Q4 2025 Earnings Call Transcript

Good morning, ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals, Inc. Q4 and Full Year 2025 Earnings Conference Call. Following the presentation, we will conduct a question-and-answer session. If at any time during this call you require immediate assistance, please press 0 for the operator.

This call is being recorded on Thursday, 02/12/2026. I would now like to turn the conference over to Christine Lindenboom. Please go ahead. Good morning. I am Christine Lindenboom, Chief Corporate Communications at Alnylam Pharmaceuticals, Inc.

With me today are Yvonne L. Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal P. Garg, Chief Research and Development Officer; and Jeffrey V. Poulton, Chief Financial Officer.

For those of you participating via conference call, the company 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 would like to remind you that this call will contain remarks concerning Alnylam Pharmaceuticals, Inc.’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 discussed 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 as of any subsequent date.

We specifically disclaim any obligations to update such statements. With that, I will turn the call over to Yvonne. Yvonne?

Thanks, Christine, and thank you everyone for joining the call today. Alnylam possesses a truly unique profile in the biotech industry, underpinned by our established and sustainable innovation engine, coupled with commercial excellence driving durable long-term growth. We are the leaders in RNAi therapeutics with a proven organic product engine and a reproducible and modular process for developing our medicines that has resulted in outsized historical success rates. We also have a high-yielding pipeline with over 25 programs currently in active clinical development.

There are now six Alnylam-invented medicines on the market that are collectively generating several billion dollars in annual revenues and treating hundreds of thousands of patients around the world. This broad execution across all areas of the business was clearly evidenced in 2025, which was a transformational year for Alnylam. In terms of commercial and financial performance, we achieved a landmark approval of Amvuttra for ATTR cardiomyopathy, and driven by the success of that launch, delivered nearly $3 billion in combined net product revenues, which was 81% growth compared to 2024. Importantly, we met or exceeded all of our ambitious Alnylam P5x25 goals.

And with today's announcement, we can now officially declare that we have achieved GAAP profitability for the 2025 full year and expect to sustain profitability going forward. On the pipeline and platform side, in 2025, we initiated three Phase 3 studies and our clinical pipeline with four proprietary CTAs in addition to five that were filed by our partners. We also developed and launched a potential best-in-class enzymatic ligation-based RNAi manufacturing platform called Cyrillis. We believe this platform will enable us to greatly expand our capacity and bring RNAi therapeutics to more patients around the world while reducing the cost of goods.

While 2025 was a defining year for the company, we are now focused firmly on the future, harnessing our success to accelerate innovation and scale impact. To that end, we are excited to have recently shared our new set of five-year goals, Alnylam 2030. And these goals rest upon three strategic pillars, starting with achieving global TTR leadership while building a durable TTR franchise. We aspire to lead this market in revenue by 2030 and across the period, and to launch nuceresiran in 2028 for polyneuropathy and 2030 for cardiomyopathy. The next pillar is growing through sustainable innovation, where we plan to deliver two or more transformative medicines beyond TTR that have blockbuster potential.

We also aspire to achieve delivery of RNAi to 10 tissue types, and have a pipeline of over 40 clinical programs by 2030. The high-yielding platform and outsized historical probability of success combined with our rigorous and disciplined approach to portfolio management, we believe this is the right place to focus our efforts and resources. And we expect to invest approximately 30% of our revenues in non-GAAP R&D across the period to accelerate organic internal innovation and selectively access external innovation. Given our expertise and leadership in this space, we believe this is a prudent allocation of capital that has the potential to deliver significant growth in the future.

The final pillar of our 2030 goals is scaling with discipline and agility to drive sustained, profitable growth. This includes striving to achieve over 25% revenue CAGR through 2030 and to deliver a non-GAAP operating margin of 30% across the period. It is important to note that this operating margin goal is only through 2030, which is the year we aim to achieve regulatory approval for nuceresiran in ATTR cardiomyopathy. And if nuceresiran is successful in demonstrating the best-in-class profile that we expect, we believe it would drive swift patient uptake and, given the lack of any royalty obligations for nuceresiran, potentially drive our operating margins to the mid-40s post 2030. Through these goals, I hope you can appreciate that we are building on Alnylam for the future, delivering continued long-term growth underpinned primarily by our RNAi innovation platform.

With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

Thanks, Yvonne. Good morning, everyone. It is a pleasure to show how we are continuing to bring Alnylam’s transformative therapies to patients around the world. Q4 represented another quarter of strong growth for Alnylam.

We delivered $995 million in combined net product revenues, representing 121% growth year over year and 17% growth versus prior quarter. While our TTR franchise remains the primary growth engine, we are also seeing continued momentum in our rare disease business. Let me start there. Our rare disease portfolio continues to deliver meaningful impact for patients and consistent performance for our business.

In Q4, our rare franchise generated $136 million in net revenue, up 26% versus the same period last year, driven by increased patient demand and favorable order timing in partner markets. As a result, GIVLAARI and OXLUMO together became a $500 million franchise in 2025, reflecting continued growth more than five years post launch. With that, let us turn to the TTR highlights. Q4 was another robust quarter for our TTR franchise, continuing the strong launch trajectory we saw in Q2 and Q3. Global TTR net revenues reached $858 million, up 18% versus the prior quarter, and representing 151% growth year over year.

In the U.S., net revenues for our TTR franchise grew 20% compared with Q3 2025 versus 222% versus Q4 2024. The quarter-over-quarter growth was primarily driven by a continued increase in U.S. patient demand, partially offset by an increase in gross-to-net deductions and an unfavorable inventory channel impact. Outside the U.S., revenues grew 13% versus the prior quarter, and 47% year over year, underscoring continued global momentum. We continue to be very pleased with the early signs in Japan roughly six months into the cardiomyopathy launch as we continue to track in line with leading launch analogs in the industry.

In Germany, we recently aligned pricing for Amvuttra for the ATTR cardiomyopathy opportunity, reflecting the significantly larger prevalence of the cardiomyopathy indication relative to the polyneuropathy indication. As expected, this will create a modest near-term impact on total TTR revenue in Q1, but importantly, it positions us to compete effectively and participate in a substantially larger cardiomyopathy market in Germany.

As we have previously mentioned,

we anticipate launching Amvuttra for ATTR cardiomyopathy in additional international markets throughout 2026 following the completion of local pricing and reimbursement reviews.

As we continue to launch across ex-U.S. markets,

we are building global momentum that we expect to carry through 2026 and beyond. Finally,

our international performance reflects the continued strength

of our hereditary ATTR polyneuropathy legacy business, which remains robust despite competition. Broader engagement in the category is expanding awareness and diagnosis, ultimately benefiting patients and reinforcing Alnylam’s leadership role in shaping the field. Now let us turn to the U.S. ATTR cardiomyopathy-specific dynamics.

Looking back on 2025, our confidence in the size, growth, and continued under-penetration of the ATTR cardiomyopathy category has been reinforced. Despite approximately 40% volume CAGR over the past six years, the majority of patients with ATTR cardiomyopathy remain untreated. Against that backdrop, we are highly encouraged by Amvuttra’s early momentum. In its first few quarters, performance relative to relevant specialty analogs supports the potential for a breakout launch, reflecting strong customer demand, the value of Amvuttra’s differentiated profile, and disciplined commercial execution.

When we look at the early launch data, what is most encouraging is not just the pace of uptake, but where Amvuttra is being used and why.

First,

Amvuttra is rapidly establishing itself as an important choice in new treatment starts. By just the second quarter post launch, Amvuttra approached parity with tafamidis in share of new starts based on available estimates. While these available data will continue to evolve, the early signal is clear. Prescribing dynamics in ATTR cardiomyopathy are shifting.

Second, we are gaining traction in first-line patients. Establishing Amvuttra as a first-line option remains our strategic priority, and we are making meaningful progress. In parallel, Amvuttra has quickly become the preferred option for stabilizer progressor patients, consistent with its differentiated and orthogonal mechanism of action. Third, this momentum is underpinned by broad and durable access.

Following completion of our 2026 payer policy discussions, we can look ahead with increased confidence to even broader patient access for Amvuttra in 2026 versus last year. Over 90% of payers now provide first-line coverage, with the large majority of patients able to initiate treatment without step-through requirements. Most patients incur zero out-of-pocket costs, and approximately 90% can access treatment within 10 miles of their home, supported by a broad, well-established network of sites of care. As we enter 2026, we remain clear-eyed about where we are.

The ATTR cardiomyopathy launch is still in its early stages, just three quarters in, and there is important work ahead. At the same time, we have established the foundations for durable growth, underpinned by a strong value proposition, broad access, and steadily increasing customer demand. Looking forward, we see meaningful opportunity to further expand the category by improving diagnosis and treatment rates, and we are investing accordingly through targeted efforts in education and awareness, evidence generation, and diagnosis enablement to ensure sustainable, long-term impact for patients. We look forward to sharing more details at our upcoming investor webinar where we will mark the one-year anniversary of Amvuttra’s U.S.

FDA approval for ATTR cardiomyopathy on 03/24/2026, and highlight our progress for patients and the long-term growth and durability of our TTR franchise. With that, I will hand over to Pushkal. Thank you, Tolga, and good morning, everyone. As Yvonne highlighted earlier, 2025 was indeed a year of substantial pipeline progress and platform innovation for Alnylam.

First, we initiated three Phase 3 studies in 2025.

ZENITH is our event-driven cardiovascular outcomes trial for zalesiran in patients with uncontrolled hypertension at high CV risk. We aim to enroll approximately 11,000 patients and, if successful, plan to launch around 2030. TRITON-CM is our event-driven outcomes trial for nuceresiran in ATTR cardiomyopathy. Approximately 1,200 patients will be enrolled in this study with launch also expected in 2030, if successful. And TRITON-PN is an open-label study of nuceresiran in approximately 125 patients with hereditary ATTR polyneuropathy.

If successful, approval in this indication is expected in 2028. We also expanded our clinical pipeline, taking four new Alnylam-led programs into the clinic: ALN-2232, our first RNAi therapeutic directed to an adipose target, ACVR1C, with the potential to lead to durable weight loss, particularly reduction in visceral fat that is associated with poor cardiometabolic health; ALN-5288 targeting MAPT or tau for Alzheimer’s disease and other rare tauopathies; and two new programs for which we are not yet disclosing details due to competitive reasons, ALN-4285 and ALN-4915. Our partnerships also continue to generate progress with five new partner-led programs entering the clinic in 2025 across a range of indications with significant unmet need.

We are also excited for our partners at Regeneron, who remain on track to submit a U.S. regulatory application in the first quarter for cemdisiran in generalized myasthenia gravis with potential approval anticipated later this year or early 2027. And finally, as Yvonne mentioned, we also launched Cyrillis, our proprietary enzymatic ligation manufacturing platform. As a result, we ended 2025 with a pipeline of over 25 clinical programs spanning multiple therapeutic areas across rare, specialty, and prevalent indications, representing a tremendous opportunity for improving patient health and creating value in the years ahead.

Among these many programs, there are several that represent the next wave of transformative near-term RNAi therapeutics from Alnylam, each of which has multibillion-dollar potential. In the cardiovascular metabolic space, we are excited about zalesiran, targeting angiotensinogen with the aim of achieving continuous control of blood pressure with just two doses per year. For metabolic diseases, we see compelling opportunities to address substantial unmet medical need and gaps in treatment left by GLP-1s in both overweight/obesity and type 2 diabetes. And in neuroscience, valesiran targets amyloid precursor protein for the potential treatment of cerebral amyloid angiopathy and Alzheimer’s disease.

APP is a genetically validated target for both of these diseases and CAA in particular represents a blue ocean opportunity. ALN-HTT02 employs a unique exon 1 targeting approach with the potential to address Huntington’s disease, a disease with no approved therapies, through deep and widespread lowering of the huntingtin protein in the brain. And in hematology, ALN-6400 offers an exciting opportunity for a pipeline-in-a-product, targeting plasminogen to address a wide range of bleeding disorders with a unique approach that has the potential to reduce bleeding without increasing the risk of thrombosis.

Our first indication is hereditary hemorrhagic telangiectasia, which affects approximately 70,000 patients in the United States. We will share important updates across many of these programs over the year, as outlined in our 2026 pipeline goals. In the first half of the year, we plan to complete enrollment in the CAPRICORN I Phase 2 trial of marvesiran in patients with CAA, and initiate three Phase 2 trials. The first of these has already been achieved, which is a Phase 2 study of ALN-4324 in patients with type 2 diabetes.

This study is now actively enrolling patients. For marvesiran in patients with Alzheimer’s disease, and another for ALN-6400 in a second bleeding disorder. Importantly, we expect to have clinical de-risking data this year on several of the programs I just mentioned. Specifically, we expect to share Phase 1 and 2 results from the ALN-6400 program and Phase 1 data on both our Huntington’s and ACVR1C programs in the second half of the year.

And 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 am pleased to be presenting a summary of Alnylam’s full year 2025 financial results and providing our comprehensive financial guidance for 2026. Let us begin with a summary of our P&L results for the full year. Total global net product revenues for 2025 were nearly $3 billion, or 81% growth versus 2024, driven by a more than doubling of revenue in our TTR franchise, primarily from the strong performance in the U.S. following our Q2 launch of Amvuttra in ATTR cardiomyopathy. These full year results were more than $800 million above the original 2025 product sales guidance we provided last year, a testament to the strength of our ATTR cardiomyopathy launch performance.

For the full year, collaboration revenue was $553 million, or 8% growth compared with 2024, and included a $300 million development milestone in Q3 associated with the dosing of the first patient in our ZENITH Phase 3 cardiovascular outcomes trial for zalesiran. Royalty revenue for the full year was $104 million, representing a 90% increase compared with last year driven by higher Leqvio sales from Novartis. Gross margin on product sales was 77% for the full year, representing a 4% decrease compared with 2024. The decrease in margin was primarily driven by increased royalties on Amvuttra, as higher revenues in 2025 resulted in an increase in the average royalty rate payable to Sanofi compared with the prior year.

Our non-GAAP R&D expenses of approximately $1.2 billion increased 17% compared to last year, primarily driven by costs associated with the initiation of three Phase 3 clinical studies, including the ZENITH Phase 3 cardiovascular outcomes trial for zalesiran and the TRITON-CM and PN studies for nuceresiran.

Non-GAAP SG&A expenses of approximately $1.0 billion increased

22% compared to last year, primarily driven by increased investments in support of the Amvuttra ATTR launch in the U.S. We achieved full year non-GAAP operating income of $850 million, representing a $755 million increase compared with last year, driven primarily by the strong top-line results that I previously highlighted. I am also pleased to share today that we achieved profitability on both a GAAP and non-GAAP net income basis both in the fourth quarter and for the full year 2025, more than delivering on our P5x25 non-GAAP profitability goal. I would like to take a moment to thank the Alnylam employees who made this milestone possible through their active engagement and scaling our business with discipline over the past five years.

Finally, we ended the year with cash, cash equivalents, and marketable securities of $2.9 billion compared with $2.7 billion at the end of 2024. The primary drivers of the $200 million increase in cash during the year include improved operating performance and proceeds from the exercise of stock options, partially offset by net proceeds utilized during our convertible refinancing in Q3. Now I would like to turn to our financial guidance for 2026. Starting with net product revenues, we are reiterating the combined net product revenue guidance for Amvuttra, ONPATTRO, GIVLAARI, and OXLUMO that we communicated in our J.P.

Morgan press release dated 01/11/2026. We anticipate combined net product sales for our four commercial products will be within a range of $4.9 billion to $5.3 billion, representing combined full year growth compared to 2025 of 71% at the midpoint of the guidance range, or more than $2.1 billion in growth. On a franchise level, the guidance is broken down as follows. Total rare, $500 million to $600 million, representing full year growth compared to 2025 of 10% at the midpoint of the guidance range. Total TTR, $4.4 billion to $4.7 billion, representing full year growth compared to last year of 83% at the midpoint of the guidance range.

As Tolga noted in his prior comments, it is still early days in the ATTR cardiomyopathy launch but we are pleased with our initial momentum and the strong fundamentals which support the long-term growth potential of our TTR franchise. As we highlighted at the J.P. Morgan conference, the 2026 TTR product sales guidance is underpinned by three key assumptions. First, we anticipate U.S.

TTR category growth will remain brisk and consistent with prior years. Second, in the U.S., we continue to expect a modest decrease in net price as our cardiomyopathy business continues to scale. Specifically, we forecast a mid-single-digit net price decrease for Amvuttra in 2026. Third, given the impact on our polyneuropathy business associated with lower cardiomyopathy launch pricing in international markets, we expect international TTR revenue dollar growth in 2026 will be consistent with 2025. I would also like to provide some color on Q1 phasing assumptions associated with our full year TTR revenue guidance.

For Q1, we expect considerably lower quarter-on-quarter TTR revenue growth compared with the $134 million of TTR growth that we delivered in Q4 2025. The lower growth expectation in Q1 is driven by a variety of factors, including the following: first, unlike in Q4, when our international markets contributed $23 million in quarterly TTR revenue growth, we are expecting an approximate $25 million reduction in Q1 international revenues, with the primary driver of the decrease attributable to our cardiomyopathy launch in Germany; second, modest quarter-over-quarter TTR growth in Q1 compared with the $111 million of U.S. quarterly growth achieved in Q4 due to fewer product shipping weeks in Q1 and the expected impact of annual insurance reauthorizations.

Beyond Q1, we expect higher quarterly growth for the balance of the year in the U.S., and we remain confident in our full year TTR product sales guidance. Now returning to our full year 2026 financial guidance. Our collaboration and royalty revenue guidance range is $400 million to $500 million, representing a decrease of 38% compared to 2025 at the midpoint of the guidance range, driven by the one-time $300 million zalesiran development milestone achieved in 2025 that I previously mentioned that will not recur this year. We expect the collaboration revenue associated with our partnerships with Roche and Regeneron as well as Leqvio royalties from Novartis will drive the majority of our collaboration and royalty revenue this year.

Our guidance for combined non-GAAP R&D and SG&A expense is a range between $2.7 billion and $2.8 billion, with the midpoint of the range representing 26% growth versus 2025. Growth drivers for R&D expense this year include increased investment in clinical studies, including the continuation of pivotal Phase 3 studies for zalesiran and nuceresiran, as well as early pipeline investment to deliver three to four new INDs and support expansion of delivery into new tissues. Growth in SG&A will primarily be driven by ongoing launch activities to support Amvuttra for ATTR cardiomyopathy in the U.S. and select international markets.

Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Jeff. Operator, we will now open the call for questions. Please limit yourself to one question each, then get back in the queue if you have additional questions.

Thank you. Ladies and gentlemen, we will now begin the question and answer session. Should you have a question, please press the star followed by the one on your touch-tone phone. You will hear a prompt that your hand has been raised.

Should you wish to decline from the polling process, please press the star followed by the two. If you are using a speakerphone, please lift the handset before pressing any key. One moment for your first question. I have Paul with Fifth.

Please go ahead.

Good morning. Can you hear me okay?

Yes. We can. Thank you.

Okay. Great. Good morning. Thanks so much, and appreciate you taking my question.

I was wondering if you could just comment on what you are seeing so far in 2026 in terms of new patient adds and the mix of first line for vutrisiran versus tafamidis switches and how you see that evolving over the course of this year and what is assuming guidance?

Thank you.

Yeah. No. That is a great question. I think it is important just to underscore how pleased we are with the Amvuttra launch so far.

Coming out of the gate strong, we are building towards an analog-beating launch and really building a long-term franchise that is incredibly important. All the fundamentals are in place to drive continued Amvuttra growth, which I think is underscored by our 2026 guidance and our 2030 goals. But, Tolga, maybe you will speak specifically to

Yeah. I mean, how you see the market. Thanks, Yvonne. Good morning, Paul.

Look. As Yvonne highlighted, what really drives our confidence in reiterating the guidance is the fundamentals. If you think about it, we have actually improved our first-line access. We are clearly seeing a strengthening physician and patient preference, and even more importantly, category growth with more patients entering the market.

Those trends were in place heading into J.P. Morgan and have continued to build, and that is why we remain confident in the year. Great. Thank you.

Next question, please.

K. Your next

question is from Salveen with Goldman Sachs. Please go ahead. If I

just follow up on the confidence here in the guide for the year for the TTR franchise. Just speak to the choppiness that we are seeing coming out of the scripts for the first quarter to date and then how you think about the pricing dynamics as you look to a new potential market entry this year or next year, as well as the growth dynamics in Europe. Thank you.

Hey, Tolga. Yeah. So let me take the pricing question

first. We feel very well positioned from an access standpoint for this year. The large majority of patients have already first-line access without required step edits, and most patients are continuing to pay zero out of pocket, partly supported by our value-based agreements. And, in fact, utilization within those agreements has been rather minimal to date.

In terms of on our pricing, our net price declined mid-single digits in 2025, and our 2026 guidance assumes a similar mid-single-digit decline, and that dynamic is fully integrated into our outlook. Now in terms of 2027, obviously too soon for us to be able to provide specific guidance, but we felt really well positioned as we entered 2026.

Thanks, Tolga. Next question, please.

Your next question is from Kostas with Oppenheimer. Please go ahead.

Congratulations on the strong year. A question on seasonality from us. Have you seen any seasonality during the fourth quarter, potentially patients who pushed the injection to the next quarter because of the holidays and whether this can be a tailwind to 2026? Thank you.

Maybe, Tolga, that question for you. And I think we only spoke to, you know, Q1 phasing, and that is actually kind of very typical in the industry. But, Tolga, do you want to

Right. So I would actually really step back and start thinking about rather than on monthly fluctuations, looking at the quarterly, you know, the total growth of this category. If you think about historically, while quarterly growth has fluctuated, the longer-term category trend has been one of robust and really well-sustained growth on the order of about 40-plus over the past several years. So even within Q4, we have seen momentum improve as we exited the quarter.

Now as Yvonne highlighted, Q1 has been rather specific across the industry in terms of the seasonality. We are certainly seeing some of that, but we believe that from that seasonality, it is really not impacting the underlying momentum that we are building in the category. Thank you.

Next question, please.

Your next question is from Ritu with TD Cowen. Please go ahead. Good morning, guys. Hi.

Good morning. Thanks for taking the question. I wanted to ask about the gross-to-net pattern over 2026. Tolga, you mentioned mid-single digits. Is that going to be sort of a stepwise adjustment in Q1 and then flat through the rest of the year, or is it going to be gradual?

Basically, I am asking are all the access discussions for the full year done? And also, if you can comment about

per Salveen’s question, whether

potential longer-term competitive dynamics are factoring into how you are thinking about gross to net over the year. Thanks.

Maybe, Jeff, you start on the general gross-to-net question, and Tolga, you may have some additional perspectives. Yeah. Ritu, again, the guidance for the U.S. market for pricing this year is a mid-single-digit

net price decrease similar to what we did in 2025. And that would be expected to be gradual over the course of the year rather than sort of all upfront in the first quarter, gradual.

Yeah. And in terms of the 2027 outlook, as we highlighted, it is really too soon for us to make any comments at this point. We do not know what their data is going to look like. We do not know what their label is going to look like.

But what I can say is given how well we are positioned in terms of Part D versus Part D, we believe we are really well positioned in terms of being able to manage our growth. And, in fact, if you think about the guidance that we provided, or I should say our objectives from 2030, we are assuring that our 2030 CAGR growth of 25% certainly incorporates some of that thinking. We believe we are going to be able to preserve and increase the value of this category.

Thank you. Alright. Thank you. Your next call comes from Maury with Jefferies. Please go ahead.

Hi. Good morning. Thanks for taking my question. You commented a little bit on this at J.P.

Morgan, but just wondering for the five-year strategy, you mentioned the select external innovation as part of the approximate 30% revenue R&D spend. Can you just elaborate on that? Should we anticipate additional partnerships like the Roche one with zalesiran? Or other forms of licensing?

And is there anything more on timing, size, scope of an external BD deal?

Yeah. No. Thanks for that question. Look.

I think it is important to highlight that we really are focused on our rich internal pipeline, which is truly spring-loaded for growth. But, given our strengthening financial position, it does make sense to start to become open to select innovation that could provide access to technologies and earlier-stage medicines that are complementing our existing commercial portfolio and our R&D pipeline. And I think important also to state that we have a very high science and financial bar, both for our internal innovation, but also as we look to assess opportunities externally as well. Thank you.

Next question.

Alright. Your next question comes from Tazeen with Bank of America. Hi, good morning. Thanks for taking my question. On nuceresiran, you talked about the time that you could potentially launch at the beginning of 2030s, let us say, 2030-ish. How should we be thinking about the impact

to your operating margin once that product becomes available? And just practically speaking, even if it might have the better profile that you described as less frequent dosing,

how long do you think it would take for patients to appreciate something like that, be it the base, switching from vutrisiran to nuceresiran when it becomes available?

Thanks.

So there are a couple of questions here. I will just reiterate maybe the remarks that I made earlier, which is, we are really excited about nuceresiran. We believe that this is, if it is successful, which we have high conviction in, it is going to have a best-in-class profile which is going to lead to swift patient uptake. And this is going to be without the royalty obligations for nuceresiran.

So, clearly, this will have a significant positive impact on our margins post 2030. And as I said, we are looking at potentially driving margins to the mid-40s by

2030. And just to

tack on to that, if you look at what consensus gross margins are for our business out to 2030, Tazeen, it is mid-70s, and I would say the vast majority of that is related to the royalty that we pay Sanofi. So that tells you about the opportunity to improve margins post 2030 if we have the kind of profile that we expect with nuceresiran.

Great.

Thank you. Next question, please.

Your next question is from Luca with RBC Capital Markets. Please go ahead.

Oh, great. Thanks so much for taking my question. Congrats on the progress. Maybe if I can pivot to the pipeline,

Pushkal. Could you just talk a little bit about Huntington’s? Again,

assuming that maybe later this year you will show us some initial pharmacodynamic data on the mutant and the CSF. But we all know that huntingtin is a relatively slow progressive disease. So I am assuming that the clinical data like cUHDRS is going to be pretty preliminary. Would that be fair?

And if so, are you willing to start the pivotal Phase 3 trial with just target engagement data in hand? Are you going to wait before doing so until you see a clear functional signal there? So I guess the question is, maybe walk us through what kind of go/no-go decision

to start a Phase 3 trial for Huntington’s. Thanks so much.

Wow. That is a great question, and thank you for asking a question about the Huntington’s program. It is a program that we have high conviction in for addressing what I think we all know is an incredibly devastating disease, but there is quite a lot in that question. Pushkal.

Yeah. Luca, happy to address it. As I mentioned, as you highlight, the unmet need in Huntington’s, I think, is undisputable. We are very excited about the approach we have.

We have an siRNA that targets the overall huntingtin protein, but specifically also targets this exon 1 segment that is thought to be necessary actually for disease propagation, and so we think we have a very unique approach. Unfortunately, prior approaches have not really addressed this. Interestingly enough, the one approach that does is the approach, and we have all seen some recent data coming from there that suggests potentially, through natural history data, there may be a favorable trend there emerging in terms of efficacy. So we are very excited about the approach.

We are in a Phase 1 program right now in Huntington’s patients where we are really trying to see convincing evidence of lowering of huntingtin as well as safety. You will recall that prior efforts in this space have been challenged because they cannot get the high levels of knockdown, beyond about 20%, and then they have been associated with safety concerns: NfL increases, ventricular enlargement, etc. So I think those are the first two things, Luca, that we are going to be looking for. Can we get to good levels of knockdown?

We would like to get to over 50%. And can we do that durably and safely for a period of time? As we have mentioned, we will put out some data at the end of this year. You are right that I would not expect a lot in terms of clinical data at that point in terms of cUHDRS.

This is a relatively modest number of patients, and so we are hoping that, again, if we see those two signs, then to your second part, look, given the unmet need, this is a program we are very much going to try and accelerate as quickly as possible. We want to do that in a responsible way, but you will look to us to see what anything we can do to bring this forward to patients as quickly as possible, and we will keep you posted on that.

Thanks, Pushkal. Thanks so much. Next question, please. Your next question

is Miles with William Blair. Please go ahead.

Hi. Thanks for taking the questions. Another one on the pipeline for obesity.

Just what is the rationale for prioritizing the ACVR1C asset over something like INHBE in your Phase 1 trial? And then is the target product profile for that that is going to come out of that data, is it something that is equivalent to what we are seeing from your peer in Arrowhead, or are you going for something superior on the efficacy side? Thanks very much.

Straight for you. Yeah. Thanks, Miles. We see a tremendous opportunity in the overweight/obesity space and the diabetes space.

GLP-1s have obviously revolutionized that space, but we think we all recognize there is a lot of unmet need to aid in weight loss, A1c reduction, without the muscle loss and the tolerability issues that happen with GLP-1s. We have prioritized ACVR1C because both in our preclinical work, based on the genetics, preclinical models, as well as some of the emerging data that you are seeing coming from Arrowhead, you see that ACVR1C appears to be the more potent target, and so we have certainly prioritized that. We are interested in INHBE, but we think ACVR1C is more interesting. I think when you look at the Arrowhead and Wave data, there are questions about the monotherapy magnitude of weight loss they can deliver.

And I think this is a space where we are going to have to be particularly thoughtful. We are uniquely positioned to be thinking about unique patient segments that we might be able to target, looking at unique combinations that can bring disproportionate benefit to patients within this space. That is the reason for prioritizing ACVR1C. And, as I said, we expect to have some results to share at the end of the year.

Thank you.

Next question.

Your next question comes from Mike with Morgan Stanley. Please go ahead.

Good morning. Thanks for taking the question. Maybe I could

ask a question just on cardiomyopathy and trends there, particularly for market share. Obviously, you have had some great share gains in the second-line setting and also

positive trends in the front line. Just

curious, particularly in frontline as we move through the year, do you expect those share trends to continue to increase? Thanks.

Yeah. No. We have been very pleased by the broad and balanced kind of access that

we are seeing.

Tolga?

Yeah. I mean, as you saw, Mike, in the data we shared particularly around new-to-brand dynamics, we are approaching near parity with tafamidis. The goal and intent was to demonstrate that in a growing and increasingly competitive category, we have been able to make meaningful and rapid headway. Now in terms of 2026, obviously, we reiterated our full year 2026 guidance.

What gives us the confidence is the continuous progress we are making in terms of first-line access, rising physician and patient preference, and also, importantly, healthy category growth. Those were the drivers heading into J.P. Morgan, and we continue to see them strengthened. That momentum supports our outlook for 2026.

And, of course, we are going to be having the investor webinar in March, which will be an opportunity to rethink about how we are building this very exciting franchise for the future. Thanks for that plug. Okay.

Next question.

Your next question comes from Ted with Piper Sandler. Please go ahead.

Great. Thank you very much. And just maybe digging a little bit deeper in terms of the external partnering. Should we be more thinking complementary technology then from your comments earlier, Yvonne? Whether that be delivery types or other RNA mechanisms? Thanks.

Yeah. No. I think that is absolutely correct. We are looking at areas where there is good strategic fit.

Some opportunities are complementary to what we are doing. You touched on delivery. That is one potential approach to consider. We have a very exciting internal pipeline, so we are going to be very judicious about what external innovation actually helps us accelerate our internal innovation and also complements our current portfolio.

But, Pushkal, do you want to add anything to that? No. I think you have covered it,

I think we are going to be looking at that landscape of things that are complementary from a technology perspective that help bring medicines to more patients more rapidly.

Great.

Okay.

Thanks. Next question, please.

Your next question is from Ellie with Barclays. Please go ahead. Hey, guys. Thanks for taking the question.

Maybe just a big-picture one across the emerging early-stage pipeline. Which programs are you most excited about, or do you think are the most de-risked? And then a second question, you mentioned for the U.S., you expect a mid-single-digit net price decrease in 2026. What would you expect for 2027? Should we expect something similar or more or less with a new competitor?

Thanks.

Wow. I think it started off with trying to get us to say what our favorite programs are. Yeah. I mean, Ellie, I think

it is like choosing between your children. We have some very exciting opportunities. In terms of your question about which are most de-risked, obviously, nuceresiran is about as de-risked as possible. We have no doubt that TTR silencing aids in both polyneuropathy and in cardiomyopathy, and that drug will get to 95% silencing in twice-a-year dosing.

Zalesiran has shown blood pressure lowering, compelling blood pressure lowering, in four studies now—Phase 1 and three Phase 2s of increasing stringency on top of background medicines with a durable profile. There is a wealth, as Professor Williams highlighted last year at ESC, of data that suggests that continuous control of blood pressure should lead to outsized benefits in terms of cardiovascular outcomes. I think that is fairly de-risked. As you look forward, we have a number of other programs where in the period of 2026 and 2027 we are going to get very compelling data that leads to de-risking.

Think about data coming out on Huntington’s, or in CAA as I just mentioned in my comments to Luca, and we will get some proof-of-concept data on a number of different programs in overweight, obesity, diabetes, and a number of programs that we actually have not named. And then, of course, the plasminogen program where we have already seen convincing data that we shared last year at R&D Day in terms of proof of mechanism, that we are seeing clot stabilization, very strong genetics. I think that has been significantly de-risked. You see confidence in there.

We have kicked off one Phase 2. We have talked about kicking off a second Phase 2, and we are moving rapidly with that program. I am excited about the opportunities that lie ahead and, as I said, the number of exciting potential to help patients and create value.

Yeah. That is great, Pushkal. I think the really unusual story about Alnylam is we actually have a de-risked organic product engine, and this gives us tremendous leverage, helping us to accelerate the pace of innovation and allowing us to scale with this proven platform into what is going to be a multi-franchise growth company. As Pushkal highlighted, there are a number of near-term opportunities for us to really turn these programs into important medicines for patients.

Just

do you want to add any perspective?

On the pricing question, I think that Ellie had asked about. Again, what we have said consistently since we have launched in the U.S. with cardiomyopathy in the label is we have expected gradual net price reductions over time as the business scales. Again, we are entering year two. Year one was mid-single-digit price decrease.

That is what we are expecting in year two. Over the longer-term guidance that we have given, 25% CAGR, that is the expectation across the period at this point.

That is great, Jeff. Apologies. When we get these multipart questions, sometimes one of the questions slips off the list. Tolga, did you have something to multipart answer to that as well?

To support Jeff’s point, in terms of how anticipating new competition may impact the pricing, as we reiterated, first of all, we are really well positioned from an access perspective. We have established credibility and durability of this franchise in 2026, and if you think about the potential emerging competition, we are already actually in that competitive field with the polyneuropathy indication, and we have been able to secure great access to the patients with limited copay. I would anticipate, and obviously we provided our goals for 2030 and that value growth of 25% CAGR remains, so we are comfortable with providing that perspective for 2027 as well.

Good. Well, I hope we covered everything you asked. Next

next question, please.

The next question comes from Corey with Evercore ISI. Please go ahead.

Hey. Good morning, guys. Thanks for taking the question. I guess

it is related somewhat to what you were just talking about, but with the competitive silencer data obviously expected this year, I am interested in your latest views on potential for that asset to attain a differentiated label based on their trial, and how you think about that having a potential commercial impact on Amvuttra if it were to actually be the case? Thank you.

Okay. That is both a commercial and a development perspective in that question. Tolga, do you want to make a few remarks, and then we will hand it

I mean, it is obviously difficult to assess the impact without seeing their data, and it would be premature to speculate on the specific role they are going to play. That said, it is really important to highlight this category remains very large and significantly underserved. Additional entrants will certainly help drive diagnosis and treatment rates, which we believe ultimately will benefit patients and expand the category. From our perspective, we feel very well positioned.

We have a head start given our rapid, deep, and sustained knockdown profiles, strong clinical data package, and, obviously, quarterly dosing.

So

maybe, Pushkal, you can

Yeah. I think, Corey, we are looking forward to seeing the results, as obviously we do not have a magic crystal ball. We will see what the results are. Our expectation is the study will be positive.

They have shown good knockdown that occurs over a period of some months, and so I would expect—and they have a large outcome study, both in monotherapy and in combination—so I would expect the results to be positive. We will be on the lookout for a couple of aspects of this. First, we will want to look at the safety profile that emerges. This is an ASO in a large population that is somewhat older and frailer, so it will be interesting to see how that emerges.

And then on the efficacy side, I expect to see favorable impacts on the outcome parameters, as we have shown with HELIOS-B with vutrisiran. There is some speculation that they will have a stronger signal, for example, in the combination because they will have a larger number of patients on top of a background stabilizer. My hypothesis would be I do not see any reason why the treatment effect size would be any different than what we have already established in HELIOS-B. They may have a tighter confidence interval or stronger p-value in that subgroup, but in terms of the effect size, I do not expect it to be materially different, and I think it would be consistent with what we saw.

Your question is the most critical one, which is how is that going to impact the label? I would just point out that our label already provides data for both on and off a stabilizer, and it specifically points out that the treatment effects were consistent in both populations, so we have a very broad label. I do not foresee how the label would be materially different based on the statistical significance in that one subgroup, but that remains to be seen. That is how I would map it out.

Very helpful. Thank you. Next question.

Next question. Next question comes from Danielle with Truist. Please go ahead.

Hey, guys. This is Alex on for Danielle. Thanks for taking the question. Just a question on Amvuttra access in community centers.

Do you have a sense of how much of the market is not currently accessible due to the high cost of Amvuttra and potential hesitancy to stock the drug? Just curious if you have a sense of what proportion of new diagnoses are coming out of the community centers versus what proportion of Amvuttra patients are actually being managed in the community settings. Thanks so much.

Let me just take that very quickly. As we highlighted from a payer perspective, first and foremost, because I think you highlighted whether there is an access issue, we feel really well positioned from an access standpoint. Again, the large majority of patients have first-line access to Amvuttra, and that is regardless of where those patients are. In terms of accessing the medication, as we highlighted, our experience is that it is very broad and balanced.

In terms of the community setting patients, we have been able to secure alternative site-of-care agreements where 90% of the patients already have Amvuttra injection within 10 miles of their residences. We are continuing to expand that network, but I think we reached that critical mass already within 2025, and we continue to work on that.

Perfect. Well, I believe that was our last question. I would like to thank everyone for joining us today. Clearly, 2025 was a remarkable year in which we delivered a blockbuster launch of Amvuttra in TTR cardiomyopathy, we made significant advancements across our pipeline, and we achieved sustainable profitability.

As we begin this next chapter of our story, we look forward to executing on our 2026 goals and the broader 2030 strategy to both accelerate innovation and scale impact. Thanks to everybody who joined the call, and have a great day.

Ladies and gentlemen, this concludes today’s conference call. Thank you for participating, and you may now disconnect.