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

Hi, everyone. Welcome, and thanks for attending Canaccord Genuity's 43rd Annual Growth Conference. My name is [ Johan Kim, ] and I'm an associate on Whitney Ijem's generic medicine and rare disease team. We're very excited to have the team from Alnylam Pharmaceuticals here, and it's my great pleasure to introduce Mr. Jeff Poulton, who is the CFO. Alnylam is a global biopharmaceutical company leading the space for RNAi therapeutics and programs to address unmet needs in generic medicines, cardio-metabolic diseases, the CNS space and many others. And so with that, I'll turn it over to the team for their presentation.

Thank you. Thanks for including us. And it's nice to be here today to give you an update on the Alnylam story. I will be making some forward-looking statements during my presentation today. So let's get started. So I think probably most of you are aware that Alnylam is the leader in RNAi therapeutics, which is a whole new class of medicines that we pioneered over the last 20 years. RNAi therapeutics targets messenger RNAs, which encode disease-causing proteins early upstream, before other classes of medicines, including monoclonal antibodies. What we've been able to deliver here with the platform has been pretty remarkable. 5 new medicines approved over the last 5 years, a robust pipeline, which I'll talk about more during the presentation that has targets that include both rare specialty and now prevalent diseases. All of this has really been driven by the platform itself, which has allowed us to organically innovate on a sustainable basis and at probabilities of success that are much higher than industry standards. And at this point, we don't really see anything that's going to impact our ability to continue to do that over the long term. So as I mentioned, 5 commercial products, 4 of which we market ourselves, and this slide highlights the results that we recently reported for the second quarter, 43% top line growth on a year-over-year basis for the quarter. And that was really driven by the TTR franchise, which is highlighted here on the left. And that makes up about 75% of our revenue today. I think what we're really excited about with the TTR franchise is the launch of AMVUTTRA. We're about a year into that now, a year into that in the U.S., less time in the market outside the U.S. But what we've seen in the U.S. is a really acceleration of growth for the franchise. We've had quarterly growth that succeeded 70% -- more than 70% on all 4 quarters that it's been on the market. And what we've seen in the market itself is really a doubling of start forms in the U.S. since we launched AMVUTTRA and a really significant increase in the number of physicians that are prescribing the product since we launched AMVUTTRA and a really nice balance as well at treating academic centers of excellence as well as those prescriptions coming from the community as well. On the right are our 2 ultra-orphan products, GIVLAARI for acute hepatic porphyria and OXLUMO for primary hyperoxaluria type 1, just over $80 million in revenue for the quarter, 37% growth. And these are typical ultra-orphan products. I would expect steady and continuous growth moving forward as we continue to drive disease education and find more patients. So now a snapshot of our pipeline. We've got more than 12 programs in the clinic today. You can see across the phases of development, nice balance. A couple of other things to highlight on the pipeline. One is the diversification that we've started to introduce over the last several years where we're moving beyond rare diseases. We've got a number of prevalent disease programs in the pipeline. I'll talk about some of that more in a few slides. And we've also moved beyond the liver for the first time in terms of the tissue type that we're targeting. Our first CNS program is in the clinic. And again, I'll talk about the early results there from a Phase I study. Last thing to highlight is the commercial rights column on the far right. We do have a nice mix of global and programs that are 50-50. Our hope is that as we move forward and continue to bring new programs through the pipeline that we're going to index towards programs that we'll own global rights to. So P^5x25 is our 5-year growth strategy. This was rolled out in 2021. This is really about establishing Alnylam as a leading global biotech. And if we think if we achieve these goals that we've laid out here that I'll start with P that that's where we'll be at the end of 2025. Just a couple of things to highlight. I think on the product, the commercial side, we're really looking at bringing innovative, high-impact therapies forward in both rare and prevalent diseases. I've already talked about where the pipeline is today. We see expansion of that over the period. And importantly, again, that engine. The goal is to have the ability to generate 4-plus INDs per year at the end of the period. And then, of course, a couple of financial goals over that period. One that's near and dear to my heart is the goal is to get the company to profitability by 2025. This is the third set of 5-year goals that the company has put out into the market. And the first 2 sets of 5-year goals, the company met or exceeded the goals that it put out. So that's how we think about these. These are goals that we expect to meet. So how do we achieve that growth? There's really 3 legs to the stool, I would say, in terms of growth, and it absolutely starts with leadership in the TTR franchise. So just a quick primer on ATTR amyloidosis. It's a rare debilitating and an oftentimes fatal disease. It's caused by misfolded TTR protein that accumulates in various tissues in the body including the heart, nerves and the GI tract. 2 forms of the disease, the hereditary disease is a smaller part of the market, about 50,000 patients and then the wild-type form of the disease, which is mostly cardiomyopathy, much larger 200,000 to 300,000 patients. And that's probably a conservative estimate. So our approach to building leadership is to do it in a step-wise fashion. And it started actually 5 years ago today with the approval of ONPATTRO in the hereditary PN part of the market. And that's still a fantastic foundation for us as we continue to grow beyond that. So the second step that we're on now is the period between 2022 and 2024. I already commented on the success that we've had with the launch of AMVUTTRA. So the approval of AMVUTTRA from a label perspective, is identical to the label that we've got for ONPATTRO. I mentioned that though that we're seeing accelerating growth, and that's driven by the very convenient subcu quarterly profile of AMVUTTRA. And then the next step that we expect to take in this period is patisiran in the much larger cardiomyopathy part of the market. And this was the strategy with the design of this study was, it was the fastest path to market for us to get to cardiomyopathy. And then the last step will be 2024 and beyond, and this is really the transformative step really where we hope we establish the franchise to be the leader in this space for the long term. And that really is focused on the HELIOS-B study for vutrisiran. Again, this is our quarterly subcu profile. We'll have results from that study early next year. And then we also have a life cycle opportunity that we've moved into the clinic this year, TTRSc04. This uses our IKARIA technology. which holds the promise of potentially 90% or greater knockdown and possibly once a year dosing. So APOLLO-B, actually, it was about a year ago that we announced the positive results for APOLLO-B. This is just a recap of that. So the 2 key endpoints in the study. First, the primary endpoint, which is a functional endpoint on the left, that's a 6-minute walk test. What I would highlight with the blue line is if you take the slope of that over that 12-month period, it really, the degradation that you had on the drug arm approximates normal healthy aging in that population. So it really speaks to stabilization of the disease over a 12-month period. We're excited about that. And then the first primary endpoint, quality of life, KCCQ on the right. Again, you can see the blue line, which is the drug arm, stabilization of the disease. So that's really how we're thinking about these results. 12-month study with about 1/4 of the patients in the study were on background TAF, so to show these kinds of results, we were really pleased with it. A little bit more on Apollo B here on the left, on the safety, very clean safety profile, which obviously was not a surprise to us. Again, this is a product that's been on the market now for 5 years. Some of the cardiac safety data was really encouraging, which frankly favored the drug and probably is another indication of efficacy in the study. Exploratory biomarkers in the upper right, again, all trending in favor of the drug. And then something I thought was really interesting. We had a subset of patients that were -- that we followed with technetium scanning through the study. And what we saw for the patients that were on drug is about 1/3 of those patients saw a reduction of amyloid in the heart over that 12-month study and didn't see any of that in the placebo arm, patients that were -- that we track that way. First time I think that's ever been shown in a clinical study. Let's see here. Just one more comment here about the significance of this data, right? I think we've got upcoming an advisory committee in September, the 13th of September, and then we've got a PDUFA date of October 8. We're really pleased with the data. We think the totality of the data, if you look at it, really everything is trending in favor of the drug, very clean safety profile, again, short study background TAF been pretty remarkable. Other agents that had similar designs didn't hit this at 12 months. So we're really optimistic about this. One comment I wanted to make about given the interactions upcoming with the advisory committee and then the PDUFA, we're going to go into an investor quiet period starting on August 24, and that will go through the PDUFA date on the 8th of October. So next, I mentioned this earlier, HELIOS-B. So this is our outcome study with vutrisiran, a much longer study, so it's about 3x as long and about twice the size of APOLLO-B. The endpoint here, primary endpoint is composite outcome of all-cause mortality and recurrent CV events. Again, has a 30-month endpoint where the last patient enrolled when they hit 30 months is when the study stops. But we follow patients that were enrolled earlier for up to 36 months. So that gives us some additional powering in the study. Again, early '24 is when we expect to have the top line data from HELIOS-B. So the second key driver of growth is the expansion beyond rare diseases. This slide really highlights the rationale for why we think this makes sense. Upper left-hand side, for me, it really started with the supportive safety profile, and I would go back to the inclisiran Phase III data, which Medicines Company reported in 2019. And the safety data that they reported in that study across thousands of patients was pristine. And I think that's really what gave us the confidence from a safety perspective that we could take this technology into a much larger patient population. So from that point, you really started to see a change in our pipeline where we started to bring more things forward for common diseases. The other elements of the technology that we think could make it well suited for these types of diseases. One is the durability. So inclisiran was 6-month dosing -- we're looking at potentially up to 6-month dosing in our hypertension program as well. Really, what that gets you is much better patient compliance. And these kinds of diseases, as we'll talk about later, that can really make the difference in terms of outcomes for those patients. And then second point there is around plant pharmacology. We'll look at that in just a second, but we think the nature of that really potentially leads to better efficacy and safety outcomes for patients. And then just on the bottom right, it just highlights in our pipeline, the programs that are focused on prevalent diseases. I've already talked about hypertension. I'll talk a little bit more about our CNS program that's looking at Alzheimer's disease, and we've also got a program for type 2 diabetes that we'll read out later this year, top -- a Phase I study in ALN-KHK. So hypertension, just a little bit. I think everybody is aware, huge market opportunity, over 200 million patients with primary hypertension across the 7 major markets. The really challenging thing though is that 80% of patients with hypertension are uncontrolled. The biggest challenge we believe, is that patients don't stay compliant to the medicines, right? They don't stay on the products. They don't take them every day, and that really causes that percentage to be as high as it is. The other things that impact hypertension really are the quality of the control. So the variability in blood pressure control is a problem with existing meds as well as lack of nighttime dipping, and I already mentioned the poor medication adherence. So taken together, there's an opportunity to contribute to really improving outcomes for these patients with innovation, and we think zilebesiran has the opportunity to do just that. So zilebesiran is our program for hypertension. What's on the slide here to the left are the Phase I results that we reported out a couple of years ago and actually were just recently published in the New England Journal of Medicine, really impressive results at the highest dose that we studied in that Phase I study. We saw greater than 90% AGT knockdown and that translated at the highest dose into more than 20 millimeters of mercury blood pressure lowering. The other thing that I like on this slide again is that bottom left, and this is that tonic control concept, where you can see through the full diurnal cycle, that you're getting the consistent benefit from the drug. And that would look really different, I think, if we were looking at standard of care medicines. And again, we think that quality improvement in controlled blood pressure will be good for outcomes as well. And then to the right is the summary of the ongoing 2 Phase II studies that we've got for zilebesiran. Cardio I is a monotherapy study that we expect to read out actually this quarter. And really, what we're looking at there are multiple doses and dose regimens, and what we hope to learn from that, then we would take forward in further development. And then Cardio II is the combination Phase II study. That completed enrollment in June and we expect top line results from that in early 2024. And again, it's a combination study looking at zilebesiran in combination with an arb, a calcium channel blocker or a diuretic. So we recently announced a partnership for our zilebesiran program with Roche. And I would tell you that the primary reason that we did the deal was about accessing and partnering with Roche from a commercial capability standpoint. We felt like maximizing the value of the program, we were going to need that help. And so we really like Roche as a partner to do that. We like the fact that they've got the global reach -- but we also like the fact that they've got a history of launching highly innovative therapies in very competitive marketplaces and performing quite well. In terms of a summary of the collaboration, it's a joint development collaboration where we'll lead global development and U.S. regulatory activities. In terms of the cost sharing for the global development, Roche will pick up 60% of the tab, Alnylam 40%. From a commercialization standpoint, it's a co-commercialization deal in the U.S. So we'll have the opportunity to commercialize ourselves alongside Roche in the U.S. and hopefully build that commercial capability so that the next time we've got a prevalent disease program, we may be in a different position to make a different decision on going it alone. Ex U.S., it's a license deal where we'll get low double-digit tiered royalties on ex U.S. sales. In terms of the milestones that we can earn -- there was a $310 million upfront, but total milestones, including that upfront, could total up to $2.8 billion. So from an out-of-pocket perspective to take this program forward to market, which will include a Phase III CVOT, this deal really sort of minimizes our out-of-pocket contribution to that. And that was one of the other strategic rationales for the deal. It's going to allow us to invest more significantly in other areas of the pipeline. So last growth driver for the company is sustainable innovation, and what enables that? Human genetics is 1 thing that enables it. We have access to different databases that we mine for drug targets. We continue to work on RNAi chemistry that has delivered some interesting innovations recently. I mentioned IKARIA for TTRSc04 that may get us to annual dosing. Reversir year could be an RNAi antidote. We're developing a Reversir for our hypertension program. And then GEMINI is that sort of that disc concept where we could potentially target 2 genes simultaneously. And lastly, extrahepatic delivery. I talked about CNS previously, and I'm going to talk about APP here in just a second, but we're continuing to innovate beyond that as well. I think we have hopes to continue to expand the number of tissues that we'll target. We've also talked about interest in adipose and muscle as well. So just a little bit now on the CNS program, ALN-APP, which is designed to lower APP production at its source, and we're targeting 2 potential diseases here, both Alzheimer's and CAA. You can see on the right, some of the NHP data that we had that gave us encouragement to progress this program. So now we've got human translation and this was data that was reported recently in Amsterdam at the AAIC conference. What you can see is that we studied APP in the Phase I Part A of the study, single-dose study across 3 different doses, about 20 patients in the study. Rapid deep knockdown and durable knockdown. We got to 84% and 90% max knockdown and APP alpha and APP beta. I think maybe even more importantly, was the durability of that up to 6 months. We had median knockdown of greater than 55% across both biomarkers and I think with intrathecally delivered medicine having that kind of durability and infrequent dosing is really going to be helpful for us. So the Part A of the study is ongoing, the single dose. And we're now moving into the Part B of the study, which is a multi-dose portion of the study in Canada. The safety data has also looked very good to this point, including no abnormalities in any of the CSF data that we've looked at. That's APP. So last slide just highlights the goals that we've got for the year. I've touched on a number of these. I think from a pipeline perspective obviously, the big focus is going to be on patisiran. I mentioned that with the upcoming advisory committee as well as the PDUFA date. A couple of other things to take note of. We've got Phase I results that we expect back from TTRSc04 as well as ALN-KHK by the end of this year. And I mentioned zilebesiran phase -- the Cardio 1 data that we expect this quarter. And then lastly, a couple of updates that we would expect from our partners at Sanofi and Vir. And I think with that, that was the whistle stop tour. I'm done here. We've got just a few minutes for questions, I'm happy to take questions as well.

I really appreciate it. At this time, I'd like to extend the invitation for anyone from the audience if they had any questions. And I can certainly start first. We appreciate that you guys cannot comment on regulatory discussions regarding AdCom Prep. But previously, it had been mentioned that a lot of the focus is going to be on KCCQ and 6-minute walk tests. And so we want to get your opinion on how do you view the current cardiomyopathy landscape with some of your competitors, such as BridgeBio's most recent data release?

Yes. Let me comment on a couple of things. I think, first, as it relates to the AdCom, our expectation is the focus of the AdCom is going to be on the interpretation of our efficacy data. You mentioned the functional endpoint 6-minute walk as well as quality of life. A reminder that in 2019, the FDA issued draft guidance that enabled a pathway for heart failure drugs to be approved based on functional endpoints as well as health status endpoints. And so that really went into -- that's consistent with the design of APOLLO-B. And so our understanding of this [ wood ] is the first drug that might be brought forward under those draft guidelines. And so I think the FDA likely has some interest in getting some input from outside experts before they would move forward potentially for the first time under that draft guidance. So that's the expectation. I would say the preparation internally, as you would expect, a lot of work ongoing right now. I think the team is in a very good position. We're doing all the things that are typical that companies do as they prepare for advisory committees. I think the second question was about, likely about the BridgeBio results and how do we interpret that? And what does that mean for the space? I mean we've commented on our earnings call very good for the space, obviously, very good for patients to have options for treatment. And the data looked pretty good, right? Obviously, it was top line data. So we'll be interested to see more detail as they provide that at an upcoming conference. In terms of what does it mean for the category, I don't think it means a whole lot. I mean it's a second stabilizer and it's still sort of TBD in terms of how does that data compare to the Pfizer data. It's not clear to me yet that there's a huge amount of differentiation there. But we'll learn more when they present more data. But I think that's probably the impact is, it's going to be a second stabilizer and that's where the competition will exist, would be between BridgeBio and Pfizer and the stabilizer part of the market. We remain confident. Actually, the results of that study, I think, give us added confidence for HELIOS-B. I think there's been a lot of anxiety about whether or not milder patients under current standards of care, whether or not you could show a treatment effect in a study like this. Certainly this seems to address that risk and that concern. And so I think that makes us feel more confident about HELIOS-B.

Fantastic. I think we're out of time today, but thank you very much for taking your time to come to this presentation.

Thank you.