Alnylam Pharmaceuticals (NASDAQ:ALNY) Q2 2026 Earnings Call

0:00 Thank you for standing by. My name is Pryla, 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. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question and answer session.

0:28 Thank you. 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 at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer Jeff Poulton, Chief Financial Officer Tolga Tangular, Chief Commercial Officer and Push Golgarg, Chief Research and Development Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events. During today's call, as outlined on Slide two, Yvonne will offer introductory remarks and provide some general context. Jeff will review our financials and guidance.

1:14 Tolga will provide an update on our global commercial progress and Pushkal will discuss our TTR franchise, our confidence in TRITON Centimeters 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 obligations to update such statements.

2:00 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 Ambutra revenues exceeded $1,000,000,000 in a single quarter, representing an annual run rate of more than $4,000,000,000 just fifteen months into the ATTR cardiomyopathy launch, a testament to both the commercial opportunity and Alnylam's execution. As we reflect on the launch, several insights reinforce our confidence in the durability of Ambutra growth over the years ahead. First, this has been an impressive launch by industry benchmarks when looking across market share, access and revenue generation.

2:54 Second, the fundamentals of our TTR business are strong, and they include Amvutra's 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 Ambutra continues to grow robustly, particularly in the first line setting, which has been our focus as we aspire to market leadership, given Ambutra'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 Ambutra prescriber base and supporting overall category growth, the latter of which has been accelerating.

3:43 Finally, our geographic expansion strategy continues to gain momentum. And today, we're pleased to announce our collaboration with B1 through which they will have exclusive commercialization and distribution rights for Amvutra in Mainline China and Macau, 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 Ambutra 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.

4:43 With that learning and our strong twenty twenty six second quarter performance, our confidence in Ambutra's growth trajectory has never been stronger. First line new patient starts are now responsible for about 80% of category growth in this accelerating market, and we believe we're making great progress in establishing Ambutra as a foundational therapy. I will now turn to recent developments in the competitive landscape, specifically the negative outcome of the cardio transformed study of eplontirsen. We recognize investor interest in understanding any potential implications of that study's failure for our probability of success in TRITON Centimeters, our Phase III cardiovascular outcomes trial of nucleaseRab.

5:31 Let me be clear, this outcome does not alter our conviction in the TRITON Centimeters study. And as Pushkol will share in greater detail, our strong confidence is grounded in the established clinical evidence for RNAi therapeutics in TTR and the 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 eploncircum dataset 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 niflisiran. Additionally in the quarter, we were pleased to announce a series of strategic AI collaborations across the enterprise, including with Inceptive to expand the next frontier in the discovery of RNAi therapeutics and the collaboration we're pleased to announce today with a large healthcare system in California aimed at supporting early identification of ATTR cardiomyopathy in routine care.

6:39 This builds on our previously announced partnerships with VIZIYA and Komodo Health. Altogether, this cohesive AI strategy from discovery and evidence generation to disease identification, clinical practice and commercial execution reflects our long term conviction that AI will fundamentally reshape how medicines are discovered, developed and ultimately delivered to patients.

7:02 Finally, we also continue to progress our deep pipeline of investigational medicines initiating a Phase two trial of ALN6400 in von Wiederbren disease and a phase two trial of mivosiran 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 one results of ALN HTT02 in patients with Huntington's disease at EHDN in October. All of this progress builds our momentum towards accelerating innovation and scaling our impact as we look to deliver on our five year vision, Alnylam 2030. And our strategy is anchored around three pillars.

7:48 The first pillar is to establish global leadership in TTR while continuing to build a durable franchise. The momentum we have built in ATTR cardiomyopathy to date, along with recent developments in the competitive landscape, including the cardio transformed phase three top line results and the delay in expected US generic entry for tafamidis until mid-two thousand and thirty one further reinforce the strength of our position and the significant opportunity ahead to establish Ambutra as a foundational therapy and realize our TTR leadership ambitions. The second pillar is growing through sustainable innovation, where we aim to deliver therapies that not only slow the progression of disease, but prevent, halt or reverse it. And the third pillar is scaling with discipline and agility to enable durable, profitable growth.

8:39 Alnylam two thousand thirty represents our commitment to becoming the leading science driven, fully integrated global biopharmaceutical company and to maximize the full potential of RNAi 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 a summary of Alnylam's second quarter twenty twenty six financial results and discussing updates to our full year guidance. Let's begin with a summary of our P and L results for the second quarter. Total global net product revenues were approximately $1,200,000,000 representing 74% growth versus Q2 last year, driven by the continued uptake of Ambutra and ATTR cardiomyopathy.

9:28 Second quarter of twenty twenty six marks the first time we achieved more than $1,000,000,000 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. Olga will share more details on our TTR performance in the quarter. In Q2, collaboration revenue was $47,000,000 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 ozobiceram.

10:14 Royalty revenue for the second quarter increased 79% to $72,000,000 driven by higher LECVIO 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 Ambutra as higher revenues in 2026 resulted in an increase in the average royalty rate payable to Sanofi. Our non GAAP R and D expenses of $377,000,000 increased 38% compared to last year, primarily driven by costs associated with our three ongoing Phase III clinical studies, including the Xenith Phase three cardiovascular outcomes trial for zolvisiran and the TRITON Centimeters and TN studies for nucresiran. Beyond the pivotal studies, we also continue to increase investment to support important programs for bleeding disorders, Huntington's disease and CAA.

11:08 Non GAAP SG and A expenses of $297,000,000 increased 14% compared to last year, driven primarily by investments in support of the Ambutra ATTR cardiomyopathy launch in The U. S. And in key international markets.

11:23 We achieved non GAAP operating income of $318,000,000 more than triple the amount we achieved last year, driven primarily by the strong top line results that I previously highlighted. Finally, we ended the second quarter with cash, cash equivalents and marketable securities of $3,300,000,000 compared with $2,900,000,000 as of year end twenty twenty five. 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 4,700,000,000 to $5,100,000,000 driven fully by an update of our TTR revenue guidance of 4,200,000,000 to $4,500,000,000 representing a $200,000,000 reduction from our original TTR guidance at the midpoint and still reflects a robust 75% growth year over year.

12:16 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 reflects 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 Ambutra 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 INVUTRA was launched in 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 to Ambutra.

13:04 As a result, second line demand volumes remain consistently robust throughout 2025, 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 greater than 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 twenty twenty six earnings call, growth in second line volumes began to moderate in early twenty twenty six to what we now recognize as a normalized level. This normalization of second line demand is the driver of the $200,000,000 reduction in TTR guidance that we are announcing today. Hogo will share more perspective in just a few moments on our confidence in future TTR growth, which is grounded in three 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.

14:10 Now back to updating our guidance. We are also updating our guidance for collaboration and royalty revenues to a revised range of $575,000,000 to $625,000,000 representing a $150,000,000 increase at the midpoint of the range, driven primarily by strong performance of ALECVIO 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 Zalviseran. 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.

14:58 Almutra is delivering a category defining ATTR Centimeters launch and is on track toward 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.

15:48 Specifically, we delivered $1,170,000,000 in combined net product revenues, up 74% year over year and 13% over Q1 twenty twenty six. In just five quarters since our Centimeters launch, we have generated over $4,000,000,000 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 $142,000,000 in rare disease net revenue, up 11% year over year. Turning to our TTR franchise.

16:36 Global TTR net revenues reached $1,030,000,000 in the second quarter, increasing 13% versus Q1 and eighty nine percent year over year, reflecting the continued strength of the launch and the robust execution of our global teams.

16:56 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 continued to exceed 90%. Outside The U. S, TTR revenues increased 7% versus Q1 and 31% year over year. Continued ATTR Centimeters uptake in Japan, The UK and Germany, along with strong whole neuropathy performance across our international markets, drove Q2 growth despite pricing headwinds related to ongoing Centimeters launches in several countries.

17:52 Double clicking on our Q2 TTR performance in The U. S, underlying demand was exceptionally strong, increasing by $129,000,000 in the quarter, more than doubling the demand growth achieving Q1. A portion of that demand was offset by inventory dynamics, which reduced reported growth by $21,000,000 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 seasonal phasing dynamics, and we are therefore pleased by the robust reacceleration in demand in Q2 and the continued strength of the business.

18:43 Ambitra's differentiated clinical profile underpins our confidence in the long term growth opportunity. We believe that Almutra stands apart as a first line choice on attributes that matter to physicians and patients. It is the first and only product approved in The U. S. For both ATTR Centimeters 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, IULTRA met 10 out of 10 endpoints and demonstrated robust treatment effects in the primary endpoint of all cause mortality and recurring CV events and secondary endpoints of functional capacity and health related quality of life.

19:36 Across all of these endpoints, consistent treatment effects with or without background stabilizers were observed. Combined with the convenience of once quarterly healthcare provided administration and real world data that suggests greater than 90% adherence, we believe Amutra is uniquely positioned to address the needs of the growing ATTR Centimeters patient population.

20:06 The first five 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 progressing patients to Butra. While those transitions continue, we are now seeing that portion of demand volume growth normalize toward a 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 Almutra as first line treatment choice has been our priority since launch, and we continue to strengthen our competitive position.

21:03 What's more, while our strategy has never depended on competitors' outcomes, two favorable developments in the external landscape have cleared the 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. Amutra is already challenging the seven year incumbent for leadership share of new patient starts, and we see a significant opportunity to continue strengthening that position years ahead of genericization of the stabilizer class. Second, based on the CARDIO TTR transform study top line results, we now anticipate one fewer branded ATTR Centimeters competitor in both the first line and stabilizer progressor segments.

21:55 Finally, category growth continues to accelerate and our competitive first line share coupled with this cleared competitive path to greater first line penetration aligns well with where we see the largest opportunity. With an estimated eighty percent of patients still untreated and additional physicians and health systems initiating treatment of ATTR Centimeters, 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.

22:44 Taken together, these insights provide great confidence in our ability to expand leadership across both ATTR Centimeters and hereditary ATTR PN and deliver on our 2,030 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 five quarters in the market, our Ultra's compelling profile and our focus efforts have driven broad coverage and efficient patient access with no meaningful reimbursement headwinds.

23:32 We believe this strong access foundation will continue to support physician confidence and patient adoption as we expand the franchise. Second, we continue to deepen adoption among physicians who have already incorporated into their practice. Among prescribers using Almutra, it now represents more than fifty percent of new patient starts, underscoring the strong physician preference that develops with experience. And from ATTR Centimeters 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 experienced with Albutra, which we estimated about a third of the growing pool of TTR prescribers.

24:29 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 ALWUTR. 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 from these efforts With accelerated growth in new ambulatory prescribers during the second quarter, we believe we are in the early stages of that expansion opportunity. We're still early in the commercialization journey, we believe Almutra is well positioned to capture the significant opportunity ahead as we bring this differentiated therapy to more patients living with ATTR Centimeters.

25:23 With that, I will now turn it over to Pushkar. Thank you, Tolga, and good morning, everyone. As Tolga just highlighted, we believe Ambutra 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 study. First and foremost, we've seen substantial benefits with regard to improving clinical outcomes, both all cause mortality and cardiovascular events with reductions of nearly forty percent over forty eight months across these two endpoints.

25:57 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 of forty seven percent, forty two percent and forty five percent 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, including TTR stabilizers.

26:27 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 staunch conviction in the value of nucreseren, our next generation investigational RNAi TTR silencer, which we believe has the potential for even greater improved efficacy by a greater knockdown, over ninety five percent with just two doses per year.

27:00 As you're aware, we continue to advance NUCRESTRAN in the TRITON Phase three program. TRITON Centimeters is a randomized double blind event driven outcome study of NUCRESTRAN versus placebo. We announced last quarter that we utilized a pre specified option in our protocol to expand enrollment by approximately 500 patients to seventeen fifteen total, further mitigating the potential risk of low event rates while maintaining or potentially even accelerating timelines for this important study.

27:29 Now given recent competitor data and given that many patients in TRITON Centimeters 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 eplentirsen results, we believe they're likely attributable to a combination of molecule and study specific issues. And as we compare what we know about nucreseren with what's been reported about eplentirsen, I want to assure you that we remain highly confident in nucreseuran 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 CARDIOTRANSFORM results at ESC to better understand the reasons why the study did not meet its primary endpoint.

28:15 First, we'll be interested to learn more about the population and baseline characteristics of the CARDIO TRANSFORM study, particularly in the two key subgroups of monotherapy and in the patients on background stabilizers. As I noted in HELIOS B, we saw the treatment effects with ANVUTRA

28:31 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 seventeen percent NYHA Class III patients, nearly double that in HELIOS B, patients with higher NAK stage and patients with higher B and Ps.

28:53 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 eplentersen PN study indicated it took longer to get to peak knockdown than Inbutra, but the depth and variability of knockdown are also important. So we'll be looking for those details.

29:15 Safety will be important given what we know about ASOs in the past and the frailty of the ATTR cardiomyopathy population. Did patients stay on drug and were there any competing risks that impacted study outcomes? We'll 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 did the individual components of their primary endpoint, CV mortality and CV events look? And what about all cause mortality, which is part of our primary endpoint?

29:46 How did these accrue over time and did the results vary in particular subgroups, particularly by disease severity? Bottom line is there are a lot of details not yet known about the failure of CARDIO TRANSFORM. However, we are in an ideal position to learn from it. With enrollment ongoing and a projected launch for an inclisiran in 2030 for ATTR cardiomyopathy, we have plenty of time to digest this information, thoroughly consider our options and implement appropriate changes to TRITON Centimeters assuming any are even warranted.

30:19 Let me return now to why we remain confident in TRITON Centimeters following the CardioTransform top line release. The reasons come down to three key factors: the specific attributes of our molecule nucreaseran, key design elements of the TRITON Centimeters study and the track record of our team here at Alnylam.

30:39 Starting with the molecule. First, RNAi therapeutics are fundamentally different than antisense oligonucleotides. In our hands, RNAi 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 ASOs and RNAIs silencing the same genetic target with very different profiles. We've also seen that the safety profiles of these two approaches differ as well.

31:09 Second, nucreseren's depth of TTR knockdown is expected to be best in class based on preliminary Phase I results showing over ninety five percent TTR knockdown with much tighter inter patient variability. I'll explain why we believe that will result in strong efficacy in a moment.

31:26 And finally, we have data from two prior studies evaluating RNAi in ATTR cardiomyopathy patients, APOLLO B and HELIOS B, both of which generated data supporting a combination benefit. You've seen the HELIOS B data and 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.

31:58 Moving to the study. TRITON Centimeters now with seventeen fifty patients will be the largest study conducted in ATTR Centimeters, which will allow us to accrue more outcome events. And further to that point, we designed TRITON Centimeters 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 to study until we have enough endpoint events to ensure sufficient study power.

32:28 Third, we've used our insights to define entry criteria that enrich for patients who are most likely to benefit based on our prior learnings.

32:37 And finally, we have an outstanding experienced team here at Alnylam. We've been focused on TTR drug development for well over fifteen years, delivering two approved products. We've amassed tremendous experience across study design, execution analysis to maximize the probability of success of a trial in this area. Part of the 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.

33:11 This was most 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 mediated silencing on top of a stabilizer.

33:33 As you'll recall, the HELIOS B study demonstrated an approximately forty one percent reduction in the risk of all cause mortality up to forty two months when Ambutra was given to patients on a stabilizer at baseline, highlighting both the residual unmet need in these stabilizer treated patients as well as the additive benefit of vutrisiran.

33:54 But what you may not know is that we saw a nearly identical effect in APOLLO B. As shown here with just twenty four months of follow-up in a comparable population in that study, we saw an estimated forty four percent reduction in all cause mortality. Hence, we have data from two different molecules in two different studies showing comparable improvements in outcomes, which provided the strongest evidence of a combo effect.

34:19 We believe these clinical data results from the knockdown profile of these two medicines. There are many ways to look at TTR knockdown, but what we believe matters is the speed and depth of knockdown 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 ninety percent at study state.

34:44 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 eighty percent 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 eighty two percent to eighty four percent of Vutrisiran treated patients reach that threshold at steady state.

35:14 So how does this compare to other molecules? Here we've plotted the same data as on the prior slide for vutrisiran, now shown as bar graphs. You see ninety one percent median knockdown with about eighty two percent of patients achieving that eighty percent threshold of deep knockdown.

35:30 So how does that compare to the data reported for eplentersen? Our team used published data from the eplentersen PN study, which showed median knockdown of 84% at steady state as well as available data on variability to model the expected proportion of patients who will reach that same eighty percent knockdown threshold. Our model estimates that only about sixty seven percent of EPLON treated patients would reach that same deep level of knockdown. Or said another way, one third of patients may not reach the threshold of knockdown we've seen to be associated with strong efficacy, nearly double that calculated for vutrisiran.

36:09 These are estimates and should be interpreted with appropriate caution, but they highlight that the TTR knockdown data in cardiotransform will be critical to review and insufficient knockdown is one plausible contributor to the failure of that study. We ran the same modeling exercise for nucresiran using the same dose and regimen that we are using in the TRITON Centimeters 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 ninety five percent and low variability over ninety nine percent of patients, TRUTH and NUCRISRAN are expected to surpass this 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 Centimeters patients who are already on a stabilizer.

37:04 More likely as we see it, 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, spanning 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 three ongoing pivotal studies, including two cardiovascular outcomes trial. We also anticipate four key data readouts in the second half, which I'll outline on the next slide. And looking ahead, we anticipate many more data readouts in pivotal trial starts in 2027 and 2028.

37:55 Additionally, in 2028, we anticipate the launch of nucreseiran 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 three to four 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 four important data readouts from three key programs. For ALN6400, 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 HG202, our Huntington's disease program and ALN-two 232 in development for obesity and weight management.

38:41 With that, let me turn it back to Josh to coordinate our Q and A session. Josh? Thank you, Pushkal. Operator, we'll now open the call for questions. To those dialed in, we'd 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. We will now begin the question and answer session. With that, your first question comes from the line of Paul Matteis with Stifel. Please go ahead. Great. Good morning. Thanks so much for taking my question. I appreciate it. I wanted to talk about, like, the change in guidance.

39:29 You know, 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 long term guidance, I was wondering if you could talk a little bit more about the next sort of twelve to twenty four 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? Thank you. Thanks for the question, Paul. Look, clearly, we're not pleased to be lowering guidance. As Jeff said, you know, we own it. But I I I think it's really important to to emphasize that that we believe that the fundamentals driving, our opportunity are are really strong, particularly market growth and our first line momentum. You know, it's difficult to know every single factor when you kick off a launch from the get go, but we are very pleased with the outlook that we have in front of us, both in the near future, but also in the longer term in reaching our 2,030 goals. Jeff, do you want to add some color? I mean, I'll just comment on the second half of twenty twenty six and what the revised guidance implies, then maybe Tolga would like to make some comments on longer term confidence in the Alnylam 2023 guide.

40:47 Paul, the revised guidance that we've given of 4,200,000,000 to $4,500,000,000 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 Ivan and Jeff's points, which is, first and foremost, we are competing in a highly untapped market. Eighty percent of patients remain untreated. And within that category, in a short fifteen months, we've already been able to actually build a very strong base for our business.

41:38 And what's exciting about that, frankly, to me is, while we're obviously normalizing our second line new business, our first line 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 basis. 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 basis. And that's why 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 adherence 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 Transform study. I mean, there's likely to be one less branded competitor on the market.

42:41 Push costs such are all the reasons why our confidence in Nu. Kri and Triton Centimeters is undiminished. So I think if anything, actually, we're sort of more confident about our future outlook given these developments. Thank you very much for that question. Next question please. It's from Salveen. Salveen? Thanks for taking our question. This is Tommy 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 capture? You.

43:27 Those are great questions, both for Togo. Yes. So, it's a good question around the early diagnosis. Frankly, when we started, just like any launch, when you have an orthogonal mechanism of action product like we do, we knew that there was going to be a level of pent up demand. And it's certainly over time, we've seen that being normalizing. So we're still seeing actually a healthy number of patients that are coming into the category. That's about twenty percent, both 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 increase the category growth and accelerating that category growth. We've already seen that. It's got 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.

44:30 Thank you. Next question, please. Your next question comes from the line of Tazeen Ahmad with Bank of America. Please go ahead. Hi, good morning. Thanks for taking my question. I wanted to get a little bit more color about your comments about frontline is 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, are looking at stabilizers as being similar in efficacy to silencers. How do you kind of maintain that growth that you're seeing in frontline with needing to balance educating physicians, presumably community based physicians on the real differences between silencers and stabilizers?

45:23 Thanks. Yes. So I'll say a few words, maybe I'll Scott will. Look, I mean, first and foremost, we continue to compete for category leadership against the product that's been in the market for approximately seven years. And obviously, we remain ahead of the other recent entrants. 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.

46:17 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 the differences are between the silences and stabilizers. Now those physicians have actually adopted Ambutra and all other stabilizers.

47:02 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 their own 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 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 Ambutra.

47:49 It starts with the outcomes data, which we think are really quite remarkable. I've shown you substantial impact on outcomes. And importantly, the fact that we've seen now in two studies additive benefits on top of stabilizers, which suggest there is efficacy left, that's not fully addressed by the stabilizers alone. It's indirect evidence, but we think it's very strong and and reproducible evidence. We've also seen that starting these class this class of agents early silencers has the greatest treatment effect, And even, you know, approaching almost forty five percent 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, etcetera. So look, our job, as Tolga has highlighted, is to continue to educate, on those attributes, continue to generate evidence. You've seen at recent meetings more and more that we're putting out, and to continue to educate. And so as Tolga has talked about expanding the prescriber base, an important aspect of this 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 is is becomes a dominant part of their practice in terms of prescribing.

49:00 So that's going to be our effort. Very good. Thank you. Next question. Your next question comes from the line of Costas Villiers with Oppenheimer. Please go ahead. Thanks for taking our question. One on Europe, given that Vyndaqel will soon be generic in Europe, to what extent do you think the commercial dynamics between Ambutra and a generic drug in Europe will reflect what may happen in The U. S. Post 2031 when tafamidis goes generic? Thank you. Thank you very much. Togo? So thank you, Kostas, for that question. First and foremost, I think we've always highlighted that the contribution of growth for Europe is going to be relatively modest, similar to the growth that we had last year. And that had a lot to do with the fact that we were going to actually make appropriate price adjustments in order to capture a larger cardiomyopathy volume. Now in terms of tafamidis, the eighty milligram, the four pills a day, option is going to be going generic. I believe sixty one milligram will continue to be available for a while. Now in respect to our ability to actually capture those reimbursements, since these are single payer systems, these systems have already anticipated that genericization transition.

50:29 And what I'm pleased to say that we've actually, in most cases, been able to secure premium pricing versus tafamidis and quite pleased with the ongoing negotiations we have, whether it's Germany, Spain, Italy and Japan, we highlighted the fact that we are competing very effectively, essentially exceeding all analogs and a good uptake. So while again, because of the pricing changes, we're going to have a modest growth contribution, particularly in 2026, we see 2027 and beyond, the launches is going to have a meaningful impact on our overall business. Thank you. Your next question comes from Ellie Merle with Barclays. Please go ahead.

51:18 Hey guys, thanks for taking the question. Just curious if you could give us more color on what a steady state level of second line starts look like. I think you said 80% of starts in 2Q were from the front line. So is 20% a steady state for second line starts? Or do you expect that to decline over time? And then I guess, what drives your confidence that the front line starts will continue at this cadence going forward? And specifically, if you could give us more color on if we strip out the second line starts, have you seen growth in first line starts or a stable number of first line starts each quarter? Thanks. Yes. Thank you, Adi, for that question. I mean, just to be clear, when we talk about eightytwenty perspective, that's mainly driven by the overall category. And what we've seen essentially is not a market share loss on second lines, but the overall volume shift into a lesser contribution of the new brands from switches for the entire category.

52:21 What I'm really pleased about is while we're continuing to maintain and having a nice gradual progression of our market share, that market share growth is actually being contributed by the first line share. So that's actually a very healthy sign of our business. And in respect to the first line contributions, as I alluded to earlier, those physicians that actually use all three products predominantly use Omuthra as their first line choice. That's the analysis that we have. So now the question is, how can we actually continue to expand the prescriber base, so more physicians actually test and understand and experience Omotra because of the experience begets preference.

53:08 And this is, where we're really honing our efforts in. And we've been able to expand that prescriber base at 1,500 new prescribers since the launch, and we believe we're going to be able to continue to do that. And again, the goal has always been actually on first line. And this normalization is just a question actually, frankly, not just the dynamic, but also the strategy. Thank you. Your next question comes from Luca Isi with RBC. Go ahead. Great. Thanks so much for taking my question. Maybe a quick one for Tolga. Pretty clear that AstraZeneca did not show any additive effect between stabilizer and silencers in their trial based on the press release. You got appreciated that's a different molecule that's pushed all nicely articulated.

53:58 But are you seeing any impact commercially based on that data? Are you seeing payers forcing docs to pick one versus the other and no longer allowing patients to be on the combo? Any color there, much appreciated. And then super quickly, can you comment on the evolution of net price in The U. S. For the rest of the year? Thanks so much. So that's a three parter, I guess. So maybe I'll start. I mean, obviously, Pushkar laid it out very clearly why we believe what we believe. Look, in terms of the payer pushback, obviously, it's too early to say, but what I can tell you is this. Overall access to Omotrex remains very strong. Some Medicare Advantage policies that are already placed that already puts limitation on combination use.

54:46 And in fee for service coverage always follows label. And frankly, continue to have pathways to pursue access when they believe particular treatment approach is medically appropriate given the severity of this disease. What's also very important is, CARDIO TRANSFORM does not change on which was evidence or its label. It was a study of a different molecule. We would not expect payers to alter ALWUTR coverage based on those results. Our priority remains ensuring appropriate patients can access ALWUTR, whether they're initiating first line therapy or switching from another treatment. So we're not seeing any pushback again, given the fact that actually the policies are already in place, and yet when the physician wants to have access, obtain it if they provide the right appropriate materials.

55:41 Yeah, thanks for that. Look, think there are many examples of drugs, know, in similar classes where one drug fails and the other succeeds, and we really believe what we have here are two distinct molecules with different mechanisms, as well as, you know, different profiles and a different study, and really our job is to get out there as Tarkov was saying and educate physicians on the compelling benefits that we see for Ambutra, the focus on first line because we believe this should be a foundational therapy as well as explaining the benefits that we've seen in two separate studies, as Vishkar has explained, with respect to combination use. There was one question on net price in terms And of what we I think the slide that Toga showed that showed the first half dynamics showed the modest quarter to quarter decreases in net price. We expect that will continue for the second half.

56:28 And if we were to show you that on a year over year basis, the way we had guided was mid single digit net price decrease year over year. We're still on track for that, Luca. Thank you. The next question comes from Jessica Fye with JPMorgan. Please go ahead. Hey, guys. Good morning. Thanks for taking my question. Question for Pushkal. Recognizing that this is hypothetical, can you elaborate on some of those potential changes available to you with TRITON Centimeters to maximize its probability of success? And then maybe as a follow-up to that, are there potentially other paths to approval for lucrisiran in ATTR Centimeters beyond Triton Centimeters?

57:14 For example, would it be feasible to run a non inferiority trial against Ambutra? Thank you. Yeah. Thanks, Jess, for your question. Look, again, we feel really good, about what we have in our hands, both in terms of the molecule and the Creosiran for all the reasons I talked about the study that we have. So again, I want to reinforce, we may not need to do anything different from what we already have ongoing. That said, we do have options at our disposal. We'll look at the data and we'll consider. I think they broadly fall into a couple of buckets. One is whether we, modify enrollment in certain subpopulations, for instance, and enrich in certain ways for those. Again, we've done that already in the context of study, but we could potentially further do that based on information that we see. The other thing would be to make modifications around the analytic plan in terms of how we think about various endpoints, the hierarchy, etcetera.

58:11 And so they're largely in those two big buckets. I mean, to the second part of your question, is there a possibility that if we wanted to, we could do additional studies? Yes, certainly those things are potential. I'm not going to speculate though further on what those might look like. But I think broadly speaking, I think there's a variety of options that are in hand. Again, we're playing the long game here. I think our commitment is to deliver a successful study. We've done that in the past. We think nucreseren has the opportunity to be an amazing medicine for patients and we're committed to delivering a positive study for that. And so we will consider all the potential options at hand. As I said, they fall into several key buckets, and we'll kind of consider all those opportunities and see if anything at all is warranted. Thank you. The next question comes from Whitney Ijem with Canaccord Genuity. Please go ahead.

59:05 Hey, guys. Thanks very much for taking my question. Just sorry if I missed it, but can you remind us on how any updated thinking, I guess, around the total U. S. Patient population or TAM for ATTR Centimeters and where you are with diagnosis rate currently? And then just as a point of comparison ahead of the 6,400 Phase II data later this year, what are the comparable numbers for HHT U. S. TAM in terms of patient numbers and diagnosis rate? Thanks. So for TTR, what I can tell you is, our less estimates, if you go back to our TTR webinar, we've highlighted we estimate around two hundred thousand patients and about eighty percent of those remain untreated. What to me is sort of a good confirmatory data set is the fact that you're seeing around forty percent year over year growth of the category with a single option on the table, that has actually accelerated since we launched. So and that remains very robust. So we believe more competitors, more awareness, more education.

1:00:10 And frankly, some of those initiatives that we've just actually laid will continue to help accelerate those patients getting diagnosed. And as you all know, we have excellent data that demonstrates those patients that are treated earlier end up actually getting more benefits from ONPATTRO. So we're very actually excited about that. And again, our position on first line gives us the confidence that we can actually continue to be the leading option on the table in this growing category. Yeah, and with regard to hereditary hemorrhagic telangiectasia, there really are no approved treatments for this disease. It's actually the second most common, rare bleeding disorder that's out there. I think globally, there's about one and a half million patients with this disease.

1:01:04 I think when we think about the addressable population in United States, I think, again, those estimates vary. I think there's a number of these patients who don't actually get to medical attention, but we think there's probably about seventy thousand or so patients in The United States who may be addressable with this condition. But, again, that epidemiology will firm up again as we've seen with rare diseases where there aren't treatments. Once there are effective treatments, more and more come to attention. So that's probably a ballpark though for you. Thank you. And that concludes our question and answer session. I will hand it back to the company for closing remarks. Thank you, Sue. To close, we continue to build momentum across our business as we execute against our strategy and advance towards our 2,030 goals. And I'd like to thank everyone who's joined us today.

1:01:52 Thank you. Thank you, presenters. And ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.