Q4 2025 Alnylam Pharmaceuticals Inc Earnings Call

February 12, 2026

Operator: Good morning, ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals Q4 and Full Year 2025 Earnings Conference Call. At this time, all lines are in listen-only mode. Following the presentation, we will conduct a question-and-answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. This call is being recorded on Thursday, February 12, 2026. I would now like to turn the conference over to Christine Akinc. Please go ahead.

Speaker #1: Good morning, ladies and gentlemen, and welcome to the ALNYLAM Pharmaceuticals Q4 and Full Year 2025 earnings conference call. At this time, all lines are in listen-only mode.

Speaker #1: Following the presentation, we will conduct a question-and-answer session. If at any time during this call you require immediate assistance, please press star 0 for the operator.

Speaker #1: This call is being recorded on Thursday, February 12, 2026. I would now like to turn the conference over to Christine Akinc. Please go ahead.

Speaker #2: Good morning. I'm Christine Akinc, Chief Corporate Communications Officer at ALNYLAM. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Research and Development Officer; and Jeff Poulton, Chief Financial Officer.

Christine Akinc: Good morning. I'm Christine Akinc, Chief Corporate Communications Officer at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer, Tolga Tanguler, Chief Commercial Officer, Pushkal Garg, Chief Research and Development Officer, and Jeff Poulton, Chief Financial Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events. During today's call, as outlined in slide 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.

Speaker #2: 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.

Speaker #2: During today's call is ALNYLAM slide 2, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress.

Speaker #2: 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.

Speaker #2: 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.

Christine Akinc: 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?

Speaker #2: 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.

Speaker #2: Any addition, any forward-looking statements represent our views only as the date of this recording and should not be relied upon as representing our views as of any subsequent date.

Speaker #2: We specifically disclaim any obligations to update such statements. With that, I'll turn the call over to Yvonne. Yvonne?

Speaker #3: Thanks, Christine. And thank you, everyone, for joining the call today. ALNYLAM possesses a truly unique profile on the biotech industry. Underpinned by our established and sustainable innovation engine, coupled with commercial excellence, driving durable long-term growth.

Yvonne Greenstreet: 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 to 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.

Speaker #3: We're the leaders in RNAi Therapeutics. With a proven organic product engine and a reproducible and modern process for developing our medicines that has resulted in outsized historical success rates.

Speaker #3: We also have a high-yielding pipeline with over 25 programs currently in active clinical development. And 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.

Speaker #3: 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 a 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.

Yvonne Greenstreet: In terms of commercial and financial performance, we achieved the 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 by 2025 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 3 phase 3 studies and expanded our clinical pipeline with 4 proprietary CTAs in addition to the 5 that were filed by our partners. We also developed and launched a potential best-in-class enzymatic ligation-based RNAi manufacturing platform called Cyrelis.

Speaker #3: Importantly, we met or exceeded all of our ambitious ALNYLAM piece of fit by 25 goals. And with today's announcement, we can now officially declare that we have achieved gap profitability for the 2025 full year.

Speaker #3: And expect a sustained 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 the five that were filed by our partners.

Speaker #3: We also developed and launched a potential best-in-class enzymatic ligation-based RNAi manufacturing platform called Cyrelis. 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.

Yvonne Greenstreet: 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 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 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.

Speaker #3: 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.

Speaker #3: To that end, we're 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.

Speaker #3: We aspire to lead this market in revenue by 2030 and across the period, and to launch new crease run in 2028 for polyneuropathy and 2030 for cardiomyopathy.

Speaker #3: 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.

Yvonne Greenstreet: 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. 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.

Speaker #3: 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-gap R&D across the period to accelerate organic internal innovation and selectively access external innovation.

Speaker #3: 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.

Speaker #3: 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.

Yvonne Greenstreet: 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 nucrisiran in ATTR cardiomyopathy. If nucrisiran 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 nucrisiran, potentially drive our operating margins to the mid-40s post-2030. Through these goals, I hope you can appreciate that we're 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?

Speaker #3: 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 new crease run in ATTR cardiomyopathy.

Speaker #3: And if new Creasrun 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 new Creasrun, potentially drive our operating margins to the mid-40s post-2030.

Speaker #3: 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.

Speaker #3: 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.

Tolga Tanguler: 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.

Speaker #3: 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.

Speaker #3: We delivered 995 million dollars 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.

Speaker #3: 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 dollars in net revenue up 26% versus the same period last year.

Speaker #3: Driven by increased patient demand and favorable order timing in partner markets, as a result, Givlar and Oxluma together became a half a billion dollar franchise in 2025, reflecting continued growth, more than five years post-launch.

Tolga Tanguler: As a result, GIVLAARI and OXLUMO together became a half a billion-dollar franchise in 2025, reflecting continued growth more than five 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 2025, 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.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: 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 six months into the CM launch, as we continue to track in line with leading launch analogs in the industry.

Tolga Tanguler: 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 it continues to track in line with leading launch analogs in the industry. In Germany, we recently aligned pricing for AMVUTTRA 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 AMVUTTRA for ATTR cardiomyopathy in additional international markets throughout 2026, following the completion of local pricing and reimbursement reviews.

Speaker #3: In Germany, we recently aligned pricing for our Mutra for the ATTR CM opportunity reflecting the significantly larger prevalence of the CM indication relative to polyneuropathy indication.

Speaker #3: 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.

Speaker #3: As we have previously mentioned, we anticipate launching ALNYLAM for ATTR cardiomyopathy in additional international markets through our 2026 following the completion of local pricing and reimbursement reviews.

Speaker #3: 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.

Tolga Tanguler: 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 under-penetration 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 AMVUTTRA's early momentum.

Speaker #3: 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.

Speaker #3: 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 six years, the majority of patients with ATTR cardiomyopathy remain untreated.

Speaker #3: Against that backdrop, we are highly encouraged by ALNYLAM's early momentum in its first few quarters performance relative to relevant specialty analogs supports the potential for a breakout launch.

Tolga Tanguler: 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's 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 the ATTR-CM are shifting. Second, we're gaining traction in first-line patients. Establishing AMVUTTRA as a first-line option remains our strategic priority, and we're making meaningful progress.

Speaker #3: Reflecting strong customer demand the value of ALNYLAM'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 ALNYLAM is being used and why.

Speaker #3: First, Alnylam is rapidly establishing itself as an important choice in new treatment starts. By just the second quarter post-launch, Alnylam approached parity with Tafamidis in share of new starts based on available estimates.

Speaker #3: 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.

Speaker #3: Establishing Alnylam as a first-line option remains our strategic priority, and we're making meaningful progress. In parallel, Alnylam has quickly become the preferred option for stabilizer-progressor patients, consistent with its differentiated and orthogonal mechanism of action.

Tolga Tanguler: In parallel, AMVUTTRA has quickly become the preferred option for stabilizer progressive 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 discussion, 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 10mi of their home, supported by a broad, well-established network sites of care. As we enter 2026, 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.

Speaker #3: 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 ALNYLAM in 2026 versus last year.

Speaker #3: 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 0 out-of-pocket costs and approximately 90% can access treatment within 10 miles of their home.

Speaker #3: Supported by a broad well-established network sites of care. As we enter '26, we remain clear-eyed about where we are. Did the ATR CM launch is still in its early stages, just three quarters in, and there is important work ahead.

Speaker #3: 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.

Tolga Tanguler: 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 24 March 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.

Speaker #3: 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.

Speaker #3: 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 ALNYLAM's US FDA approval for ATTR cardiomyopathy on March 24, 2026.

Speaker #3: 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.

Speaker #2: 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.

Pushkal Garg: Thank you, Tolga, and good morning, everyone. As Ivan 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. And TRITON-PN is an open label study of nucresiran, 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.

Speaker #2: First, we initiated three phase three studies in 2025. Zenith is our event-driven cardiovascular outcomes trial for Zalbisaran in patients with uncontrolled hypertension at high CV risk.

Speaker #2: We aim to enroll approximately 11,000 patients and have successfully planned to launch around 2030. Triton-CM is our event-driven outcomes trial for Nucrisaran in ATTR-CM.

Speaker #2: 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 Nucrisaran in approximately 125 patients with hereditary ATTR polyneuropathy.

Speaker #2: 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. ALN2232, 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.

Pushkal Garg: 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 MAP-T or tau for Alzheimer's disease and other rare tauopathies. 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 Q1 for semdesiran in generalized myasthenia gravis, with potential approval anticipated later this year or early 2027.

Speaker #2: ALN5288, targeting MAPT or TAU for Alzheimer's disease and other rare TAU opathies. And two new programs for which we are not yet disclosing details to two competitive reasons.

Speaker #2: ALN4285 and ALN4915. 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.

Speaker #2: We're also excited for our partners at Regeneron who remain on track to submit a US regulatory application in the first quarter for semdesiran in generalized myasthenia ia gravis with potential approval anticipated later this year or early 2027.

Speaker #2: And finally, as Yvonne mentioned, we also launched Sorelis, 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.

Pushkal Garg: Finally, as Ivan mentioned, we also launched Cyrelis, 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're excited about zalbisiran targeting angiotensinogen with the aim of achieving continuous control of blood pressure with just 2 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.

Speaker #2: 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.

Speaker #2: In the cardiovascular metabolic space, we're excited about Zalbisaran targeting angiotensinogen with the aim of achieving continuous control of blood pressure with just two doses per year.

Speaker #2: 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.

Speaker #2: And in neuroscience, the Velstran 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.

Pushkal Garg: In neuroscience, mevelsiran 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-HTT-02 employs a unique exon one 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 and 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.

Speaker #2: ALNHTTO2 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 Huntington protein in the brain.

Speaker #2: And in hematology, ALN6400 offers an exciting opportunity for a pipeline and 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.

Speaker #2: 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.

Pushkal Garg: 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 mevelsiran 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 mevelsiran 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.

Speaker #2: 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 Mevelsaran in patients with CAA, and initiate three Phase 2 trials.

Speaker #2: The first of these has already been achieved, which is a Phase 2 study of ALN4324 from patients with type 2 diabetes. This study is now actively enrolling patients.

Speaker #2: One for Mevelsaran in patients with Alzheimer's disease. And another for ALN6400 and a second bleeding disorder. Importantly, we expect to have clinical de-risking data this year on several of the programs I just mentioned.

Speaker #2: Specifically, we expect to share phase 1 and 2 results from the ALN6400 program and phase 1 data on both our Huntington's and ACVR1C programs in the second half of the year.

Speaker #2: And with that, let me now turn it over to Jeff to review our financial results and 2026 guidance. Jeff.

Pushkal Garg: With that, let me now turn it over to Jeff to review our financial results and 2026 guidance. Jeff?

Speaker #3: 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.

Jeff Poulton: Thanks, Kushal, 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 AMVUTTRA and 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.

Speaker #3: Let's begin with a summary of our P&L results for the full year. Total global net profit revenues for 2025 were nearly $3,081, representing percent 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 Inbutra and ATTR Cardiomyopathy.

Speaker #3: 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.

Speaker #3: 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 Xena phase 3 cardiovascular outcomes trial for Zalbisaran.

Jeff Poulton: 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 zalbisiran. 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 AMVUTTRA, as higher revenues in 2025 resulted in an increase in the average royalty rate payable to Sanofi compared with the prior year.

Speaker #3: Royalty revenue for the full year was $174 million representing a 90% increase compared with last year driven by higher Lectio sales from Novartis. Gross margin on product sales was $77% for the full year representing a 4% decrease compared with 2024.

Speaker #3: The decrease in margin was primarily driven by increased royalties on Inbutra as higher revenues in 2025 resulted in an increase in the average royalty rate payable to Sanofi compared with the prior year.

Speaker #3: Our non-gap 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 Xena phase 3 cardiovascular outcomes trial for Zalbisaran and the Triton CM and PN studies for Nucrisaran.

Jeff Poulton: Our non-GAAP R&D expenses of approximately $1 to 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 zalbisiran, and the TRITON-CM and TRITON-PN studies for nucrisiran. Non-GAAP SG&A expenses of approximately $1 billion increased 22% compared to last year, primarily driven by increased investments in support of the AMVUTTRA 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 previously highlighted.

Speaker #3: Non-gap SG&A expenses of approximately $1 billion increased 22% compared to last year primarily driven by increased investments in support of the Inbutra ATTR CM launch in the US.

Speaker #3: We achieved full year non-gap 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.

Speaker #3: 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.

Jeff Poulton: 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 P5x25 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 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.

Speaker #3: More than delivering on our P to the fifth by 25 non-gap 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 five years.

Speaker #3: 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.

Speaker #3: 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 Inbutra on PATRO, GIBLARI, and OXLUMO that we communicated in our JPMorgan press release dated January 11th, 2026.

Jeff Poulton: 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 AMVUTTRA, ONPATTRO, GIVLAARI, and OXLUMO that we communicated in our J.P. Morgan press release dated 11 January 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.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: 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.

Jeff Poulton: 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 AMVUTTRA in 2026.

Speaker #3: As we highlighted at the JPMorgan 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.

Speaker #3: 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 Inbutra in 2026.

Speaker #3: Third, given the impact on our polyneuropathy business associated with lower CM launch pricing and international markets, we expect international TTR revenue dollar growth in 2026 will be consistent with 2025.

Jeff Poulton: 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 2025.

Speaker #3: 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.

Speaker #3: 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 Inbutra pricing was adjusted downward in late Q4 as Tolga previously mentioned.

Jeff Poulton: 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 AMVUTTRA 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-on-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.

Speaker #3: 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.

Speaker #3: Second, in the US, we expect more modest quarter-over-quarter TTR growth in Q1 compared with the $100 million of US quarterly growth achieved in Q4 due to fewer product shipping weeks in Q1 and the expected impact of annual insurance reauthorizations.

Speaker #3: 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.

Jeff Poulton: 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 Zolgensma 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.

Speaker #3: Now returning to our full year 2026 financial guidance. Our collaboration and royalty revenue guidance range is $4 to $500 million representing a decrease of 38% compared to 2025 at the midpoint of the guidance range.

Speaker #3: Driven by the one-time $300 million Zalbisaran 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 Lekvio royalties from Novartis will drive the majority of our collaboration and royalty revenue this year.

Speaker #3: Our guidance for combined non-gap R&D and SG&A expense is arranged between $2.7 and $2.8 billion. With the midpoint of the range representing 26% growth versus 2025.

Jeff Poulton: 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 Zolgensma and Nusinersen, as well as early pipeline investment to deliver 3 to 4 new INDs and support expansion of delivery into new tissues. Growth in SG&A will primarily be driven by ongoing launch activities to support Embuthra 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?

Speaker #3: Growth drivers for R&D expense this year include increased investment in clinical studies including the continuation of Pivotal Phase III studies for Zalbisaran and Nucrisaran as well as early pipeline investment to deliver $3 to $4 new INDs and support expansion of delivery into new tissues.

Speaker #3: Growth in SG&A will primarily be driven by ongoing launch activities to support Inbutra for ATTR CM in the US and select international markets. Let me now turn it back to Christine to coordinate our Q&A session.

Speaker #3: Christine?

Speaker #1: Thank you, Jeff. Operator, we will now open the call for questions. Those dialed in, if you'd like to ask them yourself to one question each and then get back in the queue if you have additional questions.

Tolga Tanguler: Thank you, Jeff. Operator, we will now open the call for questions. Those dialed in, if you'd like to ask, limit yourself to one question each and then get back in the queue if you have additional questions.

Christine Akinc: Thank you, Jeff. Operator, we will now open the call for questions. Those dialed in, if you'd like to ask, limit yourself to one question each and then get back in the queue if you have additional questions.

Speaker #3: 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 1 on your touchstone phone.

Operator: 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 touchtone 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 keys. One moment for your first question. I have Paul with Fifth Cell. Please go ahead.

Speaker #3: You will hear a prompt at your hand has been raised. Should you wish to decline from the polling process, please press the star, followed by the 2.

Speaker #3: If you are using a speakerphone, please lift the handset before pressing any keys. One moment for your first question. I have Paul with Fiscal.

Speaker #3: Please go ahead.

Speaker #4: Hey, good morning. Can you hear me okay?

Paul Matteis: Hey, good morning. Can you hear me okay?

Speaker #5: Yes, we can. Thank you.

Jeff Poulton: Yes, we can. Thank you.

Speaker #4: Okay. 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 ads and the mix of first-line for Vitrisaran versus Tefamidis switches and how you see that evolving over the course of this year and what's assumed in guidance.

Paul Matteis: Okay, 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 patisiran versus tafamidis switches, and how you see that evolving over the course of this year and what's assumed in guidance? Thank you.

Speaker #4: Thank you.

Speaker #5: Yeah. No, that's a great question. I think it's important just to underscore how pleased we are with the Inbutra launch so far. Coming out of the gate strong and we're building towards an analog-beating launch.

Jeff Poulton: Yeah, look, that's a great question. I think it's important just to, you know, underscore how pleased we are with the AMVUTTRA launch so far. You know, coming out of the gate strong, we're building towards an analog-beating launch and really building a long-term franchise that's incredibly important. And 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-

Speaker #5: And really, building a long-term franchise is incredibly important. All the fundamentals are in place to drive continued Inbutra growth, which I think is underscored by our 2026 guidance and our 2030 goals.

Speaker #5: But Tolga, maybe you will speak specifically to how you've seen the market.

Tolga Tanguler: Yeah.

Jeff Poulton: I mean, how you see the market.

Speaker #4: Yeah. 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.

Tolga Tanguler: Thanks, Yvonne. Good morning, Paul. Look, as Yvonne highlighted, what really drives our confidence in reiterating the guidance is really, is 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, and, 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.

Speaker #4: 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.

Speaker #4: And that’s why we remain confident in the year.

Speaker #5: Great. Thank you. Next question, please.

Jeff Poulton: Great. Thank you. Next question, please.

Speaker #3: I think your next question is from Sylvine with Goldman Sachs. Please go ahead.

Operator: ... Your next question is from Salveen with Goldman Sachs. Please go ahead.

Speaker #1: Good morning. Thanks for taking my question. If I could just follow up on the confidence here 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 growth dynamics in Europe.

Salveen Richter: Good morning. Thanks for taking my question. If I could just follow up on the confidence here and the guide for the year for the TTR franchise. Just speak to the choppiness that we're seeing coming out of the scripts for Q1 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 growth dynamics in Europe. Thank you.

Speaker #1: Thank you.

Yvonne Greenstreet: Thanks, Tolga.

Speaker #5: Hey, Tolga. Yeah. So let me take the pricing questions 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.

Tolga Tanguler: 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, and most patients are continuing to pay 0 out-of-pocket, partly supported by our value-based agreements. And 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 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, it's obviously too soon for us to be able to provide specific guidance, but we feel really well positioned as we enter 2026.

Speaker #5: And most patients are continuing to pay 0 out-of-pocket. Partly supported by our value-based agreements and, in fact, utilization within those agreements have been rather minimal to date.

Speaker #5: In terms of on our pricing, our net price decline mid-single digits in '25 and our '26 guidance assumes a similar mid-single digit decline. And that dynamic is fully integrated into our outlook.

Speaker #5: Now, in terms of '27, it's obviously too soon for us to be able to provide specific guidance, but we felt really well positioned as we enter '26.

Speaker #5: Thanks, Tolga. Next question, please.

Yvonne Greenstreet: Thanks, Tolga. Next question, please.

Speaker #3: Your next question's from Costa with Oppenheimer. Please go ahead.

Operator: Your next question from Costa with Oppenheimer. Please go ahead.

Speaker #6: Thanks for taking our question and congratulations on the strong year. The 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?

[Analyst] (Oppenheimer): Thanks for taking our question, and congratulations on the strong year. A question on seasonality from us. Have you seen any seasonality during the Q4, potentially patients who pushed the injection to the next quarter because of the holidays, and whether this can be a tailwind for the Q1 of 2026? Thank you.

Speaker #6: Thank you.

Yvonne Greenstreet: Yeah, maybe, Tolga, that question is for you. And I think, we spoke to, you know, Q1 phasing, and that's actually kind of very typical in the industry. But Tolga, do you want to?

Speaker #5: Yeah. Maybe Tolga that question for you. I mean, I think we spoke to Q1 phasing, and that's actually kind of very typical in the industry.

Speaker #5: But Tolga, do you want to?

Speaker #4: Right. So I would actually really step back and start thinking about rather than on a monthly fluctuations, looking at the quarterly the total growth of this category.

Tolga Tanguler: Right. So I would actually really step back and start thinking about, rather than on a monthly fluctuations, looking at, you know, the quarterly, you know, the total growth of this category. If you think about the 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+ over the past several years. So even within Q4, we've 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're certainly seeing some of that, but we believe that, you know, that seasonality is really not impacting the underlying momentum that we're building in the category.

Speaker #4: If you think about the 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've seen momentum improve as we exited the quarter.

Speaker #4: Now, as Yvonne highlighted, Q1 has been rather specific for across the industry in terms of the seasonality. We're certainly seeing some of that, but we believe that from that seasonality is really not impacting the underlying momentum that we're building in the category.

Speaker #5: Thank you. Next question, please.

Yvonne Greenstreet: Thank you. Next question, please.

Speaker #3: Your next question is from Ritu with TD Cohen. Please go ahead.

Operator: Your next question is from Ritu with TD Cowen. Please go ahead.

Speaker #7: Good morning, guys.

Salveen Richter: Good morning, guys.

Yvonne Greenstreet: Hi, Ritu.

Speaker #5: Hi, Ritu.

Salveen Richter: Hi, good morning. Thanks for taking the question. I wanted to ask about the gross to net pattern over 2026. Tolga, you mentioned, you know, 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, you know? Basically, I'm 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're thinking about gross to net over the year. Thanks.

Speaker #7: 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?

Speaker #7: Or is it going to be gradual basically, I'm asking, are all the access discussions for the full year done? And also, if you can comment about per Sylvine's question whether potential longer-term competitive dynamics are factoring into how you're thinking about gross-to-net over the year.

Speaker #7: Thanks.

Speaker #5: But maybe, Jeff, you start on the general gross-to-net question. Then Tolga may have some additional perspectives.

Yvonne Greenstreet: Maybe, Jeff, you start on the general gross to net question, then Tolga may have some additional-

Tolga Tanguler: Yeah.

Yvonne Greenstreet: Perspectives.

Speaker #4: Yeah. Ritu, again, the guidance for the US market for pricing this year as a mid-single digit net price decrease, similar to what we did in '25.

Jeff Poulton: Yeah. 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 up front or in Q1. Gradual.

Speaker #4: 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.

Speaker #5: Yeah. And 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 that data is going to look like.

Tolga Tanguler: Yeah, and 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 gonna look like. We don't know what their label is gonna look like. But what I can say is, given how well we're positioned in terms of, you know, Part D versus Part D, we believe actually we're 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're ensuring that our 2030 CAGR growth of 25% certainly incorporates some of that thinking. We believe we're gonna be able to preserve and increase the value of this category.

Speaker #5: We don't know what their label is going to look like. But what I can say is given how well we're positioned in terms of Part D versus Part E, we believe actually we're really well positioned in terms of being able to manage our growth.

Speaker #5: And in fact, if you think about the guidance that we provided or I should say our objectives from 2030, we're assuring that our 2030 CAGR growth of 25% certainly incorporates some of that thinking.

Speaker #5: We believe we're going to be able to preserve and increase the value of this category.

Speaker #7: Thank you.

Salveen Richter: Thank you.

Speaker #3: All right. Thank you. Your next call comes from Mari with Jefferies. Please go ahead.

Operator: All right. Thank you. Your next call comes from Mari with Jefferies. Please go ahead.

Speaker #8: Hi. Good morning. Thanks for taking my question. You commented a little bit on this at JPMorgan, but just wondering for the five-year strategy, you've mentioned the select external innovation as part of the approximate 30% revenue R&D spend.

Maury Raycroft: 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've 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 zalbisiran or other forms of licensing? And is there anything more on timing, size, and scope of an external BD deal?

Speaker #8: Can you just elaborate on that? Should we anticipate additional partnerships like the Roche one with Zelviseren, or other forms of licensing? And is there anything more on timing, size, and scope of an external BD deal?

Speaker #5: Yeah. 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.

Yvonne Greenstreet: Yeah, I know. Thanks, 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. But you know, 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, you know, and R&D pipeline. And 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.

Speaker #5: 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 in R&D pipeline.

Speaker #5: And I think 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.

Speaker #5: Thank you. Next question.

Speaker #3: All right. Your next question comes from Tazeem with Bank of America. Please go ahead.

Operator: All right, your next question comes from Tazeen with Bank of America. Please go ahead.

Tazeen Ahmad: Hi, good morning. Thanks for taking my question. On nucresiran, you talked about the time that you could potentially launch at the beginning of the 2030s, let's 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 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.

Speaker #9: Hi. Good morning. Thanks for taking my question. I'm Lucris Aran. You talked about the time that you could potentially launch at the beginning of the 2030s, let's say 2030-ish.

Speaker #9: 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 describe of less frequent dosing, how long do you think it would take for patients to appreciate something like that vis-à-vis switching from food tree to Nucris Aran when it becomes available?

Speaker #9: Thanks.

Yvonne Greenstreet: So there are a couple of questions here. I mean, I'll just reiterate maybe the remarks that I kind of made earlier, which is, I mean, we're really excited about nucresiran. You know, we believe that if it's successful, which we have high conviction in, yeah, it's gonna have a best-in-class profile, which is gonna lead to swift patient uptake. And this is gonna be without the royalty obligations for nucresiran. So clearly, this will have a significant positive impact on our margins, you know, post-2030. And as I said, we're looking at, you know, potentially driving margins to the mid-40s by 2030.

Speaker #5: So there are a couple of questions here. I mean, I'll just reiterate maybe the remarks that I kind of made earlier, which is I mean, we're really excited about Nucris Aran.

Speaker #5: 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.

Speaker #5: And this is going to be without the royalty obligations for Nucris Aran. So clearly, this will have a significant positive impact on our margins post-2030.

Speaker #5: And as I said, we're looking at potentially driving margins to the mid-40s by 2030.

Pushkal Garg: Just to tack on to that, I mean, 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. So that tells you about the opportunity to improve margins post-2030, if we have the kind of profile that we expect with nucrisiran.

Speaker #4: And just to tack onto that, I mean, if you look at what consensus gross margins are for our business out to 2030, Tazeem, it's mid-70s.

Speaker #4: 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 Nucris Aran.

Speaker #5: Great. Thank you. Next question, please.

Yvonne Greenstreet: Great. Thank you. Next question, please.

Speaker #3: Your next question is from Luca with RBC Capital Markets. Please go ahead.

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

Speaker #5: Oh, great. Thanks so much for taking my question. Congrats on the progress. Maybe if I can pivot to the pipeline, push the can you just talk a little bit about Huntington?

Luca Issi: Oh, great. Thanks so much for taking my question. Congrats on the progress. Maybe if I can pivot to the pipeline push still. Can 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. But we all know that Huntington is a, you know, relatively slowly progressive disease. So I'm 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? Or are you going to wait before doing so until you see a clear functional signal there?

Speaker #5: Again, I'm assuming that maybe later this year, you'll show us some initial pharmacodynamic data on reduction in use of Huntington in the CSF. But we all know that Huntington is a relatively slowly progressive disease.

Speaker #5: So I'm assuming that the clinical data like pretty preliminary. Would that be fair? And if so, are you willing to start the pivotal phase three trial with just target engagement data in hand?

Speaker #5: Or 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's kind of go, no-go decision to start a phase three trial for Huntington.

Luca Issi: So I guess the question is, you know, maybe walk us through what's kind of go, no-go decision to start a phase 3 trial for Huntington. Thanks so much.

Speaker #5: Thanks so much. Wow. 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 that incredibly devastating disease.

Yvonne Greenstreet: Wow, that's a great question. You know, thank you for you know, asking a question about about our Huntington's program. It's you know, a program that we have high conviction and for addressing what I think we all know is an incredibly devastating disease. But there's quite a lot in that question, Brisco.

Speaker #5: But there's quite a lot in that question. Pushkal.

Speaker #8: Yeah. Luca, happy to address it. As I mentioned, as you highlight, the unmet need in Huntington's, I think, is undisputable. We're very excited about the approach we have.

Pushkal Garg: Yeah, Luca, happy to, happy to address it. As I mentioned, as you highlight, the unmet need in Huntington's, which I think is undisputable. We're very excited about the approach we have. We have an siRNA that targets the overall Huntington's protein, but specifically also targets this exon one segment, that is thought to be necessary actually for disease propagation. And so, we think we have a very unique approach. You know, 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, you know, through natural history data, there may be a favorable trend there emerging in terms of efficacy.

Speaker #8: We have an SIRNA that targets the overall Huntington's 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.

Speaker #8: I think, unfortunately, prior approaches haven't really addressed this. Interestingly enough, the one approach that does is the UniCure 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.

Speaker #8: So we're very excited about the approach. We're in a phase one program right now, and Huntington's patients were really trying to see convincing evidence of lowering of Huntington's as well as to safety.

Pushkal Garg: So 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 Huntington's as well as to 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, cerebral, you know, ventricular enlargement, et cetera. So 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?

Speaker #8: You'll recall that prior efforts in this space have been challenged because they can't get the high levels of knockdown beyond about 20%. And then they've been associated with safety concerns.

Speaker #8: NFL increases cerebral ventricular enlargement, etc. So 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?

Speaker #8: 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.

Pushkal Garg: 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, you know, relatively modest number of patients. And so. But, you know, 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 gonna try and accelerate as quickly as possible. We wanna do that in a responsible way, but you'll look to us to see what anything we can do to bring this forward to patients as quickly as possible, and keep you posted on that.

Speaker #8: 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 and so but we're hoping that 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.

Speaker #8: We want to do that in a responsible way. But you'll look to us to see whether anything we can do to bring this forward to patients as quickly as possible.

Speaker #8: And keep you posted on that.

Speaker #5: Thanks, Pushkal. Next question, please.

Yvonne Greenstreet: Thanks, Brisco.

Pushkal Garg: Thanks so much.

Yvonne Greenstreet: Next question, please.

Speaker #3: Your next question is Miles with William Blair. Please go ahead.

Operator: Your next question is Miles with William Blair. Please go ahead.

Myles Minter: Hi, thanks for taking the questions. Another one on the pipeline for obesity. Just what's the rationale for prioritizing the ACVR1C asset or the IL-7 over something like Inhibi?

Speaker #10: Hi. Thanks for taking the questions. Another one on the pipeline for obesity. Just what's the rationale for prioritizing the ACVR1C asset or the L7 over something like INHIBE in your phase one trial?

Myles Minter: Hi, thanks for taking the questions. Another one on the pipeline for obesity. Just what's the rationale for prioritizing the ACVR1C asset or the IL-7 over something like Inhibi?

Tolga Tanguler: ... in your phase I trial, and then is the target product profile for that, that's going to come out of that data, is it something that's equivalent to what we're seeing from your peer in Arrowhead, or are you going for something superior on the efficacy side? Thanks very much.

Speaker #10: And then is the target product profile for that that's going to come out of that data? Is it something that's equivalent to what we're seeing from your peer in Arrowhead?

Speaker #10: Or are you going for something superior on the efficacy side? Thanks very much.

Speaker #5: Pushkal, that's one straight for you.

Yvonne Greenstreet: Just go ahead, that one's straight for you.

Speaker #8: Yeah. Thanks, Miles. So 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.

Pushkal Garg: Yeah. Thanks, Miles. So look, we, you know, 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 we, I think, 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. So we're bringing, 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. And so we've certainly prioritized that. We are interested in inhibin, but we think ACVR1C is more interesting.

Speaker #8: 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.

Speaker #8: So we're bringing 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.

Speaker #8: And so we've certainly prioritized that. We are interested in INHIBE, 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.

Pushkal Garg: I think, you know, I think, like, 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, you know, the monotherapy magnitude of weight loss that they can deliver, and 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, you know, unique patient segments that we might be able to target, looking at unique combinations, that can bring disproportionate benefit to, to patients, within this space. So... But 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.

Speaker #8: And 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.

Speaker #8: That can bring disproportionate benefit to patients in this space. So but 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.

Speaker #5: Thank you. Next question.

Yvonne Greenstreet: Thank you. Next question.

Speaker #3: Your next question comes from Mike with Morgan Stanley. Please go ahead.

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

Michael Ulz: 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, you know, do you expect those share trends to continue to increase? Thanks.

Speaker #11: 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.

Speaker #11: Just curious, particularly in front line, as we move through the year, do you expect that to those share trends to continue to increase? Thanks.

Speaker #5: Yeah. No, we've been very pleased by the sort of broad and balanced kind of access that we're seeing. Tolga? Yeah. I mean, as you saw, Mike, in the data we shared, particularly around new-to-brand dynamics, we're approaching near parity with Tefamidis.

Yvonne Greenstreet: Yeah, no, we've been very pleased by the sort of broad and balanced kind of access that we're seeing, Tolga?

Tolga Tanguler: Yeah, I mean, as you saw, Mike, in the data we shared, particularly around new to brand dynamics, we're approaching near parity with tafamidis. And the goal was there, the intent was to demonstrate that in a growing and increasingly co-competitive category, we've been able to make meaningful and rapid headway. Now, in terms of 2026, obviously, we have reiterated our full year 2026 guidance. And 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. And that, obviously, that momentum supports our outlook for 2026.

Speaker #5: And the goal was there to intend was to demonstrate that in a growing and increasingly competitive category, we've been able to make meaningful and rapid headway.

Speaker #5: Now, in terms of 26, obviously, we have reiterated our full year 26 guidance. And 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.

Speaker #5: Those were the drivers heading into JPM. And we're continuing to see them strengthened. And that obviously, that momentum supports our outlook for 26. And of course, we're going to be having PTR webinar in the end of March, which will be an opportunity to really think about how are we going to build this very exciting franchise for the future.

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

Speaker #11: Thanks for that plug.

Tolga Tanguler: Thanks for that plug.

Speaker #5: Okay. Next question.

Yvonne Greenstreet: Okay, next question.

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

Speaker #3: Your next question comes from Ted with Piper Sandler. Please go ahead.

Speaker #11: 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?

Edward Tenthoff: 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 than from your comments earlier, Yvonne? Whether that be delivery types or other RNA mechanisms? Thanks.

Speaker #11: Whether that be delivery types or other RNA mechanisms.

Speaker #1: Thanks

Speaker #2: Yeah . No , I think I think I think , I think that's that's absolutely correct . I mean , we are looking at , you know , areas where there's good strategic fit .

Yvonne Greenstreet: Yeah, no, I think that's absolutely correct. I mean, we are looking at, you know, areas where there's good strategic fit. And so opportunities are complementary to what we're doing. You touched on delivery, that's, you know, one potential approach to consider. You know, we have a very exciting internal pipeline, so we're going to be very judicious about what external innovation actually helps us accelerate our internal innovation and also complements our current portfolio. But Pascal, do you want to add anything to that?

Speaker #2: And so opportunities there complementary to what we're doing . Are you touched on delivery that's you know , one potential approach to consider You know , we we we have a very exciting internal pipeline .

Speaker #2: So we're going to be very judicious about what external innovation actually helps us accelerate our internal innovation . And also complements our current portfolio .

Speaker #2: But Pushkal Garg , do you want to add anything to that ?

Speaker #3: 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

Pushkal Garg: 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.

Speaker #2: Great . Okay . Thanks . Next question please

Yvonne Greenstreet: Great. Okay, thanks. Next question, please.

Edward Tenthoff: Thanks for that, Yvonne.

Speaker #4: Your next question is from Ellie with Barclays . Please go ahead

Operator: Your next question is from Ellie with Barclays. Please go ahead.

Speaker #5: Hey , guys . Thanks for taking my 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 de-risk And then a second question , just you mentioned for the US , you expect a mid-single digit net price decrease in 2026 .

Eliana Merle: 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 de-risked? And then a second question, just, 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.

Speaker #5: What would you expect for 2027 ? Should we expect something similar or potentially more or less with the new competitor ? Thanks

Speaker #2: Wow . I think started off with trying to get us to say what our favorite programs are .

Yvonne Greenstreet: Wow! I think started off with trying to get us to say what our favorite programs are. Pascal?

Speaker #3: Yeah , I mean , Ellie , I think like choosing between your children . So we've got some very exciting opportunities . I think in terms of your question about which are most de-risked , I think look , obviously new Christian is about as de-risked as possible .

Pushkal Garg: Yeah, I mean, Ellie, I think, like choosing between your children. So, we've got some very exciting opportunities. I think in terms of your question about which are most de-risked, I think... Look, obviously, nucresiran is about as de-risked 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. Zalbisiran has shown blood pressure lowering, compelling blood pressure lowering in four studies now, at phase I and three phase IIs 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.

Speaker #3: We obviously have no doubt that TTR silencing aids in both polyneuropathy and in cardiomyopathy. And that drug will get to 95% silencing with twice-a-year dosing.

Speaker #3: Dosing . So I'll be Saran has shown blood pressure lowering , compelling blood pressure lowering in for studies . Now a phase one and three , phase two of increasing stringency on top of background medicines with a durable profile .

Speaker #3: And there is a wealth as Professor Williams highlighted last year at USC , of data that suggests that continuous control of blood pressure should lead to outsized benefits in terms of cardiovascular outcomes .

Speaker #3: So I don't think I think that's fairly de-risked . 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 de-risking .

Pushkal Garg: So I think that's fairly de-risked. I think as you look forward, we have a number of other programs where I think actually in the period of 2026 and 2027, we are going to get very compelling data that leads to de-risking. If you think about data coming out on Huntington's, or if we, 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. And 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. So I think that's been significantly de-risked.

Speaker #3: If you think about data coming out on Huntington's , or as I just mentioned in my comments to Luca . 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 .

Speaker #3: And 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 .

Speaker #3: So I think that's been significantly de-risked . And , you know , you see our confidence in there . We've kicked off one phase two , we've talked about kicking off a second phase two .

Pushkal Garg: And, you know, you see our confidence in there. We've kicked off one phase 2. We've talked about kicking off a second phase 2, and so we're moving rapidly with that program. So, I'm excited about the opportunities that lie ahead, and as I said, a number of exciting potential to help patients and create value.

Speaker #3: And so we're moving rapidly with that program . So I'm excited about the opportunities that lie ahead . And as I said , a number of exciting potential to help patients and create value .

Speaker #2: Yeah . That's great . I think , you know , the the really unusual story about Ireland is actually we have a de-risked organic product engine , and this gives us tremendous leverage , helping us to kind of accelerate the pace of innovation and allowing us to scale with this proven platform into what's going to be a multi franchise growth company .

Yvonne Greenstreet: Yeah, that's great, Pushkal. I think you know, the really unusual story about Alnylam is actually we have a de-risked organic product engine, and this gives us tremendous leverage, helping us to kind of accelerate the pace of innovation and allowing us to scale with this proven platform into what's going to be a multi-franchise growth company. And as Pushkal highlighted, there are a number of, you know, near-term opportunities for us to really turn these programs into important medicines for patients. Jeff, do you want to add any perspective?

Speaker #2: And as Pushkar highlighted , there are a number of , you know , near-term opportunities for us to really turn these programs into important medicines for patients .

Speaker #2: Jeff , do you want to add any perspective .

Speaker #6: On the pricing question ? I think that Lee 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 and year one was was mid-single digit price decrease .

Jeff Poulton: Just on the pricing question, I think, that Elliot 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? And year one was mid-single-digit price decrease. That's what we're expecting in year two. And 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.

Speaker #6: That's what we're expecting in year two . And I would say over the longer term guidance that we've given , right , 25% kegger .

Speaker #6: That's the expectation across the period at this point.

Speaker #2: That's great Jeff . And apologies . Let me get these multi-part questions . Sometimes the one of the questions kind of slips off .

Yvonne Greenstreet: That's great, Jeff. And apologies, when we get these multi-part questions, sometimes the one of the questions kind of slips off, slips off the list. Tolga, did you have something?

Speaker #2: Slips off the list . Did you have something ?

Tolga Tanguler: Yeah, I have a multi-part answer to that as well. I mean, look, just to support Jeff's point, in terms of how anticipating new competition may impact the pricing is, 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 2026. And if you think about the potential emerging competition, we're already actually in that competitive field with the polyneuropathy indication. And we've been able to secure great access to the patients with limited copay. So I think I would anticipate. And obviously we provided our goals for 2030, and that value growth of 25% CAGR remains. So we're comfortable with providing that perspective for 2027 as well.

Speaker #7: Yeah , I have a multi-part answer to that as well . I mean , look , to just to support Jeff's point in terms of how anticipated new competition may impact the pricing is we reiterated , first of all , we're really well positioned from an access perspective .

Speaker #7: We've established credibility and durability of this franchise in 26 . And if you think about the potential emerging competition , we're already actually in that competitive field with the polyneuropathy indication .

Speaker #7: And we've been able to secure great access to the patients with limited copay . So I think I would anticipate and obviously we provided our goals for 2030 and that value growth of 25% remains .

Speaker #7: So we're comfortable with providing that perspective for '27 as well.

Speaker #2: Good . Well , I hope we covered everything you asked next next next question please

Yvonne Greenstreet: Good. Well, I hope we covered everything you asked. Next question, please.

Speaker #4: The next question comes from Corey with Evercore ISI. Please go ahead.

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

Speaker #8: 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 for that asset to attain a differentiated label based on their trial and , and how you think about that .

Cory Kasimov: 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 AMVUTTRA, if it were to actually be the case. Thank you.

Speaker #8: Having a potential commercial impact on in vitro , if it were to actually be the case . Thank you .

Speaker #2: Okay . Well , I think there's a sort of both a kind of commercial . And then also a development kind of perspective .

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

Speaker #2: On that question . So I think I think , Tolga , you want to just make a few remarks and then we'll hand it over to .

Speaker #7: Yeah , I'll before I turn it over to Pushkar , I mean , look , it's obviously difficult to assess the impact without seeing their data .

Tolga Tanguler: Yeah, I'll before I turn it over to Pushkal, I mean, look, it's obviously difficult to assess the impact without seeing their data. And, you know, 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 markets. Additional entrants will certainly help drive diagnosis and treatment rates, which we believe ultimately will benefit patients and expand the category. So 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 convenient quarterly dosing. So maybe Pushkal, you can-

Speaker #7: And , you know , 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 under underserved markets .

Speaker #7: Additional entrants will certainly help drive diagnosis and treatment rates , which we believe ultimately will benefit patients and expand the category . So from our perspective , we feel very well positioned .

Speaker #7: We have a head start given our rapid and deep and sustained knock down profile , strong clinical data package and obviously convenient quarterly dosing .

Speaker #7: So maybe you can

Speaker #3: Yeah , I think , Corey , I think we're looking forward to seeing the results as obviously we don't have magic crystal ball .

Pushkal Garg: Yeah, I, I think, Corey, I think, we're looking forward to seeing the results, obviously, we don't have a magic crystal ball. We'll see what the results are. But I, I think our expectation is the study will be positive. They've shown, you know, good knockdown that occurs over a period of some months. And so I would expect... And they have a large, you know, outcome study, both in monotherapy and in combination. So I would expect the, the results to be positive. I think, you know, we'll be on the lookout for a couple of aspects of this. You know, 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, so it will be interesting to see how that emerges.

Speaker #3: We'll see what the results are . But I think our expectation is the study will be positive . They've shown , you know , good knockdown that occurs over a period of some months .

Speaker #3: And so I would expect and they have a large , you know , outcome study both in monotherapy and in combination . So I would expect the results to be positive .

Speaker #3: I think you know we'll be on the lookout for a couple of aspects of this . You know . First we'll obviously want to look at the safety profile that emerges .

Speaker #3: This is an Aso in a large population that's somewhat older and frailer . So it'll be interesting to see how that emerges . And then on the efficacy side , look , I think , you know , again , I think I expect to see , you know , favorable impacts on on the outcome parameters , as we've shown with Helios B , with Vutrisiran .

Pushkal Garg: And then on the efficacy side, look, I think, you know, again, I think that I expect to see, you know, favorable impacts on the outcome parameters, as we've shown with HELIOS-B, with vutrisiran. You know, I think there's some speculation that will they have a stronger signal, for example, in the PN combination because they'll have a larger number of patients on top of a background stabilizer. My hypothesis would be, you know, 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 a 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'd be consistent with what we saw.

Speaker #3: You know , I think there's some speculation that will they have a , 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 , you know , I don't see any reason why the treatment effect size would be any different than what we've already established in Helios B .

Speaker #3: 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 .

Speaker #3: And I think 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 ?

Pushkal Garg: Your question is, I think, the most critical one, which is: How is that going to impact the label? And I would just point out that our label already shows, gives, you know, provides data for both on and off a stabilizer, and it specifically points out that the treatment effects were consistent in both populations, and so we have a very broad label. So I don't know how, you know, I don't foresee how the label would be materially different, based on the statistical significance in that one subgroup, but that remains to be seen. But that, that's how I would map it out.

Speaker #3: And I would just point out that our label already shows it gives , you know , provides data for both on and off a stabilizer and , and is specifically points out that the treatment effects were consistent in both populations .

Speaker #3: And so we have a very broad label . So I don't know how you know , I don't foresee how the label would be materially different based on , on on the statistical significance in that one subgroup .

Speaker #3: But that remains to be seen . But that's how I would map it out .

Speaker #8: Very helpful .

Tolga Tanguler: Very helpful. Thank you.

Speaker #2: Thank you. Next question. Next question.

Yvonne Greenstreet: Next question. Next question?

Speaker #4: Next question comes from Danielle with Truist . Please go ahead .

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

Speaker #9: Hey guys . This is Alex on for Danielle . Thanks for taking the question . Just a question on Amvuttra access in community centers , I guess .

Danielle Brill: Hey, guys. This is Alex on for Danielle. Thanks for taking the question. Just a question on AMVUTTRA, 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 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 actively being managed in the community settings. Thanks so much.

Speaker #9: Do you have a sense of how much of the market is not currently accessible due to the high cost of an buttera and potential hesitancy to stock the drug ?

Speaker #9: Just curious if you have a sense of what proportion of new diagnoses are coming out of the community centers versus what proportion of patients are actively being managed in the community settings ?

Speaker #9: Thanks so much

Speaker #7: Yeah , I mean , 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 , from access standpoint .

Tolga Tanguler: Yeah, I mean, 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 AMVUTTRA, 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. And 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 AMVUTTRA, you know, injection within 10 miles of their residences.

Speaker #7: Again , the large majority of patients have first line access to a and that's regardless of where those patients are in terms of accessing the medication .

Speaker #7: As we highlighted , first of all , our experience is that it's very broad and balanced . And in terms of the community setting patients , we've been able to actually secure alternative side of care agreements where 90% of the patients already have omuta , you know , injection within ten miles of their residences .

Speaker #7: And we are continuing to expand that network. But I think we reached, actually, that critical mass already within '25. And we obviously continue to work on that.

Tolga Tanguler: And we are continuing to expand that network, but I think we reached actually that critical mass already within 25, and we obviously continue to work on that.

Yvonne Greenstreet: Terrific. Well, I believe that was our last question, so 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 AMVUTTRA in ATTR 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, everybody, who joined the call, and have a great day.

Speaker #2: I believe that was our last question . So I just like to thank everyone for joining us today . Clearly , 2025 was a remarkable year in which we delivered a blockbuster launch of Amvuttra and TTR cardiomyopathy .

Speaker #2: We made significant advancements across our pipeline , and we achieved sustainable profitability . And 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 at scale , impact .

Speaker #2: Thanks everybody who joined the call and have a great day

Operator: Ladies and gentlemen,

Yvonne Greenstreet: Bye-bye.

Operator: This concludes today's conference call. Thank you for participating, and you may now disconnect.

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