Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript & Summary

Thank you for standing by. My name is Sprila and I will be your conference operator today. At this time, I would like to welcome everyone to the Alnylam Pharmaceuticals Q2 Earnings Conference Call. [Operator Instructions] I would now like to turn the conference over to the company. You may begin.

Good morning. I'm Josh Brodsky, Vice President of Investor Relations Island. With me today are Yvonne Greenstreet, Chief Executive Officer; Jeff Poulton, Chief Financial Author; Tolga Tanguler, Chief Commercial Officer; and Pushkal Garg, Chief Research and Development Officer. For those of you participating in a 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 introductory remarks and provide some general context, Jeff will review our financials and guidance, Tolga will provide an update on our global commercial progress, and Pushkal will discuss our TTR franchise, our confidence in TRITON-CM and upcoming pipeline milestones before we open the call for your questions. I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important risks and uncertainties, including those discussed under the heading Risk Factors in our most recent periodic report available on our website and on file with the SEC. We disclaim any obligation to update such statements. And with that, I'll now turn the call over to Yvonne. Yvonne?

Thanks, Josh, and thank you, everyone, for joining the call today. During the second quarter, we demonstrated strong performance across all aspects of the business. Notably, it marks the first time and virtual revenues exceeded $1 billion in a single quarter, representing an annual run rate of more than $4 billion, just 15 months into the ATTR cardiomyopathy launch, a testament to both the commercial opportunity and Alnylam's execution. As I reflect on the launch, several insights reinforce our confidence in the durability of AMVUTRA growth over the years ahead. First, this has been an impressive launch by industry benchmarks when looking across market share, access and revenue generation. Second, the fundamentals of our TTR business are strong, and they include a virtuous compelling clinical profile and label the strong access that we established at launch, which continues to improve and our robust and expanding provider network. Third, Patient demand for AMVUTRA continues to grow robustly, particularly in the first-line setting, which has been our focus as we aspire to market leadership. Given AMVUTRA's clinical differentiation and desirability as a foundational therapy for newly diagnosed patients. Tolga will discuss how we are now further investing in broadening our AMVUTRA prescriber base and supporting overall category growth, the latter of which have been accelerating. Finally, our geographic expansion strategy continues to gain momentum. And today, we are pleased to announce our collaboration with Ben through which they will have exclusive commercialization and distribution rights for AMVUTRA in Mainland China account, subject to AMVUTRA receiving marketing authorization. Together with B1, we aim to help advance awareness and support diagnosis of ATTR amyloidosis and if approved, bring the strength of TTR silencing with AMVUTRA to patients in these underserved regions. As Jeff will describe shortly, we are lowering our 2026 revenue guidance today to reflect a better understanding with hindsight of the first few quarters of our U.S. launch. Specifically, that early second-line demand growth in 2025 benefited significantly from pent-up demand for a new therapy that has since normalized. With that learning, and our strong 2026 second quarter performance. Our confidence in AMVUTRA's growth trajectory has never been stronger. First-line new patient starts and now responsible for about 80% factory growth in this accelerating market. And we believe we're making great progress in establishing AMVUTRA as a foundational therapy. I will now turn to recent developments in the competitive landscape, specifically the negative outcome of the CARDIO-TTRansform study of eplontersen. We recognize investor interest in understanding potential implications of that failure for our probability of success and TRITON-CM, our Phase III cardiovascular outcomes trial of nucrisiran. Let me be clear. This outcome does not alter our conviction in the TRITON-CM study. And as Pushkal will share in greater detail, our strong confidence is grounded in the established clinical evidence for RNAi therapeutics in TTR and a track record of our clinical organization. At the same time, we have a variety of options at our disposal to potentially adapt the study and position it for optimal success. We will carefully review the full eplontersen data set when it becomes available. and adapt our study plan, if appropriate. We have successfully navigated complex TTR development before and believe we are exceptionally well positioned to do so again with nucresiran. Additionally, in the quarter, we are pleased to announce the [indiscernible] strategic AI corporations across the enterprise, including with inceptive to expand the next frontier in the discovery of RNAi therapeutics. And the collaboration, we are pleased to announce today with a large health care system in California aimed at support early identification of ATTR cardiomyopathy in routine care. This builds on our previously announced partnerships with Viz.ai and Komodo Health. Together, this cohesive AI strategy from discovery and evidence generation to disease identification, clinical practice and commercial execution reflects our long-term conviction that AR fundamentally reshape how medicines are discovered, developed and ultimately delivered to patients. Finally, we also continue to progress our deep line of investigational medicines, initiating Phase II trial of ALN-6400 in Von Willebrand's disease and a Phase II trial of mivelsiran in down syndrome associated Alzheimer's disease, and we look forward to a series of clinical data readouts in the back half of this year, including presentation of initial Phase I results of ALN-HTT02 in patients with Huntington's disease at EHDN in October. All of this progress builds our momentum towards accelerating innovation, scaling our impact as we look to deliver our 5-year vision on line in 2030. And our strategy is anchored around 3 pillars. The first pillar is to establish global leadership in TTR while continuing to build a doable franchise. The momentum we have built with ATTR cardiomyopathy dates along with recent developments in the competitive landscape, including the CARDIO-TTRansform Phase III top line results and in laying expected U.S. generic entry for tafamidis until mid-2031, further reinforce the strength of our position and the significant opportunity ahead to establish AMVUTRA as a foundational therapy and realize our TTR leadership ambitions. The second pillar is growing through sustainable innovation where we aim to deliver therapy but not only slow the progression of disease, could prevent, halt or reverse it. And the third pillar is scaling with discipline and agility to enable durable, profitable growth. Alnylam 2030 represents our commitment to becoming the leading science driven fully integrated global biopharmaceutical company and to maximize the full potential of RNA therapeutics for patients. With that, let me now turn the call over to Jeff for a review of our second quarter financial results and 2026 guidance. Jeff?

Thanks, Yvonne, and good morning, everyone. This morning, I'll be presenting the summary of Alnylam's second quarter 2026 financial results and discussing updates to our full year guidance. Let's begin with a summary of our P&L results for the second quarter. Total net product revenues were approximately $1.2 billion, representing 74% growth versus Q2 last year, driven by the continued uptake of AMVUTRA and ATTR cardiomyopathy. Second quarter of 2026 marks the first time we achieved more than $1 billion of TTR revenue. These results reflect a substantial improvement in quarter-on-quarter growth compared with growth in Q1 this year consistent with the phasing expectations we discussed on our year-end and Q1 earnings calls earlier this year. Tolga will share more details on our TTR performance in the quarter. In Q2, collaboration revenue was $47 million or a 23% decrease compared with the same period last year due to lower revenue recognized from our Regeneron collaboration, partially offset by increased revenue from our Roche collaboration, driven by higher reimbursable development activities related to the ZENITH Phase III clinical trial of zilebesiran. Royalty revenue for the second quarter increased 79% to $72 million, driven by higher LEQVIO sales by Novartis. Gross margin on product sales was 75% or 4% lower than Q2 last year, the decrease in margin was primarily driven by increased royalties on AMVUTRA as higher revenues in 2026 resulted in an increase in the average royalty rate payable to Sanofi. Our non-GAAP R&D expenses of $377 million increased 38% compared to last year, primarily driven by costs associated with our 3 ongoing Phase III clinical studies including the ZENITH Phase III cardiovascular outcomes trial for zilebesiran in the TRITON-CM and PN studies for nucrisiran. Beyond the pivotal studies, we also continue to increase investment to support important programs for bleeding disorders Huntington's disease and CAA. Non-GAAP SG&A expenses of $297 million increased 14% compared to last year driven primarily by investments in support of the AMVUTRA ATTR cardiomyopathy launch in the U.S. and in key international markets. We achieved non-GAAP operating income of $318 million more than triple the amount we achieved last year, driven primarily by the strong top line results they have previously highlighted. Finally, we ended the second quarter with cash, cash equivalents and marketable securities of $3.3 billion compared with $2.9 billion as of year-end 2025. The primary driver of the increase in cash year-to-date is our strong operating performance. Now turning to our full year 2026 guidance. As Yvonne noted, we are revising our total net product revenue guidance to $4.7 billion to $5.1 billion, driven fully by an update of our TTR revenue guidance to $4.2 billion to $4.5 billion, representing a $200 million reduction from our original TTR guidance at the midpoint and still reflects a robust 75% growth year-over-year. Guiding the market's expectations appropriately is important, and we didn't get it right with our original guidance. We own that. Revised guidance we are sharing today reflect a better understanding of the evolution of second-line demand as our launch has progressed. Let me provide some additional color on the basis for this revision. Overall, the AMVUTRA cardiomyopathy launch continues to perform ahead of analogs. And importantly, we are pleased with uptake in the first-line portion of the market which has been and remains the primary focus of our commercial efforts given the importance of this segment to driving long-term growth. When AMVUTRA was launched April 2025, the compelling HELIOS-B data and our team's success in establishing access enabled physicians to rapidly transition existing patients who are progressing on stabilizers on AMVUTRA. As a result, second-line demand volumes remained consistently robust throughout 2025, and which informed our original 2026 guidance. However, as the launch progressed into 2026 and with the benefit of hindsight, it is now clear that a green understood proportion of early second line volume growth was driven by pent-up demand from patients who are waiting for a new treatment option. Consistent with the trend we highlighted in our Q1 2026 earnings call, growth in second line volumes began to moderate in early 2026 to what we now recognize as a normalized level. This normalization of second-line demand is the driver of the $200 million reduction in TTR guidance that we are announcing today. Tolga will share more perspective in just a few moments on our confidence in future TTR growth, which is grounded in 3 key elements: the strength of our current market fundamentals, positive impact we expect from new investments we're making based on early launch learnings and lastly, the favorable competitive developments that Yvonne mentioned in her opening remarks. Now back to update on our guidance. We are also updating our guidance for collaboration and royalty revenues to a revised range of $575 million to $625 million, representing a $150 million increase at the midpoint of the range driven primarily by strong performance of LEQVIO and the resulting royalties from Novartis as well as higher cost reimbursement from Roche favorably impacting collaboration revenue driven by the pace of enrollment in our ZENITH Phase III study with zilebesiran. The remainder of our non-GAAP financial guidance remains unchanged. Let me now turn it over to Tolga to provide more color on our commercial performance in the second quarter. Tolga?

Thanks, Jeff, and good morning. I'm pleased to share our continued progress in bringing Alnylam's therapies to patients globally. AMVUTRA is delivering a category-defining ATTR-CM launch and is on track towards delivering on our Alnylam 2030 ambitions. As Yvonne and Jeff mentioned, we have gained valuable insights as the launch has progressed. These learnings have sharpened our understanding of demand dynamics, while also reinforcing our confidence in the fundamental drivers of sustainable growth. . Overall, we remain highly confident in our path to achieving TTR leadership. The momentum of the business, coupled with an increasingly favorable competitive landscape reinforce our conviction in achieving our long-term ambitions. Q2 marked another quarter of strong commercial execution and growth. Specifically, we delivered $1.17 billion in combined net product revenues, up 74% year-over-year and 13% over Q1 2026. In just 5 quarters since our CM launch, we have generated over $4 billion in total revenue, reflecting both a strong base and a clear growth trajectory. Our rare disease portfolio also continues to deliver meaningful impact for patients and consistent performance for our business. In Q2, we generated $142 million in rare disease net revenue, up 11% year-over-year. Turning to our TTR franchise. Global TTR net revenues reached $1.03 billion in the second quarter, increasing 13% versus Q1 at 89% year-over-year, reflecting the continued strength of the launch and the robust execution of our global teams. In the U.S., TTR revenues increased 15% versus Q1 and 114% year-over-year, reflecting robust underlying demand with reported revenue partially held back by changes in inventory days on hand during Q2. Access remained broad, pull-through was strong and adherence continue to exceed 90%. Outside the U.S., TTR revenues increased 7% versus Q1 and 31% year-over-year. Continued ATTR-CM uptake in Japan, the U.K. and Germany, along with strong polyneuropathy performance across our international markets drove Q2 growth despite pricing headwinds related to ongoing CM matches in several countries. Double clicking on our Q2 TTR performance in the U.S. Underlying demand was exceptionally strong, increasing by $129 million in the quarter, more than doubling the demand growth achieving in Q1. A portion of that demand was offset by inventory dynamics, which reduced reported growth by $21 million and to a lesser extent by the continued and anticipated modest reduction in net price. As a reminder, our Q1 U.S. TTR growth was more modest and was impacted by several sea phasing dynamics, and we are, therefore, pleased by the robust reacceleration demand in Q2 and the continued strength of the business. Our ultra differentiated clinical profile underpins our confidence in the long-term growth opportunity. We believe that ultra stands apart as a first-line choice on attributes that matter physicians and patients. It is the first and only product approved in the U.S. for both ATTR-CM and hereditary ATTR PN. It works upstream at the source, delivering rapid, deep and sustained knockdown of the disease-causing protein. In the pivotal HELIOS-B study, AMVUTRA met 10 out of 10 endpoints and demonstrated robust treatment effects in the primary endpoint of all-cause mortality and recurrent CV events and secondary endpoints of function capacity and health-related quality of life. Across all of these end points consistent treatment effect with or without background stabilizers were observed, combined with the convenience of once quarterly health care provided administration and real-world data that is greater than 90% adherence, we believe AMVUTRA is uniquely positioned to address the needs of growing ATTR-CM patient population. The first 5 quarters of launch have provided valuable insights that are informing where we increase investment and how we position the business for its next phase of growth. During the initial quarters following approval, many of our high-volume early adopters transitioned a substantial number of stabilizer treated progress in patients to AMVUTRA, while those transitions continue, we are now seeing that portion of demand volume growth normalized towards the more sustainable underlying rate, and we continue to capture leadership share of second-line starts. Today, approximately 80% of new treatment initiations are first-line starts. Establishing AMVUTRA as first-line treatment choice has been our priority since launch, and we continue to strengthen our competitive position. What's more? While our strategy has never dependent on competitive outcomes, 2 favorable developments in the external landscape have cleared a path for us to be even more competitive in the first-line setting. First, we now anticipate tafamidis U.S. loss of exclusivity in 2031. AMVUTRA is already challenging the 7-year incumbent for leadership share of new patient starts, and we see a significant opportunity to continue strengthening that position years ahead of generalization of the stabilizer class. Second, based on the CARDIO-TTRansform study top line results, we now anticipate one fewer branded ATTR-CM competitor in both the first line and stabilizer progressive segments. Finally, category growth continues to accelerate at our competitive first-line share, coupled with this clear competitive path to greater first-line penetration aligns well with where we see the largest opportunity. With an estimated 80% of patients still untreated and additional physicians and health systems initiating treatment of ATTR we expect the robust growth in first-line starts to continue. And we're helping to drive that category growth. More specifically, we're accelerating our investments in diagnosis enabling initiatives, investments to identify patients earlier to expand the treatable population and ultimately, to improve patient outcomes. Taken together, these insights provide great confidence in our ability to expand leadership across both ATTR-CM and ATTR PN and delivered on our 2030 ambitions of TTR leadership and a 25% revenue CAGR during the period. As we shared today, our differentiated profile has translated into exceptional launch momentum and that experience has sharpened our understanding of what will drive the next phase of growth. First, after 5 quarters in the market, Auto's compelling profile and our focused efforts have driven broad coverage and efficient patient access with no meaningful reimbursement headwinds. We believe this strong access foundation will continue to support physician confidence and patient adoption and as we expand the franchise. Second, we continue to deepen adoption among physicians who have already incorporated AMVUTRA into their practice. Among prescribers using our AMVUTRA. It now represents more than 50% of new patient starts, underscoring the strong physician preference that develops with experience. And from ATTR-CM launch through the end of Q2 we have added over 1,700 new prescribers. Third, and perhaps most importantly, we have significant opportunity to expand the breadth of prescribers who have experience with AMVUTRA, which we estimated about 1/3 of the growing pool of TTR prescribers. While we know that experience drives preference. There are many more physicians, including many who are new to the category, who have not yet prescribed AMVUTRA. To capture that opportunity, we are intensifying our focus and increasing our investment in customer-facing activities to expand the breadth of prescribing. We are already seeing early progress around these efforts with accelerated growth in new AMVUTRA prescribers during the second quarter. We believe we are in the early stages of that expansion opportunity. While we're still in the -- while we're still early in the commercialization journey, we believe AMVUTRA is well positioned to capture the significant opportunity ahead as we bring this differentiated therapy to more patients living with ATTR-CM. With that, I will now turn it over to Pushkal.

Thank you, Tolga, and good morning, everyone. As Tolga just highlighted, we believe AMVUTRA has a remarkable clinical profile that supports it being the first line treatment of choice for patients with ATTR cardiomyopathy. These key attributes are highlighted here with data from the landmark HELIOS-B screen. First and foremost, we've seen substantial benefits with garden proving clinical outcomes, both all-cause mortality and cardiovascular events with reductions of nearly 40% over 48 months across these 2 endpoints. Second, the treatment effects are largest when we intervene early. You can see that in the forest plot on the bottom left where patients with lower BNP, greater walking ability and younger age have had even greater reductions in the composite endpoint 47%, 42% and 45%, respectively. And importantly, in data recently presented at ESC Heart failure and shown on the lower right quadrant, we see that the treatment effect is preserved, irrespective of background medications in TTR stabilizers. These attributes, along with the quarterly dosing that supports adherence in our view, represents an ideal profile for first-line agent for patients with ATTR cardiomyopathy. Now the strength of these HELIOS-B results, along with our many learnings from our deep experience in TTR amyloidosis provide us with stance conviction in the value of nucresiran, our next-generation investigational RNAi TTR silencer, which we believe has the potential for even greater improved efficacy by a greater knockdown over 95% with just 2 doses per year. As you're aware, we continue to advance nucresiran in the TRITON Phase III program. TRITON-CM is a randomized double-blind, event-driven out study of nucresiran versus placebo. We announced last quarter that we utilized a prespecified option in our product while expanding enrollment by about -- by approximately 500 patients to 1,715 total, further mitigating the potential risk of low event rates while maintaining or potentially even accelerating time lines for this important study. Now given recent competitor data and given that many patients in TRITON-CM will be on a background stabilizer, we understand that there have been many questions raised about the feasibility of delivering positive results from this clinical trial. While we still have more to learn about the eplontersen results, we believe they're likely attributable to a combination of molecule and study-specific issues. And as we compare what we know about nucresiran with what's been reported about eplontersen, I want to assure you that we remain highly confident in nucresiran and TRITON-CM. I'll explain more in a moment, but first, let me share what we'll be looking for in the upcoming data presentations of the CARDIO-TTRansform results to better understand the reasons why the study did not meet its primary endpoint. First, we'll be interested to learn more about the population and baseline characteristics of the CARDIO-TTRansform study, particularly in the 2 key subgroups of monotherapy and in the patients on background stabilizers. As I noted, in HELIOS-B, we saw the treatment effects with AMVUTRA were greatest in early patients. And so a drug signal may be obscured if many advanced patients were enrolled. We already know from published data that the cardio transform study enrolled 17% NYHA Class III patients, nearly double that in HELIOS-B. Patients with higher NAC stage in patients with higher BNPs. Importantly, as I'll explain further in a moment, we believe deep rapid knockdown of TTR is critical to improving outcomes in ATTR cardiomyopathy. Graphs in the primary manuscript for the eplontersen-PN study indicated it took longer to get to peak knockdown than AMVUTRA, but the depth and variability of knockdown are also important. So we'll be looking for those details. Safety will be given what we know about ASOs in the past and the frailty of the ATTR cardiomyopathy population. The patients stay on drug and were there any competing risks that impact the study outcomes. We also want to look at study execution and completeness of follow-up. And finally, we'll want to take a much deeper look at the outcomes data. For example, how do the individual components are primary endpoint, CV mortality and CV events look. And what about all-cause mortality, which is part of our primary endpoint? How did these accrue over time and do the results vary in particular subgroups, particularly by disease severity? Bottom line is there are a lot of details, not yet known about failure of CARDIO-TTRansform. However, we are in an ideal position to learn from it, with enrollment ongoing and a projected launch for nucresiran in 2030 in for ATTR cardiomyopathy. We have plenty of time to digest this information, thoroughly consider our options and implement appropriate changes to TRITON-CM, assuming any are even warranted. Let me turn now to why we remain confident in TRITON-CM following the CARDIO-TTRansform top line release. The reasons come down to 3 key factors: the specific attributes of our molecule and nucresiran, key design elements of the TRITON-CM study and the track record of our team here at Alnylam. Starting with the molecule. First, RNAi therapeutics are fundamentally different than antisense oligonucleotides. In our hands, our NII has been able to deliver rapid, deep and durable TTR knockdown, which we believe has implications on treating the course of disease. There are now several recent examples of SOs and RNAi silencing the same genetic target with very different profiles. We've also seen that the safety profiles of these approaches differ as well. Second, nucresiran's depth of TTR knockdown is expected to be best in mass based on preliminary Phase I results showing over 95% TTR knockdown with much tighter interpatient variability. I'll explain why we believe that will result in strong efficacy in a moment. And finally, we have data from 2 prior studies, evaluating RNAi in ATTR cardiopathy patients, APOLLO-B and HELIOS-B both of which generated get us supporting a combination benefit. You've seen the HELIOS-B data in label, which shows a clear benefit of RNAi-mediated TTR silencing in a population that included heavy stabilizer use and consistent effects in combination in monotherapy. But as I'll show you in a moment, we saw the same effect with patisiran as well. Moving to the study. TRITON-CM, now with 1,750 patients will be the largest study conducted in ATTR-CM, which will allow us to accrue more outcome events. And further to that point, we designed TRITON-CM as an event-driven study. Given the evolving treatment landscape, patients with somewhat milder disease on baseline on average and other dynamics we determined that a time-based primary endpoint was not ideal. Instead, we'll continue the study until we have enough endpoint events to ensure sufficient study power. Third, we've used our insights to define entry criteria that enrich for patients were most likely to benefit based on our prior learnings. And finally, we have an outstanding experienced team here at Alnylam. We've been focused on TTR drug development for well over 15 years, delivering 2 approved products, we've amassed tremendous experience across study design, execution and analysis to maximize the probability of success of a trial in this area. Part of this experience in history of conducting TTR trials is our vast database of deep patient level insights that we can leverage to optimize study design and conduct. And to that last point, we have a track record of meticulous execution to ensure study success. This was more recently exemplified by how we optimize the endpoint structure and analytic plan for HELIOS-B to deliver remarkable results, resulting in a strong label that Tolga highlighted earlier. Before I move on, I'd like to underscore a few of the points I just made by sharing some clinical data that support the additive benefits of RNAi media silencing on top of a stabilizer. As you'll recall, the HELIOS-B study demonstrated an approximately 41% reduction in the risk of all causality up to 42 months when AMVUTRA was given to patients on a stabilized or at baseline, highlighting both the residual unmet need in these stabilizer treated patients as well as the additive benefit of vutrisiran. But what you may not know is that we saw a nearly identical effect in APOLLO-B. As shown here, with just 24 months of follow-up in a comparable population of that study, we saw an estimated 44% reduction in all-cause mortality. Hence, we have data from 2 different molecules in 2 different studies showing comparable improvements in outcomes, which provided the strongest evidence of a combo effect. We believe these clinical data results from the knock-down profile of these 2 medicines. There are many ways to look at TTR knockdown, but what we believe matters is the speed and depth of buck down and particularly getting as many patients as possible to deep knockdown. Here, we show TTR knockdown from our polyneuropathy studies, which had the richest sampling of TTR levels. Both show median knockdown of approximately 90% of study state. Now we don't know exactly what level of knockdown is critical for efficacy in cardiomyopathy but we have robust data in hereditary ATTR, where we have more sensitive endpoints that suggest on a population basis, achieving 80% knockdown or greater is associated with halting of polyneuropathy. And based on our depth, speed and variability of knockdown, the large majority of patients, about 82% to 84% of vutrisiran treated patients reach that threshold at steady state. So how does this compare to other molecules? Here, we plotted the same data as on the prior slide for vutrisiran, now shown as bar graphs. You see 91% median knockdown with about 82% of patients achieving that 80% threshold of deep knockdown. So how does that compare to the data reported for eplontersen? Our team used published data from the eplontersen TN study, which showed a median knockdown of 84% at steady state as well available data on variability to model the expected proportion of patients who will reach that same 80% knockdown threshold. Our model estimates that only about 67% of eplon-treated patients would reach that same level of knockdown or said another way, 1/3 of patients may not reach the threshold to knockdown we've seen to be associated with strong efficacy, nearly double that calculated for vutrisiran. These are estimates and should be interpreted with appropriate caution that they highlight that the TTR knockdown data in CARDIO-TTRansform will be critical to review an insufficient knockdown is one plausible contributor to the fail of that study. We ran same modeling exercise for nucresiran using the same dose and regimen that we are using in the TRITON-CM and PN studies. And the good news is that by these same metrics, nucresiran has the potential to be even better than vutrisiran's high mark. With median knockdown of 95% in low variability over 99% of patients, truth nucresiran are expected to surpass the deep knockdown threshold. So in sum, we don't believe that the top line results shared a few weeks ago negate the hypothesis and rationale of using a silencer for ATTR-CM patients who are already on a stabilizer, more likely as we -- they may demonstrate that the type and depth of silencing along with aspects of the study design are what really matter. With that, I'd like to remind you that we're progressing a broad pipeline of medicines beyond TTR with over 25 clinical programs multiple therapeutic areas across rare specialty and prevalent indications. This robust pipeline represents a tremendous opportunity to improve patient health and create value in the years ahead. To that end, we look forward to a lot of pipeline momentum in the next few years. This year, in 2026, we continue to execute on our 3 ongoing pivotal studies, including 2 cardiovascular outcomes trial. We also anticipate 4 key data readouts in the second half, which I'll outline on the next slide. And looking ahead, we anticipate many more data readouts and pivotal trial starts in '27 and '28. Additionally, in 2028, we anticipate the launch of nucresiran in hATTR polyneuropathy assuming positive Phase III data and regulatory approval. And of course, we'll continue to build the pipeline through the filing of 3 to 4 new INDs each year as we scale to meet our Alnylam 2030 ambitions. Coming back to '26 and our pipeline goals for the remainder of the year, we're looking forward to 4 important data readouts from 3 key programs. For ALN-6400, we plan to share healthy volunteer data from the ongoing Phase I study as well as initial results from the Phase II study in patients with hereditary hemorrhagic telangiectasia. We also expect to initiate Phase I data from both ALN-HD202, our Huntington's disease program and ALN-2232 in development for obesity and weight management. With that, let me turn it back to Josh to coordinate our Q&A session. Josh?

Thank you, Pushkal. Operator, we'll now open the call for questions. [Operator Instructions]

[Operator Instructions] Your first question comes from the line of Paul Matteis with Stifel.

Great. I appreciate it. I wanted to just talk about like the change in guidance. By our math, under the new guide, you're growing around 50-ish percent at the midpoint in the second half of this year. And for 2030, I think you still guided to this 25% CAGR given this drop off versus your original expectations and when you gave this one-term guidance, I was wondering if you could talk a little bit more about the next sort of 12- to 24-month outlook and your confidence that you can keep the growth rate on track likely above that 25% number for a while and still meet your long-term goals?

Thanks for the question. Clearly, we're not pleased to be lowering guidance, as Jeff said, we own it. But I think it's really important to emphasize that we believe that the fundamentals driving our opportunity a really strong, particularly market growth in our first-line momentum. And it's difficult to know every single factor when you kick off a launch from the get-go. But we're very pleased with the outlook that we have in front of us. both in the near future, but also in the longer term and reaching our 2030 goals. Jeff, do you want to add some comments?

I mean I'll just kind on the second half of '26 and what the revised guidance implies and then maybe Tolga would like to make some comments on longer-term confidence in the Alnylam 23rd guidance. Paul, the revised guidance that we've given of $4.2 billion to $4.5 billion in terms of the midpoint of that, just relative to the growth that we just put up in the second quarter, the midpoint to achieve the midpoint, we would need to deliver growth in Q3 and Q4 that's consistent with what we just put up in Q2. And I think we do have confidence in that given some of the things that Tolga talked about, particularly strength in the first-line part of the market in terms of demand we saw in the quarter in the U.S. But Tolga, any more comments on the confidence in the longer term?

Yes. Maybe I'll combine both Yvonne and Jeff's point, which is, first and foremost, we are competing in a in a highly untapped market, 80% of patients remain untreated. And within that category, in a short [ 15 ] months, we've already been able to actually build a very strong base for our business. And what's exciting about that, frankly, to me is while we're obviously normalizing our second-line new business, our first-time business is really rapidly replacing that. And if you think about the fact that 80% in this category comes in as new patients as first line, we really like how we're positioned with the existing prescriber bases. And as I highlighted in my remarks, one of the areas where we still need to do some work, which I believe we'll be able to do is continue to expand our prescriber bases. And that's where we're really investing our efforts, and we've already done that. So given matching that with actually the access that we've been able to secure and good achievance rates, our ability to demonstrate 25% CAGR growth year-over-year is definitely within our reach.

And if I can add, we're actually even more confident now with the results of the CARDIO-TTRansform study. I mean there's likely to be one less branded competitor in the market. And Pushkal structured all the reasons why our confidence in nucre and TRITON-CM is on diminished. So I think if anything, actually, we're sort of more confident about our future outlook given these developments. Next question please. It's from Salveen.

This is Tommie on for Salveen. Curious on if you're seeing a slower rate of second-line patients TAF progressors per year, given trends in earlier diagnosis and potentially patients staying on TAF for longer. And also, if you could maybe comment on how you expect the timing for your diagnosis and awareness efforts to start playing a key role in first line capture.

That's a great question, both for Tolga.

Yes. So it's a good question around the early diagnosis. Frankly, the when we started just like any launch when you have an artogonol mechanism of action product like we do, we knew that there was going to be a level of pent-up demand. And it certainly, over time, we've seen that being normalizing. So we're still seeing actually a healthy number of patients that are coming into category. That's about 20% of switch and combo. That will continue to be the same. What's even more important to me is these early diagnosis is actually going to hopefully help to increase the category growth and accelerating that category of growth. We've already seen that. It's gone up from the prior years into -- since we launched an acceleration of these new patients. So in fact, those patients that are getting treated early is going to be a nice tailwind for us.

Your next question comes from the line of Tazeen Ahmad with Bank of America.

I wanted to get a little bit more color about your comments about frontline, it's now about 80% of new starts. Can you just tell me what the split is for use in community physician practices versus centers of excellence? And I guess the question that a lot of people are asking is if for better or for worse right now, physicians are looking at stabilizers as being similar in efficacy to silencers, how do you kind of maintain that growth that you're seeing in front line with needing to balance educating physicians, presumably community-based physicians on the real differences between silencers and stabilizers?

\ Yes. So I'll say a few words, maybe I'll [indiscernible]. Look, I mean, first and foremost, we continue to compete for category leadership against the product that's been in the market for approximately 7 years. And obviously, we remain ahead of the other recent ended. But more importantly, how the business is evolving beneath the overall share, I think, is really, really important. Early in the launch, growth was more balanced between first and second line patients. Today, as second line demand, as we described, has moved toward a more sustainable rate, an increasing proportion of our growth is not coming from first-line patients, which represents the larger and the more durable opportunity. At the same time, I think this is really important. We are deepening adoption within existing accounts and rapidly expanding that prescriber base. So we're essentially maintaining a strong overall share while improving the underlying composition of the business through a broader physician adoption. Now you brought up the point around the COEs and community experts. What's been really encouraging for us is, as we establish that early base business, that business didn't just come from the COEs. We actually had a very healthy balance of COEs academic centers as well as community experts. What we need to continue to do is to actually expand out those community expert centers, and we know how to do that. Some of the challenges we faced with them early on was, well, okay, I don't know what differences are between the silences and stabilizers. Now those physicians have actually adopted AMVUTRA and all other stabilizers, we actually have a significantly higher market share. When it comes to, oh, well, I don't know how to buy and build this product, particularly around the community expert centers. We know how to bring them along with that, whether through building there are helping their own practice or creating alternative sites of care for their injections. So it is something we've done already, and now we're essentially intensifying our efforts to make sure that actually that adoption curve continues to get deeper.

Yes. And Tazeen, may, I'll just add to what Tolga said in response to your question. Look, there's no head-to-head data, of course, we know between these different classes of medicines. But as tried to highlight in the main presentation, we think we have actually an incredibly unique profile for AMVUTRA. It starts with the outcomes data, which we think are really quite remarkable. I've shown you a substantial impact on outcomes. And importantly, the fact that we've seen now in 2 studies, additive benefits on top of stabilizers would suggest there is efficacy left that's not fully addressed by the stabilizers alone, indirect evidence, but we think it's very strong and reproducible evidence. We've also seen it starting this class of agents early silencers and the greatest treatment effect and even approaching almost 45% reductions in mortality, which I think is quite remarkable. And we're seeing evidence of disease remodeling when we look at echocardiographic parameters, we look at cardiac MRI, et cetera. So look, our job as Tolga highlighted is to continue to educate on those attributes, continue to generate evidence you've seen it recent means more and more that we're putting out and to continue to educate. And so as Tolga has talked about expanding the prescriber base, important aspect of is educating these prescribers on the attributes of this class of medicines. And we've seen that once they gain experience with it that they find that it actually becomes a dominant part of their practice in terms of the prescribing. So that's going to be our goal.

Your next question comes from the line of Konstantinos Biliouris with Oppenheimer.