Good morning. I'm Christine Keung, 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 two, 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. 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'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'll 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're 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 evident in 2025, which was a transformational year for Alnylam.

In terms of commercial and financial performance, we achieved the landmark approval of Amvutra 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 P to the 5th by 25 goals.

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 expanded 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 CeraLys. 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're now focused firmly on the future, harnessing our success to accelerate innovation and scale impact. To that end, we're excited to have recently shared our new set of 5-year goals, Alnylam 2030.

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 nucresiran 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 the end of 2030.

With a 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 the 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 the end of 2030, and to deliver a non-GAAP operating margin of approximately 30% across the period.

It's important to note that this operating margin goal is only through 2030, which is the year we aim to achieve regulatory approval for nucresiran in ATTR cardiomyopathy. If nucresiran 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 nucresiran, potentially drive our operating margins to the mid-40s post-2030.

Through these goals, I hope you can appreciate that we're building 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, and good morning, everyone. It is a pleasure to show how we're 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're 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 half-a-billion-dollar franchise in 2025, reflecting continued growth more than 5 years post-launch. With that, let's 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 US, net revenues for our TTR franchise grew 20% compared with Q3 '25 versus 222% versus Q4 2024. The quarter-over-quarter growth was primarily driven by a continued increase in US patient demand, partially offset by an increase in gross-to-net deductions and an unfavorable inventory channel impact.

Outside the US, 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 6 months into the CM launch, as we continue to track in line with leading launch analogues in the industry.

In Germany, we recently aligned pricing for Amvutra for the ATTR-CM opportunity, reflecting the significantly larger prevalence of the CM indication relative to 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 the substantially larger CM market in Germany.

As we have previously mentioned, we anticipate launching Amvutra 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-US 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's turn to the US ATTR-CM specific dynamics. Looking back on 2025, our confidence in the size, growth, and continued underpenetration of the ATTR-CM category has been reinforced.

Despite approximately 40% volume CAGR over the past 6 years, the majority of patients with ATTR cardiomyopathy remain untreated. Against that backdrop, we are highly encouraged by Amvutra's early momentum.

In its first few quarters, performance relative to relevant specialty analogues supports the potential for a breakout launch, reflecting strong customer demand, the value of Amvutra's differentiated profile, and disciplined commercial execution. When we look at the early launch data, what's most encouraging is not just the pace of uptake, but where Amvutra is being used and why.

First, Amvutra is rapidly establishing itself as an important choice in new treatment starts. By just the second quarter post-launch, Amvutra 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-CM are shifting. Second, we're gaining traction in first-line patients.

Establishing Amvutra as a first-line option remains our strategic priority, and we're making meaningful progress. In parallel, Amvutra 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 Amvutra 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 sites of care.

As we enter '26, we remain clear-eyed about where we are. The ATTR-CM 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.

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 1-year anniversary of Amvutra's US FDA approval for ATTR cardiomyopathy on March 24, 2026, and highlight our progress for patients and the long-term growth and durability of our TTR franchise.

With that, I'll 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 zilebesiran 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 nucresiran in ATTR-CM.

Approximately 1,200 patients will be enrolled in this study, with launch also expected in 2030, if successful. TRITON-PN is an open-label study of nucresiran 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're also excited for our partners at Regeneron, who remain on track to submit a US regulatory application in the first quarter for cemdisiran in generalized myasthenia gravis, with potential approval anticipated later this year or early 2027.

Finally, as Yvonne mentioned, we also launched CeraLys, 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 multi-billion-dollar potential. In the cardiovascular metabolic space, we're excited about zilebesiran, 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. In neuroscience, mivelsiran 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.

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'll 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-1 Phase 2 trial of mivelsiran 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—the study is now actively enrolling patients; one for mivelsiran in patients with Alzheimer's disease; and another for ALN-6400 in a second bleeding disorder. Importantly, we expect to have clinical derisking 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. 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 full year 2025 financial results and providing our comprehensive financial guidance for 2026.

Let's 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 US following our Q2 launch of Amvutra 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-CM 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 zilebesiran.

Royalty revenue for the full year was $174 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 Amvutra, 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 zilebesiran, and the TRITON-CM and PN studies for nucresiran.

Non-GAAP SG&A expenses of approximately $1 billion increased 22% compared to last year, primarily driven by increased investments in support of the Amvutra ATTR-CM launch in the US. 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've previously highlighted.

I'm 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 P to the 5th by 25 non-GAAP profitability goal. I'd like to take a moment to thank the Alnylam employees who made this milestone possible through their active engagement in scaling our business with discipline over the past 5 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'd like to turn to our financial guidance for 2026. Starting with net product revenues, we are reiterating the combined net product revenue guidance for Amvutra, Onpattro, Givlaari, and Oxlumo that we communicated in our J.P.

Morgan press release dated January 11, 2026. We anticipate combined net product sales for our four commercial products will be within a range of $4.9 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 to $600 million, representing full-year growth compared to 2025 of 10% at the midpoint of the guidance range. Total TTR: $4.4 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's still early days in the ATTR-CM 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 US TTR category growth will remain brisk and consistent with prior years. Second, in the US, we continue to expect a modest decrease in net price as our CM business continues to scale.

Specifically, we forecast a mid-single-digit net price decrease for Amvutra in 2026. Third, given the impact on our polyneuropathy business associated with lower CM launch pricing in international markets, we expect international TTR revenue dollar growth in 2026 will be consistent with 2025.

I'd 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 '25.

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 CM launch in Germany, where our Amvutra pricing was adjusted downward in late Q4, as Tolga previously mentioned. For the balance of the year, we expect our international markets will return to quarter-on-quarter growth as the impact of increasing volume outweighs reduced price.

Second, in the US, we expect more modest quarter-over-quarter TTR growth in Q1 compared with the $111 million of US 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 US, 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 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 zilebesiran 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 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 zilebesiran and nucresiran, 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 Amvutra for ATTR-CM in the US 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.

Those dialed in who would like to ask questions, please limit yourself to one question each, and then get back in the queue if you have additional questions.

Hey, good morning. Can you hear me okay?

Yes, we can. Thank you.

Great. Good morning.

Thanks so much and appreciate you taking my question. I was wondering if you could just comment on what you're 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's assumed in guidance.

Thank you.

Look, that's a great question. I think it's important just to underscore how pleased we are with the Amvutra launch so far, coming out of the gate strong and we're building towards an analogue-beating launch, and really building a long-term franchise.

That's incredibly important. All the fundamentals are in place to drive continued Amvutra growth, which I think is underscored by our 2026 guidance and our 2030 goals.

Tolga, maybe you'll speak specifically to how you're seeing the market.

Thanks, Yvonne. Good morning, Paul.

Look, as Yvonne highlighted, what really drives our confidence in reiterating the guidance is really the fundamentals. If you think about it, we've actually improved our first-line access.

We're clearly seeing a strengthening physician and patient preference, and even more importantly, continued category growth with more patients entering the market. Those trends were in place heading into JPM and have continued to build, and that's why we remain confident in the year.

Great. Thank you.

Next question, please.

Good morning. Thanks for taking my question.

If I could just follow up on the confidence here and in the guide for the year for the TTR franchise, just speak to the choppiness that we're 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 kind of the gross dynamics in Europe. Thank you.

Tolga?

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. In fact, utilization within those agreements have been rather minimal to date.

In terms of our pricing, our net price declined mid-single digits in '25, and our '26 guidance assumes a similar mid-single digit decline. That dynamic is fully integrated into our outlook.

Now in terms of '27, it's obviously too soon for us to be able to provide specific guidance, but we've held really well-positioned as we enter '26.

Thanks, Tolga. Next question, please.

Thanks for taking our question, and 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 for the first quarter of 2026?

Thank you.

Maybe Tolga, that question's for you. I don't think that we've really spoke to Q1 phasing, and that's actually kind of very typical in the industry, but Tolga, do you want to?

Right, I would actually really step back and start thinking about, rather than on a monthly fluctuations, looking at 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.

Even within Q4, we've seen momentum improve as we exited the quarter. Now, as Yvonne highlighted, Q1 is being rather specific across the industry in terms of the seasonality.

We're certainly seeing some of that, but we believe that that seasonality is really not impacting the underlying momentum that we're building in the category.

Thank you. Next question, please.

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 step-wise adjustment in Q1 and then flat through the rest of the year, or is it going to be gradual? Basically, I'm asking, are all the access discussions for the full year done?

Also if you can comment about, per Salveen's question, whether potential longer-term competitive dynamics are factoring into how you're thinking about gross-to-net over the year. Thanks.

Maybe Jeff, you start on the general gross-to-net question, and then Tolga, you may have some additional perspectives.

Ritu, again, the guidance for the US market for pricing this year is a mid-single digit net price decrease, similar to what we did in '25, and that would be expected to be gradual over the course of the year rather than sort of all upfront or in the first quarter—gradual.

In terms of the '27 outlook, as we highlighted, it's really too soon for us to make any comments at this point. We don't know what their data is going to look like.

We don't know what their label is going to look like. What I can say is, given how well we're positioned in terms of Part B versus Part D, we believe actually we're really well-positioned in terms of being able to manage our growth.

In fact, if you think about our objectives from 2030, we're assuring that our 2030 CAGR growth of 25% certainly incorporates some of that thinking. We believe we're going to be able to preserve and increase the value of this category.

Thank you.

Hi. Good morning.

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

Morgan, but just wondering, for the 5-year strategy, you've mentioned the select external innovation as part of the approximately 30% revenue R&D spend. Can you just elaborate on that?

Should we anticipate additional partnerships like the Roche one with zilebesiran or other forms of licensing? Is there anything more on timing, size, and scope of an external BD deal?

No, thanks for that question. Look, I think it's important to highlight that we really are focused on our rich internal pipeline, which is truly spring-loaded for growth.

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 R&D pipeline. I think it's important also to state that we have a very high scientific and financial bar, both for our internal innovation, but also as we look to assess opportunities externally as well.

Thank you. Next question?

No, I think you've covered it, Yvonne. I think we're going to be looking at that landscape of things that are complementary from a technology perspective that help us bring medicines to more patients more rapidly.

Great.

Hi. Good morning.

Thanks for taking my question. On nucresiran, you've talked about the time that you could potentially launch at the beginning of the 2030s, or say 2030-ish.

How should we be thinking about the impact to your operating margin once that product becomes available? Just practically speaking, even if it might have the better profile that you describe of less frequent dosing, how long do you think it would take for patients to appreciate something like that vis-a-vis switching from Vutrisiran to nucresiran when it becomes available?

Thanks.

There are a couple of questions here. I'll just reiterate maybe the remarks that I kind of made earlier, which is, we're really excited about nucresiran.

We believe that if it's successful, which we have high conviction in, it's going to have a best-in-class profile, which is going to lead to swift patient uptake. This is going to be without the royalty obligations for nucresiran.

Clearly, this will have a significant positive impact on our margins post-2030. As I said, we're looking at potentially driving margins to the mid-40s by 2030.

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

Great. Thank you.

Next question, please.

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?

Again, I'm assuming that maybe later this year, you'll show us some initial pharmacodynamic data on reduction in mutant huntingtin in the CSF. We all know that Huntington is a relatively slowly progressive disease.

I'm assuming that the clinical data like cUHDRS is going to be pretty preliminary. Would that be fair?

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

Thanks so much.

That's a great question, and thank you for asking a question about our Huntington's program. It's a program that we have high conviction in for addressing what I think we all know is a incredibly devastating disease.

There's quite a lot in that question, Pushkal.

Luca, happy to address it. As I mentioned, as you highlight, the unmet need in Huntington's, I think, is indisputable.

We're 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.

I think unfortunately, prior approaches haven't really addressed this. Interestingly enough, the one approach that does is the uniQure approach, and we've all seen some recent data coming from there that suggests potentially through natural history data that there may be a favorable trend there emerging in terms of efficacy.

We're very excited about the approach. We're in a Phase 1 program right now in Huntington's patients, where we're really trying to see convincing evidence of lowering of huntingtin, as well as safety.

You'll recall that prior efforts in this space have been challenged because they can't get to high levels of knockdown beyond about 20%, and then they've been associated with safety concerns, NfL increases, ventricular enlargement, et cetera. I think those are the first two things, Luca, that we're going to be looking for: Can we get to good levels of knockdown—we'd like to get to over 50%—and can we do that durably and safely for a period of time?

As we've mentioned, we'll put out some data at the end of this year. You're right that I wouldn't expect a lot in terms of clinical data at that point in terms of cUHDRS.

This is really relatively modest number of patients. We're hoping that again, if we see those two signs, then to your second part, look, this is again, given the unmet need, this is a program we're very much going to try and accelerate as quickly as possible.

We want to do that in a responsible way. You look to us to see anything we can do to bring this forward to patients as quickly as possible and keep you posted on that.

Thanks, Pushkal. Next question, please.

Oh, hey. Thanks for taking the questions.

Another one on the pipeline for obesity: Just what's the rationale for prioritizing the ACVR1C asset, or the ALK7, over something like INHBE in your Phase 1 trial? Then is the target product profile for that that's going to come out of that data, is that something that's equivalent to what we've seen from your peer in Arrowhead, or are you going for something superior on the efficacy side?

Thanks very much.

Pushkal, that's one straight for you.

Thanks, Myles. Look, I think we see a tremendous opportunity in the overweight obesity space and the diabetes space.

I think GLP-1s have obviously revolutionized that space, but I think we all recognize there's a lot of unmet need to actually 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, I think, in our preclinical work based on the genetics, preclinical models, as well as, I think, some of the emerging data that you're seeing coming from Arrowhead, you see that ACVR1C appears to be the more potent target.

We've certainly prioritized that. We are interested in INHBE, but we think ACVR1C is more interesting.

I think look, the other point here, I think, is worth noting is that I think when you look at the Arrowhead and wave data, I think there's questions about the monotherapy magnitude of weight loss that they can deliver. I think this is a space where we're going to have to be particularly thoughtful.

I think we're 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's 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?

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've had some great share gains in the second-line setting and also positive trends in the front line.

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

No, we've been very pleased by the sort of broad and balanced kind of access that we're seeing. Tolga?

As you saw, Mike, in the data we shared, particularly around new-to-brand dynamics, we're approaching near-parity with tafamidis. The intent was to demonstrate that in a growing and increasingly competitive category, we've been able to make meaningful and rapid headway.

Now, in terms of '26, obviously, we reiterated our full year '26 guidance. What gives us the confidence is the continuous progress we're making in terms of first-line access, rising physician and patient preference, and also, importantly, healthy category growth.

Those were the drivers heading into JPM, and we continue to see them strengthened. Obviously, that momentum supports our outlook for '26.

Of course, we're going to be having our TTR webinar at the end of March, which will be an opportunity to really think about how we're going to build this very exciting franchise for the future.

Thanks for that plug.

Okay. Next question?

Great. Thank you very much.

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.

No, I think that's actually correct. We are looking at areas where there's good strategic fit, opportunities that are complementary to what we're doing.

You touched on delivery. That's one potential approach to consider.

We have a very exciting internal pipeline, we're going to be very judicious about what external innovation actually helps us accelerate our internal innovation and also complements our current portfolio. Pushkal, do you want to add anything to that?

No, I think you've covered it, Yvonne. I think we're going to be looking at that landscape of things that are complementary from a technology perspective that help us bring medicines to more patients more rapidly.

Great. Okay.

Thanks. Next question, please.

Thanks for that color.

Hey, guys. Thanks for taking the question.

Maybe just a big-picture one across the sort of emerging early-stage pipeline: Which programs are you most excited about, or do you think are the most derisked? Then a second question: You mentioned for the US, you expect a mid-single-digit net price decrease in 2026.

What would you expect for 2027? Should we expect something similar, or potentially more or less with a new competitor?

Thanks.

Wow, I think started off with trying to get us to say what our favorite programs are. Pushkal?

Ellie, I think like choosing between your children. We've got some very exciting opportunities.

I think in terms of your question about which are most derisked, I think, look, obviously, nucresiran is about as derisked as possible. We obviously have no doubt that TTR silencing aids in both polyneuropathy and in cardiomyopathy, and that drug will get to 95% silencing and twice-a-year dosing.

Zilebesiran has shown compelling blood-pressure lowering in four studies now: a Phase 1 and three Phase 2s of increasing stringency on top of background medicines with a durable profile, and 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's fairly derisked.

I think as you look forward, we have a number of other programs where I think actually in the period of '26 and '27, we are going to get very compelling data that leads to derisking. If you think about data coming out on Huntington's, or as I just mentioned in my comments to Luca, in CAA, 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 haven't named.

Then of course, the plasminogen program, where we've already seen convincing data that we shared last year at R&D Day in terms of proof of mechanism that we're seeing clot stabilization, very strong genetics. I think that's been significantly derisked.

You see our confidence in there. We've kicked off one Phase 2.

We've talked about kicking off a second Phase 2. We're moving rapidly with that program.

I'm excited about the opportunities that lie ahead, and as I said, a number of exciting potentials to help patients and create value.

That's great, Pushkal. I think the really unusual story about Alnylam is actually we have a derisked organic product engine, and this gives us tremendous leverage, helping us to kind of accelerate the pace of innovation, allowing us to scale with this proven platform into what's 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. Jeff, do you want to add any perspective?

Just on the pricing question, I think that Ellie had asked about: Again, what we've said consistently, I think since we've launched in the US with the cardiomyopathy and the labels, we've expected gradual net price reductions over time as the business scales. Again, we're entering year two, right?

Year one was mid-single-digit price decrease. That's what we're expecting in year two.

I would say over the longer-term guidance that we've given, right, 25% CAGR, that's the expectation across the period at this point.

That's great, Jeff. Apologies, when we get these multi-part questions, sometimes one of the questions kind of slips off the list.

Tolga, did you have?

I have a multi-part answer as well. Look, just to support Jeff's point, in terms of how anticipating new competition may impact the pricing, as we reiterated, first of all, we're really well-positioned from an access perspective.

We've established credibility and durability of this franchise in '26. If you think about the potentially emerging competition, we're already actually in that competitive field with the polyneuropathy indication.

We've been able to secure great access to the patients with limited copay. Obviously, we provided our goals for 2030, and that value growth of 25% CAGR remains.

We're comfortable with providing that perspective for '27 as well.

Good. I hope we covered everything you asked.

Next question, please.

Hey, good morning, guys. Thanks for taking the question.

I guess it's related somewhat to what you were just talking about, but with the competitive silencer data obviously expected this year, I'm interested in your latest views on the 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 Amvutra if it were to actually be the case. Thank you.

I think there's a sort of both a kind of commercial and then also a development kind of perspective in that question. I think, Tolga, you want to just make a few remarks, and then we'll hand it over to Pushkal.

Before I turn it over to Pushkal, look, it's obviously difficult to assess the impact without seeing their data. It would be premature to speculate on the specific role they're going to play.

That said, I think what's really important to highlight is this category remains very large and significantly underserved market. 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 and deep and sustained knockdown profile, strong clinical data package, and obviously convenient quarterly dosing.

Maybe, Pushkal, you can—

I think, Cory, we're looking forward to seeing the results. Obviously, we don't have a magic crystal ball.

We'll see what the results are. I think our expectation is the study will be positive.

They've shown good knockdown that occurs over a period of some months, and so I would expect, and they have a large outcomes study, both in monotherapy and in combination. I would expect the results to be positive.

I think we'll be on the lookout for a couple of aspects of this. First, we'll obviously want to look at the safety profile that emerges.

This is an ASO in a large population that's somewhat older and frailer, it will be interesting to see how that emerges. Then on the efficacy side, look, I think, again, I expect to see favorable impacts on the outcome parameters, as we've shown with HELIOS-B, with vutrisiran.

I think there's some speculation that will they have a stronger signal, for example, in the combination because they'll have a larger number of patients on top of a background stabilizer. My hypothesis would be, I don't see any reason why the treatment effect size would be any different than what we've already established in HELIOS-B.

Now, they may have a tighter confidence interval or stronger p-value in that subgroup, but in terms of the effect size, I don't expect it to be materially different, and I think so it would be consistent with what we saw. Your question is, I think, 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 specifically points out that the treatment effects were consistent in both populations, and so we have a very broad label. I don't foresee how the label would be materially different based on the statistical significance in that one subgroup.

That remains to be seen. That's how I would map it out.

Very helpful. Thank you.

Thank you, Pushkal.

Next question? Your

Hey, guys. This is Alex on for Danielle.

Thanks for taking the question. Just a question on Amvutra access in community centers: I guess, do you have a sense of how much of the market is not currently accessible due to the high cost of Amvutra 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 Amvutra patients are actively 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's an access issue, we feel really well-positioned from access standpoint.

Again, the large majority of patients have first-line access to Amvutra, and that's regardless of where those patients are. In terms of accessing the medication, as we highlighted, first of all, our experience is that it's very broad and balanced.

In terms of the community setting patients, we've been able to actually secure alternative site-of-care agreements where 90% of the patients already have Amvutra injection within 10 miles of their residences. We are continuing to expand that network, but I think we reached actually that critical mass already within '25, and we'll obviously continue to work on that.

Terrific. I believe that was our last question, I'd just like to thank everyone for joining us today.

Clearly, 2025 was a remarkable year in which we delivered a blockbuster launch of Amvutra 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 our broader 2030 strategy to both accelerate innovation and scale impact.

Thanks, everybody, who joined the call, and have a great day.