Alnylam Pharmaceuticals - Earnings Call - Q2 2025

Executive Summary

• Q2 2025 delivered a decisive beat: Total revenues of $0.774B and total net product revenues of $0.672B, +17% and +64% YoY, respectively; revenue beat S&P Global consensus by ~$0.111B, and Primary EPS (S&P definition) was $0.32 vs -$0.70 consensus, a major upside surprise. S&P Global values marked with *; Values retrieved from S&P Global.
• TTR franchise inflected with AMVUTTRA’s ATTR-CM launch: TTR product revenue $0.544B (+77% YoY), ~1,400 ATTR-CM patients on therapy by quarter-end; U.S. access was broad and mostly first-line with minimal step-edit incidence, underpinning raised FY guidance.
• FY 2025 guidance increased materially: Total net product revenues raised to $2.650–$2.800B (midpoint +27%); TTR franchise raised to $2.175–$2.275B (midpoint +34% vs prior guide).
• Margin headwinds reflect higher AMVUTTRA royalties; CFO expects product gross margin to trend lower in 2H25 as royalty rates step up, partly offset by strong volume and durable demand signals.
• Pipeline/strategic catalysts: Fast Track for nucresiran in ATTR-CM, international approvals for AMVUTTRA in ATTR-CM, and decision to initiate a global Phase III CV outcomes trial for zilebesiran with Roche by year-end.

What Went Well and What Went Wrong

What Went Well

• TTR launch momentum: $0.544B TTR net product revenue (+77% YoY), including AMVUTTRA $0.492B; ~1,400 ATTR-CM patients on therapy by June 30 with faster-than-anticipated payer and provider access. “Access ramped faster than expected… coverage is now confirmed… majority of patients have first-line access” — Tolga Tanguler.
• Guidance raised on strength of CM: Total net product revenue guidance lifted to $2.650–$2.800B; TTR to $2.175–$2.275B; management emphasized confidence in sustainable growth trajectory and international contributions in 2H25.
• Regulatory/clinical progress: AMVUTTRA approved for ATTR-CM in EU, UK, Brazil, Japan; nucresiran TRITON‑CM Phase 3 initiated; FDA Fast Track for nucresiran; HELIOS‑B 42‑month data reinforced ACM and CV mortality reductions, supporting first‑line positioning.

What Went Wrong

• Collaboration revenues fell sharply (-73% YoY) due to a $185M Regeneron one-time recognition in Q2’24; non-GAAP operating income declined to $95M vs $138M prior year.
• Margins compressed: Product gross margin 79% vs 84% prior year; CFO guided to further GM pressure in 2H25 given higher AMVUTTRA royalties.
• GAAP loss widened: Net loss of -$66.3M (EPS -$0.51) vs -$16.9M (EPS -$0.13) in Q2’24; higher SG&A from AMVUTTRA launch and increased R&D from Phase 3 startups contributed to higher operating costs.

Transcript

Operator (participant)

Good morning, ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals Q2 2025 conference call. At this time, all lines are in listen-only mode. Following the presentation, we will conduct a question-and-answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. This call is being recorded on Thursday, July 31, 2025. I would now like to turn the conference over to the company. Please go ahead.

Christine Akinc (Chief Corporate Communications Officer)

Good morning. I'm Christine Lindenboom, Chief Corporate Communications Officer at Alnylam Pharmaceuticals. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Research and Development Officer; and Jeff Poulton, Chief Financial Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the events section of the investors' page of our website, investors.alnylam.com/events. During today's call, as outlined in slide two, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Pushkal will review pipeline updates 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'd like to remind you that this call will contain remarks concerning Alnylam Pharmaceuticals' future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views 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. As shown in our Q2 results announced today, Alnylam Pharmaceuticals is firing on all cylinders, and we're swiftly establishing ourselves as a top-tier biotech company. We're doing so by focusing on three core elements of the business that we believe will drive sustainable growth and value creation for years to come. The first is TTR leadership. As highlighted in today's press release, the launch is off to a very strong start. Whilst it's still early days, we're encouraged by the pace, and we're deeply focused on laying the groundwork for long-term leadership in TTR. The next is growth through innovation, focused on the potential multi-billion dollar opportunities within our pipeline and an R&D engine set up to deliver sustainable innovation and value creation.

To that end, I'd like to acknowledge the recent promotion of Pushkal Garg to Chief Research and Development Officer. Pushkal has been instrumental in progressing our pipeline, and in this role, Pushkal will oversee an integrated R&D organization to drive this exciting pipeline and platform into the future. Congratulations, Pushkal. The third element is strong financial performance with robust commercial execution and a disciplined capital allocation approach, providing us with the opportunity to sustain profitability going forward. As Tolga and Jeff will highlight later, the strong therapeutic profile of AMVUTTRA and ATTR CM, combined with a large and underserved market, positions this as a flagship commercial franchise with robust and durable long-term growth potential. Of course, all of this is underpinned by a best-in-class team and our award-winning culture.

Our results this quarter fit within each of these strategic pillars and represent one of the most impactful quarters to date for Alnylam Pharmaceuticals. Our commercial performance was driven by TTR franchise revenues of $544 million, 77% year-over-year growth, with growth largely attributable to the AMVUTTRA CM launch. This was just the first full quarter of the ATTR CM launch, and as of June 30, approximately 1,400 cardiomyopathy patients were receiving AMVUTTRA, and this is a remarkable achievement. This performance reflects results from our cardiomyopathy launch in the U.S. only. International markets are coming online for AMVUTTRA for CM and are expected to begin to contribute to the CM launch in the second half of the year. Kudos to our teams for delivering these impressive early results. In addition to these commercial results, we continue to advance our leading pipeline of RNAi therapeutics.

We initiated the TRITON-CM Phase 3 study of NUCLEUSIRAN, further establishing our commitment to leadership in TTR, and are pleased to be announcing today that the FDA has granted fast-track designation to NUCLEUSIRAN for ATTR CM. We also just shared encouraging Phase 1 multi-dose data for MIVELSIRAN in Alzheimer’s disease and kicked off a Phase 1 study for ALN-APP in type 2 diabetes earlier in the quarter. With regard to financial performance, we're reporting our strongest quarter to date as a company, with $672 million in total net product revenues, or 64% growth year-over-year.

As a result, we've increased our total net product revenues guidance for 2025 from a range of $2.05 billion to $2.25 billion to a revised range of $2.65 billion to $2.8 billion, representing an increase of $575 million, or 27% at the midpoint, underscoring our confidence in the ATTR CM launch and our other commercial products in the balance of the year. Zooming out from the success of Q2, this progress represents stellar execution towards our Alnylam P5525 goals, which we seek to achieve by the end of this year. Doing so will further establish Alnylam as a unique top-tier biotech company delivering sustainable innovation to patients for many 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'm excited to share with you the results of our Q2 commercial performance. As Yvonne indicated, we are firing on all cylinders, and our Q2 performance was exceptional for the full portfolio. On a global basis, our commercial portfolio delivered $672 million in net product revenues, representing 64% year-over-year and 43% quarter-over-quarter growth. As you will see in a moment, the U.S. TTR performance was the major driver of growth given the ATTR CM launch for AMVUTTRA. It is also encouraging that we saw very robust double-digit growth compared with Q1 across both our TTR and rare franchises across the globe. All parts of our business are operating with focus and excellence. Let's quickly start with our rare franchise. Our GIVLAARI and OXLUMO teams stayed focused and delivered $128 million in combined Q2 sales, up 24% versus last year.

Growth was largely demand-driven, with a tailwind from favorable GIVLAARI gross-to-net adjustments in the U.S. Now, turning our attention to TTR franchise, where we delivered $544 million in global net product revenues during the quarter, representing a 77% increase compared with the second quarter of 2024 and a robust 51% increase compared with the first quarter of 2025. In the U.S., combined Q2 sales of ONPATTRO and AMVUTTRA rose 80%, up roughly $170 million from Q1, driven primarily by AMVUTTRA's ATTR CM launch. We closed the quarter with approximately 1,400 cardiomyopathy patients on therapy, contributing an estimated $150 million in revenue. This performance was fueled by strong execution and faster-than-anticipated access across payers and providers. Regarding the year-over-year dynamics, the U.S. TTR franchise grew 125% compared with the second quarter of 2024, primarily driven by the significant increase in demand from the ATTR CM launch that I just highlighted.

Turning to our international markets, we delivered 18% year-over-year growth, driven by continued strength in our hATTR PN business, which remains a solid growth engine. Importantly, we have yet to recognize any ATTR CM revenue internationally, as launches in Germany and Japan are slated to begin contributing in the third quarter. Now, let me provide some additional perspectives on the U.S. TTR revenue dynamics, where the franchise achieved $383 million in the second quarter, representing a very robust 80% quarter-over-quarter growth. While we don't have the ability to report revenue by indication, the underlying trend is clear. From Q1 2024 through Q1 2025, the U.S. TTR franchise delivered steady growth of around $15 million to $20 million on average every quarter. In Q2 2025, we saw a pronounced step change, indicating an estimated $150 million contribution from ATTR cardiomyopathy.

I will now provide some additional launch metrics to further contextualize AMVUTTRA's launch performance in ATTR cardiomyopathy. Our launch began on March 20, 2025, and Q2 marked our first full quarter post-approval. It is still early, and there is more work to do, but we're very encouraged by the strong momentum we're seeing. As we've described on prior calls, we've been focused on three key enablers around the U.S. launch of AMVUTTRA in ATTR cardiomyopathy: health system setup, access and affordability, and treatment choice. The headlines are here, and I will go into more detail on each in the following slides. As we've shared on prior calls, there are approximately 170 priority health systems through which approximately 80% of ATTR cardiomyopathy patient volume flows. The majority of these provider accounts now have AMVUTTRA on formulary, enabling therapy initiation throughout these health systems where ATTR CM patients present.

What's more, nearly all of the priority health systems have already begun treating patients with AMVUTTRA for ATTR cardiomyopathy. This, together with the broad network of more than 2,000 alternate sites of care, has allowed us to achieve our aspiration. Roughly 90% of patients in the U.S. are able to receive AMVUTTRA treatment within about 10 miles of where they live. Bottom line, our priority was to enable broad provider account setup in our first year of launch. This has happened faster than we had initially anticipated. Since now, at the end of our first quarter of launch, we are largely there. In addition, patients are getting first-line access to AMVUTTRA across all payer segments. Coverage is now confirmed by payers covering the majority of U.S. patient lives, inclusive of Medicare Fee-for-Service, Medicare Advantage, and Commercial.

We can therefore confirm that the large majority of patients have access to AMVUTTRA as a first-line treatment, meaning without requiring patients to step through another product first. Most patients are indeed paying zero in out-of-pocket costs. Consistent with what we've seen in polyneuropathy, there has been very limited use of our QuickStart program, quite simply because patients are not experiencing delays in coverage. We're also seeing patient initiations flowing through all payer segments: Medicare Fee-for-Service, Medicare Advantage, and Commercial. These access dynamics are consistent with what we've long seen in hATTR PN, and we're encouraged to see them replicated in ATTR CM. This reflects our deep experience engaging with payers and the advantage of our fully integrated in-house patient support services. Most importantly, physicians and patients are choosing AMVUTTRA, a testament to its highly differentiated and compelling profile, including its rapid knockdown of the disease-causing protein.

By the end of the second quarter, approximately 1,400 ATTR CM patients had initiated treatment. While we don't plan to regularly report patient numbers going forward, we felt it was important to share this clear signal of early momentum in our first full quarter post-launch. This strong uptake also gives us early insight into utilization patterns, which so far have been broad and balanced. More specifically, very early initial uptake was more pronounced among stabilizer-progressor patients. However, within just three short months, utilization has become relatively balanced between first-line new starts and stabilizer-progressor patients. We're seeing steady growth across both sources of business, and we have a clear focus on making AMVUTTRA the first-line treatment of choice. We also see balanced utilization across academic and community settings. Lastly, physician adoption has been broad. Since launch, the total AMVUTTRA prescriber base has tripled quarter-over-quarter.

This reflects growing awareness and confidence in AMVUTTRA across both cardiology and multidisciplinary practices. Bottom line, we're highly encouraged by the early progress post-launch. The trajectory supports sustainable growth and positions us for long-term leadership in TTR amyloidosis. In summary, access ramped faster than expected, and the value proposition is resonating. We've seen rapid payer adoption and broad physician engagement. The clinical differentiator of AMVUTTRA is clearly being recognized. We're seeing robust growth in an underserved and expanding ATTR CM population. Look, this is a devastating disease, and we remain deeply committed to advancing care through real-world evidence generation and development of our next-generation RNAi therapeutics, NUCLEUSIRAN. Finally, global expansion is underway. With regulatory approvals secured in Europe, Japan, and Brazil, we've now launched in Germany and Japan, unlocking access to more patients worldwide. We're also maintaining stable growth in the hATTR polyneuropathy business, both in the U.S. and globally.

These drivers underpin our increased revenue guidance and reinforce our conviction in significant revenue growth going forward. We're just getting started, and we remain focused on disciplined execution anchored in patient and customer centricity and delivering long-term innovation-driven growth. I'll now turn it over to Pushkal to share more about our work to advance the science in ATTR and beyond. Pushkal.

Pushkal Garg (Chief Research and Development Officer)

Thank you, Tolga, and good morning, everyone. I'm delighted to see the early success of AMVUTTRA in these first few months of the launch. It is a true testament to the outstanding execution of our commercial and medical teams and to AMVUTTRA's unique and compelling profile established in HELIOS-B. To that end, we continue to generate evidence from the HELIOS-B study that further supports the long-term efficacy and safety of AMVUTTRA with the aim of cementing it as the first-line treatment of choice for patients with ATTR cardiomyopathy.

This slide highlights some of the unique and profound benefits of AMVUTTRA's rapid knockdown mechanism of action that are emerging from HELIOS-B. In the left column, you can see the benefits on NT-proBNP and troponin I, important clinical biomarkers of cardiac stress and injury, respectively. Not only do you see a large effect in patients receiving drug versus those on placebo, but it's interesting to see a reduction compared to baseline in troponin I, suggesting a potential disease-modifying effect on this biomarker. Further to that point, echocardiographic data in the middle column shows improvements in critical aspects of cardiac function, both diastolic and systolic. Ultimately, we saw this translate into substantial improvements in all-cause mortality, as well as cardiovascular mortality of 33% to 36%.

In addition to data coming from the HELIOS-B study, we are continuing to generate evidence to further support the safe and effective use of AMVUTTRA by numerous registry and real-world evidence-based studies and investigator-initiated studies. We look forward to sharing data from these sources over time. Further to our leadership and commitment to innovation in ATTR amyloidosis, we announced in June the initiation of TRITON-CM Phase 3 study for NUCLEUSIRAN, which may offer greater knockdown, greater efficacy, and greater convenience for patients with ATTR cardiomyopathy. As a reminder, TRITON-CM is a randomized, double-blind, event-driven outcome study. Patients are allowed to be on background stabilizer therapy. Approximately 1,200 patients will be randomized, and the primary endpoint is a composite of all-cause mortality and cardiovascular events. The primary analysis will be event-driven and will occur a minimum of 24 months after the last patient is enrolled.

If successful, we target launching NUCLEUSIRAN in ATTR cardiomyopathy around 2030. Also, as Yvonne noted earlier, we've announced today that NUCLEUSIRAN has been granted fast-track designation by the FDA, which will enable a more streamlined review process. In parallel, we have the goal to bring NUCLEUSIRAN to patients as quickly as possible and see an opportunity to do so in hereditary ATTR PN. Though we are not yet prepared to discuss full details for TRITON-PN, we remain on track to initiate a pivotal study for the polyneuropathy indication by the end of 2025 and anticipate the potential to launch in this indication several years ahead of cardiomyopathy. We look forward to sharing more details in due course. Moving on to another exciting program, just a few days ago, we presented new multi-dose data from the Phase 1 study of MIVELSIRAN in patients with early-onset Alzheimer’s disease.

Recall previously that we observed marked reductions in A beta 40 and A beta 42, the pathogenic proteins implicated in cerebral amyloid angiopathy and Alzheimer’s disease, respectively, with single doses of MIVELSIRAN. We're pleased to see that continue with multiple doses administered every six months. In addition to the durable knockdown observed, the safety and tolerability profile also remains encouraging. The majority of AEs observed were non-serious, mild to moderate, and deemed unrelated to study drug. Importantly, we saw no evidence of changes in CSF white blood cells, protein, or neurofilament light chain, which bodes well for this program as well as our CNS platform. We look forward to further evaluating the profile of MIVELSIRAN in the ongoing Capricorn Phase 2 study in CAA, as well as a Phase 2 study in Alzheimer’s that we expect to start by the end of the year.

As Yvonne mentioned earlier, a key element of our journey towards becoming a top-tier biotech company is growth through innovation. Alnylam has one of the most robust pipelines in the industry. We are making great progress advancing promising programs across a range of therapeutic areas with multiple potential blockbuster opportunities. In addition to some of the highlights we've already discussed, in Q2, we also kicked off a Phase 1 trial for ALN-4324, targeting GRB14, an insulin sensitizer for the potential treatment of type 2 diabetes. We also remain on track to start a Phase 2 study of ALN-6400, targeting plasminogen in a bleeding disorder later this year. In summary, Alnylam continues to make remarkable progress and deliver unique innovation that puts us in a great position to have a deep, sustainable pipeline that can deliver meaningful impact to patients for many years to come.

With that, 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 Q2 2025 financial results and discussing our full-year upgraded guidance. Let's begin with a summary of our P&L results for the second quarter compared with prior year. Total product revenues for the quarter were $672 million, or 64% growth versus 2024, driven by 77% growth in our TTR franchise, with particularly strong performance in the U.S. market, primarily related to an increase in demand associated with the launch of AMVUTTRA and ATTR cardiomyopathy. Collaboration revenue for the quarter was $61 million, representing a $166 million decrease when compared with last year. The decrease was primarily driven by the modification of our SEMDSIRAN collaboration agreement with Regeneron, which resulted in approximately $185 million of revenue in Q2 2024.

As a reminder, this amendment granted Regeneron an exclusive license to SEMDSIRAN monotherapy. Royalty revenue for the quarter was $40 million, representing an $18 million increase compared with last year, driven by higher Lekpheo sales. Gross margin on product sales was 79% for the quarter, compared with 84% in the second quarter of 2024. The decrease in margin was primarily driven by increased royalties on AMVUTTRA, as higher revenues in 2025 resulted in an increase in the royalty compared with last year. For the balance of the year, our gross margin on product sales is expected to decrease as the applicable AMVUTTRA royalty rates increase, driven by higher sales of AMVUTTRA. Our non-GAAP R&D expenses of $274 million increased 11%, primarily due to increases in startup clinical trial expenses associated with our cardiovascular outcomes trial for zilebesiran and the TRITON-CM Phase 3 study for NUCLEUSIRAN.

Our non-GAAP SG&A expenses of $261 million increased 26% compared to last year, primarily driven by increased headcount and other investments in support of the AMVUTTRA ATTR cardiomyopathy launch in the U.S. Our non-GAAP operating income for the quarter was $95 million, representing a $42 million decrease compared with last year, driven primarily by the recognition of collaboration revenue related to the modification of our Regeneron agreement in Q2 2024, as I previously highlighted. We continue to be pleased with the progress we are making towards achieving our non-GAAP profitability guidance in 2025. Finally, we ended the quarter with cash equivalents and marketable securities of $2.9 billion compared to $2.7 billion as of December 31, 2024, with the increase primarily driven by cash from operations and proceeds from the issuance of common stock in connection with employee stock option exercises.

Now, I'd like to turn to our financial guidance for 2025, where we are substantially increasing our net product revenue guidance, driven by the strong early launch performance of AMVUTTRA in ATTR cardiomyopathy, with specific details as follows. We are increasing our net product revenue guidance from a range of $2.05 to $2.25 billion to a revised range of $2.65 to $2.8 billion, representing a $575 million, or 27% increase from the midpoint of the prior guidance to the midpoint of the updated guidance. The combined full-year growth compared to 2024 is a 66% increase at the midpoint of the guidance range. On a franchise level, the guidance is broken down as follows.

We are modestly increasing the midpoint of our total rare franchise guidance by raising the bottom end of our prior guidance range by $25 million and leaving the top end of our guidance unchanged, resulting in revised rare product sales guidance of $475 to $525 million. We are materially increasing our total TTR guidance range from $1.6 to $1.725 billion to a revised range of $2.175 to $2.275 billion, representing a 34% increase or more than $550 million at the midpoint. Let me provide some additional context, which highlights the impact of the cardiomyopathy launch on our TTR franchise growth based on our upgraded guidance. During 2024, when we only marketed our TTR therapies for hATTR polyneuropathy, our TTR franchise delivered approximately $300 million in revenue growth compared with 2023. In 2025, with the ATTR franchise now including cardiomyopathy sales following the U.S.

launch in Q2, the midpoint of our revised 2025 total TTR sales guidance of $2.23 billion represents an approximate $1 billion increase from 2024 total TTR sales of $1.2 billion. My last comment on our upgraded sales guidance, which now assumes foreign exchange rates as of June 30 for the balance of the year, results in approximately $60 million of our $575 million guidance increase being attributed to changes in FX from our original guidance, which utilized December 31 FX rates. The remainder of our financial guidance, including collaboration and royalty revenue, combined non-GAAP R&D and SG&A expenses, and non-GAAP operating income, remains unchanged. Let me now turn from financials and discuss some key goals and upcoming 2025 milestones. In the second half of 2025, we expect to achieve the following. Initiate the Phase 3 CBOT of zilebesiran in hypertension.

Note that we also announced today that we'll present CARDIA III Phase 2 results at the European Society of Cardiology Congress later this summer. Initiate the TRITON-PN Phase 3 study of zilebesiran in hATTR-PN, and initiate Phase 2 studies for mivelsiran in Alzheimer’s disease and AL6400 in a bleeding disorder. Let me now turn it back to Christine to coordinate our Q&A session. Christine.

Christine Akinc (Chief Corporate Communications Officer)

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 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 number one on your touchstone phone. You will hear a prompt that your hand has been raised.

Should you wish to decline from the polling process, please press the star followed by the number two. If you are using a speakerphone, please leave the handset before pressing any keys. One moment, please, for your first question. Your first question comes from Richter Salvi with Goldman Sachs. Please go ahead.

Salveen Richter (Managing Director of Global Investment Research)

Good morning. Thanks for taking my question and congratulations here on the quarter. Could you give some details here on the patient profiles for AMVUTTRA with regard to the first-line patients and whether you're seeing mostly mixed phenotype patients or more of a broader population mix? Help us understand from here what the field force is most focused on. Thank you.

Yvonne Greenstreet (CEO)

Thanks, Sibyl. I'll start by saying, look, it's early days yet, but we're incredibly pleased with where the launch is going, particularly with broad and robust uptake.

I think it also really shows us the data that we generated from HELIOS-B is really resonating with physicians. The rapid knockdown of TTR, all-cause mortality improvements, infrequent subcutaneous administration, which provides both convenience and security. We're seeing broad uptake across first-line patients as well as patients that progress on stabilizers. We're seeing use across the community physicians as well as academic physicians, as well as new prescribers, as well as repeat prescribers. The trends are really very supportive in suggesting continued growth. I think it's fair to say that the initial pickup has been faster in the stabilizer-progressor patients because you bring in a new therapy and there are patients who've been progressing on stabilizers. It's not surprising that physicians are looking for an orthogonal treatment for these patients. We're now achieving a really healthy share of first-line patients. We have a good mix of first-line, stabilizer progressors.

What we're going to be doing is really consolidating and building on the foundation of this very early picture. Tolga, you probably want to add a couple of comments.

Tolga Tanguler (Chief Commercial Officer)

Actually, you pretty much covered everything. What I would say is, again, we're just one quarter in, and what we're already seeing, what you described, validates our clinical thesis and commercial strategy.

Yvonne Greenstreet (CEO)

Thanks, Tolga. Next question.

Operator (participant)

Thank you. The next question comes from Tazeen Ahmad with Bank of America. Please go ahead.

Tazeen Ahmad (Analyst)

Hi, good morning. Thanks for taking my question. I just wanted to get a sense on how you're thinking about net price for AMVUTTRA and gross to net moving forward.

Yvonne Greenstreet (CEO)

Yeah, no, thanks for that question. Jeff, perhaps you'd like to start off answering that, and if there are any additional perspectives, Tolga and I can follow on from you.

Jeff Poulton (CFO)

Yeah, just a reminder of what we said back on the approval call in March. We said that we expected that we would reduce net price modestly and gradually over time. That does hold for our expectation for 2025. 2025 relative to 2024, I would expect mid-single-digit reduction in net price for AMVUTTRA for the year.

Tolga Tanguler (Chief Commercial Officer)

Okay. I think one thing is also important to highlight is the fact that payer dynamics are moving very much in as what we exactly expected. A lot of the payer policies are already out, both on Medicare Advantage as well as in commercial. What we're seeing is first-line access to those patients and patients actually paying minimal, in most cases, zero out-of-pocket costs. We'll obviously manage that with early engagement with payers. The impact of the gross to net is going to be, as Jeff highlighted, will evolve over time.

Yvonne Greenstreet (CEO)

Thanks. Thanks, Jeff.

Tolga. Next question.

Operator (participant)

Thank you. The next question comes from Murray Raycroft with Jefferies. Please go ahead.

Maury Raycroft (Equity Research Analyst)

Hi, good morning, and congrats on the great quarter, and thank you for taking our question. I'm wondering if you can comment on whether there was any bolus effect in cardiomyopathy scripts in second quarter. Could you also please clarify to what extent did stocking contribute to the growth of U.S. AMVUTTRA revenue in the second quarter?

Yvonne Greenstreet (CEO)

That's a great question. I think Tolga has touched on this. We've really demonstrated very solid commercial execution. That means that we've seen a little bit of faster progress than we expected, particularly around health system setup. I touched on this already, but it's meant that we had initial faster pickup with stabilizer-progressor patients. As we went through the quarter, we now have this very healthy share of first-line.

We're just in the first quarter of launch. I think the key message, number one for me, is that the results that we're sharing with you today are not just a flash in the pan. We expect continued sustainable growth, and that's the reason why we raised guidance today. I think the second key message is really just the durability of the franchise. We expect to see AMVUTTRA deliver continued sustainable growth, but we'll be bringing NUCLEUSIRAN forward as well, as Pushkal highlighted, which gives us the potential to deliver franchise growth out into the 2040s.

Jeff Poulton (CFO)

I'll comment on the second part of the question, which was about inventory. I think the headline for the quarter is, again, in the U.S., Tolga has prepared remarks, highlighted the $170 million in growth in the TTR franchise in the U.S., Q2 versus Q1.

Far and away, the biggest driver of that was the cardiomyopathy demand, 1,400 patients on therapy, $150 million in cardiomyopathy revenue for the quarter is what we're estimating. On the inventory side, we did see about a $25 million benefit in Q2 compared to Q1. That's not actually because days on hand increased between Q1 and Q2, as it actually stayed constant at around 20 days, which is at about the midpoint of the agreements that we've got in place with our distributors. What drove the increase in inventory in the quarter was the calculation of what a day of demand or a day of inventory is worth, which is based on a 12-week moving average of demand. It was demand that really drove the increase in inventory and the channel in the quarter, which is, again, a high-quality increase in channel stocking in the quarter.

Now, on the gross to net side, we had an opposite movement, so a headwind that roughly offset the benefit that we had in inventory, which is why we're highlighting demand was the key driver of growth in the quarter. On the gross to net side, a couple of things. One is that we had an increase associated with the Part D rebate that we're paying. Anybody that's got a Part D drug at this point is paying rebates on the IRA Medicare redesign. We do have a small portion of our TTR sales that go through the Part D channel, and that's the home care part of the business. Historically, that's been about 20% in polyneuropathy. There is an increased rebate that we're paying there, which was in line with our expectations. We also saw modestly higher 340B utilization in the quarter.

On price, net price Q2 to Q1 was down slightly, which is consistent with what I said on the earlier question, that we do expect net price 2025 versus 2024 for AMVUTTRA to be down mid-single digits.

Yvonne Greenstreet (CEO)

Thanks, Jeff. I think a very important question, and I think you've clarified that for our investors. So thank you. Next question, please.

Operator (participant)

Thank you. The next question comes from Jessica Five with JP Morgan. Please go ahead.

Jessica Fye (Managing Director and Equity Research Analyst)

Hey, guys. Good morning. Thanks for taking our question. Can you speak a little more in a little more detail to the assumptions underpinning the updated TTR franchise guidance as it relates to the pace of new starts? I guess just in general, can you just maybe provide a little assurance or just reaffirm that the new guidance is not somehow aggressive? Thank you.

Yvonne Greenstreet (CEO)

Okay. Two parts to that question.

Maybe, Tolga, if you start with the first part, and then Jeff, you can follow on from that.

Tolga Tanguler (Chief Commercial Officer)

Yeah, absolutely. Hi, Jessica. I mean, look, at the end of the day, what we've already laid out is we're expecting a steady growth in both first-line as well as the second-line patient flow. As Yvonne indicated, let me also provide a little additional color. As expected, we initially saw uptake concentrated in patients who had progressed on stabilizers, and these are often sicker patients. Physicians naturally look for an alternative therapy with a mechanism of action that's unique, that's accessible, easy to administer, and so forth.

What's been really particularly encouraging, and this is why the guidance we're providing is over half a billion dollar uptake from where we were, is about a month into the quarter, we began seeing a very healthy and accelerating trend in first-line use, just as we had positioned from the outset. Frankly, that makes a lot of sense. This is a progressive and fatal disease. Physicians want to hit the disease early, and it is hard and not hold back their best therapy for later as they might in less serious conditions. Today, and this is where the guidance is really anchored in, we see both first-line and second-line segments are growing. They're growing rapidly. Uptake is broad across first and second-line and academic and community. More importantly, we're seeing a good expansion of our prescriber base.

We've just expanded by threefold, and that continues to move in the right direction. As we move forward, our focus is clear to continue reinforcing AMVUTTRA as the first-line treatment of choice, supported not only by our approved label, but also by growing evidence, as Pushkal highlighted, with new imaging data, emerging cardiac biomarker trends that suggest AMVUTTRA may even help reverse disease progression. Nonetheless, we're just one quarter in and already seeing that behavior that validates our clinical profile as well as our commercial ambitions. I think the current guidance really reflects that.

Yvonne Greenstreet (CEO)

I just want to emphasize that it's early days yet. We've only just achieved our first full quarter here. When we came up with the guidance, we've given guidance that we expect to achieve. We're going to be focusing our team on continued execution. As we progress, we will continue to update and share our perspectives.

Jeff Poulton (CFO)

Maybe just a little bit more context on the guidance. Again, if you look at what I highlighted in terms of the midpoint of the guidance and what it implies in terms of year-over-year growth for TTR, about $1 billion is what I highlighted. Last year, the PN franchise grew $300 million versus 2023 and was growing at about 30%. If you just sort of assume that that's the growth that we're going to get from PN this year, that would imply $600 million plus from cardiomyopathy. We just did $150 million in the second quarter, and we feel really good about growth sustaining through the second half of the year. I do think we have a high level of confidence in the guidance that we provided, Jess.

Thanks, Jeff. Next question.

Operator (participant)

Thank you. The next question comes from Paul Matteis with Stifel. Please go ahead.

Paul Matteis (Managing Director and Head of Therapeutics Research)

Great, thanks so much for taking my question. One for Tolga and the team. As it relates to stabilizer-progressors, can you talk a little bit more about the criteria physicians are using? Now that you've been in the market, do you have a sense of what percent of patients who are on a stabilizer currently would be dictated to be a progressor and a good candidate for AMVUTTRA based on the clinical criteria that are being implemented? Thanks so much.

Yvonne Greenstreet (CEO)

We'll start with Tolga and then I'd like Pushkal to provide a clinical perspective.

Tolga Tanguler (Chief Commercial Officer)

Paul, based on our research and obviously published data, clinical evidence suggests that anywhere between a third to half the patients on stabilizer at one point progress. We see that number is continuing to grow. The only real option in terms of mechanistically and the clinical evidence suggests that it would be AMVUTTRA at this point.

Let me turn it over to Pushkal, who can also provide some more. Clinical perspective about what we're seeing and how those guidelines are actually progressing.

Pushkal Garg (Chief Research and Development Officer)

Yeah. Thanks, Tolga. Thanks, Paul. I think it's really important. We talk about ATTR cardiomyopathy, and the thing here is that it has a clear cause, which is the accumulation of TTR protein in the misfolded protein in the myocardium. As it clinically presents, it's a form of heart failure. Doctors have been treating heart failure for decades, and they know how to modify drug therapy for patients. They might add diuretics or SGLT2s or other agents as patients are progressing. I think they're well accustomed to actually looking at a variety of factors. Frankly, you have to rely on a variety of factors. There's not any one specific indicator.

An easy way to think about that is when you look at the European guidelines that were put out a couple of years ago, and they had a variety of considerations, including biomarkers, echocardiographic factors, exercise tolerance, patient's ability to lie flat at night, different things, pedal edema. I think what we're seeing now in these early days is that doctors are applying that general clinical rubric of looking at a patient, how they present, their symptoms, their signs, and other factors in terms of determining how patients will progress. We do think that over time, more and more guidelines in this category will develop. Our expectation is that there will not be some one single factor that clinicians or payers will be able to rely upon to say specifically that a patient's progressing, but rather have to look at the constellation of factors that affect a patient's symptomatology.

Yvonne Greenstreet (CEO)

Thanks, Pushkal. Thank you. We'll take the next question.

Operator (participant)

Thank you. The next question comes from Luca Issi with RBC Capital Markets. Please go ahead.

Luca Issi (Senior Biotechnology Research Analyst)

Oh, great. Thanks so much for taking my question. Congrats on this strong quarter. Maybe if I can circle back on the TTR guide, maybe, Jeff, if I assume $200 million in revenue for the year from ONPATTRO, that essentially means $550 to $650 million in revenues for the next two quarters for AMVUTTRA, which is actually not dissimilar from the $492 million that you already printed today. I guess what I'm trying to say, it feels to me that this guide has still a good degree of conservatism in it, especially given that you're going to start selling this drug in international markets like Brazil, Europe, UK, Japan, etc. We'd love it if you have a different view here. Any thoughts there? Much appreciated.Thanks so much.

Jeff Poulton (CFO)

Yeah. Luca, I appreciate the question. I'll again reiterate what I said to the earlier question here. We're guiding to $1 billion of TTR growth year over year. Last year, PN grew $300 million and is growing at about 30%. That gets you to $600 million plus for cardiomyopathy. We just did $150 million in Q2. I think we feel very confident about that. If you look at historically, the guidance that we've given and the consistency with which we've either met that or exceeded that, that's how we feel about the guidance that we're providing. I don't know if it's conservative at this point. Honestly, we're one quarter into this, and certainly we look forward to coming back at Q3 and reassessing things.

Yvonne Greenstreet (CEO)

Thank you.

Luca Issi (Senior Biotechnology Research Analyst)

Thanks so much.

Yvonne Greenstreet (CEO)

Next question.

Operator (participant)

Thank you. The next question comes from Ellie Merle with UBS. Thank you. Hey, guys.

Ellie Merle (Executive Director of Biotech Equity Research)

Congratulations on the quarter, and thanks so much for taking the question. Just to drill into this a little bit more, how should we think about the rate of new patient starts per quarter from here? 1,400 is obviously a phenomenal number. Should we think of this cadence of new starts continuing in Q3 and beyond? Second, in terms of the mix, you mentioned now seeing more balanced starts mix between the newly diagnosed and the progressors, whereas initially it was more of the progressors. How do you expect this mix to evolve over time from here? Thank you.

Yvonne Greenstreet (CEO)

Okay. I think two questions, so you can probably take both of them, Tolga.

Tolga Tanguler (Chief Commercial Officer)

Yeah. Thank you. At the end of the day, we're very pleased, obviously, with 1,400 paid patients within a three-month period.

As you had highlighted, while the patient starts initially was more predominantly stabilizer-progressor very quickly, that switched into a balanced and broad patient uptake. We certainly expect to see both of those categories continue to grow. Now, in terms of the specific numbers, we kind of went out of our way to be able to provide that clarity. As you know, AMVUTTRA is a single SKU, so we can't really isolate CM patients with precision. We're going to continue to provide additional color, and those numbers, obviously, we expect to go up. In terms of the specific precision about how it's going to go quarter after quarter, we're not going to be able to report that.

Yvonne Greenstreet (CEO)

Thank you. Next question.

Operator (participant)

Thank you. The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead.

Kostas Biliouris (Director and Biotech Equity Anayst)

Thanks for taking our question and congrats on the impressive launch.

One question on payers from us, although you already touched a little bit on that. We have seen some commercial payers requiring stabilizer use prior to AMVUTTRA treatment in cardiomyopathy. Can you comment on how common those requirements are across the different plans and what percentage of patients do these plans cover? Thank you.

Yvonne Greenstreet (CEO)

Yeah. No, that's a great question. I mean, I'll just start off by saying that as we look at this, access is just not a barrier. We're seeing broad coverage across Medicare, fee-for-service, Medicare Advantage, commercial payers, and the vast majority of patients are getting first-line with no step. This is exactly what we predicted coming into the launch and what we've been working on for quite some time. I think it really speaks to the AMVUTTRA profile as well as the nature of the disease. Tolga, you might want to add another perspective.

Tolga Tanguler (Chief Commercial Officer)

You got it, Yvonne. I think the broad headline is really, as predicted, we're not facing a significant headwind in terms of payer coverage. What I'm really pleased to see was within a short three-month period, majority of both Medicare Advantage as well as commercial payers have published policies. In those policies, AMVUTTRA, in broad strokes, are covered first-line. We also had actually flagged that there could be some commercial payers that could actually provide a separate in their policies. We're seeing that, but it is incredibly minimal. It's in the single digits. Frankly, we don't anticipate that to continue to grow as most other large commercial payers have already written policies that cover AMVUTTRA as first-line.

Now, when it comes to step edits, we have the tools and the support systems that enable us to actually, frankly, to help patients and providers to circumvent that or make sure that it's managed very carefully. We've actually built, over the years, a quiet engine driving real impact in terms of our patient services. I'm really pleased to see how we've been able to pull through on all three segments. Patients are already getting on treatment, whether it's fee-for-service, whether it's Medicare Advantage, also on commercial payers, including those plans that have actually step edits. We don't see that for now. Obviously, we are going to closely monitor and continue to engage with payers to make sure that these patients that deal with the severe condition are getting seamless access with our medicines.

Yvonne Greenstreet (CEO)

Yeah. No, that's great, Tolga.

One data point that really struck me was actually just the minimal use we are seeing of our Quick Start program. We introduced a Quick Start program with all of our launches to make sure that we can help patients with access, and we are just not seeing much use, which I think, again, is very encouraging. Next question, please.

Operator (participant)

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

Gena Wang (Managing Director of Biotech Equity Research)

Thank you for taking my questions. I also wanted to congrats on the outstanding quarter. Maybe, Yvonne, I think you mentioned that the vast majority will be the first-line patient. Is it fair to say that out of 1,400 patients treated so far, over 50% of patients is a first-line patient? Out of this 1,400 patients, how many of them receive free drug?

Yvonne Greenstreet (CEO)

Tolga, you love breaking this down.

Tolga Tanguler (Chief Commercial Officer)

Yeah. Yeah.

Look, Gena, good to hear from you. I think what we had said very thoughtfully, I would say, is our uptake has been broad and balanced. That included, again, early on, some patients that were actually progressing on stabilizers. What we are seeing is a very, very strong trend of first-line indication. We are in the early innings, and I think the job is to—we are getting, I would say, our fair share of first-line patients, but the job is not done yet. What we want to make sure is that we continue this trend and make sure that we continue to educate both patients as well as prescribers on why AMVUTTRA has a compelling product profile to be a first-line patient. I just wanted to reiterate that.

Yvonne Greenstreet (CEO)

Yeah. It is really important that we clarify exactly where we are. Jeff, you got—

Jeff Poulton (CFO)

I think it was she also had a question about the 1,400 patients and how many of them were in the Quick Start program. It was de minimis, right? It was very, very little. It was absolutely very minimal.

Yvonne Greenstreet (CEO)

Next question.

Operator (participant)

Thank you. The next question comes from Mike Ulz with Morgan Stanley. Please go ahead.

Mike Ulz (Research Analyst)

Good morning. Thanks for taking the question and congrats on the strong launch as well. Maybe just to follow up on TTR cardiomyopathy, you highlighted you are getting some nice broad use in the front line as well as the stabilizer-progressor patients. Just curious if you started to see any combination use early in the launch. I know you're not expecting it, but we've picked up some combination use in some of our KOL cardiologists as you've seen it.

Yvonne Greenstreet (CEO)

Yeah. No, that's fair. That's fair. Yeah. No, thank you.

Thank you for that question. Tolga, why don't you take that?

Tolga Tanguler (Chief Commercial Officer)

Yeah. Look, we certainly do see a very small portion of those patients getting a combination use. We would certainly expect that as tafamidis goes generic over the years to become more prominent. Right now, it's really difficult to be very specific about looking at the specific combination use. I think in where it's allowed and where access is permissible, we do some utilization of combo.

Yvonne Greenstreet (CEO)

Thank you.

Mike Ulz (Research Analyst)

Thank you.

Tolga Tanguler (Chief Commercial Officer)

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

Operator (participant)

Yes. The next question comes from Ritu Baral with TD Cowen. Please go ahead.

Ritu Baral (Managing Director and Health Care – Biotechnology Research Analyst)

Hi, guys. Thanks for squeezing me in. And congratulations on the quarter. A quick question on variance. You guys addressed the mixed phenotype, but in your first-line and first-line access, what trends are you seeing in the V122I variant population?

As KOL feedback, at least on my model, has suggested I'm underestimating that prevalence by about 6X, but it is a more severe phenotypic presentation. Just a very quick follow-up. This is probably semantics, but you guys, Tolga, you've mentioned step-through and step edits. Are they the same thing as prior authorizations, or do you have a different set of prior authorizations? Thanks.

Tolga Tanguler (Chief Commercial Officer)

Yeah. Let me take your last part first. The step-edit policies that we've seen, again, it's incredibly small. It's in the single digit, and it's mostly predominantly in the commercial setting. There are no real specific limitations other than patients putting on a stabilizer first. Frankly, there's not even a time limit or duration, and it's really up to the physician if the patient is progressing. We find these policies relatively easy to manage for the patients. There are no specific hereditary or V122I indication.

Frankly, we're not surprised about that. We have, I think, what we've demonstrated early on with the polyneuropathy hereditary condition and then later with the broad cardiomyopathy label is that AMVUTTRA is well-positioned to be a first-line patient for all diagnosed ATTRCM patients. We're really not seeing that trend. Maybe I'll turn it over to Pushkal if he has any specific commentary on the trial.

Pushkal Garg (Chief Research and Development Officer)

I think you said it well. I think what we've seen in HELIOS-B is that AMVUTTRA works equally well in wild-type patients and in V122I patients. As Tolga mentioned, this is the one class of drugs that's shown actual benefit in hereditary patients, which constitutes the wide range of mutations, and we've seen benefits across that.

Across all ranges of severity, whether it's NYHA class 1, 2, 3, whether it's hereditary or wild-type, I think that's what really cements our belief that this is really what we're hearing from prescribers in terms of the opportunity to treat patients with this drug as a first-line agent for it too.

Yvonne Greenstreet (CEO)

Thank you. Ritu, I think this brings our call to a close. I'd just like to thank everybody for joining us today on this call. Alnylam has continued to execute strongly across all areas of the business, and we're very much looking forward to providing you further updates as we progress throughout the year. Thanks a lot.

Operator (participant)

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.