Alnylam Pharmaceuticals, Inc.

in a listen-only mode. Following the presentation, we will conduct the question and answer session. If at any time during this call, we require immediate assistance, please press four zero for the operator. I would now like to turn a conference call over to the company. Please go ahead.

Good morning, I'm Christine Lindenboom, Chief Corporate Communications Officer at El Nilem. With me today are Avon Breedon-Street, Chief Executive Officer, Tolga Tangular, Chief Commercial Officer, Pushkal Garg, Chief Medical Officer, and Jeff Poulton, Chief Financial Officer. For those of you participating in a conference call, the accompanying slides can be accessed by going to the events section of the Investors page of our website, .elnilem.com slash events. During today's call, as outlined in slide two, Avon will offer introductory remarks and provide some general context. We'll be providing 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 El Nilem's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Security 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 of SEC. In addition, any forward-looking statements represent our views only at the date of this recording and should not be relied upon representing our views as of any subsequent date. We specifically explain any obligations to update such statements. With that, I'd like to turn the call over to Avon. Avon?

Thanks, Christine, and thank you, everyone, for joining the call today. 2024 was a fantastic year for El Nilem with strong research, program development, and commercial execution and significant progress across the business. This includes the highly positive results in the HEDISP Phase III study, leading to submission of global regulatory findings for vitreotirin and 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, and 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 to the year ahead, 2025 has the potential to be a landmark year for El Nilem. 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, and will take El Nilem into its next exciting chapter. The first is TTR leadership, where vitreotirin, 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 asset, Nucreaseran, following along. Next is growth through innovation, including a pipeline with numerous multi-billion 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 -in-class team and our award-winning culture. All of this represents tremendous progress against our Nilem piece of this by 25 goals, launched back in 2021. We're 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 in our next era of significant growth. We're entering a new and exciting chapter in our Nilem's history and truly believe the best is yet to come. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga.

Thanks, Ivan, 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 ,000,000 in combined net product revenue at the very upper end of our 2024 product revenue guidance range, which translates to 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 ,000,000 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 US, during our first full year of competition in an HATTR PN combined sales of Ompatra and Amutra 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 the following. A 34% increase in demand driven by the strength of ongoing Amutra patient uptake as well as continued switches from Ompatra. 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 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 US 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 increase in 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 Amutra's safety and efficacy profile which is underpinned by rapid knockdown of TTR and solid commercial execution. Now let me turn to our international market where the TTR franchise grew 12% in the fourth quarter of 2020 compared to the third quarter of 2024 and increased by 25% year over year compared with the fourth quarter of 2023. Similar to the US, the year over year growth was primarily driven by increased demand for Amutra 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 Purdue for Target action day and the potential expanded label and launch in TTRCM in late March. We're excited about the potential of bringing in 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 US regulatory review. We recently announced full year 2025 product revenue guidance at JP Morgan. Our guidance of over half a billion dollars in absolute growth versus 2024 is driven by mainly by our TTR franchise that includes our anticipated label extension into ATTRCM and reflects our confidence and excitement about the launch. For 2025, we've guided for TTR product sales of between 1.6 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 right for entirely new treatment option. In this context, we have the potential to introduce a disruptive treatment. Assuming approval, AUTSRA would be the first and only RNAi silencer approved for both ATTRCM and HHCTRPN, one that delivers rapid knockdown of TTR working upstream at the source of disease, demonstrated profound impacts on CV outcomes in Helios-V, 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 and that they can feel. All of this achieved with just four doses per year and uniquely positioned for seamless access for patients. And while there's still much work still in front of us, we are building on a strong foundation in HHCTRPN 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 durable long-term success of our CTR 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 to 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.

This means

optimizing access pathways at health systems where patients are actively managed today. Given 80% of the population is being treated at 170 health systems, we are focusing on optimizing access pathways at these health systems so that healthcare professionals can easily prescribe our MUTRA with the knowledge that the patient will receive it at an optimal location, be it an office, at an infusion center, or at home. We've 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've 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. As we previously shared at our 2024 CTR Investor Day, there currently are over 1,000 alternative sites of care available for patients. This is in addition to health systems, group practices and clinics, and at home administration. 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. That includes 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 again could also take several months once we have an approved label. Expanding our value-based agreement 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 disciplines 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. And we have an FD-ready commercial organization deeply engaged and experienced in the ATTR market. 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. Now turning to our rare franchise and the performance of Givlari and Oxluma, which delivered $108 million in combined product sales in the fourth quarter, representing a 3% decline compared with the third quarter of 2024, driven by purchase patterns and 18% growth compared with the fourth quarter of 2023. For Givlari, Q4 product sales decreased by 9% compared with the third quarter of 2024, primarily due to the timing of a large order in the partner market in Q3, which did not recur in Q4. On a -over-year basis, Givlari sales increased by 9% compared with the fourth quarter of 2023 with the following regional highlights. A 14% increase in the US, primarily driven by growth in new patients on therapy, with additional growth driven by inventory stocking dynamics, a 1% decrease in our international market where demand growth in our European markets was offset by gross net adjustments in our partner market. For Oxluma, Q4 product sales increased by 8% compared with the third quarter of 2024, primarily due to continued demand growth and increased by a solid 33% compared with the fourth quarter of 2023 with the following -over-year regional dynamics. Despite emerging competition, a 77% increase in the US, primarily driven by strong demand growth with additional growth driven by favorable gross net pricing adjustments and inventory stocking dynamics. A 12% growth from rest of world markets, primarily driven by strong growth in patient demand. In conclusion, we delivered strong results in the fourth quarter with both our PQR and rare franchises driven by continued robust growth in patients on therapy, which enabled us to close the year at the upper end of our 24 product revenue guidance range. With that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

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 Vutri-Sarans 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 23rd 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 Vutri-Saran with Nucre-Saran, formerly known as -SC-04. At AHA in November, we presented updated phase one results showing rapid knockdown of serum TTR that was robust and highly durable, greater than 90% at six 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 pair 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 Nucre-Saran orphan drug designation for ATTR-AMOID doses, encompassing both polyneuropathy and cardiomyopathy. As Yvonne announced to JP Morgan, we plan to quickly advance Nucre-Saran into a phase three study in ATTR-AMOID doses 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 25th. 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 continue to make great progress in advancing our pipeline. Let me highlight a few key milestones. We continue to advance Zalbisiran, an investigational therapeutic for the treatment of hypertension through phase two and towards initiation of a phase three cardiovascular outcomes trial expected to start in the second half of 2025. In fact, as announced this morning, we've recently completed an enrollment in the Cardia 3 phase two study. In Velsiran, our investigational therapeutic for the treatment of cerebral amyloid angiopathy and 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 two study in cerebral amyloid angiopathy and plan to start a phase two study in Alzheimer's disease in the second half of the year. And we started four new phase one programs last year. The first was for Huntington's disease where we have a unique exon one targeting approach that non-human primates has shown deep and sustained knockdown with encouraging safety and tolerability. The phase one trial is ongoing in the United States, Canada, and the UK. The other programs initiated in Q4 include Zalbisiran plus Reverseir for hypertension, ALN 6400 for a bleeding disorder, and ALN 4324 for type two 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 join or to tune in to the webcast of our R&D day that we will host on February 25th where we will provide more comprehensive reviews of the programs I've described and also highlight continued RNA platform innovation that will drive the next era of Alnylum's growth. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff.

Thanks Pushkal and good morning everyone. I'm pleased to be presenting Alnylum'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 ,000,000 representing 33% growth versus 2023 with both our TTR and rare franchises reporting strong growth at 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 mid-year from our original 2024 guidance. For the full year net revenue from collaborations was ,000,000 including a ,000,000 sales milestone in Q4 from Novartis due to Lekvio exceeding ,000,000 in annual sales. Compared with 2023, collaboration revenues decreased 7% primarily attributed to differences in certain revenue items between 2023 and 2024. During 2023, we recognized ,000,000 of revenue from the upfront payment received from Roche in connection with execution of our Zalbisiran collaboration. In comparison during 2024, we recognized ,000,000 in revenues associated with the modification to our Regeneron collaboration driven by providing Regeneron an exclusive license to develop, manufacture and commercialize CEMD-Siran as a monotherapy. Royalty revenue for the full year was ,000,000 or more than double what was recognized in 2023 driven by higher royalties from Novartis on sales of Lekvio. 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 from Patro and other adjustments to inventory. These decreases were partially offset by an increased rate of royalties payable on net sales of Ambutra. For 2025, we expect a decrease in gross margin on product sales as the average royalty rate payable to Sanofi on Ambutra is expected to be higher as sales of Ambutra continue to increase. Our non-GAAP R&D expenses increased 10% for the full year compared with 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 Zalvis-Siran Cardia 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 Ambutra for cardiomyopathy along with increased personnel costs. For the first time, we achieved full year non-GAAP operating profit of $95 million, representing a $156 million improvement compared with 2023, primarily driven by strong growth and product sales. This is a significant milestone for the company as achieving non-GAAP profitability has been a key goal associated with our P25x25 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 Patro and Vutra Givlari and Oxlumo that was communicated in our JPMorgan press release dated January 12th, 2025. We anticipate combined net product sales for our four commercial products will be within a range of $2.05 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 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 Ambutra for ATTR cardiomyopathy in the US by the PDUFA date of March 23rd. Additionally, we assume launches for Ambutra and ATTRCM in Germany and Japan in the second half of 2025. Total rare, $450 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 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 three study for Zalvisaran, which we anticipate will occur in the second half of the year. We also expect that collaboration revenue associated with our partnerships with Roche and Regeneron, as well as Lekbio royalties from Novartis, will drive the majority of our collaboration and royalty revenue in 2025. Our guidance for combined non-GAAP R&D and SGA expenses is a range between 2.1 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 three studies for Zalvisaran and Neucreasaran. Growth in SG&A will primarily be driven by the launch of Envutra for ATTR cardiomyopathy in the US, Germany, and Japan, assuming regulatory approvals. Finally, as discussed last month at JPMorgan, 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 Neucreasaran 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 a phase three study of Neucreasaran in patients with ATTR amyloidosis, cardiomyopathy in the first half of 2025. And our partners at Sanofi have a PDUFA target action date for Fetusaran of March 28th, 2025. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Jeff. Operator, we will now open the call for questions. To 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 questioning answer session. Should you have a question, please press the star followed by the one on your touchstone phone. Questions will be taken in the order received. Should you wish to cancel your request, please press the star followed by the two. If you are using a speaker phone, please lift the handset before pressing any keys. Once again, that is star one. Should you wish to ask a question? And your first question is from Azeem 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, Azeem. That's a great question. 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. Talga, perhaps you could answer a specific question around time to approvals.

Hi, Azeem. Look, obviously, we're really excited about the upcoming potential launch. And our, frankly, 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-house story. We're very much committed to the growth that we've already committed to. We have value-based agreements that we know it's going to be extended with some of these payer policies that's 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, Azeem.

Thank you. And your next question is from Costas Boliores from BMO Capital Markets. Your line is now open.

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

Well,

that's

a question

for you.

Yeah, great question. Look, I mean, first and foremost, we really appreciate and like the product profile that Ambutra has to offer, which is underpinned now by the Helios B results. And in our engagements with payers at the pre-pricing discussions, we also encourage 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 this product. And as we've already shared, very much committed to the guidance that we provided, which again underpins how we really see the growth, which is going to be accelerated in 2025.

Thank you, very helpful.

Thank you. Your next question is from Gina Lang from Workplace. Carolina, is that open?

Thank you. I know you cannot comment on the actual price for Ambutra until the approval date, but wondering if you can share the key factors that impact your decision on pricing adjustment for Ambutra. And related question I know a few already asked, can you share with us how you see the growth of what percentage of the current sites already have a G coding place that you can use for Ambutra in APTR cardiomyopsy?

Thanks. Thanks Gina for the question, recognizing that it's too early to be specific about price. And as you know, we have patient access principles. And when we think about price, we obviously consider the value that a 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 an equally good job for CM, don't we Tolga? Do you want to

add? Absolutely.

I think, maybe the specific. Yeah, I mean,

one maybe answer to your last point, we already have a J code for Ambutra, which is going to be used. Therefore, we don't expect any changes or any disruption on that. And in respect to our coverage, look, as we shared earlier on our TTR day and other forums, the current makeup of our business from Medicare perspective, as well as commercial, we expect that to remain the same. And therefore, which we believe 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 copay and we expect that dynamic to remain the same, which we believe is going to be an important driver for our patient uptake.

Thanks, Talda. Next question.

Thank you. Your next question is from Murray Raycroft from Jeffries. Your line is now open.

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. And in addition to reduction of mortality and hospitalizations, are you advocating to have anything unique on the front page of the label and indications and usage sections such as wording related to preservation and quality of life and functional capacity?

Yeah, thanks, Murray. Look, first of all, we're really very enthusiastic about how the FDA review is going and we're fully on track for an approval date by the PDUFA. So we're excited about the progress that's been made on that front. In terms of the label, look, we believe that the study was designed and clearly demonstrated the benefit on mortality and hospitalization events and we expect that there'll be, that will be reflected in the label as well as the ancillary benefits that we saw in terms of preservation, functional ability, quality of life and benefits across a series of endpoints there. So look, at the end of the day, we want a label that reflects and 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. That we're able to actually then go and educate providers and patients on. And so we look forward to sharing that when, you know, an eventual approval occurs.

Got

it.

Okay,

thanks for taking my question.

Thank you. Your next question is from Aritu Garo from TD Calend. Your line is now open.

Good morning, guys. Thanks for taking the question. My question was actually a really good follow-up to Mori's on label language. Tolga, if 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?

Well, I did. Okay. Hi, Aritu. Look, we have a pretty clear view of our understanding of how we're going to be able to promote, communicate this. Mainly, obviously, what Pushkal indicated, we had reached statistically significant results on all pre-specified endpoints, 10 out of 10. Our ability to communicate that is going to be relatively smooth. We're pretty confident in how we can actually 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 actually then demonstrate those clinical outcome benefits on both mortality as well as hospitalization, coupled with the fact that we actually have four times a year subcutaneous injectable that really provides great adherence, as we've seen on polyneuropathy, as well as our relatively smooth access, given that 70% of patients pay zero copay. All those perspectives will be carried through how we're going to actually communicate this exceptional medicine to the prescribers, which 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 pre-specified endpoints that show the impact of this drug on this disease. We would expect that to be generally reflected in the label. Again, consistent with the labeling, Toga's team, our medical teams, will be able to speak about those attributes and the results of the Heliospeed study to providers and patients and payers.

Thanks, Ritu. Next question, please. Thank

you. Thank you. Your next question is from Greg Harrison from Skillshare. The answer line is now open.

Good morning. This is Teresa Vitelli. I'm 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 Nutriseren's potential revenue mix among naive patients in the first line setting versus switches from Tifanides.

Toga, that question is for you.

Yeah. I think to our 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 RTTR franchise and 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 considered first line. But like any categories, we do also know that there is a need of another product with an orthogonal mechanism of action beyond the stabilizers. So we certainly expect a good mix of patients, some from 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 obviously as we built our guidance, all these elements were incorporated.

Great.

Thank you.

Next question.

Thank you. Your next question is from Gary Nesmin from Roman James. Your line is now open.

Hi. Good morning. Maybe you could talk about the competitive dynamics you're seeing with Wayne Newe in polyneuropathy, with both products growing at this point. And how is the difference between part B and part D playing out? And how do 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 strong CTR 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?

Yeah. So we just posted our full year results for 2024, which happened to be the first year actually we faced competition in this relatively narrow category where we always said this is going to be a category growth story. And I think what you can see particularly in our US numbers, where US 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, Wynuja 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 Wynuja, given that it's four times a year and it's HCP administered. And we had not seen any significant access headwinds. And we anticipate, frankly, this type of dynamic continue as we expand our, expand the education to cardiomyopathy.

Thanks, Tolga. Next question, please.

Thank you. Your next question is from Jessica Fai from JPMorgan. Your line is now open.

Hey guys. Good morning. What do you think the early acaramidus scripts imply for the TTR cardiomyopathy market dynamics, market expansion and interest in agents beyond defamidus as it relates to and I think folks have been kind of 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 amputra's net price as you move into this much larger patient population? Thank you.

Okay. I mean, two questions that, you know, Tolga, I mean, clearly as Tolga said, I mean, we believe that this is a market growth opportunity, which makes a very exciting category to be playing and obviously become to cardiomyopathy with a strong track record in the TTR space. Tolga, perhaps that's the first question and then the specific question around the evolution of net price.

Yeah. I mean, I think, look, 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, you know, obviously they've actually shown that this is actually a growth category. Now, when I think about amputra product profile that has really strong clinical profile, as well as, you know, the fact that it's four times a year, annual dosing with really well positioned to be in the access, we're very excited about what amputra can do given that the category is going to be continuing to be growing given the undiagnosed patient numbers.

Thank

you. Your next question is from Paul Matan, is from Stegol. Your line is now open.

Hey, 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 D and Part D? And I think, you know, again, the underlying question that everyone's 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 to feminists or acarabinists actually be a step at it? Or is that just not something that's normal in practice at this point? Thank you.

Yeah, thank you for the question. Look, I mean, there's a lot of noise around how the payers will be managing this. What we've seen is this is a rare condition, 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-eyed view, given how we've been actually managing Polnareopathy as a Part D product and how, you know, Vinyula has launched a Part D product. We expect similar dynamics in terms of our payer mix. And we do anticipate that given the patient affordability is a key driver of how patients stay on therapy is to be very favorable for Amutra.

Thank you. Next question.

Thank you. Your next question is from Salveen Richter from Goldman Sachs. Your line is open.

Good morning. Thanks for taking my question. You plan to initiate a phase three study for Nucreceran in ATTRCM 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? Thank you.

Yeah, so thanks for the question. I mean, clearly we'll be providing more detail around Nucreceran program at R&D day at the end of this month. Bisco, maybe you can share a little bit about how we're thinking about moving forward Nucreceran, which we're very excited about.

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

Great question. Thank you. Your next question is from Elvie Marl from UBS. Your line is now open.

Hey, guys. Thanks so much for taking the question. Just a couple from 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. Mix of growth, polyneuropathy, cardiomyopathy, and then a little bit more detail on how we're thinking about buying Bell post-approval.

Look, unusual to our tradition, we actually at JPM broke down our guidance between TTR and rare, but I think we'll stop there. We'll obviously continue to provide more color about how the second half of the year where we do anticipate the growth to take place. Now, can you remind me of the second question? Post-approval, how we're thinking about buying Bell? One of the value-based agreements, right. So look, we're very, very proud about the value-based agreements that we set out. Approximately, we have about 60% of the lives that are currently covered on the PN is dependent on the value-based agreements. The value-based agreements are actually essentially really provide our commitment to the clinical outcomes. So we have this experience already with PN, and we anticipate that to actually also carry over in most instances for cardiomyopathy, which should actually 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. So 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 invigoration in most cases.

Thank you. Next

question. Thank you. Your next question is from Manny from Lee Rankin Partners. Your line is open.

Hey, I'll send a question. Congrats on great results commercially and otherwise. I know that there's probably 20 more questions about amputra and pricing in the line, so I'm going to ask an actual financial question. Could you clarify the driver of the tax benefits that was noted here, and would that be recurring? Is this a NOL dynamic OUS? If you could just dig into what drove that benefit and how it might recur or not flash over the course of the year.

Yeah, it's a question for you. Good question,

Manny. We noted in the press release that we had a release of evaluation allowance, XUS, and that's really related to our Swiss entity. This is something that we have to do every quarter with our deferred tax assets is we have to assess whether or not it's more likely than not that that value is going to ultimately be recognized, and the Swiss entities had profitability for a number of periods now, so that gave us the confidence to release that. We've not released all the valuation allowances either in Switzerland, and we've not released anything in the US yet. It's very difficult at this point to predict further money, so I'd probably just leave it at that for now.

Thanks, Manny. I think we've got time for one more question. I think we've got our last question coming up.

Yes, your last question is from Luca Isi from RBC Capital Markets. Your line is now open.

Oh, great. Thanks so much for excusing me, and maybe I'll follow Manny here, I guess. But, Jeff, how do you think about gross margin here going forward? I mean, the Santa Fe royalty fee is very meaningful at 15%, 30%, but we obviously don't know the exact tiering of the royalty fee. Do you think that modeling gross margin compressing from 80% now, I think it's at low 80s now, to like low 70s or even upper 60s, is that a reasonable assumption in your mind? And you called there, much appreciated. Thanks so much.

Yeah, 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%. And I do think that'll be the direction of travel for a period of time, really driven by two things that relate to Ambutro. One is, it's our lowest margin product right now, given the royalty burden to Santa Fe, and it's our fastest growing product. So that will put pressure on margins as we move forward. And secondly, as that business grows, we also start to move up higher in the royalty tier. So the average royalty rate will likely also increase over time. The royalty that we paid on average across 2024 for Ambutro is 21%. Again, my expectation as this moves forward is 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. Now, there's a couple 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 margin on total revenue was 86%. So that uplifted it. And then secondly, I think the most important thing is that the issue with this high royalty burden, if we're successful in developing the Creaseran, we'll hear more about that at R&D Day, as Pushkull 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 really a very good year for our line. And really, 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.

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