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

Okay. Great. Good afternoon, everybody. Thanks for joining us. Welcome to the Bank of America Healthcare Conference. I'm Tazeen Ahmad, I'm one of the senior SMid Biotech analysts here. It's my pleasure to have our next presenting company with me here on stage from Alnylam Pharmaceuticals. We've got Jeff Poulton, who is, of course, CFO; and also Eric Green, who is SVP and Head of Development Programs. So Eric and Jeff, thank you for making the trip out West.

It's great to be here. Thank you.

So we usually ask everybody to give a 2-minute overview of their company, and then we go straight into Q&A. So I'll let Jeff take the honor of describing Alnylam in 2 minutes or less. .

Okay. I'll do it. I'll take you up on 2 minutes. So we're the world's leading RNAi company as a whole new class of medicines that we pioneered over the last 20 years. Over the last 5 years, it's gone from being an R&D-only company to now being one that's got fully integrated biotech 5 medicines in the market, 4 of which we're marketing and selling ourselves, a fantastically exciting pipeline that we're looking to diversify into some prevalent diseases and not just rare diseases as well as new tissue types. I think we'll have an opportunity to talk about those things today. We just presented our Q1 results last week, which were very good. Top line results are strong for our latest product launch for AMVUTTRA. And again, I think we'll have an opportunity to talk about that and lots of exciting things to come over the course of the year.

Yes, there's a lot going on, as always, at Alnylam. So maybe we can talk about as our first topic, let's talk about AMVUTTRA. So maybe, Eric, I'll direct the question to you, and you can always step in, Jeff. How are you thinking about the early metrics of the launch? It looks like there is an audience that's building up fast for AMVUTTRA. How does that dynamic play up against the market that ONPATTRO has been building? And where do you kind of see the two drugs going over the next several quarters. .

Sure. I'll be happy to take a first start, and then Jeff can always add in. Obviously, ONPATTRO was approved back in 2018 was the first-ever siRNA treatment, specifically for hereditary ATTR amyloidosis in those patients with polyneuropathy. The product has done very well, very steady, continuous growth into over 2,000 patients treated worldwide by the early part of last year. AMVUTTRA, that was our follow-on product utilizing our next-generation delivery technology, the GalNAc technology, which allows for a quarterly subcutaneous dosing administration. The two pivotal studies, APOLLO for ONPATTRO patisiran and HELIOS-B showed nearly overlapping efficacy profile. So what you really see is a profile in AMVUTTRA that has nice safety great efficacy and a more convenient dosing profile. So in -- since approval in June of last year in the U.S. and more global approvals in the later part of last year, we're seeing a lot of very natural and organic switches from ONPATTRO over to AMVUTTRA. And maybe, Jeff, do you want to talk about some of the numbers from this last quarter to that point.

Yes. So in markets where both products are available and it's been available, AMVUTTRA longest in the U.S., so it's been 3 quarters now. I would say new patients that have been initiating therapy since we launched AMVUTTRA, almost all of them are starting on AMVUTTRA and then the switch from ONPATTRO, I'd say after 3 quarters in the U.S., 2/3 of the patients or thereabouts that were on ONPATTRO when we launched AMVUTTRA have now switched or are in the process of switching. I think we found the same thing in Japan, where we launched in Q4, end of last year. It's actually happening even more rapidly there in terms of the switch. So about 80% of the business is switching which is a really good thing. I think from our perspective in terms of how the product is -- the patients are viewing the product. Obviously, from a competitive standpoint, as you move forward, it's nice to have the patients on the quarter subcu. I think the thing that we're trying to educate the market on is when you think about the performance of the TTR business, you really need to think about it on a franchise basis now. And really need to look at the total revenue across those 2 products compared to prior periods. And we don't gain revenue from switches because the value of the patients is the same. So what we're really interested in is the growth of the overall pie. And AMVUTTRA, without question, is growing, increasing the growth of the business. If you look at the U.S., so again, 3 quarters on the market, each of those quarters on a year-over-year basis, the U.S. business has grown more than 70%. So it wasn't an initial bolus where we saw it in the first quarter and then it dropped off. It's sort of been sustained. And ONPATTRO was probably growing in the mid-30s on a year-over-year basis before AMVUTTRA. So we're excited about that. There's a number of reasons why we think it's sort of expanding the opportunity, but a very good start. .

Do you think both will coexist going forward? And who would be the patient population for..

I think based on what I just described, I think what my anticipation is that over time, where both products are available for PN, it's going to be an AMVUTTRA market, right? Yes, there will be some that may stay on ONPATTRO, but we're not even actively working to get the patients to switch, right? That's happening naturally. So again, in every 3-week IV compared to once a quarter subcu and Eric talked about the efficacy and safety profile. In my mind, that's an easy choice, and we're seeing patients make that choice. .

What is the patient population that's initially getting on this? And how do you think about moving into presumably, you have room to move into earlier lines?

Yes. I mean I think what we're seeing in terms of why the U.S. is picking up growth. It's -- I think we're seeing signs of younger patients, maybe less severe patients, right, where the burden of treatment for an IV was probably they were holding off. We're seeing switching although that's more of a -- from other therapies, not ONPATTRO. That's more of an issue outside the U.S. where tafamidis is on the market in the hereditary PN part of the market. There's not a lot of patients in the U.S. on the Ionis first drug, TEGSEDI, right? There's a little bit of that switching, but there's not much there. But the other thing that we're seeing is just an expansion of the prescriber base. There's more physicians that are willing to prescribe the products. So we've seen a 30% increase or thereabouts in 9 months. And so more of the community-based physicians that we're seeing that are willing to prescribe it. So that's really what's driving the expansion of the opportunity, we think.

Okay. This is jumping ahead a couple of steps need to happen first. But as you look to AMVUTTRA and its potential second indication for cardiomyopathy, how do you think about the pickup that you're seeing for it now and what that might mean to make it easier later for that indication? .

Yes. I mean, I think maybe thinking about the cardiomyopathy progression, right, that we're hoping to see is that patisiran we get approved first, and we would be launching ONPATTRO in the cardiomyopathy indication later this fall, right, kind of October 8, PDUFA. And given the label, the expectation from a commercial perspective is that there would probably be 2 segments that would be driving demand for uptake for ONPATTRO in the cardiomyopathy population. One is patients that are not adequately responding to the existing therapy in the market and then the second are patients that can't access it for a variety of sort of out-of-pocket reasons. And so we think that will drive the initial uptake. I think we'll get some good experience with that. But then AMVUTTRA, HELIOS-B early next year. So sort of fast forward to the end of '24, early '25 hopefully, we'd be launching there with a very different label, right? So an outcome label, which, from a competitive standpoint, is really critical. And then given the convenience profile that we talked about, that's the drug that we think in our portfolio has sort of that potential best-in-class kind of profile that would really long term potentially drive a lot of revenue growth for the company. And that's sort of how we think about it.

Okay. So speaking of patisiran in cardiomyopathy for the APOLLO-B study, I believe you do have -- you've announced that you're going to have 18-month data presented at ESC later this month. Can you just kind of set expectations on what that data is and what it means?

Yes. See, the original APOLLO-B study or VA APOLLO-B study had a 12-month double-blind portion. So patients were randomized to either placebo or to patisiran. At the end of that double-blind portion, patients were offered the ability to continue with open-label patisiran treatment. So patients on patisiran continued. So you would expect to see how those patients do with another additional 6 months of treatment on patisiran. . And importantly, the placebo patients have the opportunity now to initiate treatment with patisiran. So ideally, you would see and we saw this at least in a polyneuropathy side in the original APOLLO study, placebo and mNIS of the neuropathy impairment score showed very marked progression over the 18 months of the original APOLLO as those patients on placebo switched over to patisiran kind of halted that progression. . So that may be a very extreme view of what you may see, but that idea of looking at the trends of how those patients did for the first 12 months and then how do they do with this additional 6 months. And hopefully, you would see something a little bit different in the placebo patients than they had previously been doing. .

Okay. And you've also chosen to submit that data to FDA. Did they ask for it?

We've only stated that we have submitted the data, and we don't often get into the details of our back and forth with the agencies.

I guess what additional benefit do you think that could provide on a label by having 18 versus 12 months?

Unclear if it would have much of an impact on the label. Obviously, you lose your comparison to placebo. But it does give us longer safety follow-up. It does give us an idea of how the efficacy that was shown in a pretty short study for heart failure, 12 months is a very short study. This gives the FDA and others a chance to see how those results continue to progress or not.

So as you think about preparing to hopefully launch in this indication for patisiran, what feedback have you gotten from your physician checks on what makes this an attractive option for them?

Yes. Maybe Jeff?

Feedback we've gotten is very good. I mean I think I would start with the fact that there's still unmet need in this disease, and we hear that from physicians. So the opportunity to have something else, right, that they could use to treat these patients. I think they find -- they're hopeful for that. I think probably a couple of things that we hear about the data. One is that sort of stability, right, in the 6-minute walk, I mean, the climb that we saw in the drug arm was very close to what you would see in normal healthy adults. And so that's sort of encouraging. I think the KCCQ, you saw again stabilization. So that concept of stabilizing in a disease where it's sort of constant progression I think, is encouraging. And then the consistency of the results across the study. So in addition to 6-minute walk and KCCQ, some of the BNP, troponin, the biomarkers also trended positively. The scanning data, which was really interesting, right? And then the safety data, particularly the cardiac safety data that trended favorably in the direction of the drug arm, which is really almost a sort of another efficacy measure. All of that, again, the consistency of it across the measures of the study in a 12-month study with 1/4 of the patients on background tap. I think, it is encouraging to the physicians. That's what we've heard. .

Would you need to make any tweaks to your sales force in order to market this indication?

It's a competitive space. So we're not going to give specifics. I mean, I think over time, given the much larger market opportunities, there's going to need to be incremental investment here to sort of fully cover the space and maximize the opportunity. But we're not prepared to get into specifics of exactly what that means yet. .

Okay. So maybe let's move on to some questions on vutri, on vutrisiran. So we just talked about APOLLO-B, but probably most anticipated next study for Alnylam arguably is HELIOS-B. You've guided to data in early 2024, which by Alnylam's calendar is obviously through June 30.

Q1 or Q2.

Got it. So maybe just as a reminder, what should we be expecting to see that top line data readout and then we can go into some more details.

Eric will take that one.

Obviously, we have quite a precedent, fortunately, of reading out top line results from our pivotal study. So we would expect something similar p-values on the primary and secondary endpoints and some summary of safety. But we, as our practices, hold back a lot of the detailed data until we have a peer-reviewed medical conference.

So just remind us what the differences are between APOLLO-B and HELIOS-B in the choice of primary and secondary endpoints because that's important as well. It's different molecules, but also different endpoints. .

Different molecules, but we had the fortune of having these 2 different molecules in our own portfolio. So when we were making decisions about how do we enter into this cardiomyopathy market, we had a product at the time, shortly after ONPATTRO was first approved with a known safety profile. And remember, vutrisiran at that time only had Phase I data in a relatively small number of healthy volunteers. So we had a kind of a two-pronged strategy. Fast to market with a known product, patisiran. That's what led to APOLLO-B with a short 12-month study with a 6-minute walk functional end point. And then with high hopes for the profile that we would see with vutrisiran, which has since been borne out, we went with -- we thought that could be ultimately the market leader, a best-in-class product. That's where we invested larger study. It's a 30-month to 36-month outcomes-based study. So similarities, differences, similar patient populations are intended to be enrolled in both APOLLO-B and HELIOS-B, some slight differences. But the key thing is APOLLO-B was short and very aggressive. HELIOS-B is about twice as big, almost 3x as long with a very critical outcomes, composite outcomes measure, which we think will be important for competitive nature in the market. .

Yes. So let's maybe talk a little bit more about that competitive dynamic because it appears that a lot of folks think that ATTR-CM is a valuable area to be in not just Alnylam. So if we talk about the competitive landscape, some of the other companies have made decisions to upsize their studies, delaying the readout of those studies in order to increase the chances of having presumably a statistically significant results on the primary outcome of mortality benefit. You guys have been pretty steadfast the entire time that you feel that your study size is rightsized and that the 3x longer length of the study relative to what you looked at for APOLLO-B is sufficient. So Maybe, Eric, can you give us a little bit more color on why you are confident on that, just given the fact that other companies who -- it's hard to make an apples-to-apples comparison, obviously, but other companies have chosen to mitigate some of the risks that they might see primarily because patients are being diagnosed earlier now perhaps than they were before. .

Which is the earlier diagnosis is always a great thing for patients, right? With a progressive disease like this, you want to find these patients early and hopefully intervene. We are making decisions on the design for HELIOS-B back in the day when attracted read out. We knew what the patients looked like that they had enrolled and we knew what the subgroups looked like. So that was a knowledge all companies, frankly, had at that time to make decisions. We intentionally defined inclusion/exclusion criteria to essentially exclude the worst of the worst patients. So those kind of NYHA 3 patients that we're unable to walk very far and we're likely to be very challenging to help in any way. So we intentionally went for a slightly milder patient population, but still required to have symptomatic heart failure. So I think, yes, ideally, the broader field is finding and diagnosing patients earlier, but they still had to be symptomatic heart failure patients to enroll in our studies. We accounted for -- as spokes on HELIOS-B up to 50% of patients could come into the study already on tafamidis. And therefore, we took that into account as we did the powering for the size of the study to be able to show the type of difference in the outcome composite endpoint we would hope. We operationalize that and actually came in under that percentage. Another thing we did is, track was at 30 months, they did their primary endpoint. We are going to evaluate once the last patient enrolled hits 30 months. But all patients prior to that can stay on the double blind up to 36 months. And because it's a composite endpoint that's looking at events, we have those additional 6 months for a majority of patients to be able to gather additional events and therefore, increase the power. I think the third thing I'll note is we actually overenrolled the study and it enrolled much quicker than we expected, and that's why the time between APOLLO-B and HELIOS-B is frankly a lot closer than we were expecting. So we actually get a little bit of power there by that roughly 10% increase. Some of the competitors we know has increased and changed their studies on a number of times based on the public statements I've read about that, initially, they had a much shorter follow-up, so they weren't going out to 30 months. So they first extended that study to get closer to what we are looking for. They've also, I think, didn't have the operational controls that minimize tafamidis at baseline. I've heard possibly that was very close to 100% at 1 point. So they're increasing the size of the study is really to try to dilute out that confounding effect. So I think we feel confident that we took into account all the information we knew at the time. We executed the study very well. We know the patients we're intending to enroll. And that's why we've stuck with the design as it is.

Anything to add, Jeff.

No. I think you've covered it real covered it very well.

In terms of safety, presumably, there are regularly scheduled safety check of the study..

There's an independent data monitoring committee for that.

So there is a -- and how often do they take those blinded looks at safety, is it blinded? I am assuming.

I think for the DMC, it can't be unblinded if they request that. I think those are generally quarterly meeting.

Quarterly. Okay. So as we approach the readout of the study, I think people are thinking about how to figure out what the -- what good data would look like. So is it simply that you have a statistical -- statistically significant benefit on mortality or do some of the secondary endpoints that you're going to be looking at also matter. Maybe you could share what doctor feedback you have on that.

Obviously, a primary endpoint of success and statistically significant would be something that would be necessary. We've been fortunate in all of our other studies that have a lot of consistency, and Jeff mentioned this in the APOLLO-B with other secondary and even exploratory endpoints. So, the more consistency you see across different measures of this disease, I think that would be a very welcome thing by the outside.

And what about the group of people? You said you had an upper limit of up to 50% of people could be on background TAF. Would there be analysis that could be done on those patients who are on background TAF to kind of provide a better sense of what the profile of the drug would be. .