Alnylam Pharmaceuticals, Inc.

Ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals 3Q 2025 Earnings Conference Call. At this time, all lines are in the listen-only mode. Following the presentation, we will conduct a question and answer session. And if at any time during this call you require immediate assistance, please press star zero for the operator. Also note that this call is being recorded on Thursday, October 30th, 2025. And I would like to turn the conference over to management.

Please go ahead. Good morning, I'm Christina Kinch, Chief Corporate Communications Officer at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer, Tolga Tangular, Chief Commercial Officer, Krish Kulgar, Chief Research and Development Officer, and Jeff Fulton, 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 slash events. During today's call, as outlined in slide two, Yvonne will offer some introductory remarks and provide general context. Tola will provide an update on our global commercial progress. Pushka 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 L&M's future expectations, plans, and prospects, which constitute forward-looking statements for the purpose of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with SEC. In addition, any forward-looking statements represent our views only as the date of this recording. It should not be relied upon as representing our views as any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to Yvonne.

Yvonne? Thanks, Christine, and thank you, everyone, for joining the call today. Our Nilem'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 biotech company, our focus remains on these three core pillars that we believe will drive sustainable growth and value creation for years to come. The first is TTR leadership. The Ambutra cardiomyopathy 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 through innovation, focused on the potential multi-billion 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 Ambuter CM launch in the US, 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 drove 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 ZENUS Phase III Cardiovascular Outcomes Trial of Zalbiceran in Hypertension has initiated, and the TRITON-PN study of Nucreceran 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 103% year-over-year. As a result, we've again increased our total net product revenue guidance for 2025 from a 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 Anvutra ATTRCM launch and our other commercial products for the remainder of the year. Now, with our Arnhartland piece of this by 2025 era concluding soon, we're thrilled by this incredible execution over the past five 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? Thanks, Ivan, 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, Q3 continued Alnylam's 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 five 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 demands. 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 two 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 $724 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. growth to net deductions. It is worth noting that the increase in growth to net deductions primarily impacted on PATRO, 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 Amutra ATTR-CM label expansion. Before we provide further color on the US launch, let me quickly share the ex-US dynamics. Outside the US, revenues grew 13% versus the prior quarter, and 46% year-over-year, underscoring continued global momentum. Further, international Ombudsman 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 Ambuter'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 polyneuropathy 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 Alnylam ATTR-CM launches expand worldwide. Now, let's turn to the U.S. Amutra ATTR CM launch, which recently completed its second full quarter and continues to build momentum. In Q3, our U.S. TTR franchise across both PM 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 polyneuropathy-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 ultra ATTR-CM with patient demand roughly doubling compared to Q2 as awareness and physician adoption continue to grow. Our strength is built on three 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 Amutra, driving broad utilization. Combined with our extensive treatment site network, roughly 90% of the US patients can receive their Amutra treatment within 10 miles of home anywhere in the US, a meaningful milestone in 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 Ambutra as a first-line treatment option, meaning these patients have no step edits. Of similar importance, most patients pay zero out-of-pocket. Finally, with health system setup and access and affordability in place, we are focused on treatment choice, and the profile of Ambutra continues to resonate. We're seeing broad and balanced adoption across newly diagnosed patients and those progressing on stabilizers in both academic and community settings. Prescriber growth also remains robust. Having reviewed the three strategic pillars were executing and delivering on them. Patient demand roughly doubled quarter over quarter, reflecting strong, sustained momentum for the Amutra ATTR-CM in 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-US launches are expected to begin in 26 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, Building a Durable Foundation. Pushkal and the R&D organization are leading that chapter. With that, I'll hand it over to you. Pushkal.

Thank you, Tolga, and good morning, everyone. In support of Ambutra's strong launch in ATTRCN, 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 Ambutra 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 B that demonstrate the sustained benefits of butreceran through up to 48 months, which includes 12 months from the open-label extension. Specifically, as compared to placebo, butreceran 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 butyriceran treatment was associated with a lower rate of gastrointestinal adverse events versus placebo across the overall butyriceran monotherapy and baseline tefamidus treatment groups with reductions of 37 to 49 percent. This observation is quite important because it suggests vitreous strand may reduce GI symptoms, which, as you can see from the placebo data, were 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 amyloid doses. Necresiran, 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 CN 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 Nucreceran in approximately 125 patients with HATTR-PN. Patients will be randomized four to one to receive either Nucreceran dosed every six months or to a reference arm of Vutriceran dosed every three months. The primary endpoint is the change from baseline in the modified neuropathy impairment score, or MNIST plus seven, at month nine in the Nucreceran arm as compared to the placebo arm from the Apollo Phase III trial of patriceran. You might recall that this is essentially the same study design we utilized in our Helios-A pivotal study of vitriceran in HATT-RPN, which led to its initial approval in that disease setting. We expect top-line results in TritonPN in 2028 and 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 Zalbiceran 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 3 Phase 2 study. As you can see, treatment with alveceran resulted in clinically meaningful reductions in office systolic blood pressure in patients with uncontrolled hypertension and and high cardiovascular risk at the month three primary endpoint with continuous control sustained through month six. Moreover, the treatment effect was further enhanced in a biologically-based, enriched subgroup of patients. With these results, CARDIA-3 met the objective of informing the design, patient population, and dose for the global phase three cardiovascular outcomes trial, Zenith. is a cardiovascular outcomes trial that will enroll approximately 11,000 patients to evaluate Zalvisran at a dose of 300 milligrams given every six months compared to placebo in patients with uncontrolled hypertension with either established or at high risk for cardiovascular disease on two or more antihypertensives. The endpoint is a Ventrin with a minimum follow-up of two years, and we expect a launch, assuming a successful study and regulatory approval around 2030. I'm also excited to share an update today on our ALN6400 development program. ALN6400 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 an increased risk of thrombosis, as we believe that by lowering plasminogen with ALN6400, 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 telangiectasia, HHT. HHT is the second most common inherited bleeding disorder, affecting individuals of all ages. 90% of HHT patients live with recurrent nosebleeds, which can be severe and life-threatening. And many experience 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 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 1. On the right are the results from an ex vivo assay of fibrinolysis from our Phase 1 study and shows in the top panel, without ALN6400, clot formation represented by the dark blue area quickly dissipates. Whereas with ALN6400, there's 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 ALN6400 into a phase two 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 ALN5288, which targets MAPT, or tau, for Alzheimer's disease and potentially other rare tauopathies. 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?

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of El Milam'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 Ambutra 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 SELVISARAN. Royalty revenue for the quarter was $46 million, representing a doubling compared with last year, driven by higher Lectio 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 Ambutra, 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 Ambutra royalty rates increase further, driven by higher expected sales of Ambutra. 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 Xenus Phase III Cardiovascular Outcomes Trial for SLB-Saran and the Triton-CM Phase III Study for Ducree-Saran. 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 Invutra 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 as well as 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 where we are increasing our net product revenue guidance driven by the strong U.S. launch performance of Inbutra and ATTR cardiomyopathy with specific details as follows. We are increasing our net product revenue guidance from a range of 2.65 to 2.8 billion to a revised range of 2.95 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 2.175 to 2.275 billion to a revised range of 2.475 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 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. push call mentioned earlier, the TRITON-PN trial of Nucresiran and HATTR-PN will initiate shortly. We also expect to initiate the Phase 2 trial of Mibelsiran and Alzheimer's disease. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

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

Thank you. Ladies and gentlemen, if you do have any questions, please press star followed by one on your touchtone phone. You will then hear a prompt that your hand has been raised. And should you wish to decline from the polling process, please press star followed by two. And if you're using your speakerphone, please lift the handset first before pressing any keys. Please go ahead and press star one now if you have any questions. First, we will hear from Salvin Richard at Goldman Sachs.

Please go ahead. Good morning. Thanks for taking my question. Could you just speak with regard to Amputra, 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-US pricing would be helpful as well. Thank you.

Yeah, that's 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 Amfutro and cardiomyopathy in the US. But Tolga, why don't you kind of take the question around?

Absolutely. Hi, good morning, Salveen. 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 uptake. 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 Ambuteraz Momentum. And in terms of our ex-US 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 US. And that remains to be seen throughout 26.

Yeah, 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, as FAMIDIS goes generic, we anticipate that we'll see increasing combination use. Thanks for your question. Next question.

Will be from Paul Matus at C4. Please go ahead, Paul.

Hey there. Thanks so much. This is Julian on for Paul. Just a quick question again on, on I guess, like what gives you confidence that you're going to continue to see an acceleration and inpatient ads, you know, next year and going into the end of this year. And also it seems like there was, you know, somewhat of a contribution from, you know, switches from on Patro in the U S this quarter, you know, versus last quarter. Again, any color on, you know, patient switches from, you know, stabilizers would really be helpful. And then just really quick on MAT-T, can you just talk about, you know, what led to the decision to pursue that program and your confidence in the target? You know, does this say anything about your ALN-APP program in Alzheimer's as well? Thank you.

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 a lot of the features of a very strong launch, which obviously we're delighted by, and we do see kind of a lot more potential ahead of us. Tolga, do you want to?

Yeah, maybe I can take that on Patro contribution question right off the bat. Look, I think actually you're probably misinterpreting that Ompatro declined from the prior quarter. And that really was driven by the Ompatro's favorability from last quarter's one-time Medicaid adjustment, which didn't repeat. So that really is the dynamic. We're actually seeing a pretty steady, you know, quarter over quarter maintenance of our Ompatro 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 two quarters into this launch, and we've already raised guidance twice. I think that really speaks volumes about the depth and 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 uptake, 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.

Thanks, Tolga. And I think the question with respect to MAP-T and implications for ATP, Pushkol, would you take that one?

Yeah, absolutely. Yeah, look, we're very excited about bringing MAP-T into the clinic. I think As a starting point, this just highlights what we think is the potential of RNA interference therapeutics to have a really substantial effect in neurodegenerative diseases. So along with APP, we have Huntington's program, MAPT, our colleagues at Regeneron are advancing SOD1. We've just been very excited about our ability to deliver safely and with infrequent dosing. Tau is a genetically validated target, both in Alzheimer's disease and primary tauopathies, 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.

I think that's great, Pushkar. Thank you for asking a pipeline question. We really do believe that not only have we got 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 multi-billion opportunities that we're prosecuting in Pushkar's organization as expeditious as we can. Clearly, being able to help patients with severe neurodegenerative diseases would be an incredible achievement. Thank you, Pushkar.

Next question. Next is Tazeen Ahmad at the Bank of America. Please go ahead.

Hey, guys. Good morning. Thanks for taking my question. I wanted to get some color on payer dynamics as you get into the launch on, you know, now, Laurie, like your third or fourth quarter in almost. How are you getting feedback from payers? Our survey work seems to indicate that we're not seeing any pushback yet. even as the drug gets adopted to formulary. But as you're thinking about or currently negotiating 2026 status, you know, 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, you know, ordering which of the products that are currently available they might prefer? Thanks.

Yeah, no, that's a great question. I mean, look, we're delighted that we really had no payer headwinds. And perhaps, Tolga, you want to kind of speak to the outlook as we see it as we go into 2026.

Hi, Tazin. I think it's really good to hear that you guys feel like it's already been a year almost. It's actually only two quarters that we've had the launch. And as Ivan indicated, what we're seeing is really no headwinds. in terms of every actually uh 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 uh you know whether we would be step edited or whether the the burden on the patients in terms of copay would be high and what we're really pleased to see as anticipated based on our experience in the pn uh Payers actually understand and 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 25, but also 26 policies are being negotiated, and they're almost final. And we're seeing a very similar dynamic that we had anticipated early in the launch.

Thanks, Tolga. That's great. Next question.

This is Maureen Raycroft at Jefferies. Please go ahead.

Hi, good morning. Congrats on that great quarter, and thanks for taking my question. I'm 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?

Jeff, I think that's one for you.

Yeah, 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 that the day 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 nets. Tolga mentioned on PATRA that was the biggest driver of the increase in gross to net between Q2 and Q3. Where we see gross to nets for the TTR franchise for the year continues to be, you know, 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 Tolgan may want to take that one in terms of expectations for Q4, I think he was asking about.

Is that right, Maury? Yeah, that's right. And just how to think about the ramp up in Europe as well.

Right. So I think that if I were to think in a greater scheme of things, the contribution of ex-US market is going to remain relatively modest, especially for fourth quarter, given that we only have really two markets that's going to be, that's right now available, Germany and Japan. And in Germany, we're continuing to actually have final pricing discussion. 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-US market is going to be mainly at 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-US 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 US, in the PN market, 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.

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

Next question. Next, we will hear from Jessica Phai at JPMorgan Chase. Please go ahead.

Hey, guys. Good morning. 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 two quarters into the cardiomyopathy launch. Thank you.

Yeah, I'm happy to take that, Jess. You know, 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 The guidance, it's roughly estimating total TTR global revenue of $850 to $900 million in the fourth quarter, which would reflect $125 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 developed the guidance. We're continuing to learn. As Tolga said, we're two quarters in. I think our understanding of the business and ability to forecast it as improving as we get more data points. But we're comfortable with the range, and I would think about the midpoint as the most likely outcome for Q4.

Thank you.

Good. Next question. Will be from Luca Issi at RBC. Please go ahead, Luca.

Oh, great. Thanks so much for taking my questions. Congrats on another fantastic quarter. Maybe, Tolga, you know, CMS is obviously proposing to cut reimbursement for POP scintigraphy, I think, by 57% from $1,300 all the way down to $500. I guess, what was your reaction to that news? And then maybe related, do you think that such efforts from CMS will remain insulated to just the diagnostic side of the equation? Or do you think that CMS will have to look also on the therapeutic side of the equation, given obviously the cost of therapeutics? are much higher than the diagnostic side. And then maybe super quick, quickly, can you just maybe talk about the subpoena from the US Attorney General that you put in the press release? Thanks so much, guys.

Well, look, why don't I take the subpoena question really quickly. And look, clearly, you know, we intend to work with the US Attorney's Office to produce the documents that have been requested by the subpoena and to understand and you know, 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 questions.

Yes. So PIP scans and how they're 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 system 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.

Thank you so much.

Great. Good answer. Thank you. Next question. from Gina Wang at Barclays. Please go ahead.

Thank you for taking my questions. Also, congrats on the great quarter. So maybe I just want to confirm I heard it correct that the price for Ambutro will be declined at the mid single digit year over year in the U.S. And a related question is that once you launch ATTR cardiomyopsy in Europe, how should we think about price change in Europe? Should we expect a huge dip or largely aligned with the U.S.? And then second question is regarding the N-lutro in ATTR cardiomyopsy in the U.S. Just wondering if you can share a little bit more color regarding the ratio between the first line versus the second line. Are we talking about roughly 50-50 or second line is slightly higher?

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

I mean, look, Gina, 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 impact. 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. Yeah, 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.

Yeah, and I'd just like to add how well the data from Helios B are actually resonating with physicians. I mean, being, you know, Vujic being the first and least silencer at TTR with rapid knockdown of TTR at source. I think that's having an impact. I think the data that we continue to generate is important. I mean, Pushkar touched on this in terms of 37% relative risk reduction and all-cause mortality and first CME event. I think Pushkar also touched on the multi-system nature of the disease with a reduction in GI events. That really is, I think, a compelling additional data point for physicians And of course, the quarterly regimen, I think, also resonates well where, you know, 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, you know, growing position in first line, as Tolga said, we're highly competitive here. And, you know, obviously, you know, the leading choice for for patients who continue to progress on stabilizers. So, you know, we feel we've built some really good foundations here. Thank you for the question. So I think we're on to our, just two more questions. So Ritu, apparently you're up next.

Please go ahead, Ritu Borel at TD Cohen. Hi, guys. Thank you so much for taking the question. 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, you know, 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, you know, if they're in commercial hospital systems versus patient characteristics? Thanks.

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 tefamidus in the pole neuropathy 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 UK, for instance, there is one single center, National Amnesty Center, that manages that. So it does require... intense 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's profile is well understood and appreciated.

Thanks, Tolga. So one more question. We've got our last question coming up.

Last question is from Corey Kasabov at Evercore. Please go ahead.

Hi, good morning. Thank you for squeezing us in. This is Addy on for Corey. The defamitis 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 Mvutra, you know, thinking that is it because of IRA Part D modifications in the past year or normal seasonality? Thank you.

Yeah, 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 draw 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 that are still waiting. And we've also seen this very much on polyneuropathy. 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 polyneuropathy, 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 Ivan and Pushkar 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.

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 and with respect to our pipeline, I think really demonstrates the 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.

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.