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

Welcome to Barclays' 26th Global Healthcare Conference. My name is Gena Wang. I'm SMID-cap biotech analyst at the Barclays. It is my great pleasure to introduce our next presenting company, Alnylam. With us today, we have Pushkal Garg, Chief Medical Officer and EVP Development and Medical Affairs. So Pushkal, maybe before we dive into the questions, give a high-level overview of Alnylam.

Absolutely. Well, Gena, thank you, first of all, very much for you and the Barclays team for inviting us here today. It's a real pleasure to be here. Look, Alnylam is now entering its 22nd year as a company, really founded on the promise of RNAi therapeutics. And we're incredibly proud of the progress we've made in terms of bringing an entirely new class of medicines forward that can actually silence specific genes in the genome and bring transformative medicines to change the lives of patients. We've now, in the last 5 years, brought 5 medicines forward to market, and we are on the cusp of doing even more in terms of delivering into new tissues like the CNS, where we had a major proof of concept this past year. And as we announced at our R&D Day going into even new tissues, muscle, adipose and others to bring the promise of RNAi therapeutics. And we're now selling our products, commercializing our products around the world ourselves in over 30 countries and more with distributor markets, very proud of the commercial success that we've had. And financially, we're on the path to profitability. We said that we will become profitable by 2025 and we remain on track to do that. So we're really proud of what we're doing as a company and looking forward to some major milestones this year, which I'm sure we'll talk about, and in years to come.

Great. So I would assume you alluded to HELIOS-B .

No, no. I was talking about KARDIA-2.

Okay. So HELIOS-B, we got so many questions. And I think this -- previously, APOLLO-B was one of a very major catalyst for the biotech sector and now HELIOS-B again so important, because not just Alnylam impacts so many different also other drugs in development. And so based on the -- I think in the past you comment based on the 3 data sets, you revised the statistic analysis adding monotherapy component and there's some investor pushback basically saying, is that suggesting the concerning of actually detrimental impact from both balancing together with stabilizer. From a scientific point of view, do you think [indiscernible] at all?

Yes. Look, it's no surprise that there's a lot of interest externally on HELIOS-B. We too are very much looking forward to those results. We remain as confident as ever and the design and execution of that study, and we can go into some of the specifics. Maybe one thing I will say is just as a reminder to everyone that we did recently state that the top line results will be available in late June or early July. And maybe one update to that is just to say that as -- given how important that readout is, we plan to be going entering a quiet period in mid-May in advance of those results. So we'll be engaging with investors up to that point. But in midway, we'll enter a quiet period until those results become available. With regard to your specific question, Gena. No. Look, first of all, I don't think biologically, there's any reason that I can think of why there would be a detrimental effect from the combination. And in APOLLO-B, we did have a modest sized cohort of patients who are on the combination. And look, I think all told, we saw more or less what we expected, which is that we saw on a number of endpoints in this very small cohort, some additive effects when we looked at the outcomes data in that particular subset of patients, we've seen some encouraging additive effects there as well. So it remains to be seen what the exact magnitude of that add-on effect is on top of a stabilizer, but we would expect that there will be some add-on effect and then we think that's exactly what we saw in APOLLO-B and that will be more further elucidated in HELIOS-B.

Very good. So now regarding the monotherapy arm, right, when I do the calculation, the study by itself could be very similar to BridgeBio ATTRibute study in a way that you would not allow any tafamidis in the baseline. And maybe when we look at the number of patients, your study actually has a higher bar to hit a step. So we're thinking about the number of patients, 60% of your total patients compared to maybe BridgeBio a little bit higher number of patients. And then also the dropping rate, the first 12 months, they will not allow tafamidis dropping. You allow basically right at the beginning. And your P value is smaller, 0.025. So giving all these, like do you think that you are setting very high bar for yourself?

No, not at all. Look, I think what it really shows is the confidence that we have in the mechanism of action and what we expect to see in the monotherapy [indiscernible] in combination. I'll remind you of the combination of the overall remains as part of the primary endpoint. I think I would maybe -- and I'm not sure that BridgeBio would be the appropriate reference point. I'll remind you that with 600 patients, that wasn't able to show actually a significant effect on 6-minute walk test at 12 months, which patisiran, a similar mechanism, was able to show in 360 patients in 12 months, right? So I think comparing to the ATTRibute study may not be the best benchmark there. What I'll say is that, look, our enthusiasm about the monotherapy effect comes from, first and foremost, what we saw in APOLLO-B, where we saw over 2-plus years, including after crossover, but we saw this maintenance of effect, which was quite durable where we saw evidence in powered endpoints of stabilization of disease, both on functional status and quality of life, biomarkers, et cetera, all of that's incredibly encouraging to us and suggests potentially a very differentiated effect on this disease. And I'll remind you, those are all predictors of outcomes. And so that sort of suggests to us that we may be having an outsized effect. We did see encouraging trends in terms of outcomes as well, although the PATH study was empowered for it. When we look at -- just a reminder that what we've done in this study is that we've -- a lot of that monotherapy cohort is about 400 patients, we've enriched for those patients who are most likely to benefit or show the loss therapeutic effect. NYHA Class I and II that's [indiscernible] 2 large pivotal trials now is having the largest treatment effect with the changes that we've made in terms of duration of follow-up, we ostensibly have, for all intents and purposes, more or less a 36-month study. So it's about 20% longer than both ATTRibute and ATTRACT. And so -- and then when I look at the sample size, it's about the same sample size as ATTRACT. So I think all of those things give us the confidence in the monotherapy arm.

So maybe like you do have the opportunity to extend all the way to 36. So why you chose [indiscernible] month more?

Yes. Look, I think what we did when we looked at that is we took advantage of some aspects of how the trial is done. I'll just remind you that we did not change the structure of the trial in any way, patient experience on the study remains unchanged. What we did do was take advantage of the fact that we had patients in time before patients were crossing over into the open-label extension and so we could add some extra exposure into the double-blind placebo-controlled exposure into the study. When -- by doing this, we actually felt like we actually have bought over 20% additional patients to the full 36 months. We think we're getting the lion's share of the benefit that we were hoping to get. And that's really the critical factor for us. In fact, ostensibly, this is more or less patients continuing on the study more or less a 36-month study. So we're really -- we think they've gotten the lion share of the benefit, and it didn't make sense for us to sort of go out further. And I'll remind you that this is in the period of the study, which is the most critical, which is when you actually see the greatest separation or the greatest number of events in accrue, particularly in your placebo arm. And so we think this substantially adds to the powering of the study and really helps us. I think one other point I'll just bring up, Gena, that I've heard through some conversations that there's some speculation that somehow this was informed by the DSMB or DMC, something like that. I just have to say the comments on the question a little bit farcical, frankly, this is not a change in any way the design or structure of the study, this has changed the analytic approach. It's not something that the DMC to -- based on some review of DMC data or blinded data et cetera, et cetera, et cetera. This was really a change in the analytic plan. So definitely want to dismiss those concerns or those questions inspect idle speculation.

Okay. So you mentioned that the -- adding additional 3 months or reach as many patients as possible reach 36 months that will make it very different in terms of initial -- like the final 3 months -- so could you provide a little bit quantitative numbers, like in terms of like how much more percentage event we should be able to see in that the last additional 3 more months?

Yes. Look, I can't give you an exact number, Gena. I think I would just...

[indiscernible] reference point.

Yes. No, I would look at the existing curves that you see from placebo-controlled trials in heart failure in general or [indiscernible], you could look at ATTRibute and ATTRACT, you can see what's happening in terms of placebo rates over time and how they're increasing and how active drugs really are able to slow that trajectory. And so you can kind of follow those lines forward. But certainly, as patients advance in their disease and more time those placebo patients are going to accrue a lot more events, whether they are out of randomization.

Okay. So with updated study, so then really like the monotherapy part, the one we were talking about the high bar [indiscernible] value now is under the condition that you fail overall patient population, right? Otherwise, the value will be 0.05 for monotherapy component, is that the right way...?

Yes. So the way to think about the way that we've controlled for alpha in the study is basically that look at both the overall population and the monotherapy hit and the p-value for both [indiscernible] If only 1 of the 2 hits, it has to be a p of under 0.025.

Okay. So would that...

The way to think about it, right, is that we've basically, in terms of the endpoints, we now have the overall population. It's a blended population, the monotherapy group as well as the combination group that constitutes 40% of it. We've seen encouraging data on both of those subsets out of APOLLO-B. We remain confident about that. That's 100% of the sample size, all 655 or 660 patients roughly in there. And then we've got an enriched subset of 60% 400 patients into the monotherapy group that has the potential to show an outsized benefit, and we've elevated that into the endpoints trial.

So with this updated study, do you think that you will have a [indiscernible] question, why to the secondary endpoint, why the order you gave when we look at the 6-minute walk test that will be the first, the all-cause mortality actually is relatively lower after KCCQ. So why that order?

Yes. Look, I think what we did in revising the secondary endpoint structure is really focused on those end points that we think are going to be most important to showing differentiation of vutrisiran relative to other available therapies that might be out there. And really most informative physicians in their prescribing and patients in terms of deciding which therapy to get on. And what we saw is very encouraging data out of APOLLO-B that really is recapitulation of what we saw in the neuropathy setting by silencing TTR upstream through an RNAi mechanism that we can result in rapid knockdown of TTR and result in stabilization of disease. And we've seen that for 2-plus years, in the APOLLO-B study in the cardiomyopathy setting, we've seen that previously in the polyneuropathy setting. And the best ways to demonstrate that, we think, are through what patients experience, which is their functional status every day and their quality of life every day. And that's why those 2 end points are in there. The primary endpoint, as everyone knows, is on death and recurrent all-cause mortality and recurrent CV events. That will be split out in the primary endpoint structure, the 2 components will be shown. But all-cause mortality, of course, is a higher bar. And so we've captured that in the secondary endpoint structure as well. The ordering is really that we think that with the sample size and the duration that we have, we should have a tremendous amount of power for 6-minute walk test and KCCQ, so we put them higher in the hierarchy and then we put all-cause mortality, the highest bar after that.

So for primary endpoint, you also will be able to show if you would be able to hit a stat significance with all cause mortality part, right? That will be a statistic hierarchy testing, all-cause mortality, then move to the hospitalization events.

No. So the way that we're using an Andersen-Gill approach, so it looks at the blended of mortality and recurrent CV events in the primary point. But the result will be reported out is showing the 2 components of that as well.

So when the top line release, you will be able to show both, like p-value for each one? Or was it blended together?

Yes. No, it will be for the primary endpoint, which is the blend of all-cause mortality and recurrent CV events.

I think the reason I'm asking is we're thinking, would you be able to have a chance to say [indiscernible] all-cause mortality, which in the BridgeBio case, they did not?

Yes. So we've -- so look, in the primary endpoint, it's a blend of these 2 components. And then the actual effect sizes and the confidence intervals will be ultimately come out, that would be part of the endpoint structure. And then there is a separate endpoint for the higher bar of all-cause mortality, and that was included, because we think as a stand-alone endpoint, obviously, is important. And while the study was not formally powered for that, it's possible that we may see a stat sig effect, and we wanted to be able to attribute a p-value to that. So that's why it's included in the hierarchy and an alpha conserving strategy.

Okay. Very helpful. So now see if we fast forward, if you only show some monotherapy part, so what kind of label you were thinking that could be, this current data, like whatever the data, if it's possible, what kind of label that could be and how would you compete in with, say, for example, other drugs stabilizes maybe already 2 on the market?

Yes. Look, we've talked about what we're doing from both a development perspective, but we also think that the changes in optimization that we've done really aligns very much where we see the market being as well, the external landscape. If we -- again, we remain confident about the overall effect in the overall population and seeing a combination effect. But if only the monotherapy were to hit, we think we'd be able to show that there was a -- that would imply that there is an improvement in both death recurrent CV events with monotherapy AMVUTTRA. And the -- where we see the market evolving over the next several years as there's multiple new entrants is that at the time -- until tafamidis goes generic, we think that this is largely going to be a monotherapy market. That's not to say there won't be exception. By and large, we think that from an access perspective, a pricing perspective, it's going to be quite challenging to be on multiple therapies at the same time. And so we see this largely being a monotherapy market. We see AMVUTTRA, therefore, and even in that construct being positioned either as a first-line agent or as a monotherapy that can be used in patients, who progress on a stabilizer. We know from a lot of reports, both data from the clinical trials, both AMVUTTRA and ATTRACT as well as physician reports and real-word evidence that a majority of patients on tafamidis do continue to decline over time. And so we think there's a very rich opportunity for a new therapy that may come along like AMVUTTRA, hopefully showing stabilization of the disease that might be used again as differentiated as a frontline therapy or for those patients who progress on tafamidis. Once we see -- once we expect that once tafamidis does go generic, we expect there will be more combination use at that point.

Okay. So maybe regarding these 2 scenarios, first line or second line post stabilizer progression, based on your clinical trial design, like there is no evidence showing whether it should be first line or second line, right, because there is no tafamidis progressor or -- so like what will be the data sets? So you do have the other 2 [indiscernible], the combination with tafamidis? So what kind of data sets, I know it's not powerful to text that significant, but what kind of a data set or a trend that will warrant for the first line versus, say, second line post progression?

Yes. Look, as we've been talking about, I think the data coming out of APOLLO-B in the cardiomyopathy setting as well as what we've seen in polyneuropathy really suggest that RNAi-mediated silencing of TTR and the rapid knockdown that, that causes can really result, we believe, in a differentiated effect on this disease from what other therapies now. So while there's no head-to-head study as I just said, we know that patients on stabilizers, while those drugs have done an amazing job, tafamidis, helping patients with this disease, there's a lot of unmet need. Patients do continue to decline based on the clinical trial data month-on-month in terms of losing some functional status and quality of life. We've seen that recapitulated when -- based on physician data, et cetera. And so we think that what we're seeing in APOLLO-B that needs to be shown now in HELIOS-B is that we may be stabilizing this disease by targeting TTR upstream. And we think we may -- we'll see what the mortality in the hospitalization occurs, right now, we know on the stabilizers, it can take up to 18 months for those differences to emerge. And maybe that we see some earlier separation. We certainly saw that in APOLLO-B as well. So we think there could be some differentiated effects that may emerge in the data set that we've been excited about from what we've seen in APOLLO-B and HELIOS-B shows that differentiated profile. We think that, that will allow physicians and patients to make those choices potentially to use AMVUTTRA upfront and/or to switch tafamidis patients who aren't doing well on to that. I'll just remind you, perhaps the greatest proof point of this, which is tafamidis was approved for polyneuropathy in hereditary patients in Europe. And when the APOLLO data came out on ONPATTRO and the HELIOS-A came out, then AMVUTTRA, what we saw in both settings, and there was no head-to-head data, there was no patients, who were through stabilize or progressors. But we saw was what looked -- I think many people thought was a very differentiated profile from what tafamidis has shown in that population. And as a result, we've had a lot of frontline use. And frankly, a lot of the tafamidis patients have switched over to a silencer. So I think that, again, it will remain to be seen what the HELIOS-B data set looks like. But certainly, that's a proof point that physicians and patients are going to be going to the therapy that has the greatest beneficial effect for the disease.

Okay. I will also say the competitive question later. Before we move that, maybe wanted to ask you housekeeping questions. For NYHA Class I, II for HELIOS-B, should we expect similar range or percentage of the patient if comparable to APOLLO-B?

Yes. Look, I think for all intents and purposes, the inclusion criteria for HELIOS-B and APOLLO-B were very, very similar. So I think I would look to the APOLLO-B baseline demographics to give you some sense on [indiscernible].

Okay. And then the other question is the dropping rate and I asked in the past, I know you would not disclose the specific numbers, but we do know, say BridgeBio study was also similar time frame enrollment, like is that a good benchmark regarding the dropping rate of tafamidis?

Yes. What I'm going to say is, as we've talked about in the past, Gena, that in terms of -- we took pretty conservative assumptions when we powered and designed HELIOS-B. We're happy that the dropping rates are significantly less than we had sort of factored our calculations. So we feel good about the design and the execution of the study.

Okay. And then one last question. On top line data, what exactly you will share?

Yes. So look, I think based on the endpoints that we've shared with you all over the last month or so, we will be providing for the primary endpoint, which is now in these 2 populations as well as the secondary p-value in the top line, we expect to show -- give some data and information around safety. And then we will also provide some information around subgroups and including the tafamidis subgroup. And then we'll present a more wholesome picture of the data at a medical conference thereafter.

Okay. So when you will share some information for subgroup, will you just like high level or there is a trend separation or not? Or...

Yes, I think you should just going to have to pay attention when we put it out. But I think all I can say today is that there will be information around some groups.

Okay. That's very good. And I think we have a little over 1 minute. I wanted to ask, you do have a TTRsc04, which could be, I think, very exciting and giving all the dynamic involving [indiscernible] trial design. And then by the time how many drugs will be on the market, what kind of Phase III study design for TTRsc04 that will meet your drug [indiscernible] competitive once it's launched? And given also the dynamic tafamidis could become generics by the time the drug launch.

So look, I think we're very excited about TTRsc04. I think if you take a step back, really what we're trying to do at Alnylam is we really see the opportunity to be leaders in this space, patients [indiscernible] and continue to bring innovation and transformative therapeutic patients. We've done that with ONPATTRO, then with AMVUTTRA and now sc04 gives us the opportunity to bring forward therapy that may allow for more -- for continued rapid, but even more durable knockdown potentially even once a year and even deeper knockdown. The Phase I data that we presented at our R&D Day showed up to 97% knockdown of TTR, which is really impressive. And so we're really looking forward to bringing that forward as the next level of innovation. Basically, we want patients to feel more or less free of their disease, unburden by their disease. And we think we can do that with AMVUTTRA and then with TTRsc04. It's a little early to talk about exactly what the design of that study is going to look like. Certainly, we're going to be informed by the continued Phase I data, but most importantly, by the HELIOS-B results. And so once we see those results be in a better position to talk about what that Phase III program will look like. For TTRsc04, we've said that we plan to start the study at or around year-end. And we'll share that information. But certainly, you can imagine that those people will be very informed of that. And look, we're going to bring forward development program, as I think we've done in the past, which hopefully is robust, but also highlight the urgency of bringing forward innovative therapies to this population. And so we'll be using [indiscernible] patient level data that we have now for multiple therapies in-house to sort of accelerate HELIOS-B program as well -- the TTRsc04 program as well.

Great. Thank you very much for [indiscernible]

Thank you, Gena. Great seeing you.

Thank you. Thank you, everyone.