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

Ladies and gentlemen, thank you for standing by. Welcome to Alnylam Pharmaceuticals' Conference Call to discuss HELIOS-B top line results. [Operator Instructions] Please be advised that today's conference is being recorded. I would like now to turn the conference over to Alnylam Pharmaceuticals. Please go ahead.

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Pushkal Garg, Chief Medical Officer; and Tolga Tanguler, Chief Commercial Officer. Also joining us on the line and available for Q&A are Akshay Vaishnaw, Chief Innovation Officer; Jeff Poulton, Chief Financial 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 on Slide 2, Yvonne will provide some opening remarks. Pushkal will provide an overview of ATTR amyloidosis with cardiomyopathy and discuss the HELIOS-B study and top line results in more detail. Tolga will review our commercialization strategy for vutrisiran and ATTR-CM, and we will then open the call to your questions. Before we begin, 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 under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC. In addition, any forward-looking statements represent our view only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations 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 this morning. As you saw in our press release, we're announcing positive top line results from our HELIOS-B Phase 3 trial of vutrisiran, our investigational RNAi therapeutic that was evaluated in patients with ATTR amyloidosis with cardiomyopathy. First and foremost, the study met the primary and all secondary endpoints in the overall and monotherapy patient populations. Let me be clear, this is the big win scenario. We are thrilled with these results and what they mean for patients, for physicians, families, caregivers, everyone in the ATTR amyloidosis community. 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. In fact, 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 as Pushkal will describe to 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. ATT amyloidosis is a fatal disease. It robs patients of their ability to live a normal life and the median survival ranges from 2.5 years to 5.5 years, a natural history that is worse than many cancers. And more than 80% of ATTR cardiomyopathy patients remain untreated. And for those that are treated, the majority of patients continue to progress in their disease course, so there is significant unmet medical need of this disease. With the HELIOS-B results now in hand, we intend to advance vutrisiran for supplemental NDA filing later this year for the treatment of ATTR-CM using a priority review voucher in the U.S. with additional global regulatory filings to follow. Later in this call, Tolga will walk you through how we plan to bring vutrisiran to patients around the world living with this devastating disease. And assuming regulatory approval, we believe expansion of [ ambitious ] label to include ATTR cardiomyopathy represents a major inflection point in our journey towards becoming a top-tier biopharma company. Moreover, we believe these positive HELIOS-B results provide a critical key to unlocking the next wave of our significant top line growth and our ability to achieve a self-sustainable financial profile. The results of HELIOS-B show the true power of the RNAi mechanism of action, supporting what we believe to be a highly differentiated therapeutic profile and positioning vutrisiran as a new standard of care in ATTR cardiomyopathy. Moreover, this achievement highlights Alnylam's expertise, including trial design, a deep track record of conducting trials of ATT aspects, our thoughtful approach to patient selection, conservative powering of our pivotal studies and a rigorous approach to implementation, training and oversight of clinical assessments. This is all driven by a corporate culture that's devoted to our passion for excellence and a deep commitment to patients. Before I hand it over to Pushkal, I'd like to take a moment to acknowledge the patients, their families and caregivers and the investigators and study staff across the globe who participated in HELIOS-B, and made this important clinical advance possible. I'd also like to acknowledge our team of Alnylam who went above and beyond and called over every detail to ensure trial success. I'm very proud of our team, and I look forward to the next phase of our TTR journey. With that, let me now turn it over to Pushkal to review the HELIOS-B top line results in more detail. Pushkal?

Thank you, Yvonne, and good morning, everyone. It is really a tremendous joy and an honor for me to be sharing these exciting top line results with you on behalf of all of my colleagues at Alnylam. As most of you know, ATTR amyloidosis is a multisystem disease that's caused by misfolded transthyretin protein, which deposits primarily in the heart and the nerves, resulting in cardiomyopathy and polyneuropathy that are progressively debilitating and ultimately fatal. We estimate that there are approximately 50,000 patients worldwide with the hereditary form of the disease and many multiples of that several hundred thousand in fact with the wild type form. By rapidly knocking down TTR on the liver RNAi therapeutics acts upstream to lower circulating levels of the pathogenic protein. Our therapeutic hypothesis is that this, in turn, reduces amyloid deposition in the heart nerves, thereby having the potential to halt or even improve manifestations of disease. We've seen the transformative impact of that rapid knockout TTR has had on the treatment of polyneuropathy in hereditary ATTR amyloidosis patients, where both ONPATTRO and AMVUTTRA have demonstrated substantial improvements in both neuropathy impairment and quality of life. And as I'll describe now in a moment, we have the first definitive clinical evidence demonstrating the ability of RNAi therapeutics to improve cardiovascular outcomes as well. Let me now turn to the HELIOS-B and briefly remind you of the study design. HELIOS-B enrolled 655 patients with ATTR amyloidosis with cardiomyopathy, either the wild-type or hereditary forms of the disease. Patients had to have clinical symptoms or established heart failure as assessed by a physician. Importantly, these were patients who were enrolled in a modern era where patients are identified earlier in their disease by noninvasive methods and patients' heart failure management has improved via other use of medications such as diuretics and SGLT2 inhibitors. And as we've discussed, 40% of patients were 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 the double line treatment period of up to 36 months. The primary endpoint was a composite of all-cause mortality and recurrent CV events assessed in 2 populations: the overall population and the monotherapy population defined as those patients who are not on tafamidis at baseline. In addition, the study included a number of secondary endpoints, which were also tested in both populations. Let me now review each of these endpoints in greater detail. This table shows the full list of prespecified primary and secondary endpoints for the HELIOS-B study. In addition to the primary composite of all-cause mortality and recurrent cardiovascular events, the secondary endpoints we tested focused on important clinical measures that we believe could best highlight vutrisiran's potentially differentiated profile and its impact on disease progression. These secondaries are all listed here and were tested hierarchically in this order. The first secondary endpoint was a change from baseline in 6-minute walk test to measure functional capacity. Next is change from baseline the Kansas City Cardiomyopathy Questionnaire, 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, the New York Heart Association classification, which is a common assessment that physicians use to monitor disease progression in their patients. Let me take a moment to provide a bit more context on the secondary endpoint of all-cause mortality. We wanted to use the opportunity of this pivotal trial to fully demonstrate the impact of vutrisiran on mortality alone, which is the highest bar for efficacy. With the understanding that targeted therapies for ATTR cardiomyopathy don't immediately impact mortality, 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. 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. Thus, this is indeed a stringent test of mortality. Let me now walk you through the results. Remarkably, vutrisiran achieved statistical significance on every endpoint we tested, 10 out of 10 in both populations. HELIOS-B met the primary endpoint, achieving a statistically significant reduction in the composite of all-cause mortality and recurrent cardiovascular events in both the overall and monotherapy populations. In the overall population, the hazard ratio was 0.718 corresponding to a relative risk reduction of 28% with a p-value of 0.0118. In the monotherapy population, the hazard ratio was 0.672 corresponding to a relative risk reduction of 33% with a p-value of 0.0162. On the first secondary endpoint, vutrisiran demonstrated a significant improvement in change from baseline in the 6-minute walk test at 30 months relative to placebo in both populations with p-values less than 0.025. Vutrisiran-treated patients also demonstrated improvement in health status and quality of life relative to placebo as measured by the KCCQ, also in both populations and again, with p-values less than 0.025. Next, let's turn to the prespecified secondary endpoint of all-cause mortality. Here, we were thrilled to see in both populations, statistically significant and highly clinically relevant reductions in 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 less than 0.025. In the monotherapy population, the hazard ratio was 0.655 corresponding to a relative risk reduction of 35% with a p-value of less than 0.05. The final secondary endpoint NYHA class was analyzed as a percentage of patients in each arm were either were stable or showed improvement at month 30. Here, too, we saw statistically significant benefits in both populations with p-values less than 0.025. Thus we observed truly remarkable results in this study with vutrisiran meeting an extraordinarily high bar for efficacy with statistical significance on all 5 prespecified endpoints in each of the 2 study populations, highlighting the powerful impact of vutrisiran and its mechanism of action on this disease. Finally, it was 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 tafamidis, wild type and hereditary disease and multiple measures of disease severity. And we were very pleased to see that the effects of vutrisiran on the primary and all secondary endpoints are, in fact, consistent across all key subgroups, including patients on background tafamidis where we saw evidence of additive effects. Now let me turn to the top line safety results. Vutrisiran demonstrated encouraging safety and tolerability consistent with its established profile. Rates of AEs, SAEs and AEs leading to discontinuation were similar between the vutrisiran and placebo arms. No AEs were seen greater than 3% more frequently in the vutrisiran arm compared to the placebo arm. These remarkable results of vutrisiran in a contemporary population of patients with ATTR cardiomyopathy with clinical benefits seen on every single one of its rigorous set of endpoints, highlight the the RNAi mechanism of action and suggest that vutrisiran has the potential to become the new standard of care in ATTR cardiomyopathy. Specifically, we observed 28% and 33% reduction in the composite of all-cause mortality and recurrent CV events in the overall monotherapy populations, respectively, and 36% and 35% reductions in all-cause mortality in these 2 populations, respectively. These outcome benefits were accompanied by clinically significant benefits on 6-minute walk test, KCCQ and NYHA class, all of which are key measures of disease progression. We observed consistent effects in all key subgroups, including patients who are on baseline tafamidis. And finally, vutrisiran demonstrated encouraging safety and tolerability consistent with its established profile. We look forward to presenting detailed results from this study at an upcoming medical conference. We've submitted these data as a late-breaking abstract to the European Society of Cardiology Meeting taking place August 30 through September 2 in London. As Yvonne mentioned and consistent with our previous guidance, we now plan to engage with regulators and advance vutrisiran towards the supplemental NDA filing in the United States in late 2024 with additional global regulatory filings thereafter. In the United States, we plan to use our priority review voucher to accelerate the regulatory review process in hopes of bringing this medicine to patients as quickly as possible. 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 who work with us. And most of all, I want to extend my heartfelt thanks to the patients who volunteered to participate in this study, which we hope will allow us to bring this medicine to ATTR cardiomyopathy patients around the world who need additional therapies for this devastating disease. And with that, I'm now going to turn the call over to Tolga. Tolga?

Thanks, Pushkal, and good morning, everyone. We're thrilled about the outstanding results observed in HELIOS-B and what this potentially represents for patients with ATTR amyloidosis with cardiomyopathy across the globe. Alnylam is a tremendous opportunity to transform the treatment paradigm based on these results and the significant unmet patient needs in ATTR amyloidosis with cardiomyopathy. We estimate that ATTR-CM represents a tenfold larger prevalence than hereditary ATTR with polyneuropathy, where AMVUTTRA is the current market leader. The vast majority, about 80% of the estimated 200,000 to 300,000 patients living with ATTR-CM remain untreated. The good news is that the diagnosis and treatment rates are improving rapidly and will only accelerate with more voices, including our own fueling awareness and urgency to treat. At the same time, we also know that there is significant need for new treatment options. Our research with physicians tells us that of those patients who are treated with currently available options, nearly [ 3/4 ] experienced only partial or no response to treatment. For this majority of underserved patients, this can mean debilitating and irreversible declines in functional capacity and quality of life, hospitalizations and most importantly, death. In short, the ATTR-CM market is large, it is rapidly expanding, and there remains very significant unmet needs. It is primed for a transformative medicine. In this context, assuming regulatory approval, we believe vutrisiran has the potential to address unmet patient needs and become the standard of care treatment of ATTR-CM with a first line and market-leading profile that would include, first, a unique and highly differentiated mechanism of action versus current treatment options that works upstream enabling rapid knockdown of TTR at the source that is deep and durable. Second, for a disease where the median survival is 2.5 years to 5.5 years, what patients and physicians really want is a clear impact on mortality. Beyond that, they want to see the benefits on preservation of function and quality of life. And we delivered these results across all trial subgroups. Third, an attractive quarterly dosing schedule that aligns with physician visits, supporting strong adherence and with site of care flexibility. And finally, favorable payer dynamics due to its HCP-admisted dosing resulting in lower out-of-pocket costs for patients in a market where we expect payers to favor monotherapy use for the next several years. These data also provide us the opportunity to position vutrisiran for today and beyond tafamidis loss of exclusivity. Let me also share how we're preparing for this potentially monumental launch, assuming regulatory approval. Over the last decade, we've been deeply committed to succeeding in ATTR amyloidosis and understanding the unique needs of this community. We have already established market leadership in hATTR amyloidosis with polyneuropathy, driving significant growth in the category and attaining about 90% share in polyneuropathy market with our 2 TTR targeting therapies, ONPATTRO and AMVUTTRA. Through our patient access philosophy, we've confirmed access for over 99% of patients while ensuring that about 70% of patients have 0 out-of-pocket costs. Furthermore, AMVUTTRA with its quarterly dosing schedule has demonstrated a very high rate of adherence and compliance. As we prepare for the anticipated launch of AMVUTTRA in ATTR-CM, we will leverage the foundational capabilities we built in the hereditary polyneuropathy segment while expanding into the potential treatment of a significantly larger patient population. While we appreciate that our foundational capabilities position us well for this potential launch, we also recognize that scaling these capabilities to ensure with [indiscernible] because the standard of care in ATTR-CM is absolutely critical. We have a strong foundation to build as we scale. That includes our deep relations with TTR centers, a global and highly specialized and integrated customer-facing teams that delivered a seamless experience for patients and physicians, our track record of creating strong payer and health system partnerships that support exceptional patient access, not only in the U.S. but also across all major markets, including Canada, Europe and Japan and as well as our award-winning patient support services team that have enabled us to help patients access their Alnylam treatments quickly with one of the fastest time lines in transition from start form to therapy in the industry and also supporting over 95% patient adherence. Finally, I too would like to join my colleagues in expressing how excited I am about the HELIOS-B results. It is truly a remarkable achievement for Alnylam for RNAi therapeutics and most importantly, for the ATTR amyloidosis community. With these exciting top line results, we believe Alnylam is superbly positioned to deliver this transformative medicine to patients with ATTR amyloidosis with cardiomyopathy, and we believe it has the potential to be utilized as a first-line treatment to become the new standard of care for this rapidly progressing fatal disease. I will now hand it back to Yvonne for some additional remarks.

Thanks, Tolga. As you've heard from Pushkal, we believe that the HELIOS-B results support vutrisiran's potential to become the new standard of care in ATTR cardiomyopathy. We've just heard from Tolga. 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 that are treated and continue to experience disease progression. Indeed, we believe these data support the potential for vutrisiran to become an anchor commercial franchise for Alnylam, driving robust top line growth and value creation for many years to come. This is a fundamental piece of the puzzle that we believe 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 address other high-value therapeutic opportunities like obesity, metabolic disorders, diabetes and neurological diseases. And I think about the massive number of patients around the world that we can help with our medicines, I'm energized by what the future holds. With these HELIOS-B results now announced, we're closer than ever toward realizing our vision of becoming a leading global biotech. So we're now going to go into the Q&A session. Unfortunately, I understand that the audio is not optimal. We're working on this. So hopefully, we'll have it fixed momentaritly. Christine, over to you.

Thank you, Yvonne. Operator, we will now open the call to your questions. [Operator Instructions]

[Operator Instructions] And the first question comes from Eliana Merle with UBS.

Congrats on the truly phenomenal data here. So you're going up against a pretty well-established competitor in tafamidis. Can you elaborate on why you believe vutrisiran will be a first-line therapy and the new standard of care?

The data are indeed truly remarkable. And just reprise the headline HELIOS-B hit on the primary and all secondary endpoints with high statistical significance in both the overall and monotherapy patient populations. AMVUTTRA delivered consistent results across the HELIOS-B data set, demonstrating that vutrisiran can help patients feel better, function better and survive for longer. This indeed is a home run. and particularly as the study was conducted in the contemporary era where there's early diagnosis, Pushkal talked about this, better supportive treatment. And the fact that many of the patients in the study are on tafamidis make these data even more impressive. So why first line? Why do we believe that vutrisiran will become a first-line therapy? I think we've got to think about the disease. We got to think about the context of the disease. This is a progressive and irreversible condition. When patients lose function, they can't regain it. So patients need to be treated early and they need to be treated with the best option first. And this disease needs a new option, it needs an orthogonal mechanism of action. And what do physicians and patients care most about? They care about mortality, and we've heard that half of these patients die within 5 years. And vutrisiran has demonstrated that it reduces mortality by over 1/3 in the monotherapy of the overall patient population. This is unprecedented mortality data. When you look across the entirety of the data set, vutrisiran ticks all the boxes, impact on 6-minute walk test, KCCQ, NYHA class, all measures of disease progression, established safety profile, quarterly dosing, no out-of-pocket costs for patients. So we believe this will be a new standard of care. We see use of first line in monotherapy in the near term. We believe this is where the market will be in the near term prior to tafamidis patent expiry. Now these data also deliver support for combination use. And so what we have here is durable long-term growth. In the near term, we're first-line monotherapy and longer term as combination use increases [indiscernible] pattern. So we think this will clearly be standard of care first-line therapy for patients.

The next question comes from Tazeen Ahmad with Bank of America.

Congrats from me as well on the quality data. I did want to maybe clarify some of the wording in the press release as it relates to efficacy seen with patients on background tafamidis. Can we interpret anything from the wording there that you did see better-than-expected results when combining vutrisiran with TAF, we know that the study wasn't powered to show that, but it has been a point of question and debate with the investor community. And then secondly, is there any color you can provide on the monotherapy mortality benefit as to when that benefit starts to kick in?

Yes, this is a great question. And I think as I said already that the data continues to show remarkable consistency of effect across all the endpoints and across all key subgroups, including an additive effect on top of tafamidis. Pushkal, maybe you want to go a bit more detail around our perspective on that and also the question that is raised around charity?

Absolutely. Look, as you've seen so much exciting to hit coming out of this trial case that we really want to share with you and everyone and all the other stakeholders. As you said, the study wasn't defined to sort of show power for the TAF subgroup, but there are a lot of subgroups in the study, and we have remarkably shown consistency of effect across all endpoints, primary and secondary in all subgroups. If you pictured the forest plot, you'd like what you saw here. These patients also have a lot of medical management during the course of the study as supportive care has improved, diuretic intensification, SGLT2 with [indiscernible] and the benefits in the overall and the mono group show the treatment effect is robust on all of that. Now to that point, in the TAF group, we are seeing across all the end points evidence of additive effect. One interesting hint that kind of touched on what you brought up in the data that we presented today is that the effect size and p-value on the all-cause mortality endpoint in the overall are a little stronger than in the mono group. And that can only happen with some evidence of a meaningful effect in that TAF subgroup. So all in all, we are really, really excited about this data, so I can't wait to share more of it with you all at ESC.

The next question comes from Kostas Biliouris with BMO Capital Markets.

Congrats on the huge outcome. Great day for Alnylam. Great day for the entire biotech space, I would say. One question from us on the competition, given that I think now the focus will sit on the markets there in ATTR cardiomyopathy. One of your competitors with TTR stabilizer has mentioned that the bar for the monotherapy arm of AMVUTTRA on your primary composite endpoint should be 42%. And obviously, cross-trial comparisons are biased, but can you discuss a little bit your thoughts around that, given that you achieved 33%, which is lower than the 42% that other companies believe is bar. Huge congrats again on the outcome.

That's a great question. I'll just start by making some comments around the market. This is a large, rapidly growing market. And I think it's important to remember that 80% of patients in this market are not yet treated. So this is a wide open market. And we believe that the data that we've generated as of PSP is going to be compelling and will be first-line monotherapy. Pushkal, do you want to talk specifically?

Yes., thank you for the kind words. And let me address your point maybe with just a couple of points. I mean, first of all, look, I think you're alluding to BridgeBio, and they're going to have to speak to their own data. We've searched through, for example, their peer review in New England Journal Paper, we can't find reference to the 42% or some of the other p-values that have been cited. What patients and physicians really care about is mortality. It was a secondary endpoint in the study. And in that paper, we don't see a single number that points to the magnitude or [indiscernible] [ mortality ] benefit. I think the second point is, look, moreover, despite positive data coming out of ATTRACT, stabilizers aren't a panacea. The majority of patients aren't on a stabilizer. The majority of patients on stabilizers unfortunately progress, so patients really deserve an effective alternative with an orthogonal mechanism of action, that it can help them feel, function and survive better. And from this study, we now have definitive evidence that vutrisiran can improve outcomes. We've shown 35% to 36% reduction in all-cause mortality in 2 independent tests in this study. We reduced hospitalizations. The drug reduced disease progression by 3 measures, and this is all done by the gold standard of prespecified alpha-controlled ITT analysis. We couldn't be happier about the trial results today and how they stand up.

The next question comes from Ritu Baral with TD Cowen.

Congratulations on the data and happy Monday, which I don't think I ever said. Yvonne can you or Pushkal elaborate a little bit on the time point of the mortality analysis? Obviously, those 36% and 35% are fantastic numbers. But can you elaborate on the rationale behind the 42-month time point? And any thoughts on why the 2 groups are so close, ITC versus monotherapy?

Yes. No, we'd be happy to. Look, clearly, when you kind of design a study, you really want to try and fully demonstrate the impact of your drug, and we were keen to design a study that would show the true impact of the [indiscernible].

Yes. Ritu. First of all, thanks for the kind words. I say it's truly remarkable to see this magnitude of effect on all-cause mortality in a heart failure study. It's frankly unprecedented. Look, as regards to the 42 months, we've always said that we would use the secondaries to highlight the differentiated impact of vutrisiran in this disease. We designed the trial 5 years ago for the composite, but the landscape has been evolving. There's much more competitive, and the bar for efficacy appropriately for patients is rising. And we wanted to show a mortality benefit for this drug, which we always believed was there. And we saw trends for that, as you know, both in the APOLLO study and in the APOLLO-B study. So our team had the great insight that targeted therapies for ATTR cardiomyopathy don't immediately impact mortality. And as such, we were able to include 6 months of the open-label extension. to extend the exposure time to 42 months for this secondary to give us a true estimate of vutrisiran's effect on mortality. So this analysis really this is prespecified in the ITT population alpha-control and we hit it twice showing that magnitude of benefit. That's why we did it. Now to your second question about the interesting observation that, that effect size is actually comparable in the 2 in the overall and the mono. And the mono, as you know, constitutes 60% of that population. So 40% of that effect is coming from the background TAF group. And in fact, the p-value is even a little bit stronger, as you can see in that overall population. So that, I think, should give you some hints to some of the data that we'll be able to share in the future. But again, it's all consistent with what we're seeing in terms of some additive effect on top of tafamidis that we're very excited about.

That's terrific, Pushkal. And I think this is a really stringent test of mortality and with the data that we've generated, 35% to 36% reduction. I mean, this just really highlights the power of RNAi therapeutics to help these patients.

Our next question comes from David Lebowitz with Citi.

Could you comment on the p-values for the composite endpoint, given that the monotherapy was higher than the overall, what can that tell us about the combination of patients in the ITT population?

Yes, Dave, look, I think a couple of points. Again, the results here are phenomenal. I'd focus on the magnitude of effect and that they hit very stringent criteria for statistical significance. P-value is a function of a number of different parameters. It's a function of effect size and event rate. But most of all, it's a function of just sample size. There's absolutely 0 question about the robustness of this result. We hit 10 out of 10. There is no question this was not a chance finding. This drug has profound activity in this disease.

Do you think that in the combination arm that you exceeded expectations?

David, I think we're going to share more data at the upcoming ESC. But I think, as I've said, look, overall, the data set is remarkably internally consistent, and we see evidence of additive effect on top of tafamidis. The monotherapy results you can see are quite strong, and the overall effects are quite strong, which is a blend of both the monotherapy and the combination arm.

The next question comes from Maury Raycroft with Jefferies.

I'll add my congrats. And I wanted to ask a question just about switching and how you're thinking about that? And whether you have enough data from HELIOS-B and potentially your expanded access program to encourage switching from tafamidis to vutri, and what is your latest view on what switch your patients could look like?

Look, again, we're super excited about it. And I think it's really time to rethink how this disease is going to be treated. Just to remind everyone, this is a highly progressive disease that causes irreversible damage and it is fatal. So what we're hearing from the physicians is they want to start treatment early and start with the best available treatment. That's really the argument for first line. Now we also recognize that a lot of the patients that are being treated with stabilizers either don't respond or they continue to progress. We've seen this in polyneuropathy. We have seen this in our own early access program when we announced it for ONPATTRO. So this remarkable mortality benefit that we achieved in a contemporary setting, I think, is going to be a compelling evidence for physicians once they approved to have these patients that are progressing to be switched very quickly. Now post tafamidis LOE, I think we would anticipate that maybe they would be put on, on top of AMVUTTRA. And I think that's the concept that we would like to start thinking about when it comes to how this disease is going to be treated.

The next question comes from Gena Wang with Barclays.

Congrats on the great results. I think this is a big victory for Alnylam and the patients. I think especially after all the bumpy roads with APOLLO-B regulatory path, multiple ATTR cardiomyopathy Phase 3 trial changes in the field, this is truly a very important happy day for everyone. So I wanted to ask about the 42, the all-cause mortality question. So just wanted to know that if you look at the 30 months to 36 months, was the hazard ratio higher and with additional 6 months that helped significantly regarding all-cause mortality? And was it hit also [ stats ] if you're using, say, 33 months to 36 months follow-up?

Yes. First of all, Gena, thank you for your kind words. It's been a long journey, but I couldn't be prouder of the team here, the tenacity to kind of go, deal with the ups and downs and follow through on all the details and deliver the study. People never lost in the mission here, and we're really, really excited about these results. Look, these are top line data today, the magnitude of benefit, as you know, is very large. 35% to 36% reduction in all-cause mortality and heart failure is something remarkable. And as Yvonne and Tolga stated, we think this could be the new standard of care for this disease. We'll share more at an upcoming meeting. But what I can say is that the overall effects with this drug manifest early and specifically with regards to mortality, separation grows over time just as you would expect.

Operator, can you please prompt for next question?

Christine, seems to be a delay in receiving the questions.

Our next question will come from the line of Luca Issi with RBC Capital.

Really, really, really congrats on fantastic data here. Maybe just a quick one here, given you've already have spoken about many of the other subgroups. Can you just talk about wild-type versus hereditary. Just wondering if the benefit was seen across both or it was driven a little bit more by the hereditary mutation. Again, any call there, much appreciated.

No, we saw benefits in both populations. We'll share more on all those subgroups coming forward. But again, what you're seeing is an incredibly robust result. I think it just highlights the power of the mechanism of this disease.

Our next question will come from Paul Matteis with Stifel.

Let me add my congratulations, I had one just on the specific impacts on hospitalization. Typically, there's more hospitalization events in these trials versus mortality events. And we noticed that the impact on mortality is bigger than the impact on the composite. Is the right influence here that the impact on hospitalizations was less robust than the impact on death maybe I'm [ sliding Harris ], but I was just kind of curious if you can kind of comment on that, the hospitalization secondary endpoint, given that the effects of hospitalizations across studies in this space has been so widely variable.

Yes. No, look, I think what I would say is, again, the primary endpoint and the secondary and all-cause mortality of slightly different analytic methods as we've talked about. So I wouldn't infer that from that. What we see in the primary endpoint is actually remarkable consistency on both sets of both components of the primary composite basically move in concert with each other.

Can I ask the operator to make sure we queue up the questions a bit more rapidly, please.

Our next question will come from the line of Mani Foroohar with Leerink Partners.

Congrats on positive data. In comparing the data versus competitors and versus other landmark studies, can you give us some exact detail on what the data look like at 30 months, which is sort of the appropriate apples-to-apples time point, just so we can think about competitive positioning in this market where 80% of patients remain untreated.

Yes. Mani, look, this was not a head-to-head study, right? And I think as you point out, head-to-head studies are fraught with all sorts of problems. I think what we can say here is that this is really a landmark study for a drug with an orthogonal and novel mechanism of action that directly hits the targeted protein at its source. And what we're seeing are results that we think are remarkably strong and consistent across 10 different measures of efficacy. We see over 1/3 of patients over a 35% reduction in the relative risk of all-cause mortality benefits on disease progression benefits on hospitalization. And as we've said, the benefits of this drug start to appear early. And as it relates to mortality, those curves grow and separate over time. We'll share those data in due course.

[Operator Instructions]

Let's give a moment. Apologies for the technical difficulties we're facing. We are trying to get the next question up in the queue. So give us one moment.

Our next question comes from Jessica Fye with JPMorgan.

This is Na Sun on for Jessica Fye. Congratulations for the big win scenario. My question is, can you just give us any color on how the event rate in patients on the monotherapy group compared to the event rate for patients on just background tafamidis, and how do you think the event rate in the monotherapy control arm compared to attribute as we think about other contemporary trials?

Yes. Look, thank you for the kind words. I think I probably can't get into the level of detail that you're looking for today and we'll show more data at a medical congress. Again, this is really focused on the top line where we think we've just seen superlative results for AMVUTTRA and again, seeing strong benefits both in monotherapy and overall consistency across multiple subgroups, including evidence of additive benefit on top of tafamidis. We'll share more as there's a lot of data, obviously, we're out of this trial to share in due course.

Our next question that will come from the line of Maury Raycroft with Jefferies.

I was just wondering if you can say more on baseline characteristics? And how similar or different patient baseline profile was versus attribute?

Look, I think as we've talked about this study really enrolled in a very contemporary time frame, where patients are being treated earlier in their disease course with diagnostic noninvasive methods in a very dynamic environment as well, right? We've got patients, the management of these patients is improving over time in terms of increased diuretic intensification, use of SGLT2 inhibitors. We had 40% of the patients on TAF and then in the other arm patients could actually drop [indiscernible]. So this is a very dynamic circumstance, reflecting contemporary management of these patients. And we saw that vutrisiran had a very robust effect. So I think you can imagine that this trial enrolled at the same time as APOLLO-B, and that will give you some sense in terms of the demographics here.

And our next question that will come from the line of Myles Minter with William Blair.

Congrats on the data, really impressing to see this. My question is just on your use of early separation. I think previously, when we saw the APOLLO-B data, you made a comment that there was potential for early separation when patisiran showed a mortality or favorable mortality as early as 9 months. Just wondering whether that sort of time point is aligned still with your definition of what early separation would be on mortality or whether it's better to think of that as relatively early compared to the 18, 19 months, we've seen that the peer stabilize compounds?

Look, I don't think I can give you any re color today. Again, I think there's a lot of data to share. We were sharing the top line today, and I think I'll let the comments I made stand and we'll share more at ESC.

And that's actually going to be the last question that we're going to take and our apologies to everyone on the line who tried to ask the questions, we're having some considerable technical difficulties, but know that leadership and the IR team is around all day for follow-ups and we would love to engage with you and address any questions that remain that we weren't able to get to today. With that, I'm going to turn it over to Yvonne for closing remarks.

Thanks, Christine, and thanks to everyone for joining us today. Look, as you've heard on the call, we could not be happier with these results in HELIOS-B. And we look forward, as Pushkal said, presenting full results and also bringing vutrisiran to patients with ATTR amyloidosis with cardiomyopathy. Really today reinforces the enormous promise on [indiscernible], as we build the next great biopharma company. And we cannot wait to get started. So thanks, everyone, and have a wonderful day. This concludes today's [Technical Difficulty] thank you all for participating. You may now disconnect.