Ladies and gentlemen, thank you for standing by. Welcome to Alnylam Pharmaceuticals' conference call to discuss HELIOS-B top-line results. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. Please limit to one question. To ask a question during the session, you would need to press star one one on your telephone. You would then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. 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've 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 two, Yvonne will provide some opening remarks. Pushkal will provide 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'd 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 statement represents our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any 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 III 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're 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 benefits in patients with ATTR amyloidosis with cardiomyopathy. 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. ATTR amyloidosis is a fatal disease. It robs patients of their ability to live a normal life, and the median survival range is 2.5-5.5 years, a natural history that is worse than many cancers. More than 80% of ATTR cardiomyopathy patients remain untreated. For those that are treated, the majority of patients continue to progress in their disease course, so there is significant unmet medical need in this disease.
With the HELIOS-B results now in hand, we intend to advance vutrisiran to a 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. Assuming regulatory approval, we believe expansion of our vutrisiran 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 from 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 in clinical trial design, our deep track record of conducting trials in the ATTR space, our thoughtful approach to patient selection, conservative powering of our clinical studies, and rigorous approach to implementation, training, and oversight of clinical assessments. This is all driven by a corporate culture that's devoted to a 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 medical advance possible.
I'd also like to acknowledge our team at Alnylam, who went above and beyond and pored 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 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 a 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 in the liver, RNAi therapeutics act upstream to lower circulating levels of the pathogenic protein.
Our therapeutic hypothesis is that this, in turn, reduces amyloid deposition in the heart and nerves, thereby having the potential to halt or even improve manifestations of disease. We've seen the transformative impact that that rapid knockdown of 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. 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 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 the modern era, where patients are identified earlier in their disease by a non-invasive method, and patients' heart failure management has improved via other use of medications such as diuretics and SGLT2 inhibitors. As we've discussed, 40% of patients were on an active drug. They were on tafamidis at baseline, and others were able to start stabilizers during the study. Patients were randomized 1:1 to receive a 25 mg dose of vutrisiran or placebo, administered subcutaneously once every three months during a double-blind treatment period of up to 36 months. The primary endpoint was a composite of all-cause mortality and recurrent CV events assessed in two 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 pre-specified 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 believed 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 tests to measure functional capacity. Next is a change from baseline in 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 standalone endpoint, which is recognized as the most stringent measure of efficacy in this disease.
Last is 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 six months of data from the open-label extension period to increase the exposure time for up to 42 months. This pre-specified 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 achieves 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 six-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 pre-specified 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 who 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 five pre-specified endpoints in each of the two studied 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 were, 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 this rigorous set of endpoints, highlight the power of 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% reductions in the composite of all-cause mortality and recurrent CV events in the overall and monotherapy populations, respectively, and 36% and 35% reductions in all-cause mortality in these two populations, respectively.
These outcome benefits were accompanied by clinically significant benefits on 6-minute walk tests, 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. 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 30th through September 2nd in London. As Yvonne mentioned, and consistent with our previous guidance, we now plan to engage with regulators and advance vutrisiran towards a 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 maintained 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 worked 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. With that, I'm now going to turn the call over to Tolga. Tolga.
Thanks, Pushkal. 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 has 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 2,000 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's significant need for new treatment options.
Our research with physicians tells us that of those patients who are treated with currently available options, nearly three-quarters experience 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 2.5-5.5 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. We deliver these results across all trial subgroups. Third, an attractive quarterly dosing schedule that aligns with physician visits, supporting strong adherence, and with side-of-care flexibility. Finally, favorable payer dynamics due to its HCP-adjusted 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 Amvuttra for today and beyond to 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 two 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 zero 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've 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 vutrisiran becomes a 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 team that delivers 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 timelines 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. As you'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 as 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 in hand, 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 suboptimal. We're working on this, so hopefully, we'll have it fixed momentarily. Christine, over to you.
Thank you, Yvonne. Operator, we will now open the call to your questions. As a reminder to those dialed in, we would like to emphasize that we will be fielding one question from each analyst. We ask that you please get back into the queue if you have additional questions.
Thank you. As a reminder to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. One moment while we compile the Q&A roster. The first question comes from Eliana Merle with UBS. Your line is open.
Hey, guys. Congrats on the truly phenomenal data here. So you're going up against a pretty well-established competitor, tafamidis. Can you elaborate on why you believe vutrisiran will be a first-line therapy and the new standard of care? Thanks.
Yes, thanks for your question. The data are indeed truly remarkable. Just to reprise the headlines, HELIOS-B hits on the primary and all secondary endpoints with high statistical significance in both the overall and monotherapy patient populations. Amvuttra can deliver consistent results across the HELIOS-B data set, demonstrating that Amvuttra 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 earlier diagnosis, Pushkal talked about this, better supportive treatments, and the fact that many of the patients in the study are on tafamidis makes these data even more impressive. Why first-line? Why do we believe that Amvuttra will become a first-line therapy? I think we've got to think about the disease. I think we've 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. This disease needs a new option. It needs an orthogonal mechanism of action. What do physicians and patients care most about? They care about mortality. We've heard that half of these patients die within five years. Vutrisiran has demonstrated that it reduces mortality by over a third 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 tests, KCCQ, NYHA class, all measures of disease progression, established safety profile, quarterly dosing, no out-of-pocket costs for patients. 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's 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 with first-line monotherapy and longer term as combination use increases as tafamidis goes off patent. So we think this will clearly be standard of care, first-line therapy for patients.
Great. Thanks.
Next question.
One moment for the next question. The next question comes from Tazeen Ahmad with Bank of America. Your line is open.
Hi, guys. Good morning. And congrats for me as well on the high-quality data. Yvonne, 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? Thanks.
Yeah, those are great questions. And I think, as I've said already, that the data from HELIOS-B show remarkable consistency of effect across all the endpoints and across all key subgroups, including an additive effect on top of tafamidis. Pushkal maybe wants to go into a bit more detail around our perspective on that and also the question that was raised around mortality.
Absolutely. Thanks, Tazeen. Look, so much exciting coming out of this trial, Tazeen, 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 had a lot of medical management during the course of the study. As supportive care has improved, diuretic intensification, SGLT2, and TAF dropping, and the benefits in the overall and the mono group show that the treatment effect was robust to all of that. Now, to that point, in the TAF group, we are seeing across all the endpoints evidence of additive effect.
One interesting hint that kind of touches on what you brought up in the data 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 set. Can't wait to share more of it with you all at ESC.
One moment for the next question. The next question comes from Kostas Biliouris with BMO Capital Markets. Your line is open.
Good morning, everyone. Thanks for taking our question, and 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 shift on the market share in ATTR cardiomyopathy. One of your competitors with TTR stabilizers 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 the bar? Thank you, and huge congrats again on the outcome.
Thank you. 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 out of HELIOS-B is going to be compelling and will be first-line monotherapy. Pushkal, do you want to talk specifically?
Yeah. Kostas, thank you for the kind words. 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-reviewed New England Journal paper. We can't find reference to the 42% or some of the other p-values they've 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 a statistically significant mortality benefit. I think the second point is, look, no doubt, despite positive data coming out of ATTRibute, 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 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 a 35%-36% reduction in all-cause mortality in two independent tests in this study. We reduced hospitalizations. The drug reduced disease progression by three measures. And this is all done by the gold standard of pre-specified alpha-controlled ITT analyses. We couldn't be happier about the trial results today and how they stand up.
Thanks for your question, Kostas. Next question.
The next question comes from Ritu Baral with TD Cowen. Your line is open.
Hi, guys. Congratulations on the data and happy Monday, which I don't think I've ever said before. Yvonne, can you and 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 two groups are so close, ITT versus monotherapy? Thanks.
Yeah. 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 vutrisiran on mortality.
Yeah. Ritu, first of all, thanks for the kind words. As you 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 on this disease. We designed the trial five years ago for the composite, but the landscape's been evolving. It'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 the secondary to give us a true estimate of vutrisiran's effect on mortality. So this analysis, really, this is pre-specified in the ITT population, alpha-controlled, 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 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. I think this is a really stringent test of mortality. With the data that we generated, 35%-36% reduction, I mean, this just really highlights the power of RNAi therapeutics to help these patients. Next question.
One moment, please. Our next question comes from David Lebovitz with Citi. Your line is open.
Thank you very much for taking my question. 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 patients in the ITT population?
Yeah, Dave, I think, 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 zero 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, then, with the combination arm, that you exceeded expectations?
Dave, 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.
Excellent. Congratulations, and thanks for taking my questions.
Thank you very much. Yeah. Thank you.
One moment for the next question. The next question comes from Maury Raycroft with Jefferies. Your line is open.
Hi, good morning. I'll add my congrats. 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 vutrisiran and what is your latest view on what switcher patients could look like?
Yeah. Thank you, Maury. Look, again, we're super excited about this, 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've 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 compelling evidence for physicians, once 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 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. Next question, please.
One moment. The next question comes from Gina Wang with Barclays. Your line is open.
Thank you. Congrats on the great hey, how are you? 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 III trial changes in the field. And 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 30-36 months, was the hazard ratio higher? And with additional 6 months, did that help significantly regarding the all-cause mortality? And was it hit also stats if you're using, say, 33-36 months follow-up?
Yeah. First of all, Gina, 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 a study. People never lost sight of 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%-36% reduction in all-cause mortality and heart failure is something remarkable. And as Yvonne and Tolga have 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.
Okay. Thank you, Pushkal.
Thank you, Gina. Pushkal.
Operator, can you please prompt the next question?
There seems to be a delay in receiving the question.
Our next question will come from the line of Luca Issi with RBC Capital. Your line is open.
Oh, great. Thanks so much for taking my question and really, really, really congrats on fantastic data here. Maybe just a quick one here, given we've already 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 maybe was driven a little bit more by the hereditary patient. Again, any color there, much appreciated. Thanks so much.
Thanks, Luca. 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, and I think it just highlights the power of the mechanism in this disease.
Thanks so much. Congrats again.
Thanks, Luca.
Thanks, Luca.
Yeah. Next question.
Our next question comes from the line of Saima Mejlovi from ISI.
Operator, if you could patch Simon through, please.
Your line is open. If you're on mute, please unmute yourself.
Operator, let's go to the next question and circle back to Simon.
Operator, do we have a question?
Let's give it a moment. We'll work you into the next question.
Our next question will come from Paul Matteis with Stifel. Your line is open.
Hey. Let me add my congratulations and thanks so much for taking my question. I had one just on the specific impact on hospitalizations. 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 inference here that the impact on hospitalizations was less robust than the impact on death? And maybe I'm splitting hairs, but I was just kind of curious if you could kind of comment on that, the hospitalization secondary endpoint, given that the effects of hospitalizations across studies in this space have been so widely variable. Thank you.
Thanks, Paul. Yeah. No, look, I think what I would say is, again, the primary endpoint and the secondary and all-cause mortality have 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. They basically move in concert with each other.
Thanks for the question. Can I ask you a favor to make sure we queue up the questions a bit more rapidly, please?
Will do. Our next question will come from the line of Mani Foroohar with Leerink Partners. Your line is open.
Hey. Thanks for taking the question and congrats on the positive data. In comparing the data versus competitors and versus other landmark studies, can you give us some exact detail on what the data looked 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?
Yeah. 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 target 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 a third 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.
Thanks, Pushkal. This is amazing. This is fine. Yeah. Okay. Next question.
Thank you. As a reminder, if you would like to ask a question, please press star 11. 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 J.P. Morgan. Your line is open.
Hey, guys. This is Nason, in for Jessica Fye. Congratulations for the big win scenario. Our 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 and the monotherapy control arm compare to ATTRibute as we think about other contemporary trials? Thank you.
Yeah. 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 will 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. There's a lot of data, obviously, around this trial to share in due course.
Thank you. Our next question that will come from the line of Maury Raycroft with Jefferies. Your line is open.
Hi. Thanks for taking the second question. I was just wondering if you can say more on baseline characteristics and how similar or different the patient baseline profile was versus ATTRibute.
Yeah, Maury, thanks. 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 non-invasive methods and in a very dynamic environment as well, right? We've got patients who are 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 in Taf. So this was a very dynamic circumstance reflecting contemporary management of these patients. And we saw that vutrisiran had a very robust effect. So I think when you I think you can imagine that this trial enrolled at the same time as APOLLO-B, and that'll give you some sense in terms of the demographics here.
Got it. Thank you.
Thank you. Our next question that will come from the line of Myles Minter with William Blair. Your line is open.
Hey, everyone. Congrats on the data. Really impressive to say the least. 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 vutrisiran showed a mortality or favorable mortality as early as nine 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 with the peer stabilizer compounds. Thanks very much.
Yeah. Thank you, Miles. Look, I don't think I can give you any more 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.
That's actually going to be the last question that we're going to take. 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. 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. We look forward, as Pushkal said, to presenting full results and also bringing vutrisiran to patients with ATTR amyloidosis with cardiomyopathy. Really, today reinforces the enormous promise our RNAi upholds as we build the next great biopharma company. We cannot wait to get started. Thanks, everyone, and have a wonderful day.