Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call to discuss the Complete Response Letter for Onpattro patisiran's Supplemental New Drug Application. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a Q&A session. To ask a question during the session, you will need to press star one one on your telephone. You will 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 now like to hand the conference over to the company. Please go ahead.
Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today and available for Q&A are Yvonne Greenstreet, Chief Executive Officer, Pushkal Garg, Chief Medical Officer, Tolga Tanguler, Chief Commercial Officer, Jeff Poulton, Chief Financial Officer, Rena Denoncourt, Vice President, TTR Franchise Lead, and Akshay Vaishnaw, Chief Innovation Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the events section of the investors' page of our website, investors.alnylam.com/events. We're going to keep our prepared remarks today relatively brief. Yvonne will offer some remarks and will be opening the call for limited questions.
I would like to remind you that today's 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 periodic report on file with the SEC. In addition, any forward-looking statements representing our views as of the date of this recording should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll now turn the call over to Yvonne.
Thanks, Christine, and thank you all for joining us today. Unfortunately, we have disappointing news to share with you. Specifically, and as announced in our press release earlier this morning, the U.S. Food and Drug Administration has notified us that they have completed their review of the supplemental new drug application for ONPATTRO, an investigational RNAi therapeutic that is being developed for the treatment of the cardiomyopathy of ATTR amyloidosis, and have determined that while the Apollo B study was well conducted, the observed treatment effects were not shown to be clinically meaningful, and they cannot approve the application in its present form. It goes without saying that we are extremely disappointed with this outcome, but more so, we feel tremendous sadness for the patients and families impacted by the cardiomyopathy of ATTR amyloidosis.
This is a fatal disease that robs patients of their ability to live a normal life. The cardiomyopathy manifestations include shortness of breath, fatigue, diminished exercise tolerance, and a dramatically reduced capacity to perform activities of daily living. It leads to an increase in cardiovascular hospitalizations and ultimately death, with a median survival ranging from two and a half to five and a half years, a natural history that is worse than many cancers. Despite the existence of an FDA-approved therapeutic to treat this disease, there is a significant unmet need as there are patients that continue to experience declines in their functional capacity and quality of life, as well as patients that cannot access the available therapy.
As you heard from many members of the ATTR community during the recent advisory committee meeting, these patients need new treatment options, and several of them even expressed how treatment with Onpattro had already had a profound impact on their functional capacity and their quality of life, as well as the deep sense of hope that this medicine could offer to them and other patients living with this devastating disease. Furthermore, we're quite surprised that the FDA has taken this action, considering the following points.
First, as you know, the Apollo B P 3 study has evaluated the efficacy and safety of patisiran in patients with ATTR cardiomyopathy designed in consultation with the FDA, who were fully aligned on the use of a six-minute walk test for 12 months as a primary endpoint, which is consistent with their own guidance issued in 2019 around the use of functional measures in clinical trials for heart failure. Secondly, we delivered a positive result in Apollo B, not just on the primary endpoint, but consistently across additional secondary and exploratory endpoints as well, while showing a positive safety profile. Specifically, on the primary endpoint, patisiran treatment resulted in a 62% reduction in the rate of decline compared to placebo, and we continue to be encouraged by the emerging profile of patisiran.
In fact, at the advisory committee meeting, and again at the recent HFSA meeting just this past weekend, we presented data showing that the effects of patisiran treatment on six-minute walk tests and KCCQ were maintained through 24 months of treatment. Seeing this type of relative stabilization in what is otherwise a steadily progressive disease is very encouraging. And while the Apollo B study was not designed to show benefits in cardiac outcomes, favorable but not statistically significant trends were observed for composite all-cause death and frequency of all-cause hospitalizations and urgent heart failure visits, as well as mortality analyses across the double-blind and open-label extension periods. And in fact, we see evidence of separation favoring the patisiran emerging over time, with longer follow-up and greater event accumulation. Thus, it's possible that the benefits of RNAi-mediated silencing of TTR may be maintained or even grow over time.
Finally, the advisory committee voted in favor of Onpattro with a nine to three vote, agreeing that the drug's benefits outweigh its risks for the treatment of the cardiomyopathy of ATTR amyloidosis. We're disappointed that the FDA's decision was not in alignment with the committee's position. Now, while Onpattro remains an approved medicine to treat the polyneuropathy manifestations of hereditary ATTR amyloidosis, we've made the decision, in light of this complete response letter, to discontinue our development efforts to commercialize Onpattro for the cardiomyopathy of ATTR amyloidosis in the US. As you may recall, our strategy at the time we set out to pursue label expansion for Onpattro was to execute on a development program that would bring an RNAi therapeutic to ATTR cardiomyopathy patients as rapidly as possible.
Given that ONPATTRO had been approved for the polyneuropathy of ATTR amyloidosis, we view the Apollo B study as a bridging strategy to unlock the cardiomyopathy opportunity, with our eyes ultimately on bringing our next-generation product, Amvuttra, to cardiomyopathy patients via the HELIOS-B cardiovascular outcome study. In this regard, while we had very much hoped for an approval of the sNDA, Onpattro would have represented the first step in helping this underserved population, with Onpattro and the HELIOS-B study serving as a very important next step. With a top-line readout from HELIOS-B expected in early 2024, it does not make sense for us to invest further in additional development to enable commercialization of Onpattro in cardiomyopathy.
The HELIOS-B study was designed and powered to demonstrate the benefits of vutrisiran in patients very similar to those studied in Apollo B on the composite outcome of all-cause mortality and recurrent cardiovascular events over a 30 to 36-month period. The positive data on multiple aspects of the disease in the Apollo B study and the longer-term data out to 24 months reaffirm our confidence in HELIOS-B. And the study is on track to read out in early 2024. And assuming positive data, we then plan to seek a label expansion for Amvuttra and, if approved, ultimately launch that medicine into the very large market of patients around the world with wild-type or hereditary ATTR amyloidosis with cardiomyopathy.
We believe that the convenient quarterly subcutaneous dosing regimen with a therapeutic profile that includes cardiovascular outcomes stated in its label could potentially position Amvuttra as a transformative therapy with a market-leading profile for patients with this disease. While today's news about Onpattro is an unfortunate outcome, we remain steadfast in our commitment to deliver novel and innovative medicines for patients living with a cardiomyopathy of ATTR amyloidosis. We believe that the unique and powerful mechanism of action of RNAi therapeutics could confirm meaningful differentiation across this entire disease spectrum. And here, we plan to build on the foundation and market-leading positions we've established with Onpattro and Amvuttra in the hereditary ATTR amyloidosis polyneuropathy market. In the Apollo B and Helios-A P 3 studies, respectively, we've shown the ability of our medicines to halt or improve the polyneuropathy manifestations of this disease.
Importantly, not only do these studies demonstrate the impact of TTR silencing via our drugs on polyneuropathy, but exploratory endpoints from these studies, as well as findings from investigator-initiated studies, also consistently showed the potential for cardiac benefit. More recently, with Apollo B, we've generated evidence of stabilization of functional capacity and quality of life. We've also seen consistent treatment effects on cardiac biomarkers, echo parameters, and cardiac imaging, and have demonstrated favorable trends in mortality. Collectively, we believe these results show the true power of the RNAi mechanism of action. By using a natural process to silence the production of the disease-causing TTR protein, we have observed long-term disease-modifying impacts on both the neurologic and cardiac manifestations of ATTR amyloidosis across our TTR development programs.
The next step in our journey will be achieving positive results with the HELIOS-B P 3 study of vutrisiran, where we are leveraging over a decade of Alnylam's deep expertise in designing and executing studies in ATTR amyloidosis and building on the growing body of data to give us confidence in delivering success. Top-line results are on track to read out in early 2024 from a study that is approximately twice as large and three times longer than Apollo B, and thus well set up to demonstrate the benefits of vutrisiran on cardiac outcomes. But our TTR journey doesn't stop there. We intend to become the global leader in delivering impactful and highly differentiated medicines to patients with all forms of ATTR amyloidosis. We've developed a well-established commercial infrastructure, which we will continue to strengthen to support the rapidly growing patient population.
We also have a continued commitment to further expanding our breadth of knowledge on these programs and expect that future data generation will enable us to best serve the needs of patients, and we expect to continue bringing new innovations to patients, including with ALN-TTR-SC04, which we believe could be capable of achieving over 90% knockdown of TTR with the potential for a once-annual dosing regimen. The bottom line here is that with our leadership, innovation, and commitment to helping patients, we believe we have a compelling roadmap to enable impact for patients, substantial growth, and significant value creation for years to come.
I'd like to close by taking a moment to express our deepest gratitude to the patients, clinical investigators, and study staff that participated in the Apollo B study. I'd also like to acknowledge all the patients, families, caregivers, and physicians that comprise the ATTR amyloidosis community. For more than a decade now, you have encouraged us, supported us, and inspired us as we've worked to bring our medicines to all of you. And finally, I'd like to thank my Alnylam colleagues that have worked and continue to work passionately and tirelessly towards advancing novel medicines for the cardiomyopathy of ATTR amyloidosis. With that, I'll now turn it back to Christine to coordinate Q&A. Christine.
Thank you, Yvonne. Operator, we will now open up the call for questions to those dialed in. We'd like you to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.
Thank you. As a reminder to ask a question, please press star one one or any touchtone telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Our first question comes from the line of Ritu Baral with Cowen. Your line is now open.
Good morning, guys. Thanks for taking the question. I wanted to ask about how you see your agreed-upon path for the Helios-B and Amvuttra application. Obviously, the adcom proceedings indicated that there was no agreed-upon minimal clinically important difference, some six-minute walk, and that was a topic of conversation. Do you have such an agreement for outcomes with FDA around the Helios-B Amvuttra submission, and is the SAP at this point agreed upon with the agency? Thanks. And I'll get back into you.
Thanks, Ritu. That's a great set of questions there. Look, I think the first thing to say is that we are confident in the design and execution of the Helios-B study. As I said in my opening remarks, we have an outcome study here that is three times as long and twice as large as Apollo B. And our confidence in the mechanism of RNAi therapeutics, which has demonstrated consistent benefits across both polyneuropathy and cardiomyopathy manifestations, really gives us confidence in the study. And clearly, we're laser-focused on delivering a successful outcome. And maybe, Pushkal, you can speak to where we are in terms of delivering that set of study outcomes.
Absolutely. Thanks, Yvonne. Thanks, Ritu. Look, Ritu, as Yvonne highlighted, I think the CRL doesn't change what we're seeing in the data in terms of what RNAi silencing of TTR can accomplish. We've seen both in Apollo and in HELIOS-A in post-op and exploratory analyses. And then now in Apollo B, remarkably consistent and sort of widespread internal consistency in terms of the effect of silencing on multiple aspects of the heart: patients' functional ability, their quality of life, their echocardiographic parameters, structure and function of the heart, cardiac biomarkers, and even favorable trends in outcomes.
And all of this is actually corroborated by the 24-month data where we're actually seeing relative stabilization. While we can't do any cross-trial comparisons, I think what we're seeing is emerging to be a very differentiated profile in this disease. And all of that, we think, portends quite well for HELIOS-B. With regard to HELIOS-B, we're really confident about its design and execution. It's longer and larger. It's 30-36 months. Obviously, that extra time at the end of the study helps in terms of powering. We over-enrolled it, and we already had conservative powering estimates.
As a reminder, we had assumed 50%, for example, patients would be on baseline CAP, and we came in under that, and I think further to this point, I think the recent ATTRibute results for tafamidis and they highlight that in the modern era, patients continue to decline, continue to accrue significant events, and that you can't in effective therapy show a benefit in that population, so that said, we are laser-focused on the execution and the successful delivery of this study.
We monitor external data and data sets as they come along. We have teams that are looking at blinded data internally. We always do that, and as is typical practice in the industry and as has been standard practice at Alnylam, we have the opportunity to make tweaks to the statistical analysis plan up to the point of database lock. And if we feel that will further optimize the potential for a successful study with a market-leading profile, then we will do that. So we'll keep you posted on updates as appropriate.
Thanks, Pushkal. And obviously, on track for our data readout in early 2024. Thanks for the question, Ritu. Next question.
Our next question comes from the line of David Lebowitz with Citi. Your line is now open.
Thank you very much for taking my question. Given your experience in the regulatory process this time around with Onpatro and certainly in consideration of the differences in the trials between Apollo B and HELIOS-B, are there any things regarding the upcoming data and what the potential regulatory process might be for Amvuttra that you are specifically paying attention to?
Yeah, David, I think, look, I think we feel with HELIOS-B, there's really not any read-through in this way, right? HELIOS-B really addresses. It's well designed to address some of the points that came up at the advisory committee. Instead of the focus in that study is on heart outcomes, death, and hospitalization versus the functional and quality of life outcomes. We'll be measuring those in that study, but the focus is on mortality and hospitalization, and it also is a much longer study.
It's 30 to 36 months long, and so that addresses another point that was brought up at the advisory committee. And so we, as we just said, I think we feel good that that's a well-positioned study to address some of the concerns that were raised at the advisory committee and deliver what we think will be potentially game-changing molecules for patients, medicine for patients.
Thanks for taking my question.
Thank you. Our next question comes from the line of Luca Issi with RBC Capital. Your line is now open.
Well, great job. Thanks so much for taking my question. Maybe if we can talk about the impact of the P&L here for a minute. How should we think about it in the short to medium term? I think current product sales guidance for 2023 of $1.2 billion-$1.285 billion, assume approval by the PDUFA date. So wondering if any updated thoughts there. And then maybe bigger picture, I think you're keen to assume non-GAAP profitability by the end of 2025. So wondering if that guidance is still intact. Thanks so much.
I have great questions. I mean, I'll start with a FY 2025 question. Look, we're not walking away from FY 2025. We're seeing very strong performance of Amvuttra. I think you saw that update in our last earnings call. We're delighted with our progress there. And we have confidence in delivering a successful outcome for Helios-B. As you know, we've always said that FY 2025 is contingent on delivering a successful Helios-B study and approval and launch. And we believe that that's what we'll be able to do. Jeff?
Yeah, so let me address the questions about 2023 product sales guidance, and then I'll also touch on expectations in 2024.
For 2023, you got it right, Luca. The guidance that we have put out is $1.2 billion-$1.285 billion. No change to that as a result of the news today. My expectation is that we'll land at about the midpoint of that guidance at the end of the year. For 2024, as is our normal custom, we'll put out financial guidance on our year-end 2023 earnings call in February. Let me provide just a little bit of directional guidance as it relates to Onpatro so that that's clear. Our expectation is that we'll continue to see declines in Onpatro sales on a go-forward basis. That's really two factors that are impacting that. One is the news today that we're not going to have a cardiomyopathy indication to drive growth in Onpatro next year.
But the second component of that is really the performance of Amvuttra since we've launched that a year ago. And what you've seen is that's cannibalizing Onpattro. And that's a good thing for the franchise. And we expect that to continue. We're now launched in all major markets, not only in the U.S. and Japan, but all major markets, five major markets in Europe as well. So we do expect to see continued declines from Onpattro. What that means for 2024 is I would expect Onpattro revenues next year to be in the range of $200 million-$225 million.
Next question. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open.
Good morning. Thanks for taking my question. Just with regard to the confidence here in reaching statistical significance on HELIOS-B, could you speak to that and the read-through on how the Apollo B placebo arm performed over time? And you've talked about blinded event rates. Is there any commentary you can provide on that front?
Yeah, no. I mean, we see actually the results that we've delivered for Apollo B as very supportive, actually, of a successful outcome with HELIOS-B. Just given the impact of the TTR across all the different endpoints, as we previously discussed. Pushkal, maybe you want to take the question.
Yeah, Salveen, I think I just reiterate a couple of things and expand on them. What we're seeing is that this mechanism has a profound effect on multiple aspects of the heart. We saw that reproducibly on really every endpoint that we measured in Apollo B and that those effects are durable over two years. That just appears to be a very unique and differentiated profile. It's a non-head-to-head study, but quite unique. I would point out that if you look, for example, at the acoramidis data, which was a study conducted in the same sort of time frame, what we saw at 12 months here was favorable impacts on six-minute walk test and KCCQ in contrast.
You can, in this modern era, studies show patients continue to decline with this disease and that they accrue sufficient events that you can show benefits of an effective therapy. So everything that we see tells us that we have a very potent therapy for this disease and that we have a study that's well designed to demonstrate those benefits over time for all the reasons that we talked about earlier, so we remain very confident. We do, as I said, we monitor all aspects of the study. We're not going to comment on specific things like that in terms of play-by-play. But we feel good about the overall design and execution of the study, and we'll keep you posted.
Thanks, Pushkal, and I'd just like to add that this is kind of a reason why it's great to have a platform. We're able to continuously innovate and bring forward new next-generation products to market, and we are very excited about the potential profile of the vutrisiran in helping patients with ATTR amyloidosis with cardiomyopathy. Next question.
Our next question comes from the line of Paul Matteis with Stifel. Your line is now open.
Great. Thanks very much for taking my question. I think as it relates to HELIOS-B, in the discussion within the investment community, one of the biggest sort of points of contention is probability of success as it relates to whether vutrisiran will show meaningful added benefit on top of tafamidis and how that might impact overall study powering. So I was wondering if you could just kind of comment on that point on why you're confident, why should we be confident you'll see efficacy on top of tafamidis. And then within this 24-month update for ONPATTRO, which looks pretty interesting on walk test events, are you seeing added efficacy to tafamidis if patients are followed over time? Thanks so much.
Those are two great questions. I think Pushkal pointed out, HELIOS-B's power is very conservatively overall by 10%. It's a large, long study, an outcome study, and we believe that we'll have sufficient patients to assess consistency of effect across multiple subgroups. Pushkal, you may want to add to that, but also maybe take the question around the 24-month update.
Yeah. Paul, I think, look, again, we are really very positive and excited about what we saw in 24 months with this data because, again, it corroborates the profile that we've seen across multiple data sets in terms of the impact of this class of medicines on the heart and on cardiac function and on patients with this disease. With regard to the CAP subgroup, I just remind you that there's been a lot of time spent interpreting this in the Apollo study.
That was a one-year study where there were 45 patients per arm in these two subgroups. Okay? It was a really, really tiny experience. And the results were somewhat mixed. I will point out, actually, that interestingly, it was on the outcomes analysis that we actually saw more encouraging actual impact in terms of the combination. So when we designed HELIOS-B, we made very conservative assumptions around that, including the potential additive effect on top of tafamidis, recognizing that when you might have two effective therapies, you have to sort of account for that in the context of powering the study.
And again, we made that design assuming 50% of patients would be on baseline tafamidis and we came in under that. So I think all of these things really make us feel very encouraged about the overall design and execution and powering of the study. Yeah, so we look forward to delivering the results next year.
Actually, anything to add? I know you've got some perspectives.
Yeah? Yeah, no. I think Pushkal's covered it, and then it's come up in previous questions. What's happened here, of course, is for patients, but we remain committed to Helios-B for the reasons Pushkal outlined. It's a large, longer study to a great degree. And as you look at the current 24-month data for Apollo, it just shows what time alone delivers in terms of distinguishing the performance of the active arm in our studies relative to the comparator. And so I urge you to look at the 24-month data for HFSA yesterday or Satur day and think about what happens if that stretches out now to three years in an even larger sample size and where the comparator arm is pure placebo, not placebo patients that roll over onto TTR.
And so these kinds of factors, when I look at the various endpoints that we've discussed this weekend at 24 months, just further underscore my confidence and our confidence in the ultimate outcome. And I think we can compare, and we just can imagine these data, we don't have them in hand, the ultimate outcome at three years and compared to contemporaneous studies, it looks very favorable in my mind as to where we should be. And those days are not far away now, as we observe.
Thank you, actually. Next question.
Our next question comes from the line of Kostas Biliouris with BMO Capital Markets. Your line is now open.
Hello, everyone. Thanks for taking our question. Maybe one question on Amvuttra. You have already touched on that, but some more follow-up would be helpful. If we assume that Amvuttra demonstrates a statistically significant effect in HELIOS-B, do you think there is a likelihood that FDA would compare Amvuttra's clinical effect with other drugs that may be approved by then, such as tafamidis, and still push back on the clinical meaningfulness of the effect? Thank you.
Yeah, Kostas, I mean, again, I don't want to speak for the regulators, but I think what we're excited about is that HELIOS-B really, I think, is a definitive study. It's evaluating a large population of patients with ATTR against a couple of hard outcomes. And it really addresses a couple of the points that were brought up at the advisory committee, both in terms of the endpoints and wanting to see benefits in terms of mortality and hospitalization, and two, a longer study to show the consistency of effect.
And that's also something that this study is being three years long really will help establish as well. So I think we're, again, feel good about the design and execution, the conduct of that study, and that it will address the points that were raised at the advisory committee when people were trying to interpret the Apollo B results. So all in all, we feel good about it. And it's sizable enough to demonstrate consistency of effect across all the key subgroups that we're going to be looking at in that study.
Thanks, Pushkal. I think we've got time for one last question.
Our last question comes from the line of Maury Raycroft with Jefferies. Your line is now open.
Hi. Thanks for taking my question. I was just wondering if you can talk about what you're seeing on a blinded basis from HELIOS-B from the DSMB assessments. And at this point, apart from the less than 50% of patients on a baseline CAP, is there more that you can say about the patient baseline profile of HELIOS-B patients and how these patients differ from Apollo B?
Yeah, Maury. So I think, look, overall, there's so many factors that go into a successful clinical trial of this complexity. So we're not going to be commenting on individual aspects of that. But the study is, as Apollo B has been under active monitoring of DSMB, and the study proceeds unchanged. And so, again, for all the reasons we've talked about today, I think we feel very good about both the design, the execution, the conduct of that study, and how all the data that we're seeing for this class of medicine sets us up to deliver on an effective and positive study.
Good. Well, look, thank you, everyone, for joining today's call. As you said, we're disappointed by what this complete response means for patients with ATTR cardiomyopathy. But we remain fully committed to serving the needs of this patient population. Thank you and have a great day. This concludes today's conference call.
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