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

With me is Pushkal Garg, the Chief Medical Officer; and Rena Denoncourt, Head of the TTR program, and we're all reminiscing over a great dinner we had last night. So with that, everyone knows the story. There's no need to really set the stage. I think it would be good to talk about TTR and maybe relitigate a little bit of our conversation yesterday.

Just related to sort of Helios-B what you're observing in the trial in terms of event rates and what Alnylam's reaction is to a competitor study for Ionis and AstraZeneca functionally being now twice the size because what they're saying is they need that for powering based on how the disease has changed. What's your confidence in your trial and your reaction of what's been going on?

Yes. Thanks, Paul. Thanks, first of all, for inviting Alnylam here. We appreciate it, and happy to be here and seeing all of you. And so maybe I'll just start with a couple of points. As everyone knows, we're progressing a series of molecules to treat patients with ATTR amyloidosis ONPATTRO, approved several years ago for the polyneuropathy and AMVUTTRA earlier this year, and we can talk a little bit more about how that launch is taking off. We're very excited about that. And then over the summer, the APOLLO-B results with ONPATTRO or patisiran in the cardiomyopathy population. And I guess what I'd say to start to answer your questions are that we were really excited about the results that came out of APOLLO-B. I think, look, this was something we were talking a lot about for the first half of this year.

You were?

Yes, with you and everybody else. And I think the results were, frankly, amazing for -- I mean, you have to remember, this was a really small 360-person heart failure study, and just a year long. And in that data set to see benefits on near-term indicators like the 6-minute walk test and the KCCQ with evidence potential of stabilization of those parameters, favorable signals in terms of numerical differences in mortality and outcomes, a compelling safety profile where actually some of the cardiovascular events have trended in favor of the drug, all that portends well for the longer-term HELIOS-B study with vutrisiran. You want to -- people want to compare this to what the Ionis AZ studies. I would just point out that compared to APOLLO-B, where we saw all of these signals of efficacy, HELIOS-B is twice as large and 3x longer, right? And so that's the comparison I would make. And so our teams have been looking in -- at the data, the enrollment population is more or less the entry criteria are very similar between the 2 studies. And we feel really good based on what we're seeing coming out of APOLLO-B that HELIOS-B has been designed well, it's being executed well. And so we're very excited about it. We don't anticipate making any changes to the study design at this point.

Okay. Do you -- what can you say about your monitoring of blinded event rates in real time?

Yes. So I mean, as we've said for all of our clinical studies, we have teams of people whose accountability is to ensure that the ongoing conduct of the study is robust that the data -- they look at data integrity, and they monitor event rates. It would be a bad form from a clinical development perspective to do anything other than that. And so that happens in the background, absolutely.

Okay. And so the decision to not do an interim, nothing really to do with this broader conversation related to TTR, patients identified earlier, takes longer for events to crew that doesn't relate to that?

No, not at all. Rene, do you want to touch on that?

There are multiple things that came into play in that discussion. And certainly, the positive APOLLO-B data gave us greater confidence in the readout of HELIOS-B. But we really want that study to be able to provide that best-in-class product profile for AMVUTTRA. And the best way to get that is by running it all the way to fruition with the endpoint at the month 30 after the last patient in. I also think that we don't want to take any unnecessary risk to that study. And really the timeline benefit was minimal and the timeline to that eventual readout in early 2024 is right around that corner. So we're very much looking forward to that and thought that, that was the most prudent thing to do with the program.

Okay. Great. So let's switch gears to the APOLLO-B approvability, controversy. Is controversy the right word?

Definitely not.

Controversy to some people. Maybe just take a step back and can you give us a little bit of historical context on the work you do with the FDA to design the study, the evolution of 6-minute walk as a potential registrational endpoint in heart failure, and kind of as now you finalize [indiscernible], your level of overall confidence that this data is good enough to expand the label?

Yes. So yes, it has become an interesting sort of objective conversation out there, which kind of ...

I like objective conversation better than controversy.

That's taken on a life of its own. Look, I think -- so just to remind folks, we had the original APOLLO data that read out in 2017. And there were some really interesting signals of potential efficacy and activity against the cardiac manifestations of the disease. We use those data to design the clinical development program that you see us executing on now at Alnylam with APOLLO-B and HELIOS-B, and those were developed those protocols in conjunction and discussion with the cardiorenal division at FDA. And that's -- if you kind of look at our track record of what we've done in clinical development at Alnylam, that's -- we've done that for all of our molecules, ONPATTRO, for GIVLAARI, for OXLUMO, et cetera. And so we developed the both studies, a shorter-term study with ONPATTRO, looking at 6-minute walk test and KCCQ as endpoints, and then HELIOS-B to be a very robust outcomes-based study. And that was done at that time -- if you don't entirely believe us, in 2019, the FDA published heart failure guidance where they said that 6-minute walk test is a registerable endpoint of heart failure. They also said that quality of life measures like KCCQ are registerable endpoints for heart failure. Fast forward to today, we have a study that's actually for an approved product in a very closely related, if not identical disease with ATTR polyneuropathy, that has shown a statistically and clinically significant benefit on both of those endpoints, on 6-minute walk test and KCCQ. And in our interpretation of the data and corroborated by the KOLs who -- and investigators who we shared this data with at HFSA and ISA and other congresses, a very favorable benefit risk profile where you're seeing signals of efficacy that we've just talked about and really no new safety concerns, and if anything, some evidence from some of the safety data that they're numerically trending in favor of the drug. So we feel very confident about the data package. And as we've spoken about previously, we are planning to submit the NDA by the end of this year.

Great. Anything to add or...

We are on track. That's exactly right.

Okay. Okay. I guess as part of the context around 6-minute walk in heart failure, Again, I know we talked about this yesterday evening, but what can you say about any FDA precedent there is or FDA conversation there's been on effect size in 6-minute walk. And if they've delineated at all, where they think there is a line in clinical meaningful?

Yes. So I'm not aware of any -- even the heart failure guidance doesn't call out a specific number, right? And I think all of that's because it makes sense. It's going to be context dependent, right? Who's the population? When are you seeing the benefit arise? What does it mean, right? A certain magnitude may be in very different things to someone who's 20 years old versus someone who's 70 years old. So you have to keep that in mind. I think the profile that's emerging here, though, I think, is quite interesting, right? If you think back to some of the data that have come out for both ONPATTRO and AMVUTTRA in the polyneuropathy aspects of the disease, you're seeing evidence when you look at the mNIS+7, when you're looking at the Norfolk Quality of Life of potentially halting or even reversing aspects of the disease, but certainly really halting disease progression. And what's interesting coming out of APOLLO-B that kind of points to some of the clinical significance of what we're seeing is, it looks like in this study that you're seeing 6-minute walk test that is really approaching stabilization. It's actually -- we're getting patients back to what is the normal age-related decline in walking ability that happens year-on-year to people. And again, this is in patient population that's -- on average that was about 70, 75 years old. So that's quite remarkable. And it's not just one endpoint. It's the KCCQ. Again, where you're seeing that the effect size -- the treatment effect more or less stabilized any decline in KCCQ that would have been experienced. The other point I'll mention is that KCCQ has been studied for -- and included as an end point in a lot of heart failure studies. And if you look at the magnitude of effect that we've seen in the KCCQ, it's actually on the higher end of many approved products for heart failure. So again, I think all of these things point to the clinical significance of what we're seeing and the importance of the patients.

That's great, Pushkal. Is it fair to say that this study has also been designed with the EMA in mind? And given the EMA's receptivity to the APOLLO-A cardiac subgroup data you -- are you as confident that this will expand the label ex-U.S. as well?

So I think when we designed the study, we certainly considered the global regulatory audience and community in mind. And so we think this will have the potential to satisfy European regulators, et cetera. But what we've announced so far is our filing plans for the U.S. and that we're going to be continuing then to look at the broader footprint for this and the territories after that. So we have not made any specific announcement about those plans.

Okay. Fair enough. Rena on AMVUTTRA...

Yes.

So you were talking yesterday about 60 start forms versus a 30 run rate clearly evidence that this can expand the market because of its superior dosing profile. As you kind of look at the demographics of TTR polyneuropathy, the current treatment rate, the diagnosis rate, do you look at that initial progress you saw with the 60 run rate versus the 30 as kind of an expected bolus? Or do you see it as just an early start of what is ultimately to come and maybe even a new trajectory?

So we're really excited about the initial days of the AMVUTTRA launch. It. was approved in June. And what you're referring to is basically a 30 start form average of -- for ONPATTRO before the AMVUTTRA approval. And then after the AMVUTTRA approval, we've seen about a 60 start form average per month in just the past few months. So those new patients are coming as newly diagnosed patients who are choosing AMVUTTRA or they're coming as patients who've been diagnosed recently, but had decided that they didn't want to start treatment. And because of the efficacy and safety of AMVUTTRA as well as that dosing regimen of once every 3 months subcutaneously administered, they are now deciding that they do want to begin treatment, which also allows them to start treatment earlier in the disease progression, which is a really important benefit for patients. We're also seeing more physicians get into the mix. About 17% of start forms are coming from physicians who had previously not been ONPATTRO treaters. And so those -- again, they're saying that the efficacy and safety profile are compelling, but because of the mode of administration, they're able to make the decision to start patients treatment and typically start earlier. So all good initial indicators of the future of AMVUTTRA.

Okay. Okay. Great. Well, before we wrap up TTR and then talk about some of the pipeline programs you're going to read out over the next 8 to 12 months, I just wanted to kind of turn it over to each of you. And you've heard from a lot of investors, you've got questions from lots of analysts. I mean, bottom line, right, there's a debate on APOLLO-B, there's a debate on HELIOS-B. Any kind of concluding remarks on the TTR discussion or anything else you think the Street is missing?

Look, I think what I would say is, I think we're actually sitting in a fantastic position to bring forward some incredibly novel therapies to patients. We feel really good. I mean, if you think about what we've been able to do, we've been able to construct a franchise that Reno heads up. It's got now multiple molecules to potentially address the manifestations of disease, starting with ONPATTRO, building on that with now AMVUTTRA, 2 very large robust studies coming forward in the cardiac aspects. And then following on with a new CTA that's been filed for TTRsc04, which has the potential to be a once annual drug with even greater efficacy for this disease. And so we really are, I think, building and shaping a very large franchise opportunity because we see a lot of patients that we have the potential to help. And each bit of knowledge builds upon the knowledge that we've already accumulated and the experience now that we have as a team within the company, right, both on the R&D side, but on our commercial and medical side to actually execute against that plan. And so I think we really feel very fortunate to be in the position that we are. And profile on top of that of the medicines that we're developing really do have the potential to be best-in-class. We are really confident that the silencing mechanism and has been borne out by clinical data really has the potential to be the best-in-class approach to treating this spectrum of diseases. And so yes, I think that to us is the real take home. It's something that we're really excited to be a part of. Rena, anything to add?

Very well said. But yes, I think -- as we think about the franchise as a whole, we're right where we want to be. As we map this out 5 years ago with the readout of APOLLO, we're charting this course to say, slowly expand the population one step at a time from initial polyneuropathy and hereditary then an additional polyneuropathy and hereditary product. And now with the APOLLO-B data, we've really unlocked that new potential of the wild-type population and all the remaining patients with cardiomyopathy manifestations of disease and positioning ourselves well for that next chapter with the HELIOS-B readout around the corner to then have, again, that best-in-class product profile and meet the needs across the broad array of -- broad range of patients with the disease. So right where we want to be and positioned for success in the future.

Great. So let's talk about APP. Maybe you have excellent animal data with this program, CNS knockdown. As you approach Phase I data in healthy -- or not healthy's patients, excuse me, for the SAD portion, -- is there any reason why that animal data shouldn't just be kind of a reasonable benchmark that we should hopefully expect you to replicate?

Yes. So maybe just context for everybody, right? So ALN APP represents our first foray into the CNS. All of our other molecules are really liver-directed RNAi silencing. And so we were using this novel C16 moiety to target CNS, and we're giving the drugs intrathecally. Paul, as you alluded to, the nonhuman primate data are really encouraging because they suggest that we can have knockdown of APP up to 80%. We've had 50% knockdown in a nonhuman primate with a single dose out to 6 months, and we see good penetration into the CNS across a range of deeper brain structures and various cell types. So all that's really encouraging. And in the liver, we've seen nonhuman primate data really predict very well what happens in humans. And so, yes, the going in hypothesis would be that we will see a good degree of knockdown and durability in the CNS as well of APP. That said, look, this is our first CNS program and we think everyone has to be a little humble when you're sort of doing this. And so really closely following and wanting to -- safety is going to be -- is the primary endpoint for the single ascending dose portion of the study, but we'll also be looking at biomarkers that show us evidence knockdown and there is some very readily measurable biomarkers in the CSF, soluble APP alpha and beta that can give us that signal. So we're marching forward. The studies in patients with early onset Alzheimer's disease. And we're doing ascending cohorts there. And as we recently announced, we've -- based on just enrollment timelines, we're projecting now that we'll have preliminary data in the first half of next year, and then we'll go from there.

Excellent. Now APP is a very upstream target. And I think the investor community that's followed biotech, especially by the antibody evolution, right, has been prime to think that winning strategies in Alzheimer's target oligomers or plaques, right, which are these kind of later, bigger species. And we've seen failure of some upstream approaches that are obviously different than this. But, to that point, can you walk us through the lines of evidence for while by shutting off amyloid production at the source, you think you can also generate a reduction of the actual toxic species that drive disease?

Absolutely. Yes. I think -- look, I think these patients have a tremendous, tremendous unmet need. And it's been unfortunate that what we've seen with the antibodies has not been entirely consistent across a series of programs that have been developed. I think -- my takeaway from it is that there is enough evidence of some clinical activity that you are seeing some effect in general, but it's relatively modest. And I think that's somewhat validating of the amyloid hypothesis, but suggests we may need to have different ways of approaching it. If you think about the antibodies, they really are focused on targeting extracellular amyloid and they can really focus on a single isoform, really, as you talked about, Paul. With an upstream approach, amyloid precursor protein, we have the potential to really turn off at the source all amyloid production, or at least dial it back. And that can be then address both extracellular amyloid, but as well as intracellular amyloid, which we know is present in these patients. And moreover, a variety of isoforms of amyloid, right, not just the full length, but actually fragments that we know come off of APP. And so we think that this has the potential to be a much more potent and effective approach on the efficacy side. Likewise, it's -- we don't -- because there's not going to be sort of antibody binding to amyloid in the tissue, we also wouldn't expect, for example, side effects like ARIA to happen with this kind of an approach. So we think there's really an opportunity to have an expanded therapeutic window and to actually potentially even have attack the source of the disease, higher upstream could have a much more effective way to manage this disease and prevent progression, so that's the hypothesis for exploring.

Okay. Great. Can you talk about planning for a successful scenario where these targeted engagement data look good, safety looks reasonable. What you think the actual path to proof of concept could be for this?

Yes. So right now, what we're doing is we have a single ascending dose study that will give us some evidence safety knockdown. Part B of the study goes into multiple doses in patients, and that's where we define the dose and frequency. But there's really 2 paths that we can sort to thing -- that we are thinking about advancing this medicine once we have proof of concept. And that is into: one, as we've been talking about is into Alzheimer's disease. We're obviously following closely what's happening there in terms of registrational end points, and what may be accelerated path to approval. So it's too early to comment on that, but that's certainly something that we'll be looking at. But there's certainly paths to approval there. But we'll also be looking at a parallel development plan in the closely related disease, which is called cerebral amyloid angiopathy. And there, instead of amyloid being deposited in the parenchyma of the brain, it's actually being deposited into the -- around the blood vessels, the cerebral blood vessels. And it's an important cause of both microhemorrhages and then ultimately macrohemorrhages that can be fatal. And so we think that, just like with TTR, whereby turning off a source of aberrant protein production at its source, we can actually ameliorate aspects of disease, we think by turning off APP or dialing it back, we can address both Alzheimer's, but also this related disease of cerebral amyloid angiopathy. And so look for us, we had a roundtable not that long ago where we talked about that development path and the opportunity there. But you can imagine that we'll be trying to pursue both of those pads in parallel after proof of concept.

Okay. Great. Meanwhile, we're going to get early data from your Gout program soon, I'm sure, by the end of the year, right?

That's the plan.

Okay. Great. Maybe walk through the therapeutic hypothesis there, and it's a Phase I healthy study, but you're looking at uric acid. And so to that point, can we take that data from this study and actually get some confidence that the drug really could be working clinically in later trials?

Yes. Yes. So ALN-XDH is the program, and it's targeting Gout and the target there is Xanthine dehydrogenase. Xanthine dehydrogenase is both a genetically validated and a clinically validated target in Gout. It's actually the target of allopurinol. Now you kind of go, why are these guys going after Gout. The issue there is that -- it's a very prevalent condition. But unfortunately, the treatments that are available are actually quite limited. Most patients don't get to target levels of uric acid. They have an ongoing uric acid deposition in the joints and they wind up having joint damage.

And is that more driven by these drugs don't hit the target hard enough, or people just don't stay on them?

It's actually that it's hard to push the doses up in many patients because of tolerability issues.

Okay.

And so you kind of have, again, sort of a narrow therapeutic index for many of these drugs, and you can't get people to push those. You're right, though, that adherence is also is a common problem with any chronic disease.

They are kind of similar problems in a sense.

Yes. So with XDH if we can get down the uric acid, we think that we can have a really substantial effect on this disease and it's uric acid itself is a registrational endpoint for Gout. So that's the hypothesis. What we're doing in the Phase I study, as you pointed out, Paul, is we're starting in healthy volunteers. There's good data from analog medicines, including febuxostat that healthy volunteer data will translate reasonably well into what you'll see in Gout patients in terms of uric acid production. And what we're doing there is really evaluating initially just the hypothesis that hepatic silencing of XDH is going to be sufficient to bring down uric acid. We've seen in preclinical models that we can actually get pretty significant, up to 50% or more uric acid lowering with hepatic silencing alone. But we do know that there is extra hepatic XDH expression. The exact magnitude of that in people is not entirely known, but -- so that's what we're exploring in this Phase I study of hepatic silencing will bring down the uric acid. And that's what we plan to report out on.

Okay. Okay. Great. Let's see. Should we talk about zilebesiran? I got I got it.

You got It. You are practicing.

Yes, I've been practicing. Yes. I'm trying to think about where to start, right? You already have great proof of concept. It's a validated target. Maybe let's try to tack on the last 4 minutes push go the 2 questions we talked about last night, which are really one, what really is the true target population for this drug when you think about generics and payers and things like that? And then, two, I think it would be helpful to also talk about the combo therapy question, Dual RAAS blockade, but maybe you can target question one first.

Yes. Look, zilebesiran is a program that we're incredibly excited about. It really harnesses the power of the platform to go after very prevalent conditions, but in a very differentiated, meaningful way. And what we've seen -- when you look at the Phase I data that we already have is that this medicine has the potential to address the major contributors to the persistent impact of hypertension on cardiovascular morbidity and mortality, which is to get more patients to treatment target, which are getting more and more stringent, to avoid variability in blood pressure control that all existing therapies still contribute to because of their waxing and waning pharmacology and to maintain adherence to blood pressure control. And those things, we think, will actually have a synergistic effect. If we can do all of that on ultimately in cardiovascular morbidity and mortality. And we've shown that we can actually have up to 20 millimeters of blood pressure lowering for 6 months with a single dose of this drug. So it's kind of quite remarkable. In terms of where we think we're going to be positioning it, I think -- look, I think there's a lot more to do in terms of development, which will help inform that. But when we think about it, there's probably 2 areas where you might think initially of bringing forward a medicine like this. One path that's often talked about is resistant and refractory hypertension, there is a large population of patients for whom existing therapies are just insufficient to get them to goal. And so certainly, that's a possibility of where we might be able to develop the medicine. But the other area where I think we're particularly excited about the potential of the medicine like this is in patients with high cardiovascular risk, right? So if you think about what are the goals of blood pressure control, it's to prevent poor cardiac outcomes, MIs, strokes, peripheral vascular disease, conditions like that. And there's tens of millions of patients who have -- were at high cardiovascular risk or have already had a cardiovascular event and their blood pressure is not controlled. And in that setting, there's a real urgency to treat that blood pressure and bring it down and to prevent subsequent events. And so we can see, for example, imagine a patient has had a stroke and needs a medication for that, and they're not well controlled, something like zilebesiran being really helpful. So again, more to come, but we think that high cardiovascular risk population will be an important population for us to target. Your second question was around?

Yes, I can maybe frame it. Just -- again, it feeds in perfectly, right? Because in a high cardiovascular risk population, you probably imagine these patients to already be on maybe on cheap generic that is like an [ ACR NR ] but that already blocks this RAAS pathway. And so we were talking about it last night, but for those who haven't kind of looked into this, right, dual RAAS blockade, [ ACAR ] combinations, don't have the best history from an efficacy and safety perspective. And so it'd be interesting to hear your comfort that adding on another RAAS blocker albeit with a different mechanism of action is going to produce added benefit and also be safe on the kidney side.

Yes. Important question. And I think, look, what we're doing is by targeting very far upstream, we're actually sparing the renal RAS system directly, right? We're not directly inhibiting the renal RAS system and so that's point one. The preclinical data that we have also suggest actually that there is no additive safety concern when an ACE is given on top of zilebesiran. And moreover, there's actually additive efficacy. The point you brought up is really important, Paul, which is in prior experiments or studies, I guess, clinical studies of dual RAAS blockade, not only has there been a low incidence of hyperkalemia or creatinine bumps, et cetera, but there hasn't been any additive efficacy, right? So there's no reason to tolerate any safety concerns when there's no additive efficacy. In contrast, both in preclinical data, but as well as in our Phase I study, where we had a cohort of patients who actually were given dual RAAS blockade and are on top of zilebesiran, we actually saw 6 millimeters of additional blood pressure lowering, which is clinically significant, and no evidence of renal toxicity as measured by potassium and creatinine. So I think we have very encouraging data so far, both preclinically and clinically on top of an important hypothesis to why there may be no substantive issue in terms of dual-RAAS blockade and in fact, added efficacy. In our Phase II program, we have Cardio 1 and Cardio 2. The second study is actually looking in a larger cohort of patients at that combination. So we'll have more data next year on.

Great. I think we're out of time. That's the countdown between sessions. You know I could ask you 1 million more, but I appreciate a Pushkal call Rena. It was great seeing you both. Thank you.

Thank you. Thank you, all.

Thank you.