Good morning, everyone, and welcome to the Alnylam Pharmaceuticals third quarter 2025 Earnings Conference Call. This call is being recorded on Thursday, October 30, 2025. I will now hand it over to management.

Good morning. I'm Christine Akinc, Chief Corporate Communications Officer at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Research and Development Officer; and Jeff Poulton, Chief Financial Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events. During today's call, as outlined in Slide 2, Yvonne will offer some introductory remarks and provide general context, Tolga will provide an update on our global commercial progress, Pushkal will review pipeline updates and clinical progress, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call to your questions. I 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 Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to Yvonne. Yvonne?

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 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 AMVUTTRA 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 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 broader balance 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 ZENITH Phase III cardiovascular outcomes trial of zilebesiran in hypertension has initiated, and the TRITON-PN study of nucresiran 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 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 ATTR-CM launch and our other commercial products for the remainder of the year. Now with our Alnylam P 5x25 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, 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, 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 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 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. gross-to-net deductions. It is worth noting that the increase in gross-to-net deductions primarily impacted ONPATTRO, reducing U.S. reported quarter-over-quarter 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 ATTR-CM 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’s 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 AMVUTTRA ATTR-CM launches expand worldwide. Now let's turn to the U.S. AMVUTTRA ATTR-CM 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 polyneuropathy base 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 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 now 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 home anywhere in the U.S., 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 AMVUTTRA as a first-line treatment option, meaning these patients have no step edits. Of similar importance, most patients pay nothing out of pocket. Finally, with health system setup and access and affordability in place, we are focused on treatment choice and the profile of AMVUTTRA 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, we're executing and delivering on them. Patient demand roughly doubled quarter-over-quarter, reflecting strong, sustained momentum for the AMVUTTRA ATTR-CM in the 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 2026 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?

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-B 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, vutrisiran 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 because it suggests vutrisiran 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 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 4:1 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 nucresiran arm 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 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 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 KARDIA-3 Phase II study. As you can see, treatment with zilebesiran resulted in clinically meaningful reductions in office systolic 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, KARDIA-3 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 event-driven 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 in a product. Plasminogen is a genetically validated target. High circulating levels are associated with increased bleeding. 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 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 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. 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 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 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 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 zilebesiran. Royalty revenue for the quarter was $46 million representing a doubling compared with last year, driven by higher LEQVIO 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 increase 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 nucresiran. 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 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 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 $2.175 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-PN trial of nucresiran and hATTR-PN will initiate shortly. We also expect to initiate a Phase II trial of mivelsiran in 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.

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

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 in cardiomyopathy in the U.S. But Tolga, why don't you kind of take the question around.

We're very pleased with another strong quarter. Demand for cardiomyopathy has doubled, and utilization remains broad and balanced. We're observing adoption in both academic and community settings from a diverse range of prescribers and patients, which indicates a healthy increase. Additionally, we're seeing an increasingly competitive environment for first-line treatment, and our market share in this area continues to grow each quarter. We are also maintaining strong leadership in the second-line treatment for patients who are progressing or not responding to stabilization. This breadth and balance give us confidence in the sustainability of AMVUTTRA's momentum. Regarding our pricing outside the U.S., we are engaging with various countries on pricing and reimbursement. We have observed a compelling pricing profile in Japan, and while we've launched in Germany, we are still in the early stages of pricing discussions there. We aim to ensure that the value of our innovation is recognized in Europe as it has been in the U.S., and we expect to see developments on this front through 2026.

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

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 MAPT, 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 Alzheimer's as well?

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 really highlights 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...

Yes. Maybe I can take that 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 PN 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 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.

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

Yes, absolutely. Yes, look, we're very excited about bringing MAPT 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, Pushkal. 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 multibillion opportunities that we're prosecuting in Pushkal's organization as expeditiously as we can. Clearly, being able to help patients with severe neurodegenerative diseases would be an incredible achievement. So thank you, Pushkal. Next question.

I wanted to get some color on payer dynamics as you get into the launch now more 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, 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?

Yes. 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?

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 two quarters that we've had the launch. And as Yvonne indicated, what we're seeing is really no headwinds in terms of every 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. 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. Both payers and physicians really appreciate that this disease needs to be treated early and effectively. What we're seeing is not only within '26 but also '25. Policies are being negotiated, and they're almost final. We're seeing a very similar dynamic that we had anticipated early in the launch.

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

Congrats on a great quarter. Wondering if you can comment more on just the inventory demand number for the third quarter and how to think about that for the 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.

I'll address the question about inventory and gross to net in the third quarter. We experienced similar dynamics to the second quarter. The days on hand for inventory remained relatively stable, but there was an increase in inventory within the channel due to the way inventory days are calculated, which is based on demand. The rising demand led to additional inventory entering the channel this quarter. This was more than compensated for by an increase in gross to net. The launch of ONPATTRO was the main factor contributing to the rise in gross to net between the second and third quarters. For the TTR franchise this year, we expect mid-single-digit price declines on a net basis compared to the previous year. Maury, could you please rephrase the question about Europe? I believe Tolga might want to address that. You were asking about expectations for the fourth quarter, right Maury?

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

If I consider the bigger picture, the contribution from the ex-U.S. market will likely remain modest, particularly in the fourth quarter, as we only have two available markets, Germany and Japan. In Germany, we are still in the process of final pricing discussions, which limits our potential. However, we are pleased with the momentum we've established in Japan. Despite this, the overall contribution will still be modest, and significant growth in the ex-U.S. market is more of a mid- to late-2026 story. I’m encouraged by how we are maintaining our PN business, with a year-over-year growth of 46% in ex-U.S. and TTR markets, even in the face of new competition. We are effectively competing in the PN market, capturing the majority of first-line patients. Our established ecosystem and the recognition of our treatment's value by key centers of excellence in Europe suggests we can expect more progress in 2026.

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

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.

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 developed the guidance. We're continuing to learn. As Tolga said, we're two 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.

Good. Next question.

Great. Congrats on another fantastic quarter. Maybe Tolga, CMS is obviously proposing to cut reimbursement for PYP 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 ultimately look also at the therapeutic side of the equation, given obviously the cost of therapeutics are much higher than the diagnostics side? And then maybe super quickly, can you just talk about the subpoena from the U.S. Attorney General that you quoted in the press release?

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 questions.

Yes. The reimbursement of PYP scans has been a significant factor in the growth of this category. We expect an increase in diagnoses and scanning. It's important for us to thoroughly understand how the reimbursement process will develop. So far, we haven't encountered any concerns from the health systems we are working with. We will continue to stay informed, and I believe we will manage this as the policies become clearer.

Great. Good answer. Thank you. Next question.

Also congrats on the great quarter. So maybe just want to confirm I heard it 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 ATTR cardiomyopathy 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 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?

So we got kind of a number of questions here about kind of price year-on-year in the U.S., 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?

I mean, Gena, as we've highlighted before, we expect our net price to gradually decrease over time. What you're observing may reflect some of those effects. We will continue to provide insights into our gross to net margins over time, but I don't foresee any significant changes. Regarding Europe, those negotiations are still ongoing, and we are considering the MFN and other dynamics. We will be able to offer a broader outlook on how volume and price will evolve in the coming years. As I mentioned earlier, this is primarily going to be a story for mid- to late-2026. Your other question was about the ratio of first-line to second-line treatments.

With some color on that.

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 the first month into the launch, we started seeing a much more balanced and broad uptake between first- and second-line. We certainly expect that to continue as we actually increase our first-line presence in the outer quarters.

I would like to highlight how positively the data from HELIOS-B is being received by physicians. As AMVUTTRA is the first silencer for TTR with rapid knockdown of TTR, this is making a difference. The data we are generating is significant, including a 37% relative risk reduction in all-cause mortality and first cardiovascular events, as Pushkal mentioned. He also pointed out the multisystem aspect of the disease with a reduction in gastrointestinal events, which is an important additional data point for physicians. The quarterly regimen is also favorable, ensuring that patients can reliably receive their medication through quarterly subcutaneous administration. Overall, we feel well positioned in the market, both for an expanding role in first-line treatment as Tolga noted, and as the preferred choice for patients who continue to progress on stabilizers. We have established a solid foundation here. Thank you for the question. We have just two more questions to address, so Ritu, you are up next.

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?

Thank you, Ritu. Here are some insights regarding Europe. We have an efficient team that has successfully established market leadership over tafamidis in the polyneuropathy sector. This sector, particularly in Europe, is largely managed by centers of excellence, with Germany being a possible exception. In many countries, including Italy and France, the management is centralized in these centers. For example, in the U.K., there is a single facility, the National Amyloidosis Centre, that oversees treatment. This setup requires significant collaboration and scientific engagement, although field activity remains somewhat limited. Patients with cardiomyopathy are also primarily treated in these centers. We do not anticipate considerable growth in our European operations. On the other hand, Japan's market is more fragmented, and we have invested in that area. We are committed to succeeding in this segment and will continue to invest as needed to ensure that the product's profile is well recognized and valued.

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

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?

Yes, I will address your question from the perspective of category growth and what to expect. It’s still early, and only one company has reported its quarter-over-quarter results so far. We are looking forward to seeing how Pfizer reports before drawing any firm conclusions. However, the category growth in ATTR-CM is accelerating, which isn't surprising since it is still an underdiagnosed and undertreated area with many patients waiting for treatment. We’ve noticed similar trends in polyneuropathy. With just one product entering the market, we are seeing much faster growth in this category. The positive aspect in polyneuropathy is that we maintain our position as the first-line market share leader. Within the anticipated category growth, we are exceptionally well positioned. As mentioned by Yvonne and Pushkal, our mechanism differentiates us, and we have strong outcomes supported by HELIOS-B. Additionally, we continue to invest in the category, particularly in real-world evidence and data generation across clinical and real-world settings. This strengthening of our evidence base positions us to be a market leader in this expanding 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.