Good morning, ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals Fourth Quarter Full Year 2024 Earnings Conference Call. At this time, all lines are in a listen-only mode. Following the presentation, we will conduct a question-and-answer session. I would now like to turn the conference call over to the company. Please go ahead.

Good morning. I'm Christine Lindenboom, Chief Corporate Communications Officer at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Medical 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. During today's call, as outlined on Slide 2, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Pushkal will review pipeline updates and clinical progress, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call to your questions. I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements. 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 reports on file with the SEC. Furthermore, any forward-looking statements represent our views only of the date of this recording and should not be relied upon representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to Yvonne.

Thanks, Christine, and thank you, everyone, for joining the call today. 2024 was a fantastic year for Alnylam with strong research, program development and commercial execution and significant progress across the business. This includes the highly positive results from the HELIOS-B Phase 3 study, leading to submission of global regulatory filings for vutrisiran in ATTR cardiomyopathy. We also continue to advance and expand our robust and high-value pipeline of clinical programs, and we continue to demonstrate strong commercial and financial performance, achieving combined net product revenues of over $1.6 billion at the upper end of our revised guidance range. We delivered $95 million in non-GAAP operating income for the full year, marking a significant milestone for the company. Furthermore, we maintained our award-winning culture, which has been a critical enabler of our success. As we look for the year ahead, 2025 has the potential to be a landmark year for Alnylam. We believe that there are three core elements of our business that will drive sustainable growth and value creation, not just in 2025 but for years to come. The first is TTR leadership where vutrisiran, if approved, has the potential to become a new standard of care in ATTR cardiomyopathy and establish a flagship franchise for our company with the advancement of our next-generation TTR assets, nucresiran, following along. Next is growth through innovation, including a pipeline with numerous multibillion-dollar opportunities and an R&D engine set up to deliver sustainable innovation and value creation. The third pillar is strong financial performance where we project that our robust commercial delivery and disciplined approach to capital allocation will enable us to sustain profitability going forward. All of this is underpinned by a best-in-class team and our award-winning culture. All of this represents tremendous progress against our Alnylam P5x25 goals, launched back in 2021. We are now on the cusp of turning these goals into reality and believe that in doing so, we're on track to become a top-tier biotech. Furthermore, the progress we make in 2025 will set us up for the second half of the decade and our next era of significant growth. We are entering a new and exciting chapter in Alnylam's history and truly believe the best has yet to come. With that, let me now turn the call over to Tolga for a review of our commercial performance.

Thanks, Yvonne, and good morning, everyone. Q4 was another strong quarter for our commercial portfolio with our combined TTR and rare franchises delivering 30% growth compared with the fourth quarter of 2023. On a full year basis, we delivered $1.646 billion in combined net product revenue at the very upper end of our 2024 product revenue guidance range, which translates to a 33% growth compared to 2023 as we continue to consistently increase the number of patients on therapy in both our TTR and rare franchises. Let me now turn to a summary of our fourth quarter TTR performance. Our TTR franchise achieved $343 million in global net product revenues during the quarter, representing a 35% increase compared with the fourth quarter of 2023 as we continue to increase the number of hATTR-PN patients on our therapy. In the U.S., during our first full year of competition in hATTR-PN, combined sales of ONPATTRO and AMVUTTRA in the fourth quarter increased by 10% compared with the third quarter and finished the year with a robust 42% year-over-year increase, driving strong growth momentum. The 42% year-over-year growth was primarily driven by a 34% increase in demand, driven by the strength of ongoing AMVUTTRA patient uptake as well as continued switches from ONPATTRA. We are pleased with the growth in demand which was consistent throughout the year, despite new competition entering the market at the end of 2023. The remaining growth in the quarter related to favorable adjustments in gross to net deductions, which were offset modestly by stocking dynamics as the inventory in the distribution channel decreased in Q4. I'd like to take a moment to reflect on our full year hATTR performance in the U.S., where we generated $705 million in full year revenue, representing 39% growth compared with 2023 and almost $200 million in dollar growth. The dollar growth in 2024 represents an increase relative to the dollar growth we generated in 2023 of $180 million despite the new competition that entered the market at the beginning of the year. We believe this is reflective of the leadership position we have established in the PN market over the last six years, the strength of AMVUTTRA's safety and efficacy profile, which is underpinned by rapid knockdown of TTR and solid commercial execution. Now let me turn to our international markets, where the TTR franchise grew 12% in the fourth quarter compared to the third quarter of 2024 and increased by 25% year-over-year compared with the fourth quarter of 2023. Similar to the U.S., the year-over-year growth was primarily driven by increased demand for AMVUTTRA as patient uptake remained robust. Before we discuss our Rare business, I'd like to take a few minutes to review our readiness for our upcoming PDUFA target action date and the potential expanded label and launching TTR-CM in late March. We're excited about the potential of bringing RNAi therapeutics to a patient population that is desperately in need of a product with a new mechanism of action. We've been preparing for this opportunity, which may now be only weeks away pending successful completion of the ongoing U.S. regulatory review. We recently announced full year 2025 product revenue guidance at JPMorgan. Our guidance of over $0.5 billion in absolute growth versus 2024 is mainly driven by our TTR franchise that includes our anticipated label accession into ATTR-CM and reflects our confidence and excitement about the launch. For 2025, we've guided for TTR product sales of between $1.6 billion and $1.725 billion. This would represent a 36% increase in annual revenue compared with 2024 at the midpoint of our guidance, reflecting an acceleration from the 34% growth our TTR business achieved in 2024. Now let me share with you a few reasons for our optimism and a sense of what's to come. As we said before, ATTR is an orphan disease. The category is rapidly growing and is still largely underserved. This will be a market growth story, an opportunity to help more patients in need, whether they are newly diagnosed or currently on a stabilizer therapy and experiencing disease progression. It is a category ripe for an entirely new treatment option. In this context, we have the potential to introduce a disruptive treatment. Assuming approval, AMVUTTRA will be the first and only RNAi silencer approved for both ATTR-CM and hATTR-PN, one that delivers rapid knockdown of TTR, working upstream at the source of the disease, demonstrated profound impacts on cardiovascular outcomes in HELIOS-B, including a 36% reduction in all-cause mortality versus placebo in a study population representative of today's patients with 40% on a stabilizer and a significant number on other background therapies like diuretics and SGLT2 inhibitors. Early and consistent preservation of functional capacity and quality of life impacts that are critically important to patients. All of this achieved with just four doses per year and uniquely positioned for seamless access for patients. And while there is still much work in front of us, we are building on a strong foundation in hATTR-PN and a demonstrated track record of consistent commercial execution, as you have seen from our Q4 and full year results. As we approach this important launch, we are building for the durable long-term success of our TTR franchise and building on our experience and success over the past six years in this category. This means taking the time to enable smooth access and create a seamless experience for patients and providers alike. Toward that end, we have already been at work optimizing the access and patient onboarding experience, focusing on optimizing access pathways at health systems where patients are actively managed today. We made good progress, laying the groundwork in this regard, and it is important to note that following FDA approval for the expanded indication, it can take several months for the product to be added to the system's formulary and for the access pathway to be fully optimized, which will result in a ramp-up in demand as the year progresses. In parallel, we have also been building a broad ecosystem of alternative sites of care to expand optionality for how patients can initiate therapy in a seamless way and adhere to it. Our goal is to expand these provider sites and ultimately for greater than 90% of patients to be within 10 miles of a treatment site. With regard to our field readiness, we've already scaled up all our customer teams cross-functionally with world-class sales, field reimbursement, key account management and medical and award-winning patient services teams. Looking ahead to post-approval, we will pivot our focus to securing health systems formulary approval via their pharmacy and therapeutics committee reviews and finalizing access pathway optimization, which could also take several months once we have an approved label. Expanding our value-based agreements in ATTR-CM, we've been an industry pioneer in establishing VBAs across our portfolio to deliver value and enable broad patient access. We are focused on expanding these existing ATTR VBA partnerships to cover our expanded label. Finally, driving disciplined and compliant execution across our teams following approval. In short, we see tremendous opportunity in this category. We are on the cusp of a regulatory decision for what has the potential to become a transformational product for patients in need. We plan to share relevant operational details over the course of the year to provide clarity on the progress of our launch, as we aim to achieve or exceed our full-year revenue guidance.

Thanks, Tolga, and good morning, everyone. As you all know, 2024 was a very exciting year for our TTR franchise. We shared the landmark results from HELIOS-B at several conferences throughout the second half of the year. Together, these data presentations highlighted vutrisiran's potentially transformational profile in today's population of patients with ATTR-CM with benefits across a comprehensive series of assessments. Based on these compelling data, we've completed several regulatory submissions that are now under review. In the United States, we have a PDUFA date of March 23, and parallel filings were achieved in all major regions, including Europe and Japan. Our goal is to bring this new and important therapeutic option to patients around the world as quickly as possible. We also continue to look ahead and innovate in TTR beyond vutrisiran with Nucresiran, formerly known as ALN-TTRsc04. At AHA in November, we presented updated Phase 1 results, showing rapid knockdown of serum TTR that was robust and highly durable greater than 90% at 6 months, supporting the potential for an annual or biannual subcutaneous dosing regimen and an encouraging safety profile, which in addition to offering convenience for patients, could enable broad payer coverage. Together, we believe these data support a potential best-in-class profile. I'm also happy to announce today that the FDA has granted Nucresiran orphan drug designation for ATTR Amyloidosis, encompassing both polyneuropathy and cardiomyopathy. As Yvonne announced at JPMorgan, we plan to quickly advance Nucresiran to a Phase 3 study in ATTR Amyloidosis with cardiomyopathy that is expected to start in the first half of 2025. Additional details regarding the study design will be shared at our R&D Day on February 25. Beyond TTR, our R&D efforts have enabled us to build one of the most robust pipelines in the biotech industry today, positioned to deliver strong growth and innovation across a broad range of disease areas and indications at all stages of development. In the fourth quarter, we continued to make great progress in advancing our pipeline. Let me highlight a few key milestones. We continue to advance Zilebesiran, an investigational therapeutic for the treatment of hypertension, through Phase 2 and towards the initiation of a Phase 3 cardiovascular outcomes trial expected to start in the second half of 2025. In fact, as announced this morning, we have recently completed enrollment in the KARDIA-3 Phase 2 study. Mivelsiran, our investigational therapeutic for the treatment of cerebral amyloid angiopathy in Alzheimer's disease, continues to proceed as well. We presented multi-dose data showing high levels of knockdown with single and multiple doses, along with good safety and tolerability. We have an ongoing Phase 2 study in cerebral amyloid angiopathy and plan to start a Phase 2 study in Alzheimer's disease in the second half of the year. We started four new Phase 1 programs last year. The first was for Huntington's disease, where we have a unique exon 1 targeting approach that non-human primates have shown deep and sustained knockdown with encouraging safety and tolerability. The Phase 1 trial is ongoing in the United States, Canada and the U.K. The other programs initiated in Q4 include Zilebesiran, plus Reversir for hypertension, ALN-6400 for a bleeding disorder and ALN-4324 for Type 2 diabetes mellitus. This remarkable and unique pace of innovation puts us in a great position to have a strong self-sustainable pipeline that can deliver meaningful impact to patients for many years to come. I encourage you to tune in to the webcast of our R&D Day that we will host on February 25, where we will provide more comprehensive reviews of the programs I've described and also highlight continued RNAi platform innovation that will drive the next era of Alnylam's growth.

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting Alnylam's full-year 2024 financial results and providing our complete financial guidance for 2025. Starting with a summary of our P&L results for the full year, total global net product revenues for 2024 were $1.646 billion, representing 33% growth versus 2023, with both TTR and Rare franchises reporting strong growth of 34% and 29%, respectively. These results came in at the top end of our 2024 product revenue guidance, which we had raised more than 10% at midyear from our original 2024 guidance. For the full year, net revenue from collaborations was $510 million, including a $60 million sales milestone in Q4 from Novartis due to LEQVIO exceeding $600 million in annual sales. Compared with 2023, collaboration revenues decreased 7%, primarily attributed to certain revenue items between 2023 and 2024. During 2023, we recognized $310 million of revenue from the upfront payment received from Roche in connection with executing our Zilebesiran collaboration. In comparison, during 2024 we recognized $185 million in revenues associated with the modification to our Regeneron collaboration driven by providing Regeneron an exclusive license to develop, manufacture and commercialize Zilebesiran as a monotherapy. Royalty revenue for the full year was $92 million or more than double what was recognized in 2023, driven by higher royalties from Novartis on sales of LEQVIO. Gross margin on product sales was 81% for the full year, representing a 3% increase compared with 2023. The improvement in margin was primarily due to non-recurring prior year expenses associated with canceled manufacturing commitments for ONPATTRO and other adjustments to inventory. For 2025, we expect a decrease in gross margin on product sales as the average royalty rate payable to Sanofi on AMVUTTRA is expected to be higher as sales of AMVUTTRA continue to increase. Our non-GAAP R&D expenses increased 10% for the full year compared with the prior year, primarily due to increased costs associated with our preclinical activities as we develop our clinical pipeline of RNAi therapeutics targeting multiple tissues, increased clinical trial expenses associated with the Zilebesiran KARDIA-3 Phase 2 study, and increased employee compensation expenses. Our non-GAAP SG&A expenses increased 24% for the full year compared with 2023, primarily driven by increased investments in support of our TTR polyneuropathy business and in preparation for the potential launch of AMVUTTRA for cardiomyopathy along with increased personnel costs. For the first time, we achieved non-GAAP operating profit of $95 million, representing a $156 million improvement compared with 2023, primarily driven by strong growth in product sales. This is a significant milestone for the company as achieving non-GAAP profitability has been a key goal associated with our P5x25 growth strategy. This achievement will enable further investment in our R&D pipeline as we strive to deliver sustainable long-term top and bottom-line growth. Finally, we ended the year with cash, cash equivalents, and marketable securities of $2.7 billion compared to $2.4 billion at the end of 2023, with the increase primarily driven by improved operating performance and net proceeds received from the issuance of common stock in connection with employee stock option exercises. Now I'd like to turn to our 2025 financial guidance. Starting with net product revenues, we are reiterating our combined net product revenue guidance from ONPATTRO and AMVUTTRA, GIVLAARI and OXLUMO that was communicated in our JPMorgan press release. We anticipate combined net product sales for our four commercial products will be within a range of $2.05 billion to $2.25 billion, representing combined full-year growth compared to 2024 of 31% at the midpoint of the guidance range or more than $500 million in growth. On a franchise level, the guidance is broken down as follows: total TTR, $1.6 billion to $1.725 billion, representing full-year growth compared to 2024 of 36% at the midpoint of the guidance range. Importantly, this guidance assumes approval and launch of AMVUTTRA for ATTR cardiomyopathy in the U.S. by the PDUFA date of March 23rd. Additionally, we assume launches for AMVUTTRA an ATTR-CM in Germany and Japan in the second half of 2025. Total Rare revenue is projected between $450 million to $525 million representing full-year growth compared to 2024 of 15% at the midpoint of the guidance range. Our guidance assumes foreign exchange rates as of December 31st, 2024, which are noted in the footnote of our guidance slide. We are also providing constant exchange rate growth guidance for our net product revenues with a projected range of 26% to 39%. Collaboration and royalty revenue guidance range is $650 million to $750 million representing 16% growth compared to 2024 at the midpoint of the guidance range. Our guidance assumes achievement of a $300 million milestone payment from Roche associated with the initiation of our Phase III study for Zilebesiran which we anticipate will occur in the second half of the year. We also expect the collaboration revenue associated with our partnerships with Roche and Regeneron as well as royalties from Novartis will drive the majority of our collaboration and royalty revenue in 2025. Our guidance for combined non-GAAP R&D and SG&A expenses is a range between $2.1 billion and $2.2 billion, with the midpoint of the range representing 17% growth compared with 2024. Growth drivers for R&D expense in 2025 include increased clinical investment across our early mid- and late-stage programs including the initiation of pivotal Phase III studies for Zilebesiran and Nucresiran. Growth in SG&A will primarily be driven by the launch of AMVUTTRA for ATTR cardiomyopathy in the U.S., Germany, and Japan assuming regulatory approvals. Finally, we anticipate delivering non-GAAP operating income profitability in 2025. Let me now turn from financials and discuss some key goals and upcoming milestones for early 2025. As Pushkal mentioned, we will host an R&D Day on February 25th in New York City. The PDUFA target action date for the sNDA for vutrisiran is March 23rd, 2025. Please note that given the materiality of this decision, we will be entering a quiet period beginning on March 1st. We intend to initiate the Phase III study of Nucresiran in patients with ATTR amyloidosis cardiomyopathy in the first half of 2025.

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

Thank you. Ladies and gentlemen, we will now begin the question-and-answer session. And your first question is from Tazeen Ahmad from Bank of America. Your line is now open.

Hi, good morning. Thanks for taking my question. I wanted to get a sense from your team about how long you think it's going to take to establish payer policies after the approval of vutri and how do you think that could impact the initial trajectory of the launch? Thanks.

Thanks, Tazeen. That's a great question. I mean, clearly, we're in a strong position, having already a TTR franchise supporting patients with polyneuropathy. And this really gives us a strong foundation on which to build. Tolga, perhaps you could ask a specific question around time to plan approvals.

Hi, Tazeen. Look, obviously, we're really excited about the upcoming potential launch, and our excitement is confirmed by the guidance that we've already provided. Now when it comes to the payer policies and formulary uptake, I think as you can see from my prepared remarks, this is really going to be a second-half story. We're very much committed to the growth that we've already committed to, and we have value-based agreements that we know are going to be extended with some of these payer policies that are going to accelerate. But the formulary piece takes a little bit of time. So I would expect the uptake really to be meaningful in the second half of the year. Thanks.

Thanks, Tazeen.

Thanks for taking our question. A quick one on AMVUTTRA from us. If we assume premium pricing for AMVUTTRA compared to silence, which are approved already, what are your thoughts around step edits for commercial insured patients who represent about 20% of the ATTR cardiomyopathy population? Thank you.

Tolga, that's a question for you.

Yes. Great question. Look, I mean, first and foremost, we really appreciate and like the product profile that AMVUTTRA still offers, which is underpinned now by the HELIOS-B results. And in our engagements with payers at the pre-pricing discussions, we're also encouraged that they see, one, obviously, the value of this product can bring to the market. Second of all, the predictability of how we are actually being positioned as a Part B product. So all these combined, we actually expect our uptake to be very consistent with what we have seen in the past with PN in terms of how payers will cover the product. And as we've already shared, we are very much committed to the guidance that we provided, which underpins how we really see the growth that is going to be accelerated in 2025.

Thank you. Very helpful.

Thank you. I know you cannot comment on the actual price for AMVUTTRA, but wondering if you can share the key factors that impact your decision on pricing adjustment for AMVUTTRA. And related question, I know a few already asked, can you share with us what percentage of the current sites already have a J-code place that you can use for AMVUTTRA in ATTR cardiomyopathy?

Thanks, Gena, for the question and recognizing that it's too early to be specific about price. And as you know, we have our patient access principles. When we think about price, we consider the value that our product is bringing to patients and the ecosystem as well as assuring optimal access. I think we've done a great job in PN along those dimensions, and we continue to plan to do equally good job for CM. Tolga, do you want to add?

Yes, I mean one maybe answer to your last point, which we already have a J-code for AMVUTTRA that is going to be used. Therefore, we don't expect any changes or any disruption on that. And in respect to our coverage, as we shared earlier on our TTR Day and other forums, the current makeup of our business from a Medicare perspective as well as commercial, we expect that to remain the same. And therefore, we believe this is going to result in rather smooth coverage for our product. As Yvonne indicated, we're really excited about the orthogonal mechanism and how that's going to actually bring additional value and alternative, the disruptive treatment for payers as well as patients. And then actually, frankly, most importantly, the affordability for the patient. As you know, 70% of our patients currently pay zero co-pay, and we expect that dynamic to remain the same, which we believe is going to be an important driver for our patient uptake.

Thanks, Tolga. Next question.

Hi. Congrats on the progress and thanks for taking my question. Just wondering if there's any perspective you can provide on label discussion progress. In addition to the reduction of mortality and hospitalizations, are you advocating to have anything unique on the front page of the label and the indication and usage section such as wording related to preservation and quality of life and functional capacity?

Yes. Thanks, Maury. Look, first of all, we're really enthusiastic about how the FDA review is going, and we remain fully on track for an approval date by the PDUFA. In terms of the label, we believe that the study was designed and clearly demonstrated the benefit on mortality and hospitalization events. We expect that to be reflected in the label as well as the ancillary benefits that we saw in terms of preservation of functional ability, quality of life, and benefits across a series of endpoints there. At the end of the day, we want a label that reflects the study that was designed and where we saw statistically significant results in predefined endpoints across a whole series of attributes that we think are a benefit and that we're able to educate providers and patients on. So we look forward to sharing that when an eventual approval occurs.

Good morning, guys. Thanks for taking the question. My question was actually a really good follow-up to Maury on label language. Tolga, do you think about the language in the label, specifically mortality but potentially having that mortality clinical data later in the label in the clinical data section? What sort of potential advantage could that give you or not, either detailing the product or with payers?

Okay, Ritu. Look, we have a pretty clear view of the understanding of how we're going to be able to promote and communicate this. Mainly, obviously, what Pushkal indicated, we had reached significant results on all prespecified endpoints, 10 out of 10. Our ability to communicate that is going to be relatively smooth. We're pretty confident on how we can differentiate the product from a product profile perspective, given that this is an orthogonal mechanism of action that rapidly knocks down the disease-causing protein and has the ability to demonstrate those clinical outcome benefits on both mortality as well as hospitalization, coupled with the fact that we have four times a year subcutaneous injectable that really provides great adherence as we've seen on polyneuropathy and our relatively smooth access given that 70% of patients pay zero co-pay. All those perspectives will be carried through how we're going to communicate this exceptional medicine to the prescribers who are very much in need of a disruptive treatment.

Do you still expect that to be in the actual labeling language though? Those data?

Look, at the end of the day, we think that the label will reflect the things that we've shown in the clinical trial. That's traditionally what is done, and we would expect this, as we've said, Ritu, that we had a whole series of prespecified endpoints that show the impact of this drug on this disease. So we would expect that to be generally reflected in the label. And again, consistent with labeling, Tolga's team, our medical teams will be able to speak about those attributes and the results of the HELIOS-B study to providers, patients, and payers.

Thanks, Ritu. Next question, please.

Good morning. This is Teraesa Vitelli on for Greg Harrison. Congrats on all of the updates and thanks for taking our question. I was just curious to hear what your expectations are for vutrisiran's potential revenue mix among naive patients in the first-line setting versus switches from tafamidis?

Tolga, that question is for you.

Yes. So I think to the best of our abilities, we were able to provide a pretty clear and ambitious guidance that really shows how we're going to actually accelerate this TTR franchise post-36%. Now how that mix is going to happen is, look, we believe this is a product well-positioned to be a standard of care and to be the first line. But like any categories, we do know that there is a need for another product with an orthogonal mechanism of action beyond the stabilizers. So we certainly expect a good mix of naive patients that are coming in the door that are newly diagnosed and some perhaps eligible for switches or in rare instances, some combination. So we do expect that, and as we've built our guidance, all these elements were incorporated.

Great. Thank you. Next question.

Hi, good morning. Maybe you could talk about the competitive dynamics you're seeing with Wainua in polyneuropathy with both products growing at this point? And how is the difference between Part B and Part D playing out? And how you think that's going to translate over to cardiomyopathy with that approval?

Thanks for the question. I mean, clearly, we're very pleased with our strong TTR performance in 2024, and that was with competition in the market. So I think we're doing a good job continuing to build the business. Tolga, perhaps you want to add some color to the specific dynamics?

Yes. We just posted our full-year results for '24, which happened to be the first year we faced competition. In this relatively narrow category where we always said this is going to be a growth story. I think what you can see, particularly in our U.S. numbers, where our U.S. business from a pretty good healthy base grew 42% year-over-year. And that was with the competition. And as far as I can tell, Wainua is also getting their fair share of growth, which is again very consistent with the growth story that we've been telling all along. We believe we have a highly differentiated product profile versus Wainua given that it's four times a year and HCP administered. We have not seen any significant access headwinds, and we anticipate, frankly, this type of dynamic continuing as we expand our expanded indication to cardiomyopathy.

Thanks, Tolga. Next question, please.

Hi, guys. Good morning. What do you think the early acoramadis scripts imply for the TTR cardiomyopathy market dynamics, market expansion and interest in agents beyond tafamidis as it relates to AMVUTTRA? And I think folks have been trying to ask this in a few different ways, but maybe just to try one more time. What's the right way to think about the evolution of AMVUTTRA's net price as you move into this much larger patient population?

Okay. I mean two questions there. Clearly, as Tolga said, I mean we believe this is the market growth opportunity which makes a very exciting category to be in. Obviously grows into cardiomyopathy with a strong track record in the TTR space. Tolga, perhaps you can add some color to the first question, and then the specific question around the evolution of net price?

Yes. The first sentiment that comes to mind is encouragement. Effectively seeing another stabilizer coming into the market and they've shared some numbers on the prescription that are early innings obviously. We're very encouraged because if another stabilizer that is four times a year with not really significant clinical data, they’ve actually shown that this is a growth category. Now when I think about AMVUTTRA product profile that has a really strong clinical profile as well as the fact that it's four times a year annual dosing, we're really well-positioned to be in the access. We're very excited about what AMVUTTRA can do, given that the category is going to continue to grow, given the undiagnosed patient numbers.

Hi, thanks so much for taking the question. On payer dynamics and how they evolve in this category, are you expecting the average insurer to cross manage between Part B and Part D? And I think, again, the underlying question that everyone is trying to get to on pricing is you're at a significant premium right now. Does it have to go down or not? There's a lot of moving parts, right, like the payer liability on Part D is one of them. But just as it relates to how insurers are going to manage their formularies in this space, like could tafamidis or acoramidis actually be a step edit or is that just not something that's normal in practice at this point?

Yes. Thank you for the question. Look, there's a lot of noise around how the payers will be managing this. What we've seen is this is a rare condition, a highly devastating condition, and we expect the payers to cover the product and how the market is going to evolve. I think we have a pretty clear view given how we've been managing polyneuropathy as a Part D product, and how Wainua has launched as a Part D product. We expect similar dynamics in terms of our payer mix. We do anticipate that given patient affordability is a key driver of how patients stay on therapy, it should be very favorable for AMVUTTRA.

Thank you. Next question.

Good morning. Thanks for taking my question. You plan to initiate a Phase 3 study for Nucresiran in ATTR-CM in the first half. How are you thinking about the timing of enrollment and events given the availability of new options, and how do you plan to conduct an interim here?

Yes. So thanks for the question. I mean, clearly, we'll be providing more detail around the Nucresiran program at R&D Day at the end of this month. Pushkal, maybe you can share a little bit about how we're thinking about moving forward with Nucresiran, which we're very excited about.

Yes, Salveen. Look, I think Nucresiran's profile that we've seen so far really sets it up to be a best-in-class therapy for patients with this disease, building on what we've seen with Nucresiran. This is now a derisked asset. We think we can get deeper knockdown. We've already shown over 90%, 95% knockdown, with less frequent administration, and we think that's going to help patient outcomes. When we think about the development plan for it, there are several factors. A, we want to develop and bring this to market quickly because of the value it brings. Two, we want to think about developing a clinical profile for that and a label that allows for broad uptake and a very durable franchise. You'll see how we've brought these factors together at R&D Day. We will talk more about the development program there in CM and PN and our overall approach to this disease. So stay tuned. It will just be a couple of weeks, and we'll be able to share more.

Next question.

Hi, guys. Thanks so much for taking the question. Just a couple for me. So how would you characterize the mix of growth in the TTR guidance from polyneuropathy versus cardiomyopathy? And then Tolga, you mentioned that post-approval, you'll be finalizing value-based agreements in cardiomyopathy. Can you elaborate a bit on how these could work and what this could look like for cardiomyopathy relative to polyneuropathy? Thanks.

Tolga, two questions there. What are the growth dynamics of polyneuropathy versus cardiomyopathy, and how are we thinking about value-based agreements post-approval?

Look, unusual to our tradition, we actually broke down our guidance between TTR and Rare at JPM. We'll continue to provide more color about how the launch is going, particularly in the second half of the year where we do see where we do anticipate the growth to take place. Now can you remind me the second question?

Value-based agreements.

Value-based agreements, right? So look, we're very, very proud of the value-based agreements that we set out. Currently, about 60% of the lives that are covered on the PN is dependent on the value-based agreements. These agreements essentially provide our commitment to the clinical outcomes. We have this experience already with PN, and we anticipate that to carry over in most instances for cardiomyopathy, which should provide a level of predictability for the payers about how the product is going to perform and the clinical outcomes that the payers expect us to achieve. I think that's one of the great best practices that we've established over the years, and we anticipate that to carry over with our cardiomyopathy indication in most cases.

Thank you.

Thank you for the question. Congratulations on the excellent results both commercially and otherwise. I understand there are likely two more questions regarding AMVUTTRA and pricing. Therefore, I'll pose a different financial question. Could you explain the source of the tax benefit mentioned? Will this be a recurring benefit? Is this related to an NOL dynamic outside the US? If you could elaborate on what caused that benefit and its potential recurrence throughout the year?

Yes, that's a question for you. You give me another break.

Good question, Mani. We noted in the press release that we had a release of a valuation allowance ex-U.S. That's really related to our Swiss entity. This is something that we have to do every quarter with our deferred tax assets as we have to assess whether or not it's more likely than not that this value is going to ultimately be recognized. The Swiss entity has had profitability for a number of periods now. So that gave us the confidence to release that. We have not released all the valuation allowances either in Switzerland, and we have not released anything in the U.S. yet. It's very difficult at this point to predict further, Mani. So I'd probably just leave it at that for now.

Thanks, Mani. I think we've got time for one more question. I think we have a couple of last questions coming up.

Great. Thanks so much for squeezing me in. Maybe I'll follow Mani here, I guess. But Jeff, how should we think about gross margin here going forward? I mean the same of the oral TC is very meaningful at 15%, 30%, but we obviously don't know the exact hearing of the royalty fee. Do you think that modeling gross margin compressing from 80% now, I think it's low 80s now to like low 70s, or even upper 60s? Is that a reasonable assumption in your mind? Any call there much appreciated? Thanks so much.

I appreciate the question. So in my prepared remarks, I mentioned that we expect gross margin on product sales to be lower in 2025. You're right. 2024, our gross margin on product sales was 81%. I do think that will be the direction of travel for a period of time, driven by two things that relate to AMVUTTRA. One is this is our lowest margin product right now, given the royalty burden to Sanofi, and it's our fastest-growing product. So that will put pressure on margins as we move forward. Secondly, as that business grows, we also start to move up higher in the royalty tiers. The average royalty rate will likely also increase over time. The royalty that we paid on average across 2024 for AMVUTTRA was 21%. My expectation, as this moves forward, is that over time, that number is going to probably be mid- to high 20s. So that's just sort of the incremental amount that I would expect. There are a couple of things that will move the other way, I would say, on margins. If you look at our gross margin on a total revenue basis, that also includes the impact of collaboration and royalty revenue. That's revenue that's very high margin, probably close to 100%. As an example, in 2024, the margin on product sales was 81%. But if you looked at the margin on total revenue, it was 86%. That uplifted it. Secondly, the most important thing is that the issue with this high royalty burden, if we're successful in developing Nucresiran, which we will hear more about at R&D Day, as Pushkal said, there's no royalty burden to Sanofi on that. So that would obviously offset this in the future if we're successful in bringing that to market. So hopefully, that gives you a little more clarity on direction of travel on margins.

That's super helpful. Thanks so much.

Very good. Well, look, thanks everybody for joining the call. 2024 was a really good year for Alnylam. As I said, just the beginning of the success we believe we're on track to realize in 2025. So thanks, everybody, and have a great day.

Ladies and gentlemen, the conference has now ended. Thank you all for joining. You may all disconnect your lines.