Alnylam Pharmaceuticals - Earnings Call - Q1 2025

Executive Summary

• Q1 2025 revenue and profitability outperformed expectations: total revenues $594.2M (+20% Y/Y) and non-GAAP operating income $74.8M, with non-GAAP EPS of $(0.01) vs S&P Global consensus of $(1.01), and revenue $594.2M vs $581.2M consensus; beat driven by 36% Y/Y growth in TTR franchise and steady Rare franchise growth. Revenue/EPS estimates from S&P Global marked with asterisk below.*
• AMVUTTRA ATTR-CM approved in the U.S. on March 20 and launch is “off to an exceptional start”: >50% of priority health systems (of ~170) had added AMVUTTRA to formulary within four weeks; early initiations across Medicare FFS/MA/commercial; broad first-line use and switches observed.
• Guidance reiterated: FY25 total net product revenue $2.05–$2.25B, TTR $1.60–$1.725B, Rare $450–$525M; collaboration+royalty revenue $650–$750M; non-GAAP operating income to achieve profitability; CFO noted potential ~$50M FX upside if current rates persist.
• Catalysts: Japan/EU AMVUTTRA ATTR-CM decisions (expected Q2/Q3), TRITON-CM (nucresiran) Phase 3 initiation in 1H25, and KARDIA-3 hypertension combo data 2H25; management emphasized strong early CM uptake and sustained TTR growth as near-term stock drivers.

What Went Well and What Went Wrong

• What Went Well
  • TTR franchise strength: Global TTR net product revenue $359.5M (+36% Y/Y) with AMVUTTRA $310M and ONPATTRO $49M; U.S. TTR +45% Y/Y, international +24% Y/Y, despite new competitors.
  • AMVUTTRA ATTR-CM launch momentum: inclusion on formulary in >50% of ~170 key systems in ~4 weeks; broad payer coverage, most patients with $0 copay; first-line use and switches observed; “launch is off to an exceptional start”.
  • Profitability and margin: 85% gross margin on product sales; non-GAAP operating income $74.8M vs $1.9M a year ago, reflecting leverage on strong top-line growth.
• What Went Wrong
  • Collaboration revenue down 16% Y/Y to $99.2M due to absence of prior-year $65M Roche milestone (KARDIA-3 first patient dosed) offset partly by Regeneron activity and $30M from Vir amendment.
  • GAAP bottom line impacted by non-cash items: other expense included a $58.9M charge from change in fair value of development derivative liability tied to AMVUTTRA ATTR-CM approval, pressuring GAAP EPS (−$0.44).
  • Royalty step-ups expected to compress gross margin through 2025 as AMVUTTRA sales scale and royalty tiers increase, per CFO; margin pressure likely near term despite product growth.

Transcript

Operator (participant)

Good morning, ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals Q1 2025 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. If at any time during this call you need assistance, please press star zero for the operator. This call is being recorded on Thursday, May 1st, 2025. I would now like to turn the conference over to Alnylam. Please go ahead.

Christine Lindenboom (Chief Corporate Communications Officer)

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, 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 and clinical progress, and Jeff will review our financials and guidance, followed by a summary of our 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 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 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 obligation to update such statements. With that, I'd like to turn the call over to Yvonne. Yvonne?

Yvonne Greenstreet (CEO)

Thanks, Christine, and thank you, everyone, for joining the call today. 2025 is off to a strong start at Alnylam. In the first quarter, we made notable progress towards our goal of becoming the global TTR leader, which will play a critical role in driving sustainable growth and value creation this year and beyond. Commercially, we delivered $469 million in combined net product revenues, and this represents 28% growth year-over-year. This was driven primarily by the robust 45% year-over-year growth of our U.S. TTR franchise, which in the first quarter consisted solely of continued uptake in the hereditary polyneuropathy population. We also had several exciting portfolio advancements in the quarter, most notably the expanded indication from Amvuttra in ATTR cardiomyopathy, with approvals in the U.S. and Brazil. Earlier this week, we received a positive CHMP opinion in the E.U.

We also saw approval of the sixth Alnylam discovered RNAi therapeutic, Fitusiran, for hemophilia A or B, secured by our partners at Sanofi. Lastly, we are reiterating our guidance for the year, underscoring our confidence in continued growth and a strong launch in ATTR cardiomyopathy. This also includes our goal of achieving sustainable non-GAAP profitability in 2025. Now, before I move on, I'd like to take just a brief moment to acknowledge the uncertainty that exists related to potential evolutions in certain policies, including tariffs, FDA personnel, reorganization, and other biotech industry initiatives being discussed. While much is yet to be clarified and finalized, we've taken a comprehensive look across our business, and we believe that Alnylam is well positioned and pretty well insulated from any potential impacts associated with the key initiatives that have been announced to date.

We feel that we're completely able to focus on the key tasks at hand, executing on a strong launch in ATTR cardiomyopathy and continuing to advance our robust high-value pipeline. Our achievements in early 2025 underpin the three core elements of our business that we believe will drive sustainable growth and value creation for years to come. The first is TTR leadership. Tolga will provide color on our launch of Amvuttra in ATTR-CM, but at a high level, we're very pleased with our early progress, which is focused on securing broad access, driving awareness, and supporting treatment initiation for patients in the initial few weeks since approval. The 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 element is strong financial performance, with robust commercial delivery and a disciplined approach to capital allocation to enable us to sustain profitability going forward. Of course, all of this is underpinned by a best-in-class team and our award-winning culture. This all represents tremendous progress against our Alnylam P5x25 goals, and we continue to work to turn these goals into reality by the end of the year. Doing so will further establish Alnylam as a unique top-tier biotech company delivering sustainable innovation to patients for years to come. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga.

Tolga Tanguler (Chief Commercial Officer)

Thanks, Yvonne, and good morning, everyone. I am particularly excited to share our commercial update on this call today. I am as encouraged as I have ever been, not only by the impact we're already having for patients affected by the conditions our medicines are indicated to treat, but also by the potential that is just beginning to unfold now that our ATTR-CM launch is underway in the U.S. I'll review our performance in Q1 and also provide some early perspective on our ATTR-CM launch, which only began in the final days of this quarter and will take shape over the quarters ahead. Our Q1 performance continues to be strong. Altogether, our portfolio delivered nearly $500 million in combined net product revenues, representing 28% growth year-over-year and 4% versus Q4 2024. This is tremendous growth across our portfolio, several years after our initial launches.

Quite simply, this means helping more patients affected by each of these devastating diseases. Before we dive into our TTR franchise and the exciting progress with our new CM launch, let me briefly update you on our rare disease franchise. Our rare franchise, GIVLAARI and OXLUMO, together delivered $109 million in combined product sales in the first quarter, representing 8% growth compared with the first quarter of 2024. On a year-over-year basis, the growth in GIVLAARI, patients on therapy, was approximately 15%, and growth in OXLUMO, patients on therapy, was approximately 20%. Revenue growth for OXLUMO was less than growth in patients on therapy, primarily due to gross net adjustments in European markets and the timing of orders in partner markets. We continue to expect full-year product sales growth of approximately 15% for our rare franchise, consistent with the midpoint of our 2025 rare product sales guidance.

Moving now to our TTR franchise, we continue to see strong performance in Q1. The franchise delivered $359 million in global net revenues, representing a 36% increase compared with the first quarter of 2024. Importantly, this represents continued and robust growth from our base business in hereditary ATTR-PN since the CM indication approval came in the final days of the quarter. In the U.S., combined sales of Onpattro and Amvuttra in the first quarter increased by a robust 45% compared with the first quarter of 2024, continuing to drive strong growth momentum. The 45% year-over-year growth was primarily driven by the following: a 32% increase in demand driven by the strength of ongoing Amvuttra patient uptake.

We are pleased with the growth in demand, which has been consistent over the past five quarters despite new competition entering the market at the end of 2023, which we believe is reflective of the leadership position we have established in a growing PN market over the last six years. The remaining growth in the quarter, 13%, is related to favorable adjustments in gross-to-net deductions, combined with stocking dynamics as inventory in the distribution channel modestly increased in Q1. I will share additional detail on our PN performance in the U.S. on the next slide. Now, let me turn to our international markets for just a quick moment, where the TTR franchise grew 24% compared with the first quarter of 2024. Similar to the U.S., the year-over-year growth was primarily driven by increased demand for Amvuttra as patient uptake remained robust.

Bottom line, our TTR-based business is very strong and continues to grow. Before I provide additional color on early days of our TTR-CM launch, let me touch briefly on the dynamics we're seeing in the U.S. hATTR-PN markets. A full year after the launch of a new competitor, Amvuttra remains the clear market leader in the U.S., maintaining a majority of new patient starts, with Amvuttra capturing approximately 70% of new patient starts in the first quarter of 2025. This results from a strong brand value proposition coupled with continued disciplined execution by our commercial teams. What's more, as anticipated, we are finding that in categories where the majority of patients remain untreated, more treatment options mean more voices helping to raise disease awareness, ultimately accelerating category growth and increasing the number of patients on therapy.

In other words, this continues to be a growth story, and patients are benefiting. With similar dynamics anticipated across hATTR-PN and ATTR-CM, we believe about 80% of the global addressable population remains untreated. This bodes well for the opportunity ahead in ATTR-CM. Now, on to our new indication. Momentum is building fast, and the team is laser-focused on delivering a successful launch. On March 20th, we received FDA approval for Amvuttra as the first and only silencer approved in the U.S. for ATTR-CM and the only treatment indicated in the U.S. for both the polyneuropathy manifestations of hereditary ATTR and cardiomyopathy manifestations of ATTR. Though it's still early days, we are very encouraged by what we're seeing.

Our first priority out of the gate was the access setup, and we're pleased to say it's progressing exactly to plan, thus enabling the second health growth story that we have described on our prior calls. Though it's, of course, early to quantify trends, I would like to share some examples of the very encouraging progress we're already seeing, particularly with regard to the access and health system formulary reviews that we have shared would be the early priorities and key enablers of our second health launch momentum. Let me explain why we believe this launch is off to an exceptional start with some specific examples. First, we're seeing robust patient initiations across all payer segments: Medicare fee-for-service, Medicare Advantage, and commercial. We are continuing payer engagements, and a majority of contracted lives are covered by value agreements that include the cardiomyopathy line extension.

As expected, the majority of Amvuttra patients to date pay $0 copay in ATTR-CM, like with hATTR-PN, and we continue to have widespread payer coverage exactly in line with our expectations. Second, and this is important, about 80% of TTR volume flows through approximately 170 health systems. Our team's focused effort enabled inclusion of Amvuttra on formulary in more than half of these health systems within a short four weeks of label expansion. In fact, the majority of these accounts have already initiated Amvuttra treatment for ATTR-CM patients, underscoring that with the proper setup, these accounts do indeed come online. Finally, in terms of treatment choice, we're seeing healthy demand across both prior Amvuttra prescribers as well as first-time Amvuttra prescribers. What we're hearing from prescribers is that the Amvuttra disruptive value proposition resonates and is enabling this early and encouraging launch momentum.

Early feedback from patients and physicians indicates clear excitement for a new mechanism of action in ATTR-CM that can rapidly knock down TTR. HCPs further highlighted that Amvuttra's clinically and statistically significant benefits in standalone all-cause mortality, coupled with demonstrated preservation of functional capacity and quality of life, where Amvuttra makes significant impact on KCCQ and six-minute walk distance, are highly differentiating. Furthermore, physicians appreciate how quarterly HCP-administered dosing gives peace of mind for verified adherence. In terms of early utilization, here too, we are very pleased by early signals. We see broad use in line with our expectations. More specifically, we're seeing Amvuttra used in first line. We're also seeing stabilizer progressive patients switch to Amvuttra. We're seeing broad utilization, including in academic and community settings, supported by the broad alternate site of care networks that's been established.

Simply put, the mechanism of action and the well-established safety and tolerability of Amvuttra hit home. Our consistent data speaks volumes. HCP-administered verified adherence is real, and patients are getting on therapy on Amvuttra, most with zero copay. In conclusion, the launch is off to an exceptional start. These are, of course, the early days of launch. We will continue to share more as the launch progresses, including both qualitative and quantitative launch indicators. We've provided full-year guidance, projecting robust 36% year-over-year growth in our TTR franchise revenues at the midpoint of the guidance. This reflects our confidence in the launch and the future potential of this franchise. Now, with a few early weeks of experience since launch, we remain as confident as ever.

In conclusion, we are pleased with the results in the first quarter with both our TTR and rare franchises delivering strong growth in patients on therapy, as well as delivering robust year-over-year growth in revenues, giving us confidence in our ability to deliver substantial growth, achieve profitability, and most importantly, deliver our highly differentiated and transformative medicines to more patients in need around the world. With that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal.

Pushkal Garg (Chief Medical Officer)

Thanks, Tolga, and good morning, everyone. To echo my colleagues, I'm very excited about the launch of Amvuttra and ATTR-CM at the end of Q1 and that we've hit the ground running to educate physicians and patients and drive awareness.

I'm delighted by the early progress that Tolga just described, which is based on great execution by our commercial and medical teams and the impressive Helios-B results summarized here. In a population representative of today's ATTR-CM patients, nearly half of whom were already being treated with a stabilizer, we saw a substantial benefit in Amvuttra on cardiac outcomes, including a 35%-36% reduction in the risk of all-cause mortality alone. We saw broad benefits on a series of other important clinical parameters, such as cardiac biomarkers, echocardiographic measures, and disease progression. These, together with an encouraging safety profile and an infrequent HCP-administered dosing regimen that enables a high degree of adherence, support the potential for Amvuttra to become a first-line therapy in this disease.

Based on these exceptional data, we quickly submitted filings to regulatory agencies and key geographies, and we're pleased with the pace of progress thus far. We, of course, achieved U.S. approval of the SNDA in March, followed shortly thereafter by approval in Brazil. Earlier this week, we announced that the Committee for Medicinal Products for Human Use of the European Medicines Agency has adopted a positive opinion recommending approval of Amvuttra in ATTR-CM. This should enable the European Commission to approve Amvuttra in Europe in Q3 and possibly in Q2. Things are progressing swiftly, and we look forward to launching in other important territories in the coming quarters. Now, beyond those primary results that I discussed a moment ago, we continue to share additional insights from the Helios-B data set.

At ACC last month, we shared a few new analyses that further support vutrisiran's compelling profile. In one, we highlighted echocardiographic data, which demonstrated that treatment with vutrisiran led to significant improvements in diastolic function and attenuation of declines in left ventricular and right ventricular systolic function at month 18 compared to placebo. These indicate that vutrisiran is favorably impacting cardiac function, which is truly remarkable. We also shared an exploratory subgroup analysis, which demonstrated that vutrisiran reduced all-cause mortality and recurrent CV events across a range of baseline heart failure severities in patients with this disease. Lastly, a separate analysis confirmed that vutrisiran significantly maintained or improved functional capacity and patient-reported health status and quality of life compared to placebo over 30 months. These last two analyses were also published in the Journal of the American College of Cardiology.

We look forward to continuing our analysis of this landmark study and educating the TTR amyloidosis community about the differentiated profile of Amvuttra. Further to our leadership and commitment to innovation in this disease and to these patients, at R&D Day in February, we shared updated plans for pivotal studies of zilebesiran, our next-generation RNAi therapeutic targeting TTR with the potential for deeper knockdown and biannual dosing. Triton-CM will be a randomized double-blind events-driven outcome study in ATTR-CM patients with either hereditary or wild-type disease and a medical history of symptomatic heart failure, NYHA Class I to III. All patients will be allowed to be on background stabilizer therapy. Approximately 1,200 patients will be randomized, and the primary endpoint will be a composite of all-cause mortality and CV events. The primary analysis will be event-driven and will occur a minimum of 24 months after the last patient enrolled.

If successful, we target launching zilebesiran in ATTR-CM around 2030. In parallel, we have the goal of bringing zilebesiran to patients as quickly as possible and see an opportunity to do so in hereditary ATTR-PN. Though we're not yet prepared to discuss the full details of Triton-PN, we plan to initiate the pivotal study by the end of this year and anticipate the potential to launch in this indication several years ahead of ATTR-CM. We look forward to sharing more details in due course. R&D Day also showcased a number of exciting advancements early in our pipeline that underscore the bright future for RNAi therapeutics across a broad range of diseases. Key among these updates, we disclosed two new clinical programs. ALN-4324 targets GRB14 for the treatment of type 2 diabetes with a novel mechanism of action.

It acts as an insulin sensitizer, addressing a tremendous unmet need in diabetes where insulin resistance is a major issue. We're pleased to announce today that we've initiated the phase I study for ALN-4324. The second program targets liver-derived plasminogen. And this molecule represents a potential universal hemostatic agent for the treatment of bleeding disorders without the risk of thrombosis. Another key highlight was our update on delivery solutions with best-in-class potential for adipose, muscle, heart, and kidney tissue, as well as a new approach to crossing the blood-brain barrier. As we announced at our R&D Day, our goal is to achieve delivery of RNAi therapeutics to every major tissue by 2030. Lastly, I'd like to congratulate our partners at Sanofi for securing FDA approval for fitusiran for hemophilia A or B with or without factor VIII or IX inhibitors.

With this approval, Qfitliah becomes the sixth Alnylam discovered RNAi therapeutic approved by the Food and Drug Administration. In summary, this remarkable and unique pace of innovation puts us in a great position to have a deep, self-sustainable pipeline that can continue to deliver meaningful impact to patients for many years to come. Let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff.

Jeff Poulton (CFO)

Thanks, Pushkal.

Good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q1 2025 financial results and discussing our full-year guidance. Before turning to the details on our Q1 financial performance, I'd like to further some of Tolga's comments on the early observations of our cardiomyopathy launch. I'm extremely pleased with the commercial execution demonstrated by the U.S. TTR team thus far.

We have guided CM revenue being a second-half story, with the second quarter focusing on continuing to build awareness, unlocking patient access, and supporting treatment initiation for patients. Given the early progress that Tolga described, I am confident in reiterating our financial guidance, including TTR product sales, which I will discuss later. With that, let's begin with a summary of our P&L results for Q1 2025 compared with prior year. Total product revenues for the quarter were $469 million, or 28% growth versus last year, driven by the 36% growth in our TTR franchise, with particularly strong performance in the U.S. market, as Tolga described. As Tolga also noted, Amvuttra was approved for ATTR cardiomyopathy with only one week remaining in the first quarter, so it did not contribute to our Q1 results.

Collaboration revenue for the quarter was $99 million, or a 16% decrease compared to the first quarter of last year. The decrease was primarily driven by the $65 million Roche milestone achieved in Q1 2024, related to the first patient being dosed in the CARDIA III study, partially offset by the $30 million milestone achieved from VIIR and reimbursements from our collaboration with Regeneron in Q1 2025. Royalty revenue for the quarter was $26 million, representing a $16 million increase compared to last year, driven by Novartis's increased Leqvio sales. Gross margin on product sales was 85% for the quarter, which was consistent with the first quarter of 2024, as the Amvuttra royalty rate payable to Sanofi resets at the beginning of each calendar year.

For the balance of the year, our gross margin on product sales is expected to decrease as the Amvuttra average royalty rate escalates, driven by annual sales of Amvuttra reaching higher royalty tiers. Our non-GAAP R&D expenses were $241 million, or in line with prior year, as increases in clinical trial expenses associated with our CARDIA III study for Zolbesiran, and the mivelsiran phase II CAA study were offset by reductions related to the wind-down of the Helios-B phase III study. We do expect that R&D expenses will increase compared to 2024 for the balance of the year, as phase III studies for bothzilebesiran and mivelsiran ramp up. Our non-GAAP SG&A expenses increased 12% in the first quarter compared to the same period last year, primarily driven by increased investments in support of Amvuttra for the cardiomyopathy launch.

Our non-GAAP operating profit for the quarter was $75 million, representing a $73 million improvement compared to last year, driven by the strength of our top-line growth combined with more moderate growth in operating expenses. Finally, we ended the quarter with cash, cash equivalents, and marketable securities of $2.6 billion compared to $2.7 billion at the end of 2024. Now, turning to our guidance, where, as I previously mentioned, we are reiterating our 2025 guidance as presented during our last earnings call and as summarized on our guidance slide. Additionally, I'd like to provide two additional points of perspective. Our guidance continues to assume foreign exchange rates as of December 31st, 2024, which are noted in the footnote of our guidance slide. As you are aware, the US dollar has weakened considerably in recent weeks.

If the current FX rates continue through the remainder of the year, we expect currency upside relative to our current product sales guidance of approximately $50 million. We will reevaluate our full-year guidance for FX in Q2. Secondly, I'd like to make some brief remarks on the potential impact of recently announced tariffs, as well as pharma tariffs that are currently being contemplated. As it relates to the tariffs that are now in place, we do not see a material impact on our business and believe we can absorb any resulting cost increases within our existing 2025 financial guidance. As it relates to the pharma tariffs that are being considered, there is obviously still uncertainty as we await the drafting of the final rules. However, we are comfortable sharing some high-level perspective that reflects our positioning as a company.

Our commercial supply chain is global in nature, but the majority of our products are manufactured through third-party contract manufacturing organizations in the U.S. Additionally, our intellectual property is also primarily based in the U.S. We think both of these factors position us well in terms of limiting exposure to potential future pharma tariffs. We will provide further updates as we get more clarity on tariff policy. Let me now turn from financials and discuss some key goals and upcoming 2025 milestones. We intend to initiate the Triton-CM phase III study of zilebesiran in ATTR-CM in the first half of 2025. Triton-PN is expected to initiate by the end of 2025. We expect additional approvals of Amvuttra in ATTR cardiomyopathy in Japan in Q2 and the European Union in Q3.

We plan to report data from the CARDIA III phase II trial of zilebesiran in the second half of the year. These results will help inform the final design for the phase III CVOD of zilebesiran, which we also expect to initiate in the second half of 2025. Let me now turn it back to Christine to coordinate our Q&A session. Christine.

Christine Lindenboom (Chief Corporate Communications Officer)

Thank you, Jeff. We will now open the call for your 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 additional questions.

Operator (participant)

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

Should you wish to decline from the polling process, please press star followed by the two. If you're using a speakerphone, please lift the handset before pressing any keys. The first question comes from Tazeen Ahmad at Bank of America. Please go ahead.

Tazeen Ahmad (Managing Director of U.S. Equity Research)

Hi, guys. Thanks for taking my question. I'm sorry if I missed this on the prepared remarks, but I just wanted to get a little bit of additional color of the initial patients that are starting treatment. Who are the prescriber base? Are they people that have already had previous experience with Amvuttra, or are you seeing a mix of doctors that are also completely new to the drug? Thanks.

Yvonne Greenstreet (CEO)

Yeah, that's a great question and one for Tolga.

I think what's really encouraging about the launch in cardiomyopathy is that really kind of all the indicators are flashing green, and we're really seeing broad and balanced use across all aspects. Tolga, perhaps you can speak specifically to the prescriber base.

Tolga Tanguler (Chief Commercial Officer)

Yeah, I mean, the way we see this is a really good broad uptake. We see cardiologists that have been familiar with the product, but we're also seeing a pretty good uptake in terms of those cardiologists that have not tried Amvuttra. That's really, really encouraging. The most encouraging part is that what I highlighted, our number one priority, which was out the gate to set up and enable second health momentum by actually setting up these institutions to be formulary ready. Within a short four weeks, we've been able to get into formulary of half of those accounts.

That, to me, is really opening up an incredible opportunity for us.

Yvonne Greenstreet (CEO)

Thanks, Tazeen. Next question.

Operator (participant)

Thank you. The next question comes from Gena Wang at Barclays. Please go ahead.

Gena Wang (Managing Director of Biotech Equity Research)

Thank you. I think we saw first full quarter revenue from, I think, $79 million for tafamidis and $37 million for Amvuttra in ATTR cardiomyopathy. Which one do you think is a good benchmark for Amvuttra first quarter revenue? Also, my quick calculation for your ATTR franchise this quarter versus the last quarter of roughly $17 million quarter-over-quarter growth. Any revenue was contributed from ATTR cardiomyopathy revenue.

Yvonne Greenstreet (CEO)

I think that's really for you. It was actually quite hard to hear you, Gena, but I'll try. I think there was one question around how we think about benchmarks for the CM launch. Yeah.

Tolga Tanguler (Chief Commercial Officer)

Happy to take that, Gena.

Look, first and foremost, we've already laid out our year-end guidance. That's really important to demonstrate. At the mid-year point, the midpoint of the total growth is going to be about 36%. Obviously, our goal is to meet and hopefully exceed that year-end guidance. Now, in respect to the first quarter results of those two stabilizers, I think it's really important to highlight the category is growing. If you take out the IRA impact of tafamidis, both products have grown. In fact, I think tafamidis had led that growth. That's a clear, good early sign of how this category remains untapped in terms of growth.

Yvonne Greenstreet (CEO)

I mean, that's great, Tolga. I mean, look, we really are excited to be in a class of our own in this market with a sort of orthogonal mechanism and a differentiated profile.

Gena, I'll just come back to you because I'm not sure I heard all of your question.

Gena Wang (Managing Director of Biotech Equity Research)

Sorry. Yeah. I think, yeah, sure. Can you hear me better now? Okay. Yeah, the second question is regarding this quarter number, quarter-over-quarter growth. When we look at the ATTR franchise, it's about $17 million. Just wondering, any revenue contribution from the ATTR cardiomyopathy?

Yvonne Greenstreet (CEO)

No. No. I actually made those points in our prepared remarks. It's all TTR polyneuropathy. I think, look, this speaks to, again, the profile of Amvuttra that we have in polyneuropathy and the quality of commercial execution. I'm really delighted, actually, by the strength of our polyneuropathy business with terrific growth. Tolga, do you want to add anything? Thank you, Gina. Next question.

Operator (participant)

Thank you. Next question comes from Greg Harrison at Scotiabank. Please go ahead. Hi, everyone. Good morning.

Theresa Vitale (Analyst)

This is Theresa Vitale on for Greg Harrison. Congrats on all of the progress this quarter, and thanks for taking our question. Curious to hear how you're leveraging your commercial expertise and maybe what additional strategic efforts are you making on the commercial front to be competitive in capturing tafamidis progressors. Thanks.

Yvonne Greenstreet (CEO)

That's a great question, Tolga. I think it goes straight to you.

Tolga Tanguler (Chief Commercial Officer)

Yeah. I mean, first and foremost, as Yvonne indicated, we come with an entirely new mechanism of action that clearly sets us apart in terms of any stabilizers that are out there, given that we work on upstream. That rapid knockdown clearly actually manifested itself with Helios-B results, where half the patients were both on placebo as well as on the study arm were actually already on a stabilizer. The results are obviously quite compelling.

Frankly, when you think about the disease itself, given that it's a rapidly progressing fatal disease, physicians are first and foremost interested in treating the disease early and actually treating with the best possible option they have. In that case, we believe actually Amvuttra provides a real clear first-line option. Now, in terms of those physicians who are considering a switch, we're already seeing that in our broad patient uptake. We believe that's going to continue to be the case, given that half the patients in the most recently published ACC study shows that patients do progress on stabilizers. We believe actually we're going to remain a very important option for those patients that are progressing on any stabilizer.

Yvonne Greenstreet (CEO)

Thank you, Tolga. Next question.

Operator (participant)

Thank you. Next question comes from Ellie Merle at UBS. Please go ahead. Hey, guys. Thanks for taking the question.

Ellie Merle (Executive Director of Biotech Equity Research)

Congrats on the early launch progress. Just in terms of Amvuttra, I guess, what do you expect or what are you seeing in terms of the use of the first injection-free versus those going straight to pain drug? Maybe assuming that more would go straight to pain drug, considering your comments on the formulary access. Just a follow-up on your commentary on formulary access. I guess since you're already on formulary in more than half of these 170 priority centers, are you seeing any change to the price used for polyneuropathy from these centers? Just your latest expectation on how this pricing will play out between polyneuropathy versus cardiomyopathy? Thanks.

Yvonne Greenstreet (CEO)

Two questions. I think one about our quick start program and the second around formulary.

Tolga Tanguler (Chief Commercial Officer)

Yeah. I mean, maybe I'll take the second question first.

We have a single price, and we do not see any price difference between both of our indications, which are both rare conditions. Now, in terms of our, I think you are referring to our quick start program. Look, I mean, if you take a step back, we have a plethora of services that is actually developed by our in-house patient support program, helping patients to actually navigate a very complex U.S. healthcare system. Frankly, if you look at our track record, our conversion rates when a patient comes into those patient-out programs is actually very fast and is very effective, and patients stay on Amvuttra therapy. That program itself includes a quick start program. We had it, frankly, for that program for years. So far, we are seeing a very limited use of this quick start program, as we had seen in polyneuropathy.

What we're really pleased is, frankly, those patients that are coming into the program across a different payer mix are getting on therapy, whether it's through Medicare Fee-for-Service, Medicare Advantage, as well as in commercial. I must also add, as we anticipated, most of those patients are paying zero copay, as we had seen in polyneuropathy as well. Yeah.

Yvonne Greenstreet (CEO)

Very important. We're getting good patient access. Next question.

Operator (participant)

Next question comes from Gary Nachman at Raymond James. Please go ahead. Great.

Gary Nachman (Managing Director)

Thanks for taking the question, and congrats on the progress. With tafamidis in the early launch phase and getting some traction, is that creating a headwind for Amvuttra's launch in CM, or is it helping create more noise for the entire category? What's the early read on physician receptivity to a new silencer versus a new stabilizer out there?

Just maybe specifically on the reimbursement side, how are the dynamics playing out as a Part B drug versus the stabilizers that are Part D drugs? Thank you very much.

Yvonne Greenstreet (CEO)

Yeah. No, those are two great questions. I think Tolga has made the point that we really are in a category growth story. What we're just seeing is actually continued evidence of a large, growing, and frankly unsatisfied market. I think we're very excited to be able to participate in this market with the recent launch of Amvuttra in cardiomyopathy. I think the second question was around the Part B, Part D dynamics and how that plays through.

Tolga Tanguler (Chief Commercial Officer)

I mean, I think a good example of how we've been managing Part D, Part B dynamics, frankly, is what we've already demonstrated in polyneuropathy.

We just shared with you in this past quarter, after one year of launch as a Part B product, we've actually been able to achieve 70% of all new patients and continue to grow actually in an accelerated phase based from a larger base of business. Now, in terms of what we're seeing in this new line extension we have, we're seeing no headwinds. Thankfully, with the value-based agreements we have, and we're seeing this uptake across all payer mixes. There are no signals that we can iterate right now that would suggest otherwise. In terms of differentiation and whether we're actually seeing any headwinds, look, what really sets us apart is the strength of our data. It's complete, consistent, and cohesive. We're presenting the full picture with scientific rigor. In contrast, we're seeing some in the space selectively highlighting data points with creative interpretations.

We already see and believe investors and physicians alike value the clarity and integrity of a comprehensive data set. That is exactly what we are delivering.

Yvonne Greenstreet (CEO)

Yes, it is what we have been doing for the past several years as we focused on meeting the needs of patients. Next question.

Operator (participant)

Next question from Jessica Sy at JP Morgan. Please go ahead.

Jessica Fye (Managing Director of Equity Research Analyst)

Hey, guys. Good morning. Thanks for taking my questions. You mentioned providing additional launch indicators with Q2 results. Can you just touch on what those will be? Of those 170 priority health systems, I think you mentioned more than half already have Amvuttra on formulary. Can you speak to your goal of where you want that number to stand maybe next quarter and by year-end? Thank you.

Tolga Tanguler (Chief Commercial Officer)

Yeah. Yeah. Yeah.

Look, I mean, I think we've been very consistent about how we're describing in the way we're updating the investors. In this case, our goal, frankly, was to complete the inclusion in formulary by year-end. As you can see, our progress has been faster. We're very pleased with that. It's absolutely by year-end we want to be able to get there so that we have access. What's most encouraging, frankly, about the most recent development is a big majority of these accounts not only included in the formulary, but those accounts that have included the formulary are already actually initiating patients on therapy. That's incredibly encouraging. In terms of our Q2 data, I think the biggest update is going to be our revenue uptake and the pool through and how we're actually seeing that.

Obviously, we're committed to providing additional color in terms of the broad patient uptake and what that really looks like and prescriber update and so forth.

Yvonne Greenstreet (CEO)

That's great. Yeah. We're looking forward to sharing much more with our next earnings call. Next question.

Operator (participant)

Next question from Ritu Baral at TD Cowen. Please go ahead.

Ritu Baral (Managing Director of Senior Biotechnology Analyst)

Good morning, guys. You mentioned that you're seeing first-line use already. Tolga, can you speak a little to the type of patient or profile of patient that is making up that first-line use? And then I have a clarification on formulary inclusion. When you have formulary inclusion, is that where any prior authorization requirements sort of get set for use in the health system as well? If so, how should we be thinking about what you're seeing for prior auths in formulary inclusion?

Tolga Tanguler (Chief Commercial Officer)

Yeah. Ritu, hi. I'm grateful for your question.

Let me take this last one first, meaning the type of formulary and whether that would require actually prior auth. We are talking about two types of access here. One is the access where you are dealing with the payers. That is the Medicare Fee-for-Service, Medicare Advantage, as well as commercial. There, actually, all products go through a medical exception process. It is usually essentially, if you are a Part D product, the prior authorization is in almost all circumstances required. What makes us unique is in Medicare Fee-for-Service, there are no prior auth requests. The second part, which I was alluding to, is the 170 healthcare systems. These systems are just a question of the organization saying, "We are actually going to be buying this product because now it is actually included with this new indication." That requires no prior authorization. I just wanted to make that very clear.

Now, in terms of the type of patients that we see in the first line, you know what's really exciting about this is when doctors believe actually that Amvuttra and understand Amvuttra's profile that is clearly differentiated as a rapid knockdown agent, they don't actually make a lot of differences in terms of what patients they want to put in. What they see is if the patient is progressing on a stabilizer, they immediately put that patient on Amvuttra. If they see a new patient, whether that's early onset or actually they're already progressive, they immediately put that patient on the first line. It is not so much about the type of patient, but it is also whether the doctor has clearly understood the compelling data set that we get to present with Helios-B and additional real-world evidence.

Yvonne Greenstreet (CEO)

Thanks, Tolga.

Ritu Baral (Managing Director of Senior Biotechnology Analyst)

Thank you.

Yvonne Greenstreet (CEO)

Next question.

Operator (participant)

Next question from Salveen Richter at Goldman Sachs. Please go ahead.

Hi. This is Tony on for Salveen. Thank you for taking our question. We just want to confirm some of the metrics that you gave out. So 170 health systems, over half on formularies and over 75 initiated one per system, around 65 patients, give or take. Is that accurate to think about? To follow up, we're wondering if you're seeing some more standardized guidelines for identifying stabilizer progressors among HCPs now that we have new options. Thank you.

Yvonne Greenstreet (CEO)

Tolga, why don't you take the first question, and then I think Pushkal will take the second.

Tolga Tanguler (Chief Commercial Officer)

Yeah. I mean, just to be clear, we clearly laid those out on the slide, which essentially says 80% of the TTR treatments are initiated through these 170 U.S. healthcare systems.

These are some regional networks, maybe local networks, as well as national networks. Once those institutions include a product because it's a buy-and-build product in their formulary, that means actually that institution can acquire and can initiate therapy. What we're alluding to is, of those 170, within three to four weeks, those systems are already set up as online. Now, the big majority of those systems are already initiating treatments in the setting. That's what we're referring to. I don't know if that captures.

Yvonne Greenstreet (CEO)

I think that's covered the question. Maybe we get on to the second question, Pushkal.

Pushkal Garg (Chief Medical Officer)

Yeah. Tony, in terms of the stabilizer progressors, maybe just a couple of points on this because it does come up non-frequently. Doctors are well-trained cardiologists to evaluate patients with heart failure and whether they're doing well or not well on therapy.

That's why you've seen over the years many studies that have said, "Hey, how are patients doing on stabilizers?" and they report 30%-50% of patients do progress on those therapies. I think that's where that's coming from. I think they're well-trained. I think if you look, for example, at ESC heart failure guidelines that were set up for ATTR-CM, they show that doctors look at factors like clinical symptoms. Are they hospitalized? What's their walking ability? What's their shortness of breath? What's happening on imaging like echocardiograms, for example? What's happening with critical biomarkers like NT-proBNP and troponin? I think doctors are well attuned to looking at those factors and examining them.

I think what's, again, really heartening to us about the profile of Amvuttra is that on actually every one of those parameters, we see a benefit in terms of delaying or favorably impacting disease progression. I think that's a core aspect of this disease. As I mentioned, we just published data showing that actually there's actually improvements in aspects of cardiac function with this drug, which indicates the potential for a disease-modifying profile. That's what's compelling about this. I think there will be more guidelines, etc., around this. I think really what we're seeing is that doctors know how to recognize heart failure in patients who aren't doing well and then reaching for the best therapy for their patients.

Yvonne Greenstreet (CEO)

Great. Thanks, Pushkal. Next question.

Operator (participant)

Next question from Kostas Biliouris at BMO Capital Markets. Please go ahead.

Kostas Biliouris (Director of Biotech Equity Analyst)

Thanks for taking our question and congrats on the progress.

One question from us on Amvuttra. I'll try to push my luck here a little bit for some more granularity. BridgeBio recently mentioned that they saw an impact from Amvuttra launch on the number of ATTR scripts. This impact was particularly from switch patients. That said, I wonder whether you see the majority of the early Amvuttra uptake coming from switch patients or new patients. Any quantitative or directional color there would be very helpful. Thank you.

Tolga Tanguler (Chief Commercial Officer)

I'll take that question. Hi, Kostas. Look, I think the way we best describe, given that it's still early days, is broad. What I'm really, really excited is, again, we're taking all kinds of patients, including definitely first-line patients, as well as switch patients. Those physicians that choose to switch, they also start new patients on Amvuttra. That's definitely an early trend that we start seeing.

By the way, before we move on, I also want to take a quick moment since I know the team is always listening in to call out their phenomenal work, what they've done. Honestly, what I've witnessed leading up to this launch and in these early days has been nothing short of world-class. Our customer-facing and patient support teams are really firing on all cylinders, bringing the exceptional profile of Amvuttra to a patient community that's long waited for a breakthrough medicine. The early momentum, Kostas, as I shared, is strong. All signs point to us being right on track to deliver something truly impactful.

Yvonne Greenstreet (CEO)

Tolga, thanks for those perspectives. Next question, please.

Operator (participant)

Next question from Luca Issi at RBC Capital Markets. Please go ahead. Oh, great. Thanks so much for taking my question. Congrats on the progress. Maybe, Tolga, a quick one here on access.

Luca Issi (Senior Biotechnology Analyst)

At least based on our checks, it sounds like step edits are likely going to be implemented for commercial patients, but are much, much less likely on the Medicare Fee-for-Service patients. One, is that a fair characterization? Two, if so, how should we think about the Medicare Advantage patients, the one kind of in between the two buckets? Are they conceptually closer to commercial patients where step edits are likely, or are they closer to Fee-for-Service patients where step edits are less likely? Any thoughts there? Much appreciated.

Tolga Tanguler (Chief Commercial Officer)

Yeah. No, I appreciate the question. Look, first and foremost, what we've already seen is a very nice broad uptake on all payer mix. We are really not seeing any headwinds in terms of any restrictions on the product.

Now, when it comes to Fee-for-Service, since surely there will not be any limitations, so definitely half of those Medicare patients will be able to have access very seamlessly. We are seeing that with zero copay, I must say, in most of the patients. In terms of commercial and Medicare Advantage, we are not seeing any step edits so far. We obviously have established a great infrastructure through our value-based agreements that enables us to be able to actually demonstrate clinical value. That clinical value provides us that similar advantage. If there were to be any step edits, we certainly have the tools to be able to address that if that were to be the case. Look, we have seen it in polyneuropathy. We are now seeing in CM.

We have the patients getting on treatment in a very quick, short amount of time and staying on treatment thanks to, again, the product profile and the support that we provide.

Yvonne Greenstreet (CEO)

This one. Two more. Two more. Okay. Next question, please.

Operator (participant)

Next question from Paul Matteis at Alnylam. Please go ahead.

Paul Matteis (Managing Director)

Thanks. Paul from Stifel. Appreciate you taking the time. As it relates to uptake so far, Tolga, when we had dinner five weeks ago, you talked about how there are certain physicians who they actually can use the drug without going through a P&T committee. Any metrics there? What percentage of the prescriber base is that, and what have you seen from that population?

As it relates to Medicare Fee-for-Service patients, given the ease of access, is this the kind of thing where over time you think a patient who's covered by Medicare Fee-for-Service could actually get the first dose of drug the same day that it's prescribed? Thank you.

Tolga Tanguler (Chief Commercial Officer)

Yeah. I mean, maybe I'll take care of your last question first. Look, at the end of the day, this is a healthcare professionally administered product, which requires actually injection by and bill. That requires some level of coordination. It will never be a one-day administration. It is certainly very quick given the kind of support that we provide. We obviously track those patients. What's also very encouraging is whether you're a Fee-for-Service Advantage or commercial patient, these patients come in through a start form where we don't actually see any distinction based on their insurance coverage.

We are neutral to the payer mix. Despite that, those patients start getting on therapy. The main reason is, and I really want to underline this, whether it's step edit or prior auth, this is a rare and a very, very severe disease that's rapidly progressing. Because of this, we see really great coverage of this category as a whole. Given what we have to offer, and based on the value-based agreements that we've established, we believe actually we have the ability to have the appropriate patients put on therapy as the physician requires.

Yvonne Greenstreet (CEO)

Thanks, Tolga. I think we've got time for one last question.

Operator (participant)

Next question from Mike Ulz at Morgan Stanley. Please go ahead. Good morning. Thanks for taking the question.

Mike Ulz (Executive Director of Biotechnology Equity Research)

Maybe just another one. Cardiomyopathy.

I wonder if you can talk about the rate of diagnosis and maybe if you've noticed a shift since the beginning of the year now that there's two additional products on the market. Then maybe just secondly, with about 20% of patients currently diagnosed, what do you think that could look like at the end of the year? Thanks.

Tolga Tanguler (Chief Commercial Officer)

Two great questions.

Yeah. No, thank you. Look, I think we actually have empirical evidence now. What you see in cardiomyopathy from 50% growth rate to 60% just with another product in cardiomyopathy already accelerated that, and we remain the market leader. Now, when you look at actually the Q1 results of both stabilizers, actually in the U.S., the stabilizer has grown the fastest ever in the quarter. I think that's somewhat also supported by IRA changes as well. We see this category growth only accelerating.

We used to provide analogies with multiple sclerosis and other products. Now we see it in our own category. So there's definitely evidence of that. Now, in terms of how large the category and how much diagnosis rate's going to go up, it's going to be very difficult for us to predict that now. But I think we will all see, and I'm sure all voices in this category is going to help accelerate that in the future.

Yvonne Greenstreet (CEO)

Good. Okay. Look, thank you, everyone, for joining us on the call. As you can hear, 2025 is off to a great start at Alnylam. We look forward to providing with further updates as the year progresses. Thanks, everybody.

Operator (participant)

Ladies and gentlemen, this has been your conference call for today. We thank you for participating, and we ask that you please disconnect your lines.