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

Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss complete response letter for ONPATTRO (patisiran) supplemental new drug application. [Operator Instructions] 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 before 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 provisions of 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 represent our views 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 obligation to update such statements. With that, I'll now turn the call over to Yvonne. 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 patisiran, an investigational RNAi therapeutic that has been in development 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. Look, it goes without saying that we're 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 2.5 to 5.5 years. And that shows history that it's 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 decline 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 patisiran had already had a profound impact on their functional capacity and their quality of life as well as a 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 Phase III study that evaluated the efficacy and safety of patisiran in patients with ATTR cardiomyopathy, with design and consultation with the FDA, who are fully aligned on the use of the 6-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 sharing 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 6-minute walk test 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 decided to show benefits in cardiac outcomes, favorable but non-statistically significant trends were observed for composite all-cause [ stat ] 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 arm 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 patisiran with a 9 to 3 vote, agreeing that the drug benefits outweigh risks for the treatment of the cardiomyopathy of ATTR amyloidosis. And we're disappointed that the FDA's decision was not in alignment with the committee's position. Now while patisiran remains an approved medicine to treat the polyneuropathy manifestations of hereditary ATTR amyloidosis, we've made a decision in light of this complete response letter to discontinue our development efforts to commercialize patisiran for the cardiomyopathy of ATTR amyloidosis in the U.S. 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 in RNAi therapeutic to ATTR cardiomyopathy patients as rapidly as possible. And 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 for the HELIOS-B cardiovascular outcome study. In this regard, while we have very much hoped for an approval of the sNDA, ONPATTRO would have represented a first step in helping this underserved population, with vutrisiran in HELIOS-B study serving as a very important next step. And with the top line readouts from HELIOS-B expected in early 2024, it does not make sense for us to invest further in additional development to enable commercialization of patisiran in cardiomyopathy. The HELIOS-B study was designed and powered to demonstrate the benefits of patisiran 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 data in its label could potentially position AMVUTTRA as a transformative therapy with a market-leading profile 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 to patients living with a cardiomyopathy of ATTR amyloidosis. We believe that the unique and powerful mechanism of action of RNAi therapeutics can confirm meaningful differentiation across this entire disease spectrum. And here, we plan to build on the foundation and market-leading position we've established with ONPATTRO and AMVUTTRA in the hereditary ATTR amyloidosis with polyneuropathy markets. In the APOLLO and HELIOS-A Phase III studies, respectively, we've shown the ability of our medicine to halt or improve the polyneuropathy manifestations of this disease. Importantly, not only do these studies demonstrate the impact of TTR [ learning ] by our drugs on polyneuropathy but exploratory endpoints from these studies as well as findings to investigate, to initiate the studies also consistently showed the potential for cardiac benefits. 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 Phase III study of vutrisiran, where we are leveraging over a decade of our [ miles-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 3x longer than APOLLO-B [ and as ] well set up to demonstrate the benefits of patisiran 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 for 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 innovation to patients, including with ALN-TTRsc04, 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 road map 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, 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 have 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 the call for questions. [Operator Instructions].

[Operator Instructions] Our first question comes from the line of Ritu Baral with Cowen.

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 for 6-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, Ritu. That's a great set of questions there. Look, I think the first thing to say is that we are confident for the design and execution of the HELIOS-B study. As I said in my opening remarks, we have an outcome study here, but it's 3x as long and twice as large as APOLLO-B. And our confidence in the mechanism of RNAi therapeutics, which has demonstrated consistent benefit across both polyneuropathy and cardiomyopathy manifestations, really give us confidence in this study. And clearly, we're laser-focused on delivering a successful outcome. But maybe Pushkal, you can speak to where we are in terms of delivering that study outcome.

Absolutely. Thanks, Yvonne. Thanks Ritu. Look, Ritu, I think, 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-hoc, exploratory analyses and then now in APOLLO-B, remarkably consistent and sort of widespread internal consistency in terms of the effect, silencing on multiple aspects of the heart, patients functionability, 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 was actually corroborated by the 24-month data, where we're actually seeing relative stabilization. And while we can't do any cross-study 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 to 36 months. Obviously, that extra time at the end of the study helps in terms of powering. We overenrolled it, and we already had conservative powering estimates. As a reminder, we had assumed 50%, for example, patients would be on baseline path, and we came in under that. And I think further to this point, I think the recent attribute results for our [ parameters ] highlight that in the modern era, patients continue to decline, they continue to accrue significant events and that an effective therapy can 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. And we always do that. And as this 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 until the point of database lock. And if we feel that will further optimize the potential for a successful study with a market-leading profile, and we will do that. So we'll keep you posted on updates as appropriate.

Thanks, Pushkal. And obviously, on track for our data read out in early 2024. Thanks for the question, Ritu. Next question.

Our next question comes from the line of David Lebowitz with Citi.

Given your experience in the regulatory process this time around with ONPATTRO and certainly in consideration of these 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?

Yes, Dave, I think -- look, I think we're -- 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 hard 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 a game-changing molecule for patients -- medicine for patients.

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

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 are $1.2 billion to $1.285 billion, assume approval by the PDUFA date. So wondering if any updated thought there. And then maybe bigger picture, I think your [ P^5x25 ] assume non-GAAP profitability by the end of 2025. So wondering if that guidance is still intact.

Great question. I mean I'll start with a [ P^5x25 ] question. Look, we're not walking away from [ P^5x25 ]. 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 [ P^5x25 ] is contingent on delivering a successful HELIOS-B study and its approval and launch. And we believe that, that's what we'll be able to do. Jeff?

Yes. So let me address the questions about 23 -- 2023 product sales guidance, and then I'll also touch on expectations in 2024. So for 2023, you got it right, Luca, the guidance that we have put out is $1.2 billion to $1.285 billion, no change to that as a result of the news today. And 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. But let me provide just a little bit of directional guidance as it relates to ONPATTRO, so that's clear. Our expectations is that we'll continue to see declines in ONPATTRO sales on a go-forward basis, and that's really a fact of 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 ONPATTRO 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, 5 major markets in Europe as well. So we do expect to see continued declines for ONPATTRO. What that means for 2024 is I would expect ONPATTRO revenues next year to be in the range of $200 million to $225 million.

Next question.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

Just with regard to the confidence here in reaching statistical significance on HELIOS-B, could you speak to that [indiscernible] 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?