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

Good afternoon, everyone. Thanks for joining us at our Bank of America Healthcare Conference, usually held in Vegas. Of course, this year is virtual. We hope to go back to Vegas sometime soon. It's our pleasure to be hosting our next presenting company, Alnylam. Presenting for Alnylam is none other than John Maraganore. John, you don't need an introduction. So I think we should probably just go straight into Q&A.

Sure.

For those who might not be as familiar with Alnylam, maybe we can do with super quick overview in 2 minutes, which I know is a challenge because you've got a lot going on. But hopefully, we'll be able to get into a little bit more detail on some of the key items over the course of the next 30 minutes, if that's okay.

Sounds great. Yes, very high level, Alnylam is the pioneer in RNAi therapeutics where we've been successful in bringing 4 RNAi medicines to the market, and that includes 3 that were directly commercializing ourselves. And then on top of that, we've got a portfolio of about a dozen clinical programs and then an organic product engine that's delivering sustainable [Technical Difficulty] for new INDs per year. Recently, we announced our P5x25 5-year goals. And I think those goals speak for themselves. They're very exciting, and they position Alnylam in a very strong way for the future.

Okay. Great. So you've got a lot of things going on in the pipeline that we can talk about each of them probably for more than 30 minutes, but let's try to be efficient. Let's maybe start with Vutrisiran. So that is in development to treat ATTR, of course. And you had an update actually that maybe we can talk about in terms of dosing frequency. Maybe you can give us a quick summary of what was announced today and why that's important.

Yes. Absolutely. Well, Vutrisiran is an exciting and very, very important molecule for our overall ATTR franchise. We filed our NDA for Vutrisiran initially based on the HELIOS-A data for polyneuropathy patients. And then we have the ongoing HELIOS-B study, which is in cardiomyopathy. But what we released today was that we've started our biannual dosing regimen with Vutrisiran, which should generate data in 2022, which, if positive, will support a supplemental NDA that will enable a biannual dosing regimen for Vutrisiran for the future. Now while we're also enabling Vutrisiran with this 6 monthly regimen, we also announced today that we're working on life cycle management and a succession plan, if you will, for the king. The king always needs a successor. And so we announced today a program coming out of a new platform that we call IKARIA that enables highly potent knockdown of target genes with RNAi and RNAi mechanism of action with an annual dosing regimen. So we believe that this type of approach will provide almost like a vaccine-type dosing schedule for patients in the management of their disease. So we're very excited about that as well for the future. But obviously, in the near term, we've got Vutrisiran well on its way, both with the polyneuropathy segment, on HELIOS-A, 6 monthly dosing regimen and then also the cardiomyopathy opportunity with HELIOS-B.

Okay. And so -- sorry, I guess to clarify, and John, I am not sure your camera might have turned off at least on my end. But I can hear your...

Okay. I can hear you. I don't know if you can see me, but I can -- I don't know what to do about that.

We'll keep going.

Okay.

So in terms of the overall strategy for Alnylam, why is it important to have the potential for multiple dosing regimens for Vutrisiran do you think?

Yes. Well, look, I mean we're really committed to continuing to deliver the best innovation we can for the patients with hATTR amyloidosis with polyneuropathy today and in the future, depending on results for cardiomyopathy as well. And a q6 monthly regimen is going to be a very attractive treatment option for patients, being able to align their treatment with when they would ordinarily visit their physician. So that type of approach will be a very, very welcome treatment option. And then for the future, the work that we're doing with this new platform that enables annual dosing even provides a better and stronger approach for the future. But for right now, obviously, Vutrisiran is very well positioned with first quarterly dosing and then in the future 6 monthly dosing, and we're excited about that progress for sure.

And I guess, as it relates to the competitive landscape, I -- my take might be that this makes the program more competitive because there are some that might think that maybe a one-and-done treatment were awaiting data from a competitor for a potential one is on treatment using gene editing might also be compelling. But if you're offering something that's so infrequent, I would imagine that makes that position a little bit less fierce. Would you agree?

I completely agree, Tazeen, because, look, I think any time you're targeting DNA, you have a lot of uncertainty from a safety perspective as to what the implications are of that. And if you can instead have a once every 6 monthly or once annual dosing regimen, we think there are many advantages of that.

Right. So when would be the next...

At the end of the day, one-and-done therapies...

When would the next -- sorry. I'm not sure if we're a little bit delayed on time between when you can hear me and I can hear you. So I apologize in advance. So I guess when would be the next data readout for this program for Vutrisiran based on where we are today?

Yes. So the next data readout for Vutrisiran is going to be in 2022 with our 6 monthly regimen. Of course, we do expect the approval in early 2022 as well. So that will be an important readout. We also have 18-month data from our HELIOS-A study that will read out later this year, and that will include a number of exploratory endpoints on cardiac endpoints.

Okay. So speaking of HELIOS, we did see the 9-month data recently presented. And so what should we be looking for in terms of continuity going from 9 months to 18 months?

Yes. Absolutely. Well, look, I mean we know from the APOLLO study with patisiran that the 9-month results that we obtained there continued to show continued benefit at 18 months. And so we would expect a similar type of result from the HELIOS-A study. But the other part of HELIOS-A, as I mentioned just a minute ago, is that we also have a lot of cardiac endpoint data that will also be part -- these are exploratory endpoint data that we'll be reading out at 18 months as well. And so we'll see how those data look in the second half of this year.

And would there be any kind of read-through from that cardiac data to just looking at cardiomyopathy?

Well, I think those data are very helpful, exploratory endpoint data that are certainly hypothesis generating. I think, obviously, the key thing out of the cardiomyopathy studies are the results of the randomized study. So we have APOLLO-B that will read out in the middle of next year, and then HELIOS-B, which will read out thereafter. So it's really those randomized studies that will provide the definitive evidence and, if positive, will lead to us filing NDAs globally. But ultimately, in the near term, these are very helpful data that strengthen our hypothesis that will be tested in randomized studies.

Okay. Fair enough. Before we leave this topic of ATTR, for ONPATTRO, consensus estimates for sales for this year do indicate meaningful growth year-on-year. I think it's, the last we checked, around $460 million or so. As we think about the launch trajectory for ONPATTRO, what do you think are the key drivers that are going to help accelerate sales this year, both in the U.S. and Europe?

Yes. Thanks for that, Tazeen. I mean, look, we're very proud of how ONPATTRO has performed. It is a very important medicine for patients with polyneuropathy. We reported $102 million of Q1 revenues. That's our first triple-digit quarter for the product, which is a wonderful milestone. And we do expect steady and continued growth for ONPATTRO throughout the course of the year. The key drivers of this growth are really around new patient finding and also the opening up of the health care system increasingly following the pandemic year that we had last year. We all know that the health care system had ups and downs, including Q2 of last year that was a tough quarter. And we've been seeing an increasing opening up of the health care system. We think that will help in finding patients with polyneuropathy that can be benefited by ONPATTRO. In addition to that organic growth around new patient finding, we also continue to see switching happening in -- outside the U.S. for patients that are progressing in their polyneuropathy while they're on a stabilizer drug, and that's a phenomenon that we see as well. And we continue to see a greater recognition of the burden of disease associated with polyneuropathy across patients with mixed phenotypes, especially in the U.S. market. So these are all the different market dynamics that exist. But at the end of the day, for patients with polyneuropathy, ONPATTRO is making a big difference.

Yes, agreed. I guess I lied. Before we leave the topic of ATTR, maybe one more question. So for HELIOS-B, to go back to that for one second. [ In rough, assets are ] complete by the end of this year, and you would have a potential interim read. And when you do have this interim read, just to set expectations, is there a scenario where the data would be encouraging enough that you could potentially apply for approval prior to achieving the longer-term primary endpoint?

Yes. Well, look, let's not get too far ahead of ourselves in this regard. I mean, obviously, we have talked about an interim analysis in the HELIOS-B study. We're going to engage with regulators around the design at that interim analysis. We're also going to have the benefit of APOLLO-B data before we pull the trigger on any interim analysis, and that will be really instructive because we'll be looking at 6-minute walk distance, but we also have CV event and mortality data out of the APOLLO-B study that will be informative for whatever interim analysis we might do on the HELIOS-B study. So lots of things to get done before we can say clearly what the interim will look like from a design standpoint and what the timing would be. But obviously, if we do align with regulators on an interim, that could be an opportunity for getting the product to the market sooner. That's correct.

Because it is an area of high undermet need. So the idea itself probably is not out of the realm of the possible scenarios. I don't want to set expectations, but just wanted to ask your thoughts on that.

Absolutely.

Okay. So let's move on to some of the other products. Specifically, spend a minute, if we could, talking about GIVLAARI and OXLUMO. How are you thinking about the trajectories of those launches thus far? Those are obviously more in the ultra-rare indications, but how should we be thinking about what kind of market opportunity these have on a go-forward basis?

Yes. Well, let's start with GIVLAARI, and this is our treatment for acute hepatic porphyria. And it's a wonderful transformational medicine for patients. It's really helped a lot of patients deal with this terrible disease. We ended last year with about 150 patients on commercial GIVLAARI, and we've been making strong progress. We reported $25 million in Q1 revenues. Now one of the drivers of growth for GIVLAARI this year is going to be geographic expansion based on pricing and reimbursement that we expect to receive in many European countries. Last year, we only had a couple of countries where we had active sales. That includes Germany and an ATU in France. So we'll have a lot more pricing and reimbursement happening in the rest of Europe for GIVLAARI. And then importantly, Japan will open up in the middle of this year. We expect approval in Japan for GIVLAARI. So in addition to new patient finding, the big driver for growth in 2021 for GIVLAARI is going to be geographic expansion. And then in the case of OXLUMO, we've only had one full quarter of launch. So far, so good, let's say. I mean we had $9 million in our first launch -- first quarter of launch, exceeding all of our estimates and I think estimates from the outside as well. And the real drivers of growth for 2021 for OXLUMO is really around new patient finding, opening up additional geographies in Europe, their pricing and reimbursement, and, of course, just the growth of the market through disease awareness efforts that we're engaged with to help physicians find these patients at the end of the day. But so far, what we've seen with OXLUMO is very encouraging. We're seeing patients of all age groups receiving therapy, and we're seeing a wide array of patient severity in terms of GFR levels for patients that are coming on to commercial products. So that's an encouraging sign, both in the U.S. and also in Europe.

Okay. Now maybe staying on OXLUMO for a second. I believe we are going to be seeing some additional data later this year for PH1 patients with renal impairment.

That's right. That's right. And -- go ahead.

Right. That -- maybe give us some context around that.

Yes. Well, it's very important data. So we'll have readout from that study -- this is ILLUMINATE-C -- in the middle of the year. And this is looking at patients with severe renal impairment, patients with GFRs that are less than 30. And that, of course, is an important patient population because these are the patients that also have the greatest risk for developing systemic oxalosis. Now the primary endpoint in ILLUMINATE-C is going to be the levels of plasma oxalate, right? So this is looking at systemic levels of oxalate in the body. And if we can see significant and meaningful reductions of plasma oxalate, that bodes well for potential improvements in clinical endpoints like systemic oxalosis clinical events in the skin, the bones, the eye, the heart and other tissues. And so we're looking forward to those data. Clearly, the availability of those data will strengthen the overall evidence that exists for OXLUMO and help educate physicians around how this agent can work across the whole spectrum of the PH1 disease.

Okay. That's going to be coming up soon and we'll [Technical Difficulty] for that. So let's spend a minute or 2, if we could, on the hypertension program, which I think a lot of folks are interested in for obvious reasons, so ALN-AGT. You recently announced that the next step in the program is to run 2 studies, one is monotherapy and one as add-on therapy, to establish agents to treat hypertension. I guess what is the longer-term development plan for hypertension? And how do these 2 studies kind of set up where you think this drug would fit in the treatment -- overall treatment regimen?

Yes. Well, Tazeen, we're very excited about ALN-AGT in hypertension. It really provides an opportunity of reimagining the treatment of hypertension, which, as you know, is the leading cause of cardiovascular morbidity and mortality worldwide. So enormous unmet need. And the real issues in hypertension today are that patients do not achieve a tonic control of their blood pressure, and they also are rarely adherent to therapy. So compliance is a major factor. And a drug at RNAi therapeutic that's given once a quarter or maybe even once every 6 months would obviously be a revolutionary advance in the management of hypertension, especially if we can achieve tonic blood pressure control. We've already showed very robust knockdown of angiotensinogen as well as lowering of blood pressure in our Phase I study in over 15-millimeter mercury reduction of blood pressure in the Phase I as monotherapy. And that same endpoint is the same endpoint we'll be using in our Phase II and our Phase III study. So very much like the inclisiran story where LDL lowering remained the primary endpoint from Phase I to Phase III, a similar story is going to take place here with our hypertension program. We're about to start our 2 Phase II programs for this product that will treat about 1,000 patients with moderate hypertension. This will include as monotherapy in KARDIA-1 and also in combination therapy with other antihypertensives, including RAS inhibitors in the KARDIA-2 study. And those studies should read out in late '22 or into early '23. And based on enrollment time lines, of course, we'll update people when we have better visibility and better line of sight on that, which would lead to a Phase III program that would probably be multiple thousands of patients. They'd probably be 2 separate studies. But again, here, too, the primary endpoint will be blood pressure.

So you said a lot in that description. And based on how you've designed the study, I guess, a couple of questions. How many sites will you have for this program? And then are they distributed geographically?

Yes. I mean it's going to be -- these are going to be -- the KARDIA-1 and KARDIA-2 studies are going to be global studies. They'll have well over 50 sites at the end of the day to enroll a diverse population. I should say that we're also very eager and very committed here to getting diversity in this clinical program, especially in African-American patients where hypertension is a major problem. So we are going to be enriching and aiming to enrich the study for a diverse population as well. So I think we're very committed to -- in this program. But it's going to be a large number of sites. It will be done globally. And obviously, it'll be done in a high-quality manner as we have done in the past.

Okay. Now I think people are intrigued by this program for a number of reasons, one of which is that the market opportunity is quite meaningful. As you move this program forward and think about how it fits into Alnylam as a company, how are you thinking about wanting to keep full rights to this program or having a partner potentially to help because, of course, there are millions of potential patients that could ultimately be put on this drug?

Yes. Well, first of all, I think the fact that this is going to be used in a prevalent disease setting is notable. But we're very inspired by the results that have been generated with inclisiran, which is now being commercialized by Novartis. As you know, we have a front-row seat on the commercialization of inclisiran. And much of the work that Novartis is doing really is around innovative approaches to access, look at what they've done with the National Health Service in the U.K. around the access agreement that we think is really the wave of the future. The other phenomenon here is that RNA medicines, of course, are a lot better known these days because of what's happened with COVID and mRNA vaccines. And so the modality of targeting RNA is something, which is -- or using RNA as a drug is far more understood worldwide. Now our goal is to commercialize ALN-AGT directly ourselves. We expect to be in cardiology to begin with, assuming our APOLLO-B and HELIOS-B studies read out positively. So we'll be already addressing the unmet needs in that patient -- in that setting. And that obviously will bode well for how we would think about commercializing our ALN-AGT program if it's successful at the end of the day. So that's how we're thinking about it. Now if we need access to primary care physicians, we can always set up a promotional agreement in the future with another larger pharmaceutical company, but we don't have to make that decision today. We certainly will be directly commercializing the product on our own. Whether we add some additional boots on the ground or not is something we can decide on later.

Okay. Now in terms of the full development program, it's your assumption that you would need to run the pivotal program after 2 Phase IIs would read out. Is that right?

Absolutely. Yes. We'll have to run 2 Phase III studies to support the approval of ALN-AGT. And ultimately, we'll run additional studies in the future to support the overall clinical impact of this type of treatment, including potentially outcome studies. But that will not be needed for an initial approval, consistent with current FDA guidelines.

So that's also on the docket. Let's talk a little bit about Huntington's, which is an area that I think investors have a lot of interest in because a lot of companies have tried. And recent updates are reiterating the view that Huntington's might be an indication that's difficult for drug. But I'd love to hear your thoughts, John, about that disease itself and the attractiveness of using the Alnylam approach to try and see if you could find a therapeutic option for patients and maybe where you guys are in moving your program for Huntington's into the clinic.

Yes. Thanks for that, Tazeen. I mean, frankly, it's hard to imagine a disease that's more devastating than Huntington's. I don't think anybody -- I mean it's absolutely disastrous for patients and their families because of the inherited nature of the disease. And the recent data from Roche and then the Wave program, all of these data points, of course, are just also devastating for the patient community because there was so much hope for those programs. I think that as we looked at the data, we believe -- we're of the belief that the results were confounded by an inflammatory or pro-inflammatory feature of the single strands of antisense oligos that are used in both of those programs. And we've seen data points, including elevated NfL levels, elevated protein levels in CSF, that clearly indicate a pro-inflammatory profile for those agents. And so when we've looked at our preclinical data in nonhuman primates and even done comparative studies, we've been encouraged by the overall safety profile. We're about to start our first CNS program targeting amyloid precursor protein, and our Huntington's program is the second one that's queued up at this point in time. And as we've said before, we're also interested in targeting exon 1, which is believed to be potentially an important mediator of pathogenesis in this disease. And we remain committed to our Huntington's program and believe that we can potentially bring an agent that will provide deeper knockdown of Huntington than what's been seen with the antisense oligo platforms, but also a platform that hopefully shows a better tolerability profile than what we've seen from the Roche Ionis program. Again, the first program that we take at the clinic with a filing -- IND filing this year is going to be an important harbinger of how that plays out as well.

Okay. And so as you think about the programs that you're investing in now, you've got a lot of things that are going to be moving into the clinic that are already in the clinic. What do you think if there is such a thing that might be not fully appreciated by investors on any particular program?

I mean there is a lot there, I would say. I mean, obviously, in the near term, we're very excited about the potential for the cardiomyopathy studies with both patisiran and Vutrisiran. But we've talked already about the hypertension program. I think what's -- what we haven't talked about are programs like our NASH program, ALN-HSD, which targets a genetically validated target that's currently in Phase I. That should be going into Phase II next year. I think in many ways, the target of that program is like the PCSK9 of NASH. And an emerging program that should be in the clinic this year as well with an IND filing is a program targeting gout and another prevalent disease opportunity within the portfolio. So I think if you look across the spectrum, there's many programs to look out for in terms of how we're thinking about building the company for the future. And then we have some partner programs like our HBV program with Vir, alpha-1 antitrypsin program with Dicerna and our combination complement program with Regeneron, together with some [ Desaran ]. So a lot going on as we think about how we bring important new innovations to the market.

Yes, there is, and probably spend another hour talking about all of those, but we are just about out of time. So we'll make some time to speak about those again sometime soon, hopefully. But I wanted to thank you, John, for spending the last half hour with us. It is always educational to learn about what's going on at Alnylam. And we're going to be looking out for all the different catalysts that we just talked about here and then some.

Sounds great, Tazeen. Thank you so much, and we'll talk soon.

Thank you, John, and thanks, everyone, for joining.

Bye, bye.