Alnylam Pharmaceuticals Inc

NASDAQ:ALNY

Q3-2025 Earnings Call

[Operator]

Good morning, ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals 3Q 2025 Earnings Conference Call.

[Operator Instructions]

Also note that this call is being recorded on Thursday, October 30, 2025. And now I would like to turn the conference over to management. Please go ahead.

[Christine Lindenboom, executive]

I'm Christine Akinc, Chief Corporate Communications Officer at Alnylam. Good morning ladies and gentlemen and welcome the 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 on Slide 2, Yvonne will offer some introductory remarks and provide general context. To will provide an update on our global commercial progress. Pushkal will review pipeline updates and clinical progress, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call to your questions.

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purpose of the safe harbor provision under the Private Securities Ligation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to Yvonne. Yvonne?

[Yvonne Greenstreet, executive]

Thanks, Christine, and thank you, everyone, for joining the call today. Alnylam's Q3 results announced this morning demonstrate the exceptional progress we are making across all aspects of the business. As we continue to evolve into a top-tier bisect company, our focus remains on these 3 core pillars that we believe will drive sustainable growth and value creation for years to come. The first is TTR leadership. The AMVUTTRA launch delivered another strong quarter. It's still early, but we're very encouraged by the progress and dedicated to establishing long-term leadership in TTR.

Next is growth to innovation, focused on the potential multibillion-dollar opportunities within our pipeline, and an R&D engine positioned to deliver sustainable innovation and value creation for many years to come. The third element is strong financial performance, with robust top line growth and disciplined capital allocation, providing us with the opportunity to sustain profitability going forward. And of course, all of this is underpinned by a best-in-class team and our award-winning culture. The quarterly results announced this morning represent strong execution on each of these fronts. Our commercial performance was driven by TTR franchise revenues of $724 million or 135% year-over-year growth, with growth largely attributable to the AMVUTTRA CM launch in the U.S., where we achieved total TTR revenues of $543 million, representing 194% year-over-year growth. As Tolga will describe, the broad and balanced uptake in the second full quarter of launch drive an approximate doubling of TTR cardiomyopathy revenue compared to the prior quarter.

In addition to these commercial results, we continue to advance our leading pipeline of RNAi therapeutics. Two new Phase III trials are getting underway. The ZENITH Phase III cardiovascular outcomes trial of zilebesiran in hypertension has initiated and the TRITON PN study of icrisiran in hATTR-PN will be initiating shortly to complement the TRITON CM study that was initiated last quarter. We're also excited by earlier-stage pipeline advancements in bleeding and neurologic disorders. And with regard to financial performance, our third quarter results show continued growth with $851 million in total net product revenues, up 13% year-over-year. As a result, we've again increased our total net product revenue guidance for 2025 and from the range of $2.65 billion to $2.8 billion, to a revised range of $2.95 billion to $3.05 billion representing an increase of $275 million or 10% at the midpoint, underscoring our confidence in the AMVUTTRA TTR CM launch and our other commercial products for the remainder of the year. Now with our Alnylam piece of is by '25 era concluding soon.

We're thrilled by this incredible execution over the past 5 years, reflecting tremendous progress on these ambitious goals. This is indeed a strong foundation on which to build our next phase of significant growth. and we look forward to harnessing this momentum. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

[Tolga Tanguler, executive]

Thanks, Yvonne, and good morning, everyone. It is a pleasure to show how we're continuing to bring Alnylam's transformative therapies to patients around the world. Following an exceptional Q2 continued on [indiscernible] strong trajectory of growth and execution. We delivered $851 million in combined net product revenues representing 103% growth year-over-year and 27% growth versus the prior quarter. Our TTR franchise remains the primary growth engine. And we're also seeing continued momentum in our rare disease business.

Let me start there. More than 5 years after launch, our rare disease portfolio continues to deliver meaningful impact for patients and steady performance for our business. In Q3, the rare portfolio achieved $127 million in sales, up 14% versus Q3 2024, driven largely by ongoing patient demand. While the timing of orders in our partner markets created some short-term shifts, the overall trajectory remains strong. I'm proud of the focus and dedication of our rare disease and partner teams who continue to reach patients with these 2 transformative medicines globally, even as much of the organization focuses on the TTR growth opportunity. With that, let's review the TTR highlights. Q3 was another exceptional quarter for our TTR franchise, continuing the strong launch trajectory we saw in Q2.

Global TTR net revenues reached [ $72 million, ] up 33% versus the prior quarter and representing 135% growth year-over-year. This performance was primarily driven by an increase in U.S. patient demand with an increase in U.S. channel inventory more than offset by an increase in U.S. gross to net deductions. It is worth noting that the increase in gross to net deductions primarily impacted ONPATTRO, reducing U.S. reported Q-over-Q growth in our hATTR-PN business relative to our recent quarterly run rate. In the U.S., net sales for our TTR franchise grew 42% quarter-over-quarter and 194% versus Q3 2024, reflecting continued robust adoption following the AMVUTTRA-ATTRCM label expansion. Before we provide further color on the U.S. launch, let me quickly share the ex U.S. dynamics. Outside the U.S. revenues grew 13% versus the prior quarter and 46% year-over-year, underscoring continued global momentum. Further, international AMVUTTRA ATTR-CM launches are anticipated across 2026, following the completion of local pricing and reimbursement reviews.

Having said that, we're particularly pleased with the early progress in Japan where the CM launch is advancing well and tracking in line with leading launch analogs, a strong validation of AMVUTTRA's profile and first-line potential. In Germany, launch activities remain in the early stages as final reimbursement decisions continue, and we're encouraged by how the product differentiated profile is resonating at key treatment centers. More broadly, our international performance reflects the continued strength of our hATTR pull neuropathy legacy business, which remains robust despite new competition. Broader engagement in the category is expanding awareness and diagnosis, ultimately, benefiting patients and reinforcing Alnylam's leadership role in shaping the field. Building on our global presence, we're positioned to extend our momentum as AMVUTTRA ATTRCM launches expand worldwide. Now let's turn to the U.S. on AMVUTTRA ATTRCM launch which recently completed its second full quarter and continues to build momentum.

In Q3, our U.S. TTR franchise across both PN and CM indications, delivered $543 million in net product revenues representing an increase of approximately $160 million versus the prior quarter. If we assume steady and consistent growth of $50 million quarter-over-quarter in the pulmonaropathy-based business, then we estimate the CM indication represents approximately $300 million of net product revenues this quarter. or doubled from Q2. This reflects sustained launch momentum in AMVUTTRA ATTRCM with patient demand roughly doubling compared to Q2 and as awareness and physician adoption continue to grow. Our strength is built on 3 key pillars as part of our launch strategy. First, health system setup. It is not complete. Nearly all of our 170 priority health systems are now using AMVUTTRA, driving broad utilization, combined with our extensive treatment site network, roughly 90% of the U.S. patients can receive their AMVUTTRA treatment within 10 miles of [indiscernible] anywhere in the U.S. and meaningful milestone and accessibility.

So again, the health system setup is effectively complete. As such, we plan to no longer report on this launch enabler on future calls. Second, access remains strong. Payer coverage is broad and nearly all patients have access to AMVUTTRA as a first-line treatment option, meaning these patients have no step edits. Of similar importance most patients pay 0 out of pocket. Finally, with health system setup and access and affordability in place, we are focused on treatment choice and the profile of our AMVUTTRA continues to resonate. We're seeing broad and balanced adoption across new diagnosed patients and those progressing on stabilizers in both academic and community settings. Subscriber growth also remains robust. Having reviewed the 3 strategic pillars, we're executing and delivering on them. Patient demand roughly doubled quarter-over-quarter, reflecting strong, sustained momentum for the AMVUTTRA-ATTRCM and U.S. launch.

In summary, it is still early in the journey, but the results to date highlight the substantial long-term opportunity ahead and underscore our strong positioning for leadership in this expanding underserved TTR category. Looking ahead, the majority of ex U.S. launches are expected to begin in 2016 as pricing and reimbursement processes wrap up, extending our global reach and providing a measured contribution to launch momentum. We continue to invest in the TTR category, advancing science, enhancing patient experience, and building a durable foundation. Pushkal and the R&D organization are leading that chapter. With that, I'll hand it over to you. Pushkal?

[Pushkal Garg, executive]

Thank you, Tolga, and good morning, everyone. In support of AMVUTTRA's strong launch in ATTR-CM, we continue to share new data from the HELIOS-B study that further underscore the unique and compelling profile of this medicine with the aim of cementing AMVUTTRA as the treatment of choice for patients with ATTR cardiomyopathy. To that end, as shown on the left, at ESC, we presented new data from HELIOS PE that demonstrates the sustained benefits of vutrisiran through up to 48 months, which includes 12 months from the open-label extension. Specifically, as compared to placebo, which substantially reduced the risk of the composite of all-cause mortality or first cardiovascular event by 37% in the overall population and 42% in the monotherapy group.

More recently, at HFSA, as shown on the right, we shared important new data from the double-blind period demonstrating that vutrisiran treatment was associated with a lower rate of gastrointestinal adverse events versus placebo across the overall vutrisiran monotherapy and baseline tafamidis treatment groups with reductions of 37% to 49%. This observation is quite important, so that suggests vutrisiran may reduce GI symptoms, which as you can see from the placebo data, we're seen in approximately 40% of patients. These symptoms arise from the multisystemic nature of ATTR cardiomyopathy and are a major source of concern for patients with this disease. With these continued insights from HELIOS B, we're excited about the prospects for RNAi therapeutics to become the standard of care in TTR amyloidosis. Nucresiran, our next-generation silencer may offer even greater TTR knockdown with subcutaneous biannual dosing is now being evaluated in the TRITON Phase III program. We announced last quarter the initiation of the TRITON CM trial in cardiomyopathy patients. Today, I'm happy to share additional details about the TRITON PN trial in hereditary TTR polyneuropathy patients, which we'll be initiating shortly. This will be an open-label trial of Nucresiran in approximately 125 patients with hATTR-PN. Patients will be randomized 4 to 1 to receive either nucresiran dosed every 6 months, or to a reference arm of vutrisiran, dosed every 3 months. The primary endpoint is the change from baseline in the modified neuropathy impairment score or mNIS+7 at month 9 in the nucresirian par as compared to the placebo arm from the APOLLO Phase III trial of patisiran.

You might recall that this is essentially the same study design we utilized in our HELIOS-A pivotal study of vutrisiran in hATTR-PN, which led to its initial approval in that disease setting. We expect top line results from TRITON PN in 2028 look forward to sharing additional details as the trial gets underway. Now moving on to another exciting program. We made great progress this quarter with our zilebesiran program in hypertension. This program represents an amazing opportunity to address some of the major shortcomings of existing antihypertensive therapies. By targeting angiotensinogen upstream of the RAS cascade we believe we can help more patients get to goal, not only in terms of the quantity of blood pressure lowering but also the quality of blood pressure control, reducing blood pressure variability, improving adherence, and restoring nocturnal dipping. Ultimately, we believe continuous control of blood pressure will drive long-term improvements in cardiovascular outcomes. At ESC in August and shown on the right, we shared results from the CARDIO II Phase II study.

As you can see, treatment with zilebesiran resulted in clinically meaningful reductions in [indiscernible] is tolled blood pressure in patients with uncontrolled hypertension and high cardiovascular risk at the month 3 primary endpoint with continuous control sustained through month 6. Moreover, the treatment effect was further enhanced in a biologically based enriched subgroup of patients. With these results, Cardia I met the objective of informing the design, patient population and dose for the global Phase III cardiovascular outcomes trial, Zenith. Zenith is a cardiovascular outcomes trial that will enroll approximately 11,000 patients to evaluate zilebesiran at a dose of 300 milligrams given every 6 months compared to placebo in patients with uncontrolled hypertension with either established or at high risk for cardiovascular disease on 2 or more antihypertensives. The endpoint is a vent trip with a minimum follow-up of 2 years, and we expect to launch, assuming a successful study and regulatory approval around 2030.

I'm also excited to share an update today on our ALN 6400 development program. ALN-6400 targets plasminogen, and we believe it has the potential to be a universal hemostatic agent that can address significant unmet needs across a range of bleeding disorders effectively becoming a pipeline and a product. Plasminogen is a genetically validated target, high circulating levels are associated with increased bleeding. And conversely, individuals with loss of function variants have reduced rates of bleeding. Importantly, loss of function is not associated with the increased risk of thrombosis. As we believe that by lowering plasminogen with ALN-6400, we potentially can slow down the process of fibrinolysis thereby stabilizing clots and preventing bleeding without increasing the risk of thrombosis. Today, we're announcing the first indication we'll focus on with ALN-6400, hereditary hemorrhagic tolangictasia, HHT. HHT is the second most common inherited bleeding disorder, affecting individuals of all ages. 90% of HHT patients live with recurrent nose bleeds which can be severe and life-threatening and many experienced gastrointestinal and heavy menstrual bleeding as well.

And importantly, more than half of patients face iron deficiency anemia. So this is a burdensome condition and from one for which there are very limited treatment options. Importantly, we've already demonstrated initial proof of mechanism for this program in healthy volunteers in Phase I. On the right are the results from an ex vivo assay of fibrinolysis from our Phase I study and shows in the top panel without ALN-6400, clot formation represented by the dark blue area quickly dissipates. Whereas with ALN-6400, there is an antifibrinolytic effect as represented by the dark blue area, which extends for a much longer time, and this effect is maintained after 43 days. We've now moved ALN-6400 into a Phase II trial in HHT patients and look forward to providing updates as this program progresses. We also continue to advance new programs into clinical development building a pipeline that has the potential to drive sustainable growth and long-term value creation.

Today, for example, we announced the initiation of a Phase I trial of ALN-5288, which targets MAPT or TAO for Alzheimer's disease and potentially other rare [indiscernible] . The trial will evaluate the drug safety, tolerability, pharmacokinetics and pharmacodynamics in adult patients with Alzheimer's disease. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?

[Jeffrey Poulton, executive]

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q3 2025 financial results and discussing our full year upgraded guidance. Let's begin with a summary of our P&L results for Q3 2025 compared with the same period in 2024. Total product revenues for the quarter were $851 million or 103% growth versus 2024, driven by 135% growth in our TTR franchise, primarily from the continued strong performance of the U.S. launch of AMVUTTRA and ATTR cardiomyopathy. Collaboration revenue for the quarter was $352 million, representing a $294 million increase when compared with last year. The increase was primarily due to revenue recognized under our collaboration and license agreement with Roche, including $300 million of milestone revenue associated with the dosing of the first patient in our ZENITH Phase III cardiovascular outcomes trial with [indiscernible] .

Royalty revenue for the quarter was $46 million representing a doubling compared with last year, driven by higher [indiscernible] sales as Novartis continues to successfully grow the product globally. Gross margin on product sales was 77% for the quarter, compared with 80% in the third 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 rate compared with last year. For the fourth quarter, our gross margin on product sales is expected to decrease as the applicable AMVUTTRA royalty rates increased further, driven by higher expected sales of AMVUTTRA. Our non-GAAP R&D expenses of $310 million increased 23% compared to last year, primarily driven by costs associated with the initiation of multiple Phase III clinical studies including the Zenith Phase III cardiovascular outcomes trial for zilebesiran and the TRITON CM Phase III study for ducrisiran.

Our non-GAAP SG&A expenses of $263 million increased 35% 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 $476 million, representing a $507 million increase compared with last year, driven primarily by strong top line results both in product sales, a well's revenue from collaborations as previously highlighted. We continue to be pleased with the progress we are making towards achieving our non-GAAP operating profitability guidance in 2025. We ended the quarter with cash, cash equivalents and marketable securities of $2.7 billion compared with a similar amount at the end of 2024. Cash for the quarter was impacted by our refinancing in September. We raised more than $600 million via the issuance of new convertible notes, which was more than offset by the use of $1.1 billion of cash to repurchase a large portion of our convertible senior notes due in 2027.

Additionally, we also entered into a $500 million revolving credit facility, providing a new source of flexible liquidity if necessary. Now I'd like to turn to our financial guidance for 2025 and where we are increasing our net product revenue guidance driven by the strong U.S. launch performance of AMVUTTRA and ATTR cardiomyopathy with specific details as follows: we are increasing our net product revenue guidance from a range of $2.65 billion to $2.8 billion to a revised range of $2.95 billion to $3.05 billion representing a $275 million or 10% increase from the midpoint of the prior guidance to the midpoint of the updated guidance. The combined full year growth compared to 2024 is an 82% increase at the midpoint of the guidance range. On a franchise level, the guidance is broken down as follows: we are increasing our total TTR guidance range from $2.17 billion to $2.275 billion to a revised range of $2.475 billion to $2.525 billion, representing a 12% increase at the midpoint.

We are reiterating our guidance range for our total rare franchise of $475 million to $525 million. We are also narrowing the range of our non-GAAP operating expense guidance to $2.15 billion to $2.2 billion as we expect to end the year at the upper end of our original 2025 operating expense guidance. The remainder of our financial guidance, including collaboration and royalty revenue and non-GAAP operating income remains unchanged. Turning now from financials to our key remaining goals for 2025. As Pushkal mentioned earlier, the TRITON TN trial of nucresiran and hATTR-PN will initiate shortly. We also expect to initiate a Phase II trial of [indiscernible] in Alzheimer's disease. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

[Christine Lindenboom, executive]

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]

[Operator Instructions]

First, we will hear from Salveen Richter at Goldman Sachs.

[Salveen Richter, analyst]

Could you just speak with regard to AMVUTTRA how the momentum is going in the first line versus switches population and maybe talk about any combo use? And any clarity here on ex U.S. pricing would be helpful as well.

[Yvonne Greenstreet, executive]

Yes. This is a great question. We're obviously really pleased with the continued momentum that we're seeing with respect to growth in our TTR business, particularly having doubled the patient demand volume for AMVUTTRA cardiomyopathy in the U.S. But Tolga, why don't you kind of take the question around.

[Tolga Tanguler, executive]

Absolutely. Look, we're really pleased with another strong quarter. As we indicated, demand doubled in cardiomyopathy and utilization remains very broad and balanced. So let me double-click on that. What we're really seeing is an adoption across both academic and community settings and also from a wide range of prescribers and patient types. And essentially, that really demonstrates a very healthy uptick. Within that, what we also like to see is what we're seeing is we're getting in a place of very competitive setting in terms of first line. And our first-line share continues to grow quarter-over-quarter. And we're obviously maintaining a clear leadership in second line among those patients that are progressing or not responding to a stabilizer. So that breadth and balance gives us real confidence in the durability of [indiscernible] momentum.

And in terms of our ex U.S. pricing, we're still continuing to engage with a broad range of countries in terms of pricing and reimbursement. What we've so far seen is a really compelling pricing profile for in Japan. We're also launched in Germany, but we're actually in the early stages of pricing and reimbursement negotiations. And obviously, what we're really trying to make sure is the right value for our innovation is being recognized in Europe as well as we have in the U.S. And that remains to be seen throughout '26.

[Yvonne Greenstreet, executive]

Yes. And there's a question on combination use. And I think, look, we're seeing some use in combination. But overall, the majority of the use is as a monotherapy. And as we've always said, the [indiscernible] goes generic, we anticipate that we'll see increasing combination use. Thanks for your question. Next question.

[Operator]

Will be from Paul Matas at Stifel.

[Unknown Analyst]

This is Julian on for Paul. Just a quick question again on AMVUTTRA. I guess like what gives you confidence that you're going to continue to see an acceleration in patient adds next year and going into the end of this year? And also, it seems like there was somewhat of a contribution from switches from ONPATTRO in the U.S. this quarter versus last quarter. Again, any color on patient switches from stabilizers would really be helpful.

And then just really quick on [indiscernible] , can you just talk about what led to the decision to pursue that program and your confidence in the target. Does this say anything about your ALN-APP program in all sites as well?

[Yvonne Greenstreet, executive]

Okay. So a couple of questions here, and we'll try and kind of unpack them Look, I think what Tolga shared in the prepared remarks were really the features of a very strong launch, as obviously, we're delighted by them. We do see kind of a lot more potential ahead of us. Tolga, do you want to...

[Tolga Tanguler, executive]

Yes. Maybe I can take that on ONPATTRO contribution question right off the bat. Look, I think actually, you're probably misinterpreting that ONPATTRO declined from the prior quarter, and that really was driven by the ONPATTRO's favorability from last quarter's onetime Medicaid adjustment, which didn't repeat. So that really is the dynamic. We're actually seeing a pretty steady quarter-over-quarter maintenance of our ONPATTRO business, albeit very minimal. And also, our PM business remains very, very stable. So in terms of our ability to actually continue to robustly continue this momentum. Look, we're only 2 quarters into this launch. And we've already raised guidance twice.

I think that really speaks volume about the depth and the durability and our confidence in how we see these categories continue to grow. And as I mentioned, I think we do have a very balanced and broad uptick. And we certainly look forward to increasing our presence in first line, which is highly competitive as it is and maintain our leadership in those patients that are progressing on a stabilizer.

[Yvonne Greenstreet, executive]

Thanks, Tolga. And I think the question with respect to [indiscernible] implications for APP. Pushkal, would you take that one?

[Pushkal Garg, executive]

Yes, absolutely. Look, we're very excited about bringing Matto the clinic. I think as a starting point, this just highlights what we think is the potential of RNA interference therapeutics to have really substantial effect in neurodegenerative diseases. So along with APP, we have Huntington's program, APT, our colleagues at Regeneron are advancing SOG. We've just been very excited about the -- our delivery -- our ability to deliver safely and with infrequent dosing.

[indiscernible] is a genetically validated target both in Alzheimer's disease and primary [indiscernible] , which are all neurodegenerative diseases where we get these neurofibrillary tangles that cause neurodegeneration and cognitive decline in patients. So very excited. We're building really a portfolio of therapeutics that we think hopefully can address some of the most intractable diseases in mankind. And I think this just speaks to the strength of the platform and hopefully being able to deliver a second and additional pillars in 2030 and beyond.

[Yvonne Greenstreet, executive]

I think that's great. Thank you for asking a pipeline question. We really do believe that not only who we bought a very well developing revenue trajectory with respect to our TTR franchise, but we really do have a clinical pipeline that has a number of multibillion opportunities that we're prosecuting in fiscals, organizations, expeditious as began, clearly being able to help patients with severe neurodegenerative diseases would be an incredible achievement. So thank you, Pushkal. Next question.

[Operator]

[indiscernible] at Bank of America.

[Tazeen Ahmad, analyst]

I wanted to get some color on payer dynamics as you get into the launch now Lari,like your third or fourth quarter in almost -- how are you getting feedback from payers or survey work seems to indicate that we're not seeing any pushback yet even as the drug has adopted to formulary. But as you're thinking about or currently negotiating 2026 status, can you share with us some of the feedback that you're getting from payers? Is there going to be any risk of payers preferring a stabilizer to a silencer or at least ordering which of the products that are currently available, they might prefer.

[Yvonne Greenstreet, executive]

Yes. No, that's a great question. I mean, look, we're delighted that we really had no payer headwinds. And perhaps, Tolga, do you want to kind of speak to the outlook as we see it as we go into 2020.

[Tolga Tanguler, executive]

Hi Tazeen, I think it's really good to hear that you guys feel like it's already been a year almost. It's actually only 2 quarters that we've had the launch -- and as Ivan indicated, that what we're seeing is really headwinds in terms of every actually payer piece, whether it's fee-for-service, Medicare Advantage or even in the commercial setting. I know there has been a lot of debate around whether we would be step edited or whether the burden on the patients in terms of co-pay would be high.

And what we're really pleased to see, as anticipated based on our experience in the PN, payers actually understand and they appreciate the value that this product brings. Clearly highly differentiated in a disease that's actually fatal and highly progressing. And both payers and physicians really appreciate that this disease needs to be treated early and effectively. And what we're seeing is not only within actually '26 but -- sorry, but '25 but also '26. Policies are being negotiated, and it's -- they're almost final. And we're seeing a very similar dynamic that we had anticipated early in the launch.

[Yvonne Greenstreet, executive]

Thanks, Tolga. That's great.

[Operator]

Next is Maurice Raycroft at Jefferies.

[Maurice Raycroft, analyst]

Wondering if you can comment more on just the inventory demand number for third quarter and how to think about that for fourth quarter, along with gross to net and can you walk us through your expectations for fourth quarter revenues in the EU and how to think about the ramp up there?

[Yvonne Greenstreet, executive]

Jeff, I think that's one for you.

[Jeffrey Poulton, executive]

Yes. I'll take the question on inventory and gross to net in the third quarter, very similar dynamics to what we saw in the second quarter. From an inventory standpoint, days on hand stayed pretty constant -- for the quarter, but there was growth in inventory in the channel, and that's because of the way the day on -- of inventory is calculated. It's based on demand. And given the ramping demand, that's what created additional inventory going into the channel for the quarter. that was more than offset in the quarter by an increase in gross to net. Tolga mentioned ONPATTRO. That was the biggest driver of the increase in gross to net between Q2 and Q3, where we see gross to net for the TTR franchise for the year continues to be mid-single-digit price decline on a net price basis on a year-over-year basis.

I think that Maury, maybe if you could repeat the other question about Europe and maybe -- today want to take that one. In terms of expectations for Q4, I think he was asking about. Is that right, Maury?

[Maurice Raycroft, analyst]

Yes, that's right. And just how to think about the ramp up in Europe as well.

[Tolga Tanguler, executive]

Right. So I think the -- if I were to think in a greater scheme of things, the contribution of ex U.S. market is going to remain relatively modest, especially for fourth quarter, given that we only have really 2 markets that's going to be -- that's right now available. Germany and Japan. In Germany, we're continuing to actually have final pricing discussions. So that's obviously going to be rather limited. In Japan, we're very pleased with the momentum that we built. But again, in the greater scheme of things, the contribution is going to be very modest.

So ex U.S. market is going to be mainly 2026, mid- to late 26 story. What I really like seeing is how we're actually maintaining our PN business. If you look at year-over-year, the growth now is 46% in ex U.S. and TTR markets. That suggests that -- and this is actually in the presence of a new competitor now. So look, I mean, I think just like what we've done in the U.S., in the PN markets, we are competing very effectively capturing majority of the first-line patients. And we've actually established a great ecosystem and these key centers of excellence in Europe really recognize the value of our treatment and the product profile. So I would expect more to come on that in '26.

[Yvonne Greenstreet, executive]

That's great, Phil. Look, I mean, I think as a company, we've built a really phenomenal R&D engine. And I think now we established a very robust commercial engine. So thanks to Tolga and his team with their achievements over the last quarter.

[Operator]

Next, we will hear from Jessica Fye at JPMorgan Chase.

[Jessica Fye, analyst]

Congrats on the quarter. I was curious if you could just elaborate on the approach you took to updating the TTR franchise guidance this time around in light of the fact that, as you said, we're still just 2 quarters into the cardiomyopathy launch?

[Jeffrey Poulton, executive]

Yes. I'm happy to take that, Jess. We updated the guidance. So obviously, what we're really doing here is predicting what we're going to see in the fourth quarter because that's the only time point we've got left in the year relative to the guidance that we've just issued. And if you look at the guidance, it's roughly estimating total TTR global revenue of $850 million to $900 million in the fourth quarter, which would reflect $125 million to $175 million of quarter-on-quarter growth on that range. The upper end of that range is very close to what we've delivered in both Q2 and Q3. And so I would say that's really how we've develop the guidance.

We're continuing to learn. As Tolga said, we're 2 quarters in. I think our understanding of the business and the ability to forecast it is improving as we get more data points. But we're comfortable with the range, and I would think about the midpoint is the most likely outcome for Q4.

[Operator]

Will be from Luca Issi at RBC.

[Luca Issi, analyst]

Great. Thanks so much. I think congrats on another fantastic quarter. Maybe Tolga, CMS is obviously proposing to cut reimbursement for [indiscernible] I think, by 57% from $1,300 all the way down to $500. I guess what was your reaction to that news and maybe related, do you think that such efforts from CMS will remain insulated to just the diagnostic side of the equation? Or you think that CMS will optimal look also on the therapeutic side of the equation, given obviously the cost therapeutics are much higher than the diagnostics side? And then maybe super quickly, can you just maybe talk about subpoena from the U.S. Attorney General that you put in the press release?

[Yvonne Greenstreet, executive]

Well, look, why don't I take the subpoena question really quickly. And look, clearly, we intend to work with the U.S. Attorney's office to produce the documents that have been requested by the subpoena and to understand, and address any potential concerns with respect to government price reporting. And of course, as you know, we don't generally comment on legal matters, but thank you for the question. And I'll hand it over to Tolga to take the remainder of your question.

[Tolga Tanguler, executive]

Yes. So scans and how they are being currently reimbursed is obviously has been an important driver for the growth of this category. We actually anticipate more diagnosis and more scanning. We need to really fully understand how that reimbursement is actually going to play out. We haven't really seen any anxiety or concerns in the health systems that we're engaging with. So we're obviously, again, staying in tune and I'm sure we'll be able to manage that as the policy becomes more clear.

[Operator]

From Gena Wang at Barclays.

[Huidong Wang, analyst]

Also congrats on the great quarter. So maybe just want to confirm I heard correct that the price for AMVUTTRA will be declined at the mid-single digit year-over-year in the U.S.? And a related question is that once you launch your [indiscernible] , in Europe, how should we think about price change in Europe? Should we expect a huge dip or largely align with the U.S.?

And then second question is regarding the AMVUTTRA in ATTR cardiomyopathy in the U.S. Just wondering if you can share a little bit more color regarding the ratio between the first line versus second line. Are we talking about roughly 50-50 or second line is slightly higher?

[Yvonne Greenstreet, executive]

So we got kind of a number of questions here about kind of price year-on-year in the U.S. price and color on the first line, second line split. I think all of those are for you Tolga. Why don't you go ahead.

[Tolga Tanguler, executive]

I mean, look, Gena, as we had highlighted before, we would actually anticipate our net price to be gradually going down over time. And what you're seeing is perhaps some of those impacts and we'll continue to provide, obviously, what gross to net actually margins will look like over time. But I wouldn't expect a serious or significant shift in that. Now when it comes to Europe, obviously, those negotiations are continuing. And what we're making sure is that we are taking into account MFN and a number of other dynamics. And we'll obviously be able to provide a much more broader outlook in terms of how the volume and price is going to play out in the outer years.

As I said before, this is really going to be a mid- to late '26 story. And your other question is around remind me again, is ratio of first line and second line. Yes. I mean, look, I think what we really like to see so far, what we've been seeing is, we are increasingly getting more competitive in first line, second line in terms of stabilizer that obviously is an existing patient pool that has actually started very early in the launch, but what we like seeing is after first month into the launch, we start seeing a much more balanced and broad uptake between first and second line. And we certainly expect that to continue as we actually increase our first-line presence in the outer quarters.

[Yvonne Greenstreet, executive]

Yes. And I'd just like to add how well the data from HELIOS-B are actually resonating with physicians. I mean, being -- cabin the first silence TTR with rapid knockdown of TTR resource. I think that's having an impact. I think the data that we continue to generate is important. I mean, Pushkal touched on this in terms of 37% relative risk reduction in all-cause mortality and first CV events. I think Pushkal also touched on the multisystem nature of the disease with a reduction in GI events. That really is, I think, I think, a compelling additional data point for physicians.

And of course, the quarterly regimen, I think, also resonates well where physicians can be sure that patients are actually going to receive their drug given the quarterly subcutaneous administration. So all in all, I think we feel really well positioned in this market. Both for a growing position in first line as Tolga said, we're highly competitive here and obviously, the leading choice for patients who continue to progress on stabilizes. So we feel we've built some really good foundations here. Thank you for the question. So I think we're on to our -- just 2 more questions.

[Operator]

Please go ahead, Ritu Baral at TD Colin.

[Ritu Baral, analyst]

Just back to Europe, Tolga. Can you talk about what degree of commercial investment is needed in Europe to expand beyond the PN indication. We're trying to figure out how to balance that against any potential lower cost? And then just a very quick follow-up. As we think about that first line dynamics, how much does center type impact first-line use, basically, if they're in commercial hospital systems versus patient characteristics?

[Tolga Tanguler, executive]

No, that's helpful. Thank you, Ritu. So here are a few points around how you should be thinking about Europe. So we actually have quite an effective team that has been able to establish a market leadership versus tafamidis in the polyneuropathy organization. And the main reason why that organization is so effective is because this is a category, particularly in Europe, is really managed by centers of excellence, perhaps maybe with the exception of Germany. In most other centers, this is in countries. This is really managed by centers, albeit Italy or France, and some other major other European countries. We know in the U.K., for instance, there is one single center national media center that manages that. So it does require in test collaboration and obviously, a scientific engagement.

But in terms of the field activity, that's rather limited. And cardiomyopathy patients are actually mostly treated in these centers as well. So we wouldn't expect a significant expansion of our European businesses. Now when it comes to Japan, that market is a little more fragmented, so we do actually invest. We certainly play to win in that category, and we will obviously continue to invest what's necessary to make sure that the product profile is well understood and appreciated.

[Yvonne Greenstreet, executive]

Thanks, Tolga. So one more question with our last question coming out.

[Operator]

Last question is from Cory Kasbah at Evercore.

[Unknown Analyst]

This is Adi on for Cory. The tafamidis trends show a clear NRx jump from fourth quarter to first quarter in both 2024 and 2025. Should we model a similar jump up for AMVUTTRA, thinking that is it because of IRA Part D modifications in the past year or normal seasonality?

[Tolga Tanguler, executive]

Yes. So maybe I'll take your question more from a perspective of category growth and what you should be expecting. Look, first and foremost, it's obviously still early days. And only one company has reported so far in terms of their quarter-over-quarter dynamic. But -- and we still like to see how Pfizer is going to report before we drove some firm conclusions about how that dynamic is working. But that said, everything that we're seeing, the category growth in ATTR-CM is accelerating.

And it's no surprise because we all know that this is an underdiagnosed and undertreated category, and there are a lot of patients are still waiting. And we've also seen this very much on [indiscernible] neuropathy with just one product coming in on top of us, we've seen the category growing, accelerating a lot faster. And the good news on polderopathy, we still remain actually the first-line market share leader. And within the expected category growth I would say we are exceptionally well positioned. As Yvonne and Pushkal mentioned, we are well differentiated in terms of our mechanism. We obviously have the robust outcomes supplied by HELIOS-B and importantly, we are continuing to invest in the category, especially on real-world evidence and data generation across both clinical and real-world setting. So our evidence base is strengthening. That really positions us to become a market leader in this growing category.

[Yvonne Greenstreet, executive]

Great. Well, I think that brings our call to a close. And I'd just like to thank everybody who's joined us today. Look, our execution this quarter commercially in respect to our pipeline, I think it really demonstrates the new unique trajectory we have at Alnylam to become a top-tier biotech company and we look forward to sharing with you additional updates as we embark on realizing this vision. So thank you, everybody, and have a great day.

[Operator]

Thank you. Ladies and gentlemen, this does indeed conclude your conference call for today. Once again, thank you for attending. And at this time, we do ask that you please disconnect your lines.