excited about is the growing physician experience has been leading to increased adoption in the first-line setting. I think that's a really important element to highlight. So we see this as a really positive and expected progression that you would see early in the launch dynamics. Today, the business is modestly weighted towards first line, while second line remains an important and ongoing contributor to growth. And obviously, we are -- given our orthogonal mechanism of action, we are the -- we have the highest share in that respect. But what's also important is this is a gradual shift in mix as physicians move from early adoption to more established prescribing patterns. And from a strategic standpoint that you've asked, our focus remains on strengthening first-line positioning, which in turn supports both broader and more durable utilization, including second line given our differentiated product profile. So for us, the key driver from here is really going to be about expanding the prescriber base, bringing more physicians into the AMVUTTRA experience, which we consistently see that translates into deeper and early line use over time.

Our next question comes from the line of Paul Matteis with Stifel.

Congrats on the quarter. I was wondering, Jeff, if you could try to help do some math for us on the call as it relates to the headwind this quarter from selling weeks. I know you talked about 2 selling weeks, but I think that might be related to one specific SP. And then conversely, maybe if there was any sort of inventory headwind or benefit this quarter? And sort of when you net it out and take a step back, how would you sort of simplify for us what we're seeing in terms of actual demand growth from 4Q to 1Q for AMVUTTRA in the U.S.

Great. Thanks for the question, Paul. Look, good question. I think Q1 played out generally in line with our expectations in the quarter. If you look at the U.S. results, $59 million in growth. That was primarily demand driven. There was some positive inventory impacts in the quarter, but that was offset by pricing, which is continuing to trend in the direction that we expect. Just to remind you on the things that we talked about impacting the quarter, insurance reauthorizations in the U.S. were part of the story. And we did see that. I mean, if we look at demand and start form generation across the quarter, January was the lowest, and we saw sequential improvement in February and March. So that played out as we expected. And then you hit on the ordering patterns. Yes, that's correct. The number of Wednesdays in the quarter actually does make an impact in terms of comparisons quarter-to-quarter just because of the way the ordering works in the U.S. So the way things work in the U.S. for us is there's one wholesale distributor that we work with that drives about 80% of the volume. They order every week on Monday in the U.S., product ships on Tuesday and inventory is received and is recognized on Wednesday. Just the way what the calendar fell last year and then into this year, there were 14 Wednesdays in Q4 last year and 12 in Q1. So that contributed. Look, if you looked at the TTR growth in Q4 last year in the U.S., it was $111 million and again, $59 million in Q1. So I think, again, this all played out as we expected.

We have the Wednesday dynamic...

Sorry.

I was just going to say we have the Wednesday -- I just wanted to clarify on the selling weeks. We have that dynamic at like close to an 11% sequential headwind. Is that an exaggeration of selling week dynamic or kind of roughly where we should be modeling it?

Yes. Again, I'm not going to get into maybe the specific detail on that, Paul, per your question, but it did have an impact and which was one of the reasons why we flagged it on the call in February. Just thinking about going forward, right, for Q2, there will be 13 Wednesdays. Q3 will have 14 and then Q4 will have 13, right? And so over the course of the year, there's 52 Wednesdays, but that's how they're going to fall. So again, it's one of the things that drives confidence in our view in terms of growth going forward, higher levels of growth on a quarterly basis going forward in the U.S.

If I could add in terms of how the quarter should be characterized from a demand perspective, it was really largely driven by demand. So we did have some inventory benefit, but that was really offset by the gross to net adjustments. So net-net, this was really about demand growth.

That's spot on, Tolga, and thanks for providing some color to the quarter. I mean we were really pleased to be able to maintain patients, how well the authorizations went, how patients were able to kind of get access with our commitment to make it as easy as possible for them. So we're really seeing kind of good progress from 2025 to 2026. Thank you. Next question.

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

There's a study coming up for a competitor who has a silencer. I think there's a lot of eyes on the portion specifically related to adding that silencer onto a stabilizer. So I wanted to get your thoughts if that portion of the study proves to be robust, is there any reason to think that a result like that would not have been replicated with AMVUTTRA if you had designed that trial? And looking ahead, how do you think physicians would interpret that type of data? Would that be specific to the drug itself? Or do you think it would be validating for silencers overall?

Thanks, Tazeen. Maybe I'll take a question and Tolga may have something to add as well at the end. Yes, look, I think we're obviously looking to see the CARDIO-TTRansform results as they come out. I think we're expecting a little later this year based on the announcements yesterday. But I think as it relates to the combination portion of that study, yes, it's -- they've got an upsized portion in that study. And we fully expect that, that study will be positive and that those results will be positive. The reason we believe that is because we have the HELIOS-B results, which have already shown that the silencing mechanism is effective in monotherapy and in combination therapy when it added on a background of stabilizer. We saw strong results in that category. It was not powered specifically for that group, but we saw additive benefit that was commensurate with the benefit we saw as a monotherapy and that was realized then in the product labeling as well, where it was recognized that there was equal effectiveness on or off tafamidis, and that's captured in the label. And so we're obviously able to communicate that appropriately with prescribers and then Tolga can talk more about that dynamic. So I do expect that they'll see a static benefit there, but I think it really -- it just enhances and further validates the signal that we've already seen with this drug. The other thing I would just mention is that we talked today about the nucresiran study with TRITON-CM. And that is going to, as we've talked about before, be primarily a study adding on top of patients who are on a stabilizer. And with today's announcement, I think we'll have perhaps the largest experience coming out of that study. So a very, very rich data set showing the benefits of adding a silencer on top of a stabilizer. So I think we're looking forward to those results as well. So I think we're very well positioned both for how treatment patterns are today and how they're going to evolve over time. But Tolga, maybe you have anything to add.

It's worth making a kind of commercial comment or 2 here, Tolga, I think you've kind of focused very well on how we think about eplon. But I think it's worth referencing our success in the PN indication.

I mean I think as you have seen in PN, there are 2 real dynamics that works in our favor. First and foremost, obviously, we have a significant -- we had a significant lead time when eplon came out in PN. And what you now see is we have a pretty robust and durable market share in terms of new patient starts over 75%. And then the good news is the category continues to grow in PN. And when you actually translate it into the CM, which is a much larger, obviously, category, when you have a deeper, more durable and sustained knockdown effect, which we already have with AMVUTTRA, it's going to be only advanced by nucresiran, hopefully. We are really well positioned given the lead time that we have. And again, from a label perspective, we already have combination use in our label. We really feel good about another study actually confirming some of the benefits of the silencer class.

Our next question comes from the line of Kostas Biliouris with Oppenheimer.

Congrats on the quarter. Maybe I'd like to reverse Tazeen's question and ask about the scenarios that CARDIO-TTRansform fails to show an effect under the silencer stabilizer combo, but nucresiran can demonstrate an effect under the stabilizer silencer combo. Do you think that your competitor will be able to leverage nucresiran's combo data or it will be specific to nucresiran because of the potency and the durability of the drug?

Yes, Kostas, it's -- there's a lot of scenarios there to work through. I appreciate the nature of your question. I don't know that I can answer it directly. Look, I think again, I think there are commonalities between the eplon approach and what we're doing in that they both knock down TTR, although at the same time, there are different molecules and they use different mechanisms. We use an RNAi mechanism, they use an ASO mechanism. Their knockdown tends to happen a little bit longer over time based on the data that they've seen -- that I've seen published, whereas we get to higher levels of knockdown a little bit earlier. So I think it's really difficult to sort of prognosticate all the different scenarios. I think maybe they'll see an effect, maybe it's not static. I don't know. I don't want to speculate at all, but these are different molecules, but there are overlapping areas. And I think as we get the data sets, there'll be some inferences made in terms of where we can connect the dots and where there may be unique aspects of the molecules or study designs, for instance, that may have contributed. Our studies are event-driven, for instance. And so we may -- that may give us as we've talked about, additional insurance and help with powering of the studies overall. So again, I think we'll wait to see how those studies pan out. But I think we feel very good based on the HELIOS-B results, our patient level insights that we have from those studies and the detailed data we have in terms of how to design TRITON-CM and to establish its success. And so we feel very good about that. And that is why part of the reason we had talked about the sample size increase as well today.

That's great. I think the quarterly subcutaneous regimen as well for AMVUTTRA provides additional differentiation. I think that's one of the reasons why we're seeing such good adherence to AMVUTTRA as well as obviously, the compelling clinical profile that we provide.

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

With regard to AMVUTTRA, how are you thinking of the trajectory in 2026 post the headwinds that played out in 1Q? And in particular, could you just comment on the ex U.S. pricing dynamics in Germany and elsewhere and whether those have stabilized yet or are still ongoing?

The question is referring to the ex U.S. picture. I think Tolga, clearly you'll answer that, but I just want to say how pleased we are with the progress of our launches ex U.S. Tolga touched on this in his prepared remarks. And I think it's a testament actually to our pricing and reimbursement organization that we've been able to move forward with a number of AMVUTTRA CM launches in Europe and in Japan. Tolga, maybe you want to comment on pricing specifically.

Sure. Thanks, Salveen, for that question. So let's unpack that a little bit in terms of our ex U.S. pricing dynamics. And we touched upon this in our earnings call, the prior earnings call. And obviously, it worked out better than what we had anticipated. That was primarily driven by our Japan launch progress that's going really well as well as obviously the robustness business in our PN. But if you look at the rest of the year, I think the way we should be thinking about it is when we launch the CM indication in markets outside the U.S., it does typically involve a price adjustment for AMVUTTRA, which can have an impact on the existing -- our PN business base. The magnitude of that impact obviously varies by market, primarily driven by the size of the price adjustments and the relative scale of that business, existing business. In that context, Germany did represent the most significant impact in Q1 across all our international markets. And importantly, this was obviously a deliberate and expected step in expanding into a larger opportunity. Over time, the CM volume more than offset the impact of the initial price adjustments on the PN base. And a helpful way to think about this is a mix shift. We're effectively trading a smaller, higher-price segment for access to a significantly larger patient population. And then as the mix evolves, the overall value of the market will expand. And what does this mean for the rest of the quarter is we expect this to become a net positive growth for starting in Q2, building throughout the year and contributing incrementally on a full year basis. I think what we had said is essentially, the contribution of growth is going to be about the same net-net as ex U.S. did contribute last year.

Our next question comes from the line of Cory Kasimov with Evercore.

Apologies for asking another one related to CARDIO-TTRansform. But assuming that does, in fact, read out positively, how do you think about the evolution of pricing as another silencer enters the picture, especially given the Part B versus Part D dynamic? Is there any reason to think that pricing could materially change? Or is the PN experience applicable in CM in this case as well?

pricing.

Look, it's never a good idea to speculate your competitors' pricing. But what we've seen so far is we've done really well in '26 in terms of how we've been able to actually increase our first-line access with payers. We anticipate that to continue. Payers are taking this disease very seriously and price sensitivity right now is not really in the works as we've seen and being able to demonstrate that. Currently, Wainua is slightly more premium than our product on an annual basis. What we've seen so far, and they had priced it after us. I think they're also seeing how the pricing is working. We don't really anticipate any significant shift in the moment. And of course, we have been managing this very, very thoughtfully and monitoring it very carefully.

Our next question comes from the line of Ellie Merle with Barclays.

Congrats on the quarter. In your prepared remarks, you commented on how second-line use is reduced to a normalized level. But can you comment on the trends you're seeing in the first line? Are you seeing a steady number of naive starts or an acceleration in the number of naive starts? If you could just help characterize what you're seeing there, that would be helpful.

You touched on that, Tolga, but maybe to add a little bit more color.

Yes. I mean I think what's really exciting is what we've been seeing consistently is that when physicians initiate patients on AMVUTTRA, utilization deepens and shifts towards earlier using over time, and that really strengthens our first line. So early adoption has largely been driven by treating patients progressing on stabilizers in the second-line setting and the opportunity is to work through prescribing naturally evolves toward a greater proportion of first-line use. Therefore, we feel very good about so far how we've been able to managing this. And essentially, our aspiration is to continue to grow that first-line use by expanding our prescriber base.

Our next question comes from the line of Jessica Fye with JPMorgan.

I was wondering if you could touch on how, if at all, the recently announced Pfizer settlement for Vyndamax impacts how you think about the TTR cardiomyopathy landscape looking out over the next several years?

Yes. Great question, timely. Look, I think we've been rather consistent in how we've been characterizing that our growth outlook is really not dependent on the timing of a generic entry in the stabilizer class. We do expect the impact on our TTR outlook from the settlement to be rather limited. This -- just to remind everyone, this remains a significant underserved category with a large proportion of patients untreated. And we know that nearly half of those patients that are on a stabilizer continue to progress and they are in need of an orthogonal mechanism of action. Importantly, demand for AMVUTTRA reflects a fundamental shift toward treating this disease at its source, which we see as durable and independent of pricing dynamics within the stabilizer class. We also believe that the TRITON-CM study positions us really well to generate a robust data package for nucre, supporting continued leadership in an evolving treatment landscape. Today, we're really well established with broad first-line access, strong patient affordability, growing physician preference and well ahead of any potential LOE considerations. So taking it all together, I think we feel very well positioned to sustain growth through both continued AMVUTTRA adoption and frankly, the advancement of our next-generation pipeline.

Our next question comes from the line of Luca Issi with RBC Capital Markets.

This is Shelby on for Luca. Yesterday, Astra

Yes. I mean, look, I think it is customary to see some softening in the first quarter of the dynamic. When I look at our numbers throughout PN, we had certainly seen that, but that tends to actually recover in March, and we've always been able to post good growth based on our base business. So I think you guys should raise that question with them. What we know is even before the CM indication, we have been able to establish a very strong new patient market growth -- market share upwards of 75%, while the category continued to grow. So we are very pleased with that experience, and we certainly have every plan to replicate that success in the CM landscape as well. When it comes to Part D and Part B, look, I think we're really well positioned in terms of how we've been able to provide that access. The fact that our product is a quarterly subcutaneous injectable meets very nicely with the cadence of how those patients actually visit those offices. And it's -- and by the way, again, we've been able to expand our actually access nearly 100% when it comes to overall access and over 90% in terms of first-line access without any step edits with 0 patient out-of-pocket costs. Those dynamics not only been secured, but also improved versus last year. So -- and that's, again, testament to the product profile as well as actually testament to the payers who really understand this disease and they leave it up to the physician and their choice in how they want to manage this category.

Our next question comes from the line of Myles Minter with William Blair.

This is John on for Myles. Maybe to switch gears just a little bit. Just wondering where you're seeing cemdisiran sitting in the MG competitive landscape, along with some of the next-gen complement CD19, or FcRns. And any thoughts as to why more complete complement inhibition in the combo therapy didn't result in better efficacy there?

No, we're clearly pleased with the progress of cemdisiran in patients with MG. The results were really quite supportive of use in this disease. Pushkal, are there any additional perspectives you'd like to add?

No. Look, I think -- I guess I'll just echo what Yvonne said. I think we're really excited that Regeneron has advanced cemdisiran. I think the data in myasthenia are incredibly compelling that they've generated. We think this is going to be -- and we hope and expect this will be a formidable drug for these patients where there's a lot of unmet need. I think the detailed questions in terms of the market and the opportunity, I think we should leave for our colleagues over there, but we're very excited about the molecule and its opportunity to help patients.

Our next question comes from the line of Mike Ulz with Morgan Stanley.

And maybe just a follow-up on the generic question. Would you anticipate increased combo use in the frontline setting? Or would that be more of a second-line setting effect? And then do you think you need the data from nucresiran combo to kind of accelerate that? Or do you not need that?

Yes. Look, I think as I explained, we've been able to establish ourselves as a first-line treatment over 35% in a short 9 months since the launch as the third entrant. That really is the fundamental question in a way, how the market is going to be unfolding. In respect to combination use, as we had shared before, there are physicians who prefer to have a second-line use in a switch or combo. And if that were to happen so far, we haven't seen any significant headwinds. we don't really speculate on that, how payers are going to be managing that. I think once goes generic, certainly, that dynamic will evolve. And I think, obviously, nucre will be in a great position given the data we're generating. We already also do have combo data in our label as well as obviously, physicians have been experiencing it already over a year. So what we, again, appreciate the fact that it is how we got out of the gate in terms of our launch dynamics, and we continue to maintain that posture.

Yes. No, absolutely. I think the key point here is that, as you said, Tolga, our fortunes aren't tied to the genericization of the stabilizer class, and we're quite excited about the TRITON-CM design for nucresiran to deliver a very robust data package to support the evolving treatment landscape. I think we've come to kind of our last question. So I will just wrap up by thanking everybody for joining us today. I think we're off to a good start in 2026. And as we maintain momentum with the ongoing launch of AMVUTTRA in ATTR cardiomyopathy, we also continue to deliver significant advancement across our really quite exciting and deep pipeline of innovative RNAi therapeutics. Thanks, everybody. All the very best.