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

Welcome, everyone, to the second day of the 44th Annual TD Cowen Healthcare Conference. I'm covering analyst Ritu Baral. And welcome to the Alnylam Fireside Chat. With us this morning is CEO, Yvonne Greenstreet. Yvonne, thank you for joining us and squeezing this in before you have to hop on yet another plane in advance of all your data readouts.

So I was going to start with HELIOS-B because -- HELIOS-B. But you did have a release this morning on the KARDIA-2 data, a release that did not contain a single number However, everything looks good, and you did say that you were going to present the data at ACC. So looking forward to that data, but can you sort of go over what you have said holistically on the KARDIA-2 data to date?

Yes. No, sure. Good morning, everybody. It's a real pleasure to be here. And it's an even greater pleasure to be kicking off a fireside chat and talking about zilebesiran and so is the HELIOS-B. So thank you. It's a clearly hot off the press today with our release sharing very top line reports from our KARDIA-2 study. Now I'm sure most of you know that zilebesiran is our investigational RNAi therapeutic for treating patients with hypertension. And we think given the potential profile, this has a real opportunity to transform the lives of patients with hypertension, not just in terms of blood pressure lowering, but also in terms of [ tonic ] control. The KARDIA-2 study is a very important study on the step to bring this [ transformative ] program to patients. So the KARDIA-2 study is the second of our Phase II study with zilebesiran. And this study is assessing zilebesiran on top of existing standard of care. Our previous study K-1 was a monotherapy study. And what we were delighted to see were clinically significant additive reductions in systolic blood pressure on top of 3 important classes of standard antihypertensives, so diuretics, carton channel blockers and ARBs. So we are really pleased with the results, importantly also really encouraging safety and tolerability. It is really important in this indication, where you are potentially treating patients, millions and millions of patients around the world. So we're really pleased with the data. So sorry, we can't share any numbers with you. We'd have loved to, but ACC is quite restrictive about what you're able to say, and we've indicated -- we shared that we're going to be presenting more [ fulsome ] results at ACC, as you said [indiscernible], it's just around the corner. So stay tuned for that.

And this is twice yearly administration?

We're looking at 6 month administration...

And we did cover zilebesiran actually yesterday during the KARDIA panel with [ Dr. Pena ], and there were 2 things that emerged. One, she said that the minimum millimeters of mercury difference that she would need on top of standard of care to be meaningful would be 5 to 10, she wants to see 5 to 10. Does that sort of align with your market research and your medical affairs understanding of the definition of meaningful?

Yes. I mean we're really pleased with what we've delivered thus far. I think you've all hopefully seen the results from our Phase I study as well as KARDIA-1 in the monotherapy setting, showing reductions of systolic blood pressure of the order of 16 millimeters of mercury. So I think this is really encouraging. The other thing I'd also add is that from a regulatory perspective, what we have to deliver is a reduction of 5 millimeters of mercury with systolic blood pressure. So we're obviously progressing with the program. Next up is KARDIA-3. We're delighted that we have kicked off that study as well. This is a really important study because it sets us up for the cardiovascular outcomes study. This study is looking at patients who have uncontrolled hypertension on top of 2 or more standard antihypertensive treatments. So that, again, is important, but also patients with -- who are at risk of cardiovascular disease. So this is the kind of population that we're going to be looking at studying in our cardiovascular outcomes trial. And the K-3 study, the KARDIA-3 helps you derisk of that, so we can march into doing a cardiovascular outcome study with confidence. This is a really important program for us.

So 2 things. Dr. Pena mentioned that one of her concerns around this program was the long-acting nature of the blood pressure reduction. But you did say that safety has been good. So we're not -- we shouldn't be expecting any signals of [ hypotension ] unmanageable [ hypotension ] or severe [ hypotension ]?

No, we're not concerned about [ hypotension ], but we do recognize that it's going to be on prescribing physicians' minds. So we're also progressing an agent called REVERSIR, which can be administered if physician's are at all concerned about hypertensive episodes. But even if patients have an episode of hypertension, these are easily managed in the clinic with pressors and fluids, et cetera. So I think it's more of a theoretical concern than an actual concern at this point in time. We're really pleased about the safety profile thus far.

And KARDIA-3, that is a 3-month endpoint, primary endpoint, I believe?

It's a 3 and 6 months endpoint...

3 and 6 months endpoint. Okay. So the data will be at 6 months. Wonderful. So that is the zilebesiran data -- news from this morning. Let's move to HELIOS-B now. I mean, the biggest question -- one of the biggest questions we've gotten around the updated HELIOS-B SAP, where you now dual -- essentially dual primary endpoints, the composite -- well, dual analyses, composite outcome of all-cause mortality and recurrent CV events in the ITT overall population and then the monotherapy population sort of the 60% of patients not at baseline. Why now? People are convinced you've seen the blinded data, and you're seeing the event rates, and it's not what you're hoping, and this is why. Has anybody at Alnylam seen the event rates?

So here's the thing. We are confident in the outcome of the HELIOS-B study. We are confident that we vutrisiran is going to deliver benefits and outcome to patients in this study. Now we made these changes because we saw opportunities to optimize the probability of success as well as deliver robust and competitive profile for vutrisiran for patients with cardiomyopathies. I think it's really important to kind of emphasize that and also be recognized that it's an incredibly important study for the company, but also for patients. And I think most people who've sat down and thought about the changes that we've made have said to us, well, yes, these are really logical changes. I mean they make a lot of sense. And the question has been, well, why did you make the changes at this point in time? But if you think about it, we don't want to be doing is coming up with incremental changes over the course of the study. So what we wanted to do, we indicated to everybody that we may well make tweaks up until database log. And what we wanted to do is really assess all the information that we're going to have on this study. And really, the most important information in our mind is building on the foundation that we already have with RNAi therapeutics. And APOLLO-B was a very confirmatory study for us. It really encouraged us about the likelihood of success of HELIOS-B, and we've been able to not just share the 12-month data and the 24-month data from APOLLO-B, but we obviously continue to assess these patients. We've also been informed by other studies in the field. So we wanted to take all of that information. It's also important to us that we align with regulators, not just the FDA, but other regulators, around the direction to travel. That takes some time. So announcing these changes at our last earnings call was in the sweet spot between understanding all the information we're going to have, aligning with the regulators, but actually affecting the changes prior to database lock. So that's...

So really, it was APOLLO-B.

That's -- that was the primary set of information that helps us decide on the changes that we were going to make. Now you talked about blinded event rates. We -- all companies -- I mean we obviously have a small team inside the company that...

Not you.

Not me. No, not me. That assess blinded event rates on an ongoing basis. And this is important because it allows them to monitor data quality and ensure that we have data integrity at the end of the study. And I think what we've demonstrated to you kind of in our track record of [ delivering ] successful studies that we pay a lot of attention to how -- not just the design of our studies, but also the execution of our studies. So the real driver for making the changes was APOLLO-B. I think it's also -- people get very engaged in kind of blinded event rates, but they're actually hard to interpret. That's very hard to interpret. If you've got a high blinded event rate, what does that mean? You've got lots of events or maybe your drug is not working? And conversely, if you have low event rates. So we've made these changes now. We're very pleased with the changes. Obviously, our focus is on delivering a successful study here. And I tell you, we can't wait to open that envelope end of June, early July.

And how much did the BRIDGE trial inform this as well, just given the similarities in population?

So look, kind of -- we've talked about it. What you want to do is you want to have access to all the information that you possibly can around the population that you're studying, the specifics of the disease that you're studying, to make sure that you're as fully informed as you're ever going to be before making decisions. So obviously, everything is brought into consideration as we -- and we didn't make these changes because we woke up one morning and felt like it, right? This was a very thoughtful process.

How much more confidence do you have in the data given the additional 3 to 6 months? I mean how many more events is that tail end going to capture? Should we simply think about it as 10% more because it's 10% longer? Or is there like a tail...

So look, I don't think it's kind of me to speculate on specific percentages, et cetera. But I think the important takeaway here is that TTR cardiomyopathy is a progressive disease. So the longer you observe patients, the more events you're going to see and kind of extending that duration, so the changes, the database lock is going to happen for the last patient at month 30, now it's happening at month 33, which means many patients are getting an extended period of observation, many of them out to 36 months, to be honest. It is actually the longer study that's been done in TTR cardiomyopathy. And what happens at the tail end of the study is actually that's where you start to see the most events occur and that's where you start to see the greater separation between active and placebo. So we do think that the extra 3 months is actually meaningful. What percentage that leads to, I think, is speculation.

But it should be weighted. It'll be weighted.

It will enhance the power of the study, yes, absolutely.

But I'm sorry, it's not speculation because the biostatisticians are constantly making...

Yes, but we're not going to speculate with you.

Fair enough. I mean, I guess, are we thinking about it the right way, for the -- basically, to the same point, these events do tend to be later weighted as patients progress, and there's a richer sort of event rate. But also, as you think about the Taf drop-ins, you're also giving Taf some more time to work. So how do you sort of think about [ balance ]?

Actually, I think we've got tailwinds with respect to Taf. Recall, we were assuming 50% of Taf patients at baseline. We ended up with only 40% of Taf patients on baseline. We've also talked about kind of very low numbers of Taf drop-ins, and that remains the case. So I think from a Taf perspective, we actually feel we've got more tailwinds here in the study than we'd anticipated at the get-go.

How are you going to report top line data right now? I mean so you have variable follow-up by patients, so the curves will -- at least towards the tail end. Is there imputation of data out to [ 33 ] weeks? Is the hazard ratio going to be an event rate?

Yes. So look, I mean what we've said is, at this point in time is what we're going to communicate is, what we generally communicate, which is P values for the primaries, secondaries and obviously, importantly, information on safety. We've also said that we will present some information on subgroups. I don't think we'll be particularly interested in seeing the Taf subgroups. So we will be presenting some additional information that, at this point in time, that's the information we've committed to sharing...

That's the information you've committed, leave yourself open to potential of [indiscernible].

I mean, I'm -- again, I'm not going to comment on that. I think what I am going to say is...

But you're not saying no...

That's a -- you never say no, right? You always reserve a right. But I think, look at our historical practice, we're quite disciplined about what we share in the top line because it's really important that we're able to get data reviewed in important medical congresses. At the end of the day, you're a very important stakeholder here. But incredibly important, from a patient perspective as to make sure prescribers are able to get fulsome information in a timely fashion. So we will be looking for the most proximal meaningful cardiac congress after top line...

So if we look forward to that, potentially ESC, at that point, how is the data reported? This is a question I've gotten from investors. How will the data be reported given the variable follow-up? Is it normalized? Is it...

I think we'll wait until we have the data. And then we'll obviously prepare the data for presentations, not just either press releases or engagements with the Street, but also the specifics of what we present at an upcoming congress.

So what [ effect size ] are you hoping for? What's the -- as you think about the landscape, as you think about your focus on monotherapy, what's the [ effect size ] you need?

So look, I mean, look, here's the thing. This is an outcome study. And if you speak to patients, physicians, regulators, when it comes to outcomes, these are really meaningful endpoints for all those constituencies. So we would be delighted if we're able to show a benefit and outcomes of vutrisiran in the study. And if we do that, we feel very confident about being able to bring this medicine forward to patients.

Do you need to -- do you feel like you need to show as much as acoramidis did?

Again, I think it's not the right time or place to make comparisons with competitor studies. If we deliver positive outcomes in the study, I think we really set up the foundation for a successful vutrisiran launch for patients with TTR cardiomyopathy.

Have you had any conversations with FDA on what they're thinking, especially after that last AdCom, right, where Norman Stockbridge got up and said things outside of statistics, any communication on what they're thinking as far as minimal separation?

So I think, again, this being an outcome study, it's a very different situation to a study that was a 12-month small study. It was really focused on endpoints of how patients function and feel, so KCCQ and 6-minute walk test. And these are endpoints that there can be conversations around what is the magnitude of clinical benefit that you need to see for this to be a meaningful medicine. I think with outcomes, that's really not a factor here. I think it's also important to recognize that, whilst there is existing treatment out there, with tafamidis, 75% of patients continue to progress onto [indiscernible]. There's a real need for additional therapeutic intervention here. I think that level of unmet medical need I think is going to be very important in helping physicians understand in how they can best treat their patients.

So yesterday, on the cardiac panel, we pressed Dr. [ Gagan ] on that, the percentage of patients progressing. Just first -- for those of you who are in the doorway, there's actually some room over by the sound booth, if you want to come in and stand here with good audio and visual, just come on in. The 75% that you mentioned, the progressors, where did that come from? Is that sort of a real-world database?

So it comes from a variety of sources that we've triangulated to come to that number. And I think as time progresses and more publications are brought to bear, I think that number will become more recognized within the community.

I'm trying to reconcile what I heard on this panel, this cardiac panel, with what I heard on our fall cardiac panel, where we had a doctor who basically says, if you start -- forgetting now who it was, maybe, Anvita, you can help me. But he basically said, if you start patients on Taf early enough, they are stable, they don't progress. And then our doctor yesterday said the exact opposite. She said -- I asked if they progressed in 5 or 10 years, she's like, no, Taf hasn't been around for 5 or 10 years, it's more like 2 to 5 years. So...

So here's the thing. We're innovating in TTR. This is a relatively new area of understanding. I think all the studies that we do, us and other companies, they're all beginning to inform how people think about the field. I mean I just think about the [ epi ]. When we started on this field, many people thought they were like 60,000, 70,000, 80,000 patients with wild-type TTR cardiomyopathy. Now people are talking about 300,000 or 400,000 patients. So I think this is a field that's going to continue to evolve, and we're going to continue to improve our understanding.

[ Anderson Gil ], my favorite topic, statistics...

You and me together.

I know. So awesome. Does it reserve any alpha for the secondaries? You're splitting the alpha between the dual analysis.

Yes. So I mean I think the way to think about the study is that if we achieve a P value less than 0.025, okay, in any one of the 2 populations, so either mono or combo the studies, if we achieve a P value of less than 0.05 in both those populations, then we start to progress down the hierarchy of secondary endpoints. They will be assessed and power in both the monotherapy, patient population and the combination patient population. And that's the best way to think about the secondaries. I do want to make a couple of points about the secondaries, whilst we're on that topic. I mean I'm sure you've noticed that actually we've improved the stringency, if you like, of the secondary endpoints that we're going to be focused on in the study. Now clearly, a number of other endpoints will be exploratory endpoints, all that data will be available. But we've really focused on what we believe is the most clinically meaningful endpoints here, also the endpoints where we believe that we'll see differentiation. So if you look at the data that we have shared from APOLLO-B, particularly the 24-month data, you'll see that really what RNAi therapeutics are able to do for these patients is actually stabilize disease. I think that's going to be very important to physicians and patients. So we're focused on those kinds of endpoints. We've included NYHA class as well because that's an important measure of progression for both patients and the physicians. And again, an endpoint where we believe will show a differential benefit.

So the streamlining of the secondaries almost seems like there was the hand of marketing behind it, in the sense that you could really start talking to patients about how it might make them feel better because, again, from the panel yesterday, we had an expert who said she would go right back to proBNP. She wants to see the echo measures for her as a TTR specialist. That's what's going to drive her assessment of a stable Taf patient. Because if her echos show thickening, that's not stable, and she wants to put them on maybe a silencer.

So I mean the important thing to say is it's kind of actually just reiterating what I said already, which is that we focus the secondaries on what are the most important, clinically meaningful endpoints. But of course, we'll have all the data that you're talking about like NT-proBNP et cetra, et cetra. I think what this also speaks is there's is a real need as this field evolves, to have more consistent kind of guidelines as to when to treat patients, how to treat them, how to assess progression. And that's clearly something that we're going to be contributing together with experts in the field to help get a -- because at the end of the day, this is about patients, right? And it's quite clear that the earlier you treat patients, the better they do. And actually, the earlier you treat patients with the most efficacious intervention, the better you do. What was really striking to me from the APOLLO-B 24-month data, how many of you are familiar with this, but the patients from placebo crossed over onto active treatment with vutrisiran. And whilst the addition of vutrisiran helps us stabilize their disease, they never get back to where those patients who started on vutrisiran are. So there really is something very important here about educating physicians, making them aware of the disease, so that the patients can actually get the treatments that they need in a timely fashion.

Sure dealing with clinicians is relatively pleasant, but what about the payers? What -- have you talked to them about what they need to see to not implement crazy step edits, crazy clinical record requirements for the step edits to silencers. Have you had conversations about potential combination use even if you are focusing on monotherapy?

So look, as we've sat back and looked at the evolution of this marketplace, it seems pretty intuitive to us, and it is backed up by some research and engagements with peers, and actually our historical context with respect to treating mixed phenotype patients that payers are going to be very sensitive to cost. And the cost of combination therapies is quite significant. So I think it's going to mean that there's going to be payer sensitivity in managing combination use. Now we believe that vutrisiran has got -- shown additive benefits on top of tafamidis. But we also recognize that it's going to be challenging for payers to pay for widely expand the market, which is what's going to happen with cardiomyopathy, but also increased cost. So even in the current situation where we've got non-overlapping labels with Taf, when you think about the mixed phenotype patients, there are actually restrictions around combinations. So we do believe that up until Taf patent expiring, it is going to be primarily a monotherapy market. And we believe that vutrisiran, if it delivers on the profile we expect, will be first-line monotherapy. We'll also see switches from agents to vutrisiran. We've seen that in polyneuropathy in Europe. And there'll be some limited combination use.

And AMVUTTRA, we'll be positioned for in-office delivery, so it would be a Part B question?

That's correct. And also, we are providing services that allow patients to receive therapy in a home setting. So it's a very flexible approach to allow patients to either receive therapy at home or in the office.

And one of the things that does tend to help with payers is the updated guidelines we talked about, potential guideline updates. Is there anything in the works, what with the PDUFA for acoramidis coming up, or anything that you know of in the works for updating TTR, either management diagnostic guidelines from the medical associations, that could be helpful or impactful...

Most of the guidelines in the works are focused on you have to diagnose patients because there's only been kind of one treatment available. I think when we see the introduction of additional treatments, I'm sure there will be guidelines that start to emerge that actually help physicians understand the context to treat patients.

I've left 4 minutes for the rest of your pipeline...

[indiscernible]

I know. [indiscernible] here will be throwing things at me right now. APP, you -- your Phase I Part B recently got the FDA clearance on that partial clinical hold. Can you tell us how you're progressing in this trial now both in the U.S. and ex U.S. sites? And is MAD data still guided for late 2024?

So we're absolutely -- look, I am -- I'm so excited about the potential of RNAi therapeutics to help patients with new degenerative diseases that there's just a huge unmet medical need. I think the important thing about APP that I just want to emphasize is that, with success in APP, it starts to open up the whole vista of our platform being able to address the needs of patients with new degenerative diseases. Now we were delighted that the FDA have allowed us to progress into multi-dose studies. And whilst we're not fully off clinical hold, the doses that the FDA are supporting are well above what we plan to use going forward. So we're already progressing with the multi-dose portion of the study, Part B, in the U.K., Netherlands and Canada. So that study is up and running. And obviously, we can now include U.S. sites as well. So we are still committing to data from Part B of the study later this year. What I do want to say that I'm really excited about is also kind of initiating Phase II for patients with cerebral amyloid angiopathy. I think that's another indication for people to spend some time thinking about.

2024 start, or will that be next year, the Phase II start?

Yes, 2024.

2024 start. And I have left you a very generous 90 seconds to highlight your favorite children from the rest of the platform, including -- I mean, you have like 10 cardiometabolic...

I've got loads of favorite children. Look, I think, the other exciting thing to say is that we really are spring loading the pipeline for growth. I know a lot of the focus is on TTR right now, and I absolutely get that. But we're going to be doubling the size of this pipeline by the end of 2025, just so much more potential for our RNAi therapeutics to help patients in a wide range of diseases. I think maybe just to focus on the upcoming opportunities. So we've already talked about zilebesiran, so look out for those data. We talked about APP, look out for those data. KHK, look out for those data. We don't often talk about partner programs, but actually Sanofi have guided that they will be filing an NDA for vutrisiran for patients with hemophilia sometime in 2024. And obviously, there's an economic benefit to the company there, but also, I think just bringing RNAi therapeutics to another group of patients, those with hemophilia A and B, with or without inhibitors. So, excited about that, too.

Great. We are exactly at time. Thank you, Yvonne. Thanks for the time.