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

Good day, everyone, and welcome to today's Alnylam Pharmaceuticals conference call to discuss the results from the HELIOS-B Phase III study. [Operator Instructions] Please note that this call will be recorded. [Operator Instructions] It is now my pleasure to turn today's call over to the company. Please go ahead.

Hello, I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; and Pushkal Garg, Chief Medical Officer. We are also pleased to be joined by Dr. Scott Solomon, Professor of Medicine at Harvard Medical School, who will be providing his perspective on the results of HELIOS-B and will be available for Q&A. Also joining us and available for Q&A are Jeff Poulton, Chief Financial Officer; Tolga Tanguler, Chief Commercial Officer; and John Vest, Senior Vice President of Clinical Research. For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the Investors page of our website, alnylam.com/events. Now turning to today's call as outlined in Slide 2, Yvonne will provide some opening comments. Pushkal will provide an overview of ATTR amyloidosis with cardiomyopathy and discuss HELIOS-B study and full results in more detail. Dr. Solomon will share some perspectives on HELIOS-B, and we will then open the call to your questions. Before we begin, I would like to remind 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 under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recently quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to Yvonne. Yvonne?

Thanks, Christine, and thank you, everyone, for joining the call today. My colleagues and I are excited to be speaking to you from the European Society of Cardiology Congress in London, where, earlier this morning, we presented detailed of the HELIOS-B Phase III trial for vutrisiran, our investigational RNAi that was evaluated in patients with ATTR amyloidosis with cardiomyopathy. Back in June, we shared our positive top line results in the study. And today, we revealed the full breadth of these data that we believe clearly demonstrates Vutrisiran's transformative potential and the profound impact it could have for patients living with ATTR amyloidosis with cardiomyopathy, their families and caregivers, physicians and the ATTR amyloidosis community at large. In addition, this is a landmark moment for Alnylam. It's been a remarkable journey in our quest to address this major unmet medical need. Indeed, it's been over 10 years since we first began to explore the potential of RNAi mediated knockdown of TTR to achieve transformative therapeutic benefit in patients with ATTR amyloidosis with cardiomyopathy. And Pushkal will show you in a moment, we now have hard outcomes-based evidence that rapid knockdown of toxic TTR can significantly improve cardiovascular outcomes in these patients. So but before he does that, I'd like to start with some overall context. First, as I said earlier, we view the HELIOS-B results as very impressive. Vutrisiran met every primary and secondary endpoint in both the overall and monotherapy populations, 10 out of 10, with highly statistically significant and clinically meaningful results. This included the primary endpoint, the composite of all-cause mortality and recurrent CV events at 33 to 36 months with each of the components of the composite endpoint in the overall population also achieving robust and statistically significant results, and all secondary endpoints, including a prespecified analysis of all-cause mortality and evidence of stabilization of functional capacity, health status and quality of life. Vutrisiran also demonstrates an encouraging safety and tolerability consistent with its established profile. Second, we believe that, if approved, vutrisiran has the potential to become the new standard of care in ATTR cardiomyopathy. HELIOS-B is the most contemporary ATTR cardiomyopathy study completed to date, with many patients on effective background therapies. And yet against the incredibly high bar of this contemporary therapeutic backdrop, vutrisiran showed a profound impact over and above progressive background standards of care and on the most important endpoints, mortality and CV events, while also stabilizing disease as measured by functional and quality of life measures. Furthermore, vutrisiran offers an attractive dosing schedule with quarterly dosing that aligns with doctor visits, support strong adherence and provides the flexibility of in-office or at-home dose administration by a health care professional. Therefore, we expect favorable payer dynamics with medical benefit coverage. The third point I'd like to make is that we're also now focused on preparing for the launch of vutrisiran in ATTR cardiography, assuming regulatory approval. We remain on track to initiate global regulatory filings later this year, beginning with the submission of a supplemental NDA with the U.S. FDA using a priority review voucher that could enable U.S. approval in the first half of 2025. Medical and commercial investments are planned to support a strong launch, and we plan to leverage and scale up our well-established commercial infrastructure for ATTR cardiomyopathy. We believe vutrisiran is well positioned to address the significant unmet need in ATTR amyloidosis with cardiomyopathy, given the large and growing population of those untreated. And for those whose treatment can be optimized beyond what background treatments alone provide. We could not be more excited about the prospect of launching vutrisiran in ATTR-CM based on our HELIOS-B. Given these results, we believe regulators, payers and prescribers recognize a strong profile of vutrisiran in ATTR amyloidosis with cardiomyopathy and its potential to help patients living with this serious debilitating and progressive disease. There's really nothing more important than strong clinical evidence in bringing new medicines to the market, and we believe we've got wind in our sails with the HELIOS-B results. And finally, we believe the HELIOS-B results support the potential for vutrisiran to become an anchor commercial franchise for Alnylam that will secure our next wave of significant top line growth and allow us to achieve sustainable non-GAAP profitability. This will provide the capacity for us to strategically reinvest in our highly productive organic R&D platform, and pursue other high-value therapeutic opportunities like obesity, diabetes, neurological diseases. So with these HELIOS-B results now in hand, we are closer than ever towards realizing our vision of becoming a leading global biotech company. With that, I will now turn it over to Pushkal to review the full scope of the Helios View results in more detail. Pushkal?

Thanks, Yvonne, and welcome, everybody. I am really excited to be able to share the highly positive results from our HELIOS-B Phase III study, which Dr. Fontana presented just a few hours ago at the ESC Congress here in London. Now as most of you know, ATTR cardiomyopathy is a progressive and debilitating disease caused by misfolded transthyretin protein, which forms amyloid fibrils that deposit in the heart, resulting in thickening and stiffening of the myocardium. This reduces the heart's ability to pump blood resulting in heart failure as well as arrhythmias. As amyloid deposition increases, shortness of breath and fatigue worsened and exercise tolerance declines. It becomes more and more difficult for patients to walk and perform activities of daily living. Cardiovascular hospitalizations become longer and more frequent and the disease is ultimately fatal. The median survival of ATTR cardiomyopathy ranges from 2.5 to 5.5 years, a natural history that is worse than some cancers. Over the past few years, we've witnessed an evolution towards earlier diagnosis and improved heart failure management. And as a result, contemporary patients have less advanced disease and many patients are managed with effective treatments such as tafamidis, SGLT2 inhibitors and diuretics. We estimate that there's approximately 200,000 to 300,000 patients worldwide with ATTR cardiomyopathy, with the majority of patients having the wild-type form of the disease. Now by rapidly knocking down TTR in the liver, RNAi therapeutics lower circulating levels of the pathogenic protein, which we believe offers the potential to halt or even improve patients' heart failure manifestations and reduce the risk of hospitalization and death. Let me now turn to the HELIOS-B study itself. But before I walk you through the detailed results, I thought it would be helpful to outline our key takeaways from the data. First, vutrisiran demonstrated profound that unequivocal reductions of mortality and cardiovascular hospitalization in patients with ATTR cardiomyopathy. And of note, this was in a contemporary cohort of patients who are diagnosed noninvasively with substantial concomitant use of other effective therapies, including tafamidis, SGLT2 inhibitors and diuretics. Patients given vutrisiran also experienced benefits on functional capacity, health status and quality of life, NYHA class and NT-proBNP. These are all key measures of disease progression. Importantly, consistent efficacy was seen across all patient subgroups. This includes patients who receive vutrisiran monotherapy and patients on baseline tafamidis, where we saw evidence of additive efficacy. We also saw particularly large effects in patients with characteristics of early disease, highlighting the importance of initiating effective treatment as early as possible. And finally, vutrisiran demonstrated an encouraging safety and tolerability profile consistent with its established profile. Taken together, we believe these data support vutrisiran, if approved, as a new standard of care for patients with ATTR-CM, which can be used as first line and as a switch or add-on therapy. Now I'll turn to the detailed results. HELIOS-B enrolled 655 patients with ATTR cardiomyopathy, either the wild-type or hereditary forms of the disease. Patients had to have clinical symptoms of established heart failure as assessed by a physician. As we've discussed, 40% of patients who are already on an active drug tafamidis at baseline and others were able to start stabilizers during the study. Patients were randomized 1:1 to receive a 25-milligram dose of vutrisiran or placebo administered subcutaneously once every 3 months during a double-blind treatment period of 33 to 36 months. The primary endpoint was a composite outcome of all-cause mortality and recurrent CV events assessed in 2 populations: the overall population and the monotherapy population, defined as the subset of those patients were not on tafamidis at baseline. In addition, the study included a number of secondary endpoints, which were also tested in both populations. These secondary endpoints focused on important clinical measures that we believe could best highlight Vutrisiran's potentially differentiated profile and its impact on disease progression. The first secondary endpoint was a change from baseline in the 6-minute walk test to measure functional capacity. Next was the change from baseline in the Kansas City cardiomyopathy question here, a validated measure of health status and quality of life in patients with heart failure. Third was all-cause mortality as a stand-alone endpoint, which is recognized as the most stringent measure of efficacy in this disease. And last was New York Heart Association classification, which is a common assessment that physicians use to monitor disease progression in their patients. The patients we enrolled in the study were representative of the ATTR-CM population in the modern era. The average age was 76 to 77 years, and the large majority were men, had wild-type disease and were NYHA Class II. Importantly, baseline characteristics in the overall population were balanced in vutrisiran and placebo arms. Further reflecting the modern era, there was substantial use of other effective therapies. As I mentioned, 40% of the enrolled patients run background tafamidis to study entry. These patients in the combo arm were generally healthier than those who are not on tafamidis, i.e., the monotherapy arm based on multiple measures of baseline disease severity. Baseline tafamidis was a key stratification factors, so was balanced between the placebo and vutrisiran arms. And in those patients not on tafamidis at baseline, a little over 20% began tafamidis over the course of the double-blind period. In addition, about 1/3 of patients in the overall study started taking SGLT2 inhibitors during the double-blind period. And moreover, about 80% of patients in each treatment arm were on baseline diuretics, and we saw diuretic intensification in 56% and 48% of patients in the placebo and vutrisiran arms, respectively. Turning now to the results. Let me begin with the primary endpoint in the overall population where vutrisiran reduced the risk of the composite of all-cause mortality and recurrent CV events by 28% with a p-value of 0.0118. The effects are shown here is the time to first event curve, where you can see the separation growing over time. The impact on time-to-first event was very similar to the primary analysis with a 28% reduction. We next look at the contributions of the individual components to the primary composite outcome during the double-blind period. Here, you can see that the results were driven by similar effects of vutrisiran on mortality as well as recurrent CV events. In fact, in the overall population, the study achieved statistically significant effects on both components with a 31% reduction in all-cause mortality and a 27% reduction in CV events during the double-blind period. In the prespecified secondary end point of all-cause mortality in the overall population, the hazard ratio was 0.645 corresponding to a relative risk reduction of 36% with a p-value of 0.0098. And as we've previously described, in this analysis, we included up to 6 months of data from the open-label extension period to increase the exposure time for up to 42 months, given the understanding that targeted therapies for ATTR-CM don't immediately impact mortality. This prespecified ITT analysis, therefore, compares the experience of patients who are randomized to vutrisiran against those who received placebo during the double-blind period and then crossed over to receive active drug during the open-label extension. Thus, this positive result further corroborates the significant effect on mortality that we observed during the double-blind period. It's also important to assess the consistency of treatment effect across key patient subgroups enrolled in HELIOS-B. In particular, we assessed the consistency of effect in patients receiving baseline tag, wild-type and hereditary disease and multiple measures of disease severity. And we were very pleased to see the effects of vutrisiran on the primary composite endpoint as well as the secondary endpoint of all-cause mortality were robust across all key subgroups, indicating the strength of the data and that vutrisiran may be effective across a broad spectrum of patients. That said, I'd like to draw your attention to 2 notable observations. First, we saw trends towards particularly large effects in patients with characteristics indicative of early disease, such as age less than 75 or NT-proBNP less than 2000. In these subgroups, we saw reductions of all CAS mortality recurrent cardiovascular events of 46% and 48%, respectively. We saw 45% and 65% reduction of all-cause mortality alone in these 2 subgroups. These results highlight the importance of early treatment. Second, we also saw consistent benefits of vutrisiran as a monotherapy and in patients on background tafamidis. Let me review those data in the next 2 slides. Here, we show the effects of vutrisiran on the primary composite and secondary endpoint of all-cause mortality in the monotherapy population. On the primary composite endpoint, the hazard ratio was 0.672, corresponding to a relative risk reduction of 33%, with a p-value of 0.0162. And for the secondary endpoint of all-cause mortality, the hazard ratio was 0.655, corresponding to a relative risk reduction of 35%, with a p-value of 0.0454. Next, let's turn to the results in the subgroup of patients who were on tafamidis at baseline, which comprise 40% of the overall population. As a reminder, the HELIOS-B study wasn't designed or powered to assess the additive effect of vutrisiran on top of tafamidis. Nonetheless, we were delighted to see favorable trends in the baseline TAF group in both the primary composite endpoint and in all-cause mortality. Specifically on the composite of all-cause mortality recurrency events, the hazard ratio of 0.785, corresponding to a relative risk reduction of 22%, with a p-value of 0.2701. And on all-cause mortality, the hazard ratio in the tafamidis subgroup was 0.588, corresponding to a relative risk reduction of 41% with a p-value of 0.0983. We find these trends have added benefit on both of these endpoints in the tafamidis subgroup to be encouraging as they suggest that adding vutrisiran on top of tafamidis may be more effective in reducing -- in improving CV outcomes than tafamidis alone. Now in addition to hard outcomes of death and hospitalization, patients and physicians care about how patients feel and function with this disease when they're alive. So we were pleased to see benefits of vutrisiran multiple measures of disease progression, 6-minute walk test, KCCQ and NYHA class, as shown on the left side of this slide in the overall population. And we saw similar benefits on each of these endpoints in the monotherapy population. One important caveat to the calculations for the 6-minute walk test and KCCQ results on the left is that they impute results for patients who died, assuming them to be at the worst 10th percentile or nearly 0. Now this makes sense for a statistical endpoint as you don't want to declare a win on either of these measures if the drug also increases mortality. But now that we see favorable impact of vutrisiran on mortality, what's the greatest interest to patients is how much will my disease progress while I'm alive? The curves on the right which will observe data without that worst case imputation or death help to answer that question. And what's encouraging is that the median values for both 6-minute walk test and KCCQ are relatively stable over 30 months for patients on vutrisiran, similar to what we saw with patisiran in the APOLLO-B study and in contrast to the steady decline seen in placebo-treated patients. Another important measure of disease progression used by clinicians is NT-proBNP, which is a well-established cardio biomarker prognostic and mortality in ATTR cardiomyopathy. In HELIOS-B, NT-proBNP steadily increased the placebo patients where it was much flatter in patients treated with vutrisiran, both in the overall population and monotherapy populations, and both of these results were highly statistically significant. Thus, these biomarker results further corroborate the clinical data on the prior slide, and that indicate that vutrisiran treatment appears to significantly delay disease progression in ATTR-CM. Turning to safety. In the HELIOS-B study, vutrisiran demonstrated an encouraging safety and tolerability profile, consistent with the established profile of the drug. Rates of adverse events, serious AEs, severe AEs and agent drug discontinuation were similar between the vutrisiran and placebo arms. The majority of AEs were mild or moderate, and none were seen in 3 or more percent more frequently in the vutrisiran arm compared to the placebo arm. And rates of cardiac AES were similar or lower in the vutrisiran arm compared to placebo. So in conclusion, we are thrilled with these results. HELIOS-B met the primary and all secondary endpoints in both the overall and monotherapy populations, with highly statistically significant and clinically meaningful results in a contemporary patient population, many of whom were concurrently treated with other effective therapies. Specifically, Vutrisiran demonstrated profound and uncritical benefits on mortality and cardiovascular hospitalization in patients with ATTR-CM. Patients treated with vutrisiran also experienced benefits on multiple clinical and laboratory measures of disease progression, including functional capacity, health status, quality of life, NYJclass and NT-proBNP. Importantly, consistent efficacy was seen across all patient subgroups. This includes patients who received vutrisiran monotherapy and patients who are on baseline tafamidis where we saw evidence of additive efficacy. We also saw particularly large effects in patients with characteristics of early disease, highlighting the importance of initiating treatment as early as possible. And importantly, vutrisiran demonstrated an encouraging safety and tolerability profile. We're also delighted that the HELIOS-B results have simultaneously been published in the New England Journal of Medicine and are available online. This marks Alnylam's 13th publication in this prestigious journal, and we're proud to continue our legacy of scientific innovation. Looking ahead, we plan to continue sharing detailed results from HELIOS-B at upcoming medical conferences, including HFSA later in September. Also, as we announced on our Q2 earnings call, we'll be hosting a TTR Investor Day on October 9 in New York City. And importantly, as Yvonne mentioned, and consistent with our previous guidance, we remain on track to submit a supplemental NDA filing for vutrisiran in the U.S. in late 2024, with additional global regulatory filings thereafter. In the U.S., we plan to use our priority review voucher to accelerate the regulatory review in hopes of bringing this medicine to patients as quickly as possible. Before I wrap up, I'd like to extend my thanks and admiration to my many Alnylam colleagues who always maintain their belief in our mission and sweated every detail to deliver a high-quality study. Likewise, I'm grateful to the investigators, site staff and partners and vendors work with us. And most of all, I want to extend my heartfelt thanks to the patients who volunteered to participate in the study, which we hope will allow us to bring this medicine to ATTR-CM patients around the world who need additional therapies for this devastating disease. It's now my pleasure to welcome Dr. Scott Solomon of Harvard Medical School to provide some additional reflections on the HELIOS-B data set. As many of you know, may know, Dr. Solomon is the Edward Frohlich Distinguished Chair and Professor of Medicine at Harvard Medical School and Brigham and Women's Hospital. He directs the Clinical Trials outcome center and the cardiac imaging core laboratory. His research interest have focused on understanding the effects of heart failure on cardiac structure and function, modifiers of risk and outcomes in heart failure and therapeutics for heart failure. These are well renowned clinical trialists having led numerous Phase II and Phase III clinical trials in heart failure, including in patients with heart failure with reduced ejection fraction, mildly reduced and preserved ejection fraction, amyloidosis and hypertrophic cardiomyopathy, and this work has led to the introduction of several key therapeutics in heart failure, so I think his opinions here would be very helpful. Dr. Solomon?

Pushkal, thanks. And there's very little for me to add actually to what has been really an extraordinary morning. These results truly speak for themselves. When I reflect on the fact that just a decade ago, we really had virtually no therapy, certainly no targeted therapies for patients with ATTR cardiomyopathy. And how that has changed and today, I think, has really moved the field even further. I'll just make a couple of comments. First of all, I can't stress how important it is to realize that this is a progressive disease. If you don't treat it, these patients are going to develop heart failure. They're going to be hospitalized for heart failure and they're going to die. And you see that in even the treatment arms that you see in the results of this trial, that there is progression in this disease and what new therapies can do sometimes is to attenuate progression. I think that the robustness of these results need to be considered in light of the fact that in heart failure, we rarely see relative risk reductions of the magnitude that was seen in the HELIOS-B trial. And the fact that this was the case, not just in the overall population, in the monotherapy population, but also that there was consistency in every single subgroup, importantly, in the subgroup that received tafamidis makes us think that there's actually incremental value here in the mechanism of action of the silencer on top of tafamidis. It's a small subgroup that's important to recognize of those patients, but the data suggests that there's consistency of those results. So I'm extremely excited about these results. I think that you're going to learn a lot more that will come out over the next year or so or even sooner, including other mechanistic data and additional data that's going to support this overall -- the magnitude of this outcomes result that you saw today. So I congratulate the sponsor for doing an incredibly well performed trial that's going to clearly change the way people practice.

Thank you, Scott.

Thanks, Dr. Solomon. Operator, we will now open the call to your questions. [Operator Instructions].

[Operator Instructions] We will take our first question from Eliana Merle with UBS.

Can you give us a little bit more color on how you think the month 30 all-cause mortality results compared to the stabilizers? So specifically, the discussant slide showing the relative risk reduction on all-cause mortality at month 30 was 13.8%. Is that correct? We're just trying to reconcile this with the 31% all-cause mortality benefit in the overall population at the 33 to 36 month time point.

Yes. Thanks, Ellie. Look, I think, obviously, cross-study comparisons are always hazardous. -- first of all, these are different populations at different points in time. And I think what Dr. [indiscernible] was actually trying to convey there was how treatments actually have been benefiting patients. And over time, and we're seeing sequentially greater improvements in treatment outcomes. We've been in touch with Dr. Cuddy. I think there was actually a calculation error on this slide, so the hazard ratio that's shown is 0.69. If you just do the simple math, the relative risk reduction would be 31%. So I think there was just a typo on the slide. So it was about 31%, which is in line with the 30% to 36% reductions that we've cited in terms of relative risk reduction across all the hard outcomes in the study.

We'll take our next question from Mary Raycroft with Jefferies.

Congrats on the data. I'm just wondering if you can contextualize your patient baseline data as well as the extensive background meds and HELIOS-B versus the acoramidis and tafamidis Phase III? And how this contributes to the timing of her separation for HELIOS-B outcomes versus the other study?

Yes, that's a great question, and I'm glad you've noted the baseline characteristics. And I think this really continues to underscore the point that Dr. Solomon made about how patients are being diagnosed earlier and being treated with many, many therapies for this condition. So I think the fact that we're able to demonstrate such impressive results of vutrisiran in this context, I think, is remarkable. Pushkal?

Yes. Maury, thanks. Look, I get why looking at sort of timing of curve separation is an appealing concept. But maybe these 2 problems I would just sort of highlight, I mean, first of all, it's a somewhat subjective parameter, right? It's kind of an eyeball test is 2 versus 1 event or 11 versus 9 events is that separation. And it's very event dependent. You just need to have enough events over time for curves to separate. Now in this study, we purposely enrolled an earlier population. That's going to lead to a lower event rate. We also allowed patients in a modern setting to be on [indiscernible] over half were on tafamidis at 1 point or another, 30% were an SGLT2 inhibitor. So that also leads to lower event rates. So the curves here are actually what we expected as we designed the study. And I'll point out, as Dr. [indiscernible] did this, there are many parameters that show an early treatment effect, when you look at BNP, 6-minute walk test, et cetera, all of which suggests the quick manifestation of the rapid knockdown that vutrisiran offered. So I would really just focus on more robust measures of efficacy. And I think here in this contemporary population, to see reductions in mortality and hospitalization which, as Dr. Solomon pointed out, are sort of on the high end of what's typically seen in heart failure studies to date, impact on progression and consistent data that seem to be applicable across a broad spectrum of patients, we think is fairly unprecedented and quite remarkable.

We'll take our next question from Paul Matteis with Stifel.

This is James on for Paul. And congrats on the data. Maybe just a quick question. If you could remind us in terms of when you made the changes to the Alnylam, the stats plan kind of exactly what and when the discussion with the FDA and just your confidence that they're 100% on board with the changes as you kind of now approach to filing and potential regulatory approval?

Yes. Thanks, James. So as we've talked about, we were in discussions with FDA and other regulators and other health authorities after we saw the APOLLO-B results last fall, the 2-year data, really looking to strengthen the endpoint structure so that we could demonstrate outcomes benefits. We recognize the higher bar. We wanted to demonstrate a mortality benefit and focus on clinically relevant endpoints. And also, to highlight benefits both as a monotherapy and in the overall population. All of those changes were made and discussed with the health authorities and codified in a prespecified statistical analysis plan. And I'll point out that, that analysis plan, the protocol and the results go through a pretty rigorous review by editors of the New England Journal of Medicine. And all of those were published online today. So you can look at those as well. So we feel good the study was designed to show -- to demonstrate a mortality and hospitalization benefit, and we think it's convincingly done that.

We'll take our next question from Kostas Biliouris with BMO Capital Markets.

Congrats on the detailed data. Would you be able to break down for us the CV versus non-CV debts under the old cost mortality, as I know -- this is important for some people. I'm sorry if it's somewhere and we missed it. But I'm wondering whether you are planning to present it or you can take it down for us here?

Thanks, Kostas. It's a great question. We'll ask John Vest to respond to your question.

Yes. Thanks for the question, and I certainly understand why you're asking. But I think we should back up. First of all, death is death, okay? And if anything, we would consider all cause mortality to be the highest possible bar. Now that said, all cause mortality, of course, encompasses CV mortality. And what we can say is that as we would expect, the vast majority of deaths on the study were indeed CV. And when we look at the results, considering CV mortality, the results are entirely consistent.

We'll take our next question from Gena Wang with Barclays.

I have 1 question for Dr. Solomon. So which they acquire more important when we look at the tetanus monotherapy. And when we look at the vutrisiran monotherapy group, the baseline back calculate to team is 1,700 for the actually very high at 2,400. I know the NYHA Class III grows only 5% a model, particularly is 30%. So which data point is more important to determine patients are more severe?

That's a great question. Gena, I have to say it's not difficult to understand that the lines are not terribly good, but we'll do our best. And maybe, Pushkal, you can start off, I think it's around which data points are the most convincing in the study. Perhaps if you start and then Dr. Solomon.

Yes. Why don't I start. Gena, I think you were trying to look across the baseline severities of the TAF patients and the VUTRI patients. And look, I certainly get the nature, but this is -- they're really quite different. And this wasn't a head-to-head study of TAF versus Vutri. In fact, the TAF patients were primarily U.S. patients. They were healthier. And I think we put on the baseline demographic slide across a variety of parameters, NT-proBNP, 6-minute walk test, KCCQ troponin all of those sort of suggested it was a somewhat healthier population, and they've been on drug for a median of about 11 months before they entered the study as opposed to the Vutri patients who are de novo. So in trying to do that comparison, you're kind of trying to compare U.S. patients versus ex U.S. patients or healthier versus sicker patients, those who started on drug versus those who had been on drug. So you can't really do that. I think maybe the couple of takeaways, before I turn it over to Dr. Solomon are that the struggles study is a modern era on patients on multiple background medicines. And what we see is actually, as Dr. Solomon pointing out, we're seeing benefits both in mono and evidence of benefit on top of tafamidis. And that suggests that tafamidis stabilized maybe leaving some efficacy on the table that Vutri is able to address. But Dr. Solomon, maybe you may have some other points to add.

Yes. And you may want to make some more general comments about the insights that you believe the medical community take away from the study results.

Yes. So first of all, to answer or at least to address this question, I look at this as the only comparison that is valid in a trial like this is the randomized comparison vutrisiran versus placebo, whether patients are on TAF or not, whether they're on SGLT2 inhibitors or not, whatever they're on. What you can do, of course, is to look at the consistency of that result, and we do this statistically by looking at the interaction, the formal interaction between the subgroups in the therapeutic arms. And here, there was no evidence whatsoever of an interaction suggesting that there was no heterogeneity, that patients had similar benefit, whether they were on the tafamidis -- in the tafamidis group or in the monotherapy group. And I think we are loath to make comparisons of tafamidis monotherapy with vutrisiran monotherapy because then you're breaking the randomization. As we've mentioned before, these are still relatively small subgroups, but the data are suggestive that there should be, as Pushkal said, incremental value when we add a silence or to a stabilizing.

We'll take our next question from Mike Ulz with Morgan Stanley.

Maybe just more of a follow-up on the TAF subgroup benefit. And maybe to get a little bit more of context from Dr. Solomon as well in terms of the benefit and what's meaningful and in that context, what percentage of your patients would you consider putting on the combo?

Yes. So look, Mike, I think -- I mean, first of all, it's important to remember, we're talking about mortality and hospitalization. And so there is sort of no minimum floor for that. We want to improve those outcomes as much as possible. And what we're seeing overall, I'd just point out, is a pretty substantial effect if you just look in aggregate at what we're seeing in terms of relative risk reduction. We're talking about a 30% to 35% if you look across a variety of the hard endpoints. So this is quite sizable. We actually put some of the absolute risk reductions [indiscernible] in the order of 10% to 20%, which leads to actually very small numbers needed to treat, if you kind of do the calculation there. So these are pretty substantial. And again, not to draw too much from small subgroups, but in that TAF subgroup, we saw a 41% relative risk reduction in mortality in patients with evidence of earlier disease, we saw 65%. And so we can look across this, but I think what you're seeing is remarkably consistent results across a broad range of patients. And -- but maybe Dr. Solomon, do you want to speak a little bit more in terms of what you consider meaningful?

Well, let me just provide some context here. In the general heart failure field, we've been using multiple therapies for many years. So we now put patients on beta blockers and ACE inhibitors and RNAi and SGLT2 inhibitors. We have literally 4 pillars of therapy. I think what these results show is that vutrisiran alone reduces morbidity and mortality in these patients. But they are very suggestive that in combination with therapies like stabilizers, tafamidis, they would also reduce morbidity and mortality incrementally. And obviously, there are going to be other challenges to getting patients on both of these drugs. But scientifically, it makes sense. There's nothing in these data that would suggest there would not be incremental benefit.

We'll take our next question from David Lebowitz with Citi.

I guess 2 things. One, could you just comment on the nature of the sensor data in the charts and just what that exactly is? And also, could you characterize the functional data? I know certainly, the mortality is -- I mean the outcomes are more of a focus, but how would you characterize the functional data vis-a-vis stabilizes?

Those are 2 great questions. Clearly, with respect to the functional data, I mean we are really impressed by what we've been able to see here in terms of stabilizing disease. And we believe that it's going to be really important to patients, as Pushkal said. First of all, you're concerned about mortality, CV outcomes and then obviously, how you function and feel is incredibly important. I think what we're seeing here is actually the power of the RNAi mechanism in terms of rapid knockdown and pretty early impacts on both quality of life and 6-minute walk test. Pushkal, perhaps you'd like to comment a little bit on the sensor data or John.

I can start, and then John, you can add in. Look, the sensoring, Dave, is just because as we -- a reminder, we actually lost the database when the last patient got to month 33, right? And so there are going to be some patients with all patients are on 33 to 36. So you see some censoring that happens in the primary endpoint after that. And then for the month 42 analysis, that was somewhat opportunistic, right? So we actually, again, locked when people were at 33 to 36 months when they completed the double-blind period, not all patients have made it to 42 months up to that point. In fact, about 20% of the patients have gotten to month 42, other patients were in that spread of data time points between 33 and 42 months, and so you see that censoring there. What's important is that you see that curve steadily separating over time, and they continue to separate. Dr. Solomon would like to add something.

I just want to add something about the functional data because as a clinician, I would say that patients will thank you when they feel better and they can -- and when they can do more. And I can tell you that in most heart failure therapies do not have the magnitude of improvement that we saw in this trial. We've looked at this with SGLT2 inhibitors. We looked at this with the angiotensin receptor-neprilysin inhibitor. And we never see an improvement in 6-minute walk. So that alone is impressive, but the magnitude of the Kansas City cardiomyopathy questionnaire score is way bigger than we typically see in our traditional heart failure trials. And this is the kind of thing that patients will come back and say, thank you doctor for putting me on this medicine.

We'll take our next question from Luca Issi with RBC Capital.

Congrats on the data. Maybe pushout at high level, Obviously, 1 of the challenges here is that you, Pfizer, BridgeBio, obviously have run trials in different eras. And so not only the baseline characteristics are very different, but obviously, you have a much higher rate of drop in both tafamidis as well as SGLT2 However, I think you did mention during your top line data that you believe HELIOS-B established on vutrisiran first-line therapy. Can you just maybe articulate why you think docs should actually pick this therapy over tafamidis or acoramidis for newly diagnosed patients? Any color there much appreciated.

Sure, Luca. Let me start and then Tolga may have something he wants to add as well. Look, I think there's a couple of points. First of all, I do think we should just step back and recognize that there's a tremendous unmet need in this disease. The majority of patients are not treated, if not even diagnosed. Some don't respond and many progress on current therapy. And so there's a sore need for new therapies in this progressive and ultimately fatal disease. The study we did here was in the modern era. This is a really stringent test of efficacy. I think you heard that from the podium as well today. To be able to show efficacy in a modest-sized study on top of rigorous and effective background therapies is actually quite remarkable. And in that context, the drug hit 10 out of 10. Now when you look in the data set itself, what you see is pretty strong results as a monotherapy, 35%, 36% reduction in mortality, which Dr. Solomon has commented on, is on the high end of what's typically seen in heart failure study. So that in and of itself is quite remarkable. Now the other thing that we see is evidence of additive benefits on top of TAF. This, I think, suggests 2 things. One, I think it suggests, just again, the possibility that there's additive effects, but also that the stabilizers may be leaving some efficacy on the table that vutrisiran is able to fulfill. And so that, I think, is a pretty remarkable finding as well. And so what we also then see is benefits in terms of disease progression, which Dr. Solomon pointed out, is really important to clinicians. They want to be able to start to feel better. They don't want to lose that function that allows them to go to their kids' ball game or the grand kid's ball game or do other activities. And so that's very important. So look, physicians and patients will have additional choices now. And we think that's a good thing given the unmet need that's here. But we do think that when you look at these data in totality, they stand up quite well to what's available, and we'll make this drug suitable both for first-line use as well as for patients who may be progressing on another therapy.

Yes. Just to add on a few points that Pushkal highlighted, and I know these will be maybe a little repetitive, but I think it's really important to underline. We do believe upon approval of vutrisiran will have a clear opportunity to be a first line in standard of care. And when the dust settles, these are the key drivers that will really matter. One, as Pushkal highlighted, this remains an underdiagnosed, undertreated category. There's a significant amount of patient needed that's out there. And as you heard from Dr. Solomon, for a disease where the median survival is 2.5 to 5.5 years. physicians and patients, they want to really hit this disease hard and they want to hit fast. And the disease-causing protein that's showing a clear impact on mortality in a contemporary patient population, including data on top of TAF is really compelling. And you also want to see the benefits on preservation of function and quality of life, and we've delivered on all those results in all trial subgroups. It's really critical that we underline this. And last but not least, in a crowded category, which are the unique and highly differentiated mechanism of action, that works upstream enabling rapid knockdown of TTR at the source that is deep and durable. So with an attractive quarterly dosing schedule that aligns with physician visits, supporting strong adherence with site of care flexibility, favorable payer dynamics, we believe all those elements will enable us to position this important medicine upon approval as a first-time stature.

We'll take our next question from Gary Nachman with Raymond James.

So how early are patients typically getting diagnosed now with ATTR-CM? And what's the likelihood you can get these patients on treatment as early as possible? That's clearly where you saw the best results in the study. And do you think physicians would think differently about how they'll use Vutri later on in more severe patients, given that dynamic?

Great for Dr. Solomon to start answering that question then, Tolga, you may have some perspective.

Yes, let me start. I mean, I think 1 of the remarkable things we've seen over the past decade is that as we have realize that there are now therapies for this disease. We're starting to make this diagnosis earlier and earlier. We're thinking about it more. The estimates in the typical heart failure with preserved ejection fraction group of patients that I study tends to be about between 5% and about 15% might actually have ATTR-CM. And this is something that we just -- was completely unrecognized until several years ago. So we're starting to think about it more, but we're not thinking about it enough. We certainly need to pay more attention to this disease because this is really one of the first truly targeted therapies in heart failure. And one of the reasons I think we are seeing such a profound risk reduction here is because most of the therapies we use in heart failure are not targeted to the molecular problem, but this one is. But I think your point is that we are beginning to diagnose these patients earlier in the course of disease. As we do that, of course, their event rates are lower. They will live longer. And the benefit that they're going to see accrue from treatments like this are going to extend to longer years of considerably longer years of life, the earlier we cash them.

That's terrific, Dr. Solomon. I think what we believe we have in our hands is actually a game changer for these patients with ATTR cardiomyopathy. Anything to add to?

Two quick points, completely aligned with Dr. Solomon's view. Since the approval of the first stabilizer, the diagnostic rates went to unfold in a quick short amount of time of 6 years, and it continues to grow. So that's a very encouraging sign because of the uniqueness of scintigraphy and other diagnostic tools. So that's #1. #2 is about how we want to be able to actually position this product? What HELIOS-B has provided us is that we've been actually able to demonstrate consistent benefit across all severity of patients. And of course, despite the fact that the bar is much higher for moderate patient severity, we've still been able to demonstrate that. And we believe we're going to be well positioned first line, but we also have data available for more severe patients. So in combination of all these elements enables us to position the product first line, but if patients want to be switched off of other products, I think we're well positioned to do that.

Maybe just 1 last point. I just -- I think it's important because what you're asking about in terms of early treatment is just such a critical aspect of moving the needle for these patients. And I think that's a key finding from this study, and that's where the field is going. I think recognizing this is a targeted therapy in a disease that can be treated early. I think what you're seeing also beyond technetium scanning is pilot work that's going on in terms of red flag symptoms, right? So patients presenting bilateral carpal tunnel syndrome often have underlying amyloid or patients who have spinal stenosis. So these are all clinically -- these diseases present. They can -- these patients can then be screened, and we're seeing the pilot programs like that, that are happening around the world. So look for earlier diagnosis to continue.

We will move next to Whitney Ijem with CGF.

Just to follow up on the diagnosis rate question. I guess, can you remind us or talk about kind of the existing efforts from a screening or genetic testing perspective? And in particular, I think I'm remembering a partnership with 23andMe. Can you, I guess, talk about what you're seeing with some of the genetic screening efforts and maybe any acceleration in terms of patient identification or early screening efforts in that regard from a genetic perspective that are planned or ongoing.

Tolga?

Yes. I mean, obviously, any genetic testing efforts that we've had were very appropriate for polyneuropathy and mix vanity patients, and that's actually been able to, I think, you can see from our earnings results, we've been very successful about getting more patients treated in polyneuropathy. Now when it comes to cardiomyopathy, I think Pushkal highlighted a number of important points. Given that scintigraphy is easily accessible and relatively inexpensive, education of community cardiologists and most importantly, as Pushkal highlighted, having red flag symptoms through electronic medical records, system integration of these so that these patients can be actually diagnosed just by early symptoms beyond cardiac biomarkers is something I think we are working on. We're going to be working on, obviously, other competitors will be working on, which is a great thing for the patients.

Thank you. So clearly, one of our advantages is having been the TTR market for some years now, and that has allowed us to really understand some of the dynamics here, and we're obviously looking forward to getting vutrisiran approved so we can turn our effects to helping patients with ATTR cardiomyopathy.

We will move next to Ritu Baral with TD Cowen.

Now that we've seen that you guys have actually hit statistical significance on the double-blind portion mortality, how should we think about mortality as explained in your label and the potential for that? And will that be impacted at any point -- could that be impacted by that little, I guess, blip that we saw in the monotherapy curves where the curves crossed and then uncrossed sort of early on?

Yes. Thanks, Ritu. Look, I'm not going to prognosticate the details of the label by any stretch, but what I can say is it's a -- I agree with your general premise here, which is, not only did we hit the mortality at the month 42, which was the prespecified stand-alone endpoint, but obviously, the rigor and strength of the data are only compounded by hitting mortality during the double-blind period with statistical significance. And so this study was designed for an indication of reducing mortality and hospitalization in patients with ATTR-CM. And we think it's convincingly done that. Now as you see, we have multiple data points on mortality alone that show the rigor of the data and the strength of the data. So we feel good about that.

We'll take our next question from Salveen Richter with Goldman Sachs.

It's a question for Dr. Solomon. In the context of the data set presented, what is your view on ambitious separation and mortality view a few months after chromites is this meaningful for practice? And as you think now with the [indiscernible] that you're going to have here, help us understand how your treatment paradigm might change within your practice?

Well, first of all, I think you need to be very careful when we look at the separation of curves in general when the number of events are very small. And I think Pushkal, you already made that comment. It really depends on the patient populations. If you look at the other endpoints in this trial, for example, the cardiovascular event endpoints or even the functional endpoints, you really see separation occurring much earlier. There's no question in my mind that biologically, this drug is working early. But if you don't have events, you can't show a difference until a certain point in time. And that is dependent on the ambient event rate and the overall health or degree of sickness of the population among other things. So I wouldn't try to compare across trials. In terms of practice, when this drug is approved, I think that it becomes another weapon in our armamentarium for the treatment of this disease. And I'm very pleased that it is really apparent, as I've said a few times, that there's going to be potentially incremental value because I'm a strong believer that we probably do need to combine mechanisms. This mechanism absolutely works. We know that stabilization also works, but I think that what we have to think about is getting the best overall results for our patients.

We'll move next to Tazeen Ahmad with Bank of America.

This is Daniel on for Tazeen. I just had a question on the functional endpoint side. I was wondering if you could help us frame sort of the magnitude of effect that you saw in the walk on the KCCQ and how going through your relevance those are -- and maybe comment on how relevant that is versus just looking at the stabilization in the vutri arm. And if you can also comment on what additional analysis you're pointing 2% about HSFA?

Yes. So maybe I can start on the functional endpoints and HFSA and then Dr. Solomon may have another few words to say about the functional endpoints from a clinical relevance perspective. Look, I think on the functional end points, we were really pleased to see -- if you'll recall back in APOLLO-B days, we looked and talked about these functional endpoints being relatively stable over an extended period of time when we looked at the 2-year data. In this study, we now have the opportunity to look at patients randomized over 3 years. And again, in the context of this steadily progressive disease to see what looks like relative stabilization on these end points over such an extended period of time in contrast to what you're seeing in the placebo patients, I think, is really quite impressive. That's obviously after you subtract out any imputation. You just look at the observed patients who are surviving on this drug and how they're doing, it's quite impressive. And it's corroborated by even more sensitive biomarkers of clinical progression, which is the NT-proBNP, which, again, Dr. Solomon has a lot of experience, and he can comment on having seen these data -- that parameter across a lot of studies is quite remarkable actually to see what we're seeing there over an extended period of time. So all of this, I think, points to, hopefully, patients who get on this drug, not only surviving longer, avoiding the hospital, but actually maintaining their ability to function and their quality of life for an extended period of time. As it relates to HSFA, we will be presenting some more data, particularly from exploratory endpoints at HFSA, and we'll look forward to sharing that in a few weeks. But Dr. Solomon?

Yes. Just a brief comment. I mean with respect to the biomarker end points, the fact that you see the magnitude of reduction of NT-proBNP, it's substantially more than we see with Entresto, for example, in typical heart failure. It's substantially more than we see with SGLT2 inhibitors in typical heart failure, again, getting to the fact that we have a targeted mechanism here, I think. In addition to that, when you look at the KCCQ and the 6-minute walk benefits, remember, you're looking at means. What we really care about is what percentage of patients -- and you will probably see more of this data as they are analyzed, what percentage of patients cross specific thresholds? And these means are of such a substantial magnitude that we expect that we will see that there is a very high percentage of patients who have substantial increases in their measures of quality of life, and that's what they care about very much.

We'll take our next question from Liisa Bayko with Evercore ISI.

A question for Dr. Solomon. As you look at this data and sort of think of some of the other treatment options tafamidis, acoramidis, may be available soon, there may be another sound as well, like what attributes are you going to consider when you're kind of choosing which therapy to put a patient on? And then how many -- how do you think it will ultimately break down between sort of tafamidis, vutrisiran and acoramadis? And how many do you think you'd put on combination therapy?

Yes. So that's a difficult question. Why don't we wait and see after the approval of this drug, I mean, I think that as I said before, the fact that clinicians are going to have options for these patients. We will obviously consider options in patients who are already not on anything. Getting somebody on our therapy is going to be incredibly important from my perspective. And then I think there is going to be room for, as I've said before, combination therapy in this disease.

Tolga has been thinking about this question quite hard as well. So maybe Tolga, may be you've got to...

Yes. And obviously, we have an inherent bias here. But maybe what I can refer to is we actually looked at a third-party market research by Ipsys. They've done their own cardiology research across U.S. as well as Europe and Japan. And there, based on the available information, and I completely agree with Dr. Solomon, I mean at the end of the day, the label of what's going to really define and determine how we can actually promote this product. But based on the available data, more than 2/3 of the physicians you see vutrisiran as a standard of care first-line product, which essentially confirms what we've been seeing in our own research and our own discussions.

Thank you, Tolga. I think we've got time for 1 last question.

We will take our final question from Jessica Fye with JPMorgan.

Curious if you could speak to how the 6-minute walk and KCCQ results look in the monotherapy population task the group. Was there consistency there? I think we saw this for the overall population. Curious if you could sine any light on the subgroups? And then I did just have a housekeeping one, which was, can you just confirm what percent of patients were on background task by the end of the trial? I think you mentioned earlier more than half, so it was about 40% at baseline? And then just where did it land at the end after all those TAF drop in?

I think you could take the last 2 questions.

Yes. Thanks. So I think the first part of the question was about the effects on 6-minute walk test and KCCQ in the monotherapy population. And the short answer is that the results were we're entirely consistent. We shared this, I believe in the press release, it was about 32 meters was the LS mean difference in 6-minute walk test and around 9 points on the KCCQ. And similar stability in the median changes over time, reflecting the results in the patients surviving on the trial. So highly consistent results there. And likewise, as we saw in every endpoint that we looked at the results in the background families subgroup where similarly, I can say.

Good. Okay. Well, I think that brings our call to a close and...

There was a question on background TAF -- sorry, total TAF use, I apologize. Yes. So that was. At baseline and then 20% in the monotherapy group dropped in. So -- and that's sort of -- so if you add it all up, you kind of get to about 50%, 52% in the overall population by the end of the study. Sorry, to interrupt.

That's fine. I just wanted to end by saying thanks to everyone for joining us. You've heard on the call that we are absolutely delighted with these results from HELIOS-B. And we're looking forward to rapidly moving the regulatory filings forward, and assuming regulatory approval, bringing vutrisiran patients with ATTR amyloidosis with cardiomyopathy. Thank you, everybody and have a great day.

Thank you. This does conclude today's program. Thank you for your participation. You may disconnect at any time.