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

Thank you everyone for joining us for the Alnylam Pharmaceuticals Fireside Chat at the 43rd Annual TD Cowen Conference. I'm covering analyst, Ritu Baral, and with us today from Alnylam, we have Pushkal Garg, CMO; as well as Rena Denoncourt, VP and TTR program lead at Alnylam. Welcome Rena and Pushkal. Good to have you back.

Thank you.

Thank you.

All right, let's start with your sNDA. You know where I'm going with this. Have you had any more recent communication with the FDA about the sNDA for ATTR-CM? Have you been notified of any emerging review issues? You mentioned that at one point you had been told there were none.

Yes. So, first of all, good to see you, too, and thanks to you and TD Cowen for inviting us here today. We're really excited to be participating in the conference. Look, in terms of our ONPATTRO or patisiran review of the sNDA, we announced as we did on February 17th that we've gotten a letter saying that the file had been accepted, that the FDA was planning for an advisory committee, and that there were no review issues identified to date. There's always, in the context of a review, some back and forth that happens in terms of data clarifications, et cetera. But in the context of the AdCom, we don't have any more information at this point.

Okay. Now if FDA identifies a review issue as part of the sNDA, are they mandated by the statute by PDUFA to tell you?

Look, I think the FDA is going to be doing their review and going through all the data that's been provided to them, and it's their prerogative what they want to raise to us and when. Certainly, we're always going to be facilitating the review. And when issues are raised to us, we'll certainly address them.

Okay. I'm still trying to wrap my head around the fact that they know they want an AdCom, but they don't know of a review issue. What are the topics that you're then preparing around? Because usually most developers will just go straight to the review issues. What topics have you prepared around and how do you even start preparation if you don't have review issues to serve as the core of the conversation?

Yes. So I think maybe a couple points there. First of all, I think it's important to note that as part of FDA's armamentarium of things that they can do in terms of reviewing an application is they can, it's their prerogative to convene an advisory committee of independent experts to give them advice. And so that's part of the process and, again, it's something that we'll support. We don't have specific insights at this point. We may learn in due course of issues and topics that the FDA wants to raise to the panel. It's possible, while I don't have any specific information, that this may fall in the realm of efficacy. You'll recall that the FDA issued guidance in 2019 on heart failure, and as part of that, that was where they announced that both functional measures like the 6-minute walk test, quality of life measures like the KCCQ in the absence of outcomes could be registrable endpoints for heart failure and to our knowledge, patisiran would be the first drug reviewed under that guidance.

And that guidance did not have any specified threshold for effect size for either of those 2?

Not to our knowledge. But again, we're waiting to see what the FDA brings forward and they will raise in due course what the topics that they want to cover. As far as we -- our preparation, look, we're here to really facilitate the agency's review and the questions that the advisory committee panelists want to ask. And so we feel very good about the study that we've designed, conducted, executed and the data that we have. And so we'll be preparing across all fronts. That's our responsibility is to be able to speak to all aspects of the study and the results. Design, conduct, safety, efficacy, statistics, clinical pharmacology, whatever it is, we'll be prepared to speak to them.

So this would potentially be the first heart failure-related approval on 6-minute walk and Kansas City -- KCCQ, correct?

To our knowledge, with any absence of the outcomes data.

Which would then present precedent for future applications for future developers?

Potentially.

Potentially.

Yes. I don't speculate...

Okay. Are you going to be submitting 120-day safety data?

We will be, as part of our obligation is to provide a safety update to the agency, and so we'll be doing that, as you noted, 120 days roughly after the [indiscernible], we do that.

Well, aside from that, are there any -- again, anything in the statute -- anything in the PDUFA statutes that specifically mandate or prescribe additional communication points in an sNDA? I'm a little triggered by this. I've been burned before [ tracking ] sNDA, so I'm hoping you're telling me that you can tell me that there's a point of communication that you were expecting that's in PDUFA.

Yes. So from our understanding, in the context of an sNDA, there's not some of the typical things that you might have for original NDA in terms of, for example, a mid-cycle review meeting, et cetera. But we do expect that in the context of planning for an advisory committee that the guidance would indicate that the FDA will let us know more about the topics for that advisory committee roughly 2 months before scheduling the meeting -- before the scheduled date of the meeting.

Got it.

So we'll look forward to hearing more from the agency. And again, it's their prerogative. As they conduct the review, they'll keep us posted, and we'll certainly be responsive to any requests and needs that they have.

Understood. So how are you gearing up for the potential launch? You've indicated that ONPATTRO for these patients is going to be for the most, not your words, mine, but the most desperate patients with the biggest unmet need, which is seemingly a smaller population. Are you going to be expanding call points, hiring additional reps? How are you thinking about that?

So let's talk about the patient population in a bit. But to your specific question about the call points, there are a number of new treating physicians who would be potentially treating wild-type ATTR amyloidosis or the patients with the cardiomyopathy of hATTR amyloidosis in addition to the physicians that we see today. So I would say we would be planning to expand both our commercial and medical teams to support a potential launch. That's included in our OpEx guidance that has been provided. But further granularity to that, it's a competitive space, so we aren't going to get into much more detail there. I think importantly, we have a well-established infrastructure of our commercial teams with the field-facing teams for physicians, for payers, and we'll be leveraging that, and so really not building this from scratch, but rather taking the knowledge and the relationships that we have established and being able to position ourselves well for that.

Is a cardiology and -- was a cardiology call point, is a cardiology rep a materially different hire than a rare neuro rep?

So I think we're looking for general traits in a rep that are able to take a specialty call point. It's really taking new HCPs and new centers of excellence, but many of them have already been seeing patients with hATTR amyloidosis with polyneuropathy at these centers of excellence. They see all the different forms of hATTR amyloidosis.

I see, okay. Yes.

So as we expand or as we potentially expand the label, there'll be many pieces of the existing footprint that we can leverage. They either have experience -- these treating physicians may have experience with ONPATTRO for the treatment of the polyneuropathy manifestation of disease or they have experience already seeing these types of patients because they're the mixed patient population that is going to these potential treating physicians already, so there's a lot to leverage there.

Understood. Any changes to the hub around this? And what do you think the profile of the ideal ONPATTRO TTR cardiomyopathy patient is?

Sure. So nothing materially changes in the hub. It's consistent with our existing approach of making sure that we work diligently to make sure that patients who are prescribed our treatments can get access to them and get the support that they need for treatment. When we're thinking about the potential indication in ATTR amyloidosis with cardiomyopathy, the existing landscape is that these patients are experiencing disease progression or inadequate treatment and there remains to be a significant unmet medical need in this population. So you have patients who are getting access to the existing therapy and having an inadequate response or you have patients who can't even get access to therapy. So those are some examples of patient populations that might have the potential to benefit from ONPATTRO should we get the approval in that indication.

And what do you expect to be approximate -- I think this is independent of pricing, but with the price, partly co-pay, for these patients.

Right. So what the important piece is there is that the out-of-pocket co-pay and the payer dynamics are not cost prohibitive for patients to get access to it. But further details along that, it's still a little too early to discuss. But what we've seen in the polyneuropathy space, of course, is good, low barriers to having patients get access to ONPATTRO for polyneuropathy or AMVUTTRA for polyneuropathy because of streamlined access processes.

And the Part B co-pays do tend to be lower than the Part D cops, correct?

They do. In general.

In general. And would this really expand a real possibility for combination with a stabilizer upon potential approval?

So again, it's early. Without having a label and without having [ approval ]...

Hypothetically.

To be determined, right? We want the physician to make the decision based on the data and based on what the individual patient needs would be.

And nothing in the statute says no, you couldn't?

No, we're just in...

Like Medicaid, Medicare, there's no...

That would be based on the individual plans and the expectations for the individual patient. It's theoretically possible, but again, label to be determined and things like that.

Of course. So you're not pursuing the biannual treatment regimen anymore.

That's right.

Has that had any impact to your internal models about how much ONPATTRO could sell for cardiomyopathy?

So the biannual regimen is for vutrisiran.

Oh, yes. I'm sorry, AMVUTTRA could sell for cardiomyopathy.

Right. So for AMVUTTRA. So let me maybe review some of the rationale for the strategic decision to not further pursue the biannual dosing regimen at this time, and it's really 3 different reasons that have come together to lead us to this decision. So the first is that the 25 mg quarterly regimen of AMVUTTRA has had a very successful early launch. The first 6 months of that have exceeded our expectations. We're really, really pleased with what we've seen there, and it's been essentially a gamechanger for the space. You have the efficacy, the safety, and the quarterly regimen, that uptake from physicians and patients has been -- we're very pleased to see the favorable results there. Now when you look at the biannual dosing data, the 50 mg biannual regimen, the study was the HELIOS-A randomized treatment extension. We did confirm that it was -- the mean TTR knockdown was noninferior to the 25 mg regimens at 9 months.

So essentially after 2 doses.

Yes. So it achieved its intended endpoint on the noninferiority and the safety profile. But what we did see was some return of the TTR reduction at the end of the biannual regimen, so towards the end of the 6 months. And that's not aligned with the optimal target product profile that we would like to bring forward.

You want coverage.

We want robust and sustained TTR knockdown. And the third element that's really relevant to this decision is the TTRsc04 molecule that's right behind and just started dosing in the Phase I study. So having that as an option that we can now focus on to provide another option of bringing innovation to patients with the potential for the robust and sustained efficacy and the infrequent dosing that, that molecule has the potential to provide led us to say, let's streamline this franchise development and focus on sc04 for that next molecule in the line.

Were there potential [ IRA ] considerations into that strategy as well?

No, that's not key to the decision.

On HELIOS-B, can you review for us what you've said on the powering of the study, TAF -- baseline TAF use and allowances and observations for TAF drop-ins.

Yes. So maybe a couple points there. So HELIOS-B is our outcome-based study for AMVUTTRA or vutrisiran in ATTR cardiomyopathy. And look, I think, first and foremost, we're really encouraged because the APOLLO-B data that we talked about at the beginning of this discussion really portends well, we believe, for HELIOS-B. We validated the therapeutic hypothesis that silencing with an RNAi therapeutic can actually have beneficial effects across a whole range of endpoints in this disease, clinical, biomarkers, echocardiographic, technetium, and from a safety perspective. So that, first of all, really helps us a lot in terms of thinking about the -- and all of those are important prognostic factors that relate to outcomes, right? HELIOS-B is roughly twice as large. And instead of being a 12-month study, it goes out to 36 months, 30 to 36 months, so considerably larger and longer. So we feel very good about the design and conduct of the study. As we tend to be pretty conservative in our powering assumptions, and we feel really good about that, we have factored in that up to 50%...

But you won't tell us what they are.

But we have factored in that allowance of up to 50% was our operational target in terms of percent of patients on baseline tafamidis. We've come in south of that. And the last we spoke about when we talked about TAF drop in, those rates have been low, and we've been comfortable with that as well. So overall, we feel really good about the design and the conduct of the study, and we're looking forward to seeing the results in early '24.

Are you looking at the blinded event rate?

So we have teams -- in any clinical trial that we're doing, we have teams looking at the data overall, primarily for study integrity purposes, to make sure that the study is being conducted properly at the sites, that there's outlier data points, those are addressed, et cetera. As part of that, they are looking at blinded data, and we're very comfortable with what they're seeing. And so we feel good, again, about the conduct the study. It's also being reviewed by a data monitoring committee, and they also continue to -- and we feel good about the fact that their reviews have been uneventful. So everything is moving forward.

In the event that the event rate was coming in way too low, something would be triggered internally at Alnylam. There would be an awareness of that underpowering -- potential underpowering, hypothetically.

Yes. Look, I think we are really committed to bringing forward this medicine in patients with this disease because, obviously, there's a huge unmet need, as Rena referred to. We want to bring forward this medicine, and we're going to do everything that we can to optimize our clinical trial to deliver that. And again, we feel good about what we've designed and what's being executed here.

So you said -- I think it was you who said on the earnings call that you have no current plans to change the analysis to an event-driven plan. This is something you and I discussed in January. But could you? Is it impossible?

This is -- Ritu it's so speculative. But I think what I would say is we think about all the different possibilities in terms of optimizing the design and conduct of the trial, and we feel good about where we're at.

Okay. The next catalyst people focused on ALN-APP.

Yes.

So you've set the bar at 50% knockdown. Just to clarify for folks, this is the protein itself in the CSF, correct?

Not exactly. So what we're looking at, maybe just as a zooming out for the moment, this is our first foray with an RNAi therapeutic into the CNS. It's a really exciting opportunity to take all the learnings that we've gotten from liver-directed RNAi therapeutics now into a new tissue compartment where there's a whole bunch of diseases that I don't have to educate anyone in this room about that have tremendous unmet need and with their genetic underpinnings that we can potentially address. So this becomes a very important medicine in that regard. And ALN-APP itself is targeting and being addressed for patients with potentially Alzheimer's disease and another disease called cerebral amyloid angiopathy with tremendous unmet need. The data that we're -- the Phase I study that's going on right now that we'll be planning to report data out on in the first half of this year and in the second quarter is really from the -- is an interim look at data from the single ascending dose portion of the study we'll be looking for to show safety and tolerability. Again, this is the first time delivering a drug into the CSF space in RNAi therapeutic, and also then knockdown. And to your point around that, we're not measuring APP directly, but we're measuring downstream cleavage products of that, which is soluble APP alpha and soluble APP beta. And these are very good -- these are proximal indicators of what level of knockdown that we're seeing.

Got it. So it's the soluble APP alpha, soluble APP beta that you are expecting to hit that 50% threshold.

Yes. And what I would say is, just to be clear, this is an interim look at data emerging from the study. This doesn't necessarily mean it's going to be the final results of all the dose escalations, right?

Okay.

And when we talk about 50%, that's really a crude threshold from the context of when we've been asked what is the level of targeting a knockdown that we'd like to see where we might expect to see therapeutic benefits and longer-term clinical trials, right? And that comes from genetic data where we think that if we can get to about 50%, that would be a good hypothesis to be exploring in longer-term trials and larger numbers of patients with Alzheimer's disease or CAA. Right now, we're in the dose escalation phase. And so really just looking for safety, tolerability, target engagement, dose-related knockdown, durability, factors like that.

Is there preclinical support for that 50% or genetic support for that 50%?

There's some genetic support for that 50%. But I will say that models here, preclinical data are limited, right? And so we have a strong therapeutic hypothesis that the antibodies have actually validated that the A-beta hypothesis that lowering amyloid can be beneficial. But certainly, there's a tremendous amount of residual unmet need. I think all of us, we believe, want to see better therapies for patients with Alzheimer's disease. And so we think that by this mechanism, by going upstream, we can actually turn off the tap here in terms of amyloid production, not only a full-length amyloid, but various oligomers and fragments that are developed and not just extracellularly in the parenchyma of the brain, but actually intracellularly as well. And so we think we have the potential to have a more upsized benefit in this disease. That remains to be seen, and we'll do the clinical trials to do that. And again, in accordance with that, we think the genetic data would suggest that getting to about 50% knockdown should put us in the range to explore therapeutic efficacy.

Are there any regional or structural considerations when we think about the alpha and beta APP -- soluble APP alpha, beta reductions? This is -- it's a disease of cognition. And, of course, those -- that tissue is easy to access. It's just the gray matter essentially on the outside. Basically, if that occurs, if it's only knockdown on those tissues on the outside of the brain rather than the deeper tissue, would that have any implications to potential downstream clinical effect?

No, I think we do know that in Alzheimer's patients, certainly, that there's amyloid that's deposited in multiple regions of the brain. Certainly, there's a lot of cortical involvement potentially, particularly in more advanced disease. But we don't have the -- we're going to be measuring the APP alpha and beta in the cerebrospinal fluid, which is really going to be coming from the total mass of the brain.

Got it. Is there any way to figure out if you're seeing knockdown in the deep brain structures?

There's no -- we're not directly measuring that. Certainly, what we've seen from nonhuman primate studies, however, really tells us that this mechanism we are able to actually get access deeper brain structures and a variety of cell types, and we've shown data now looking at that. You can see good deep brain...

Which cell types?

Across neurons, astrocytes, glial cells and into deeper structures in terms of striatum, thalamus, et cetera, so a variety of cell types and tissues.

And that's nonhuman primate...

That's nonhuman primate data, yes.

Got it. Okay. Any other biomarkers you're going to be releasing with the top line data? And if so, what do they mean and what movement?

Yes. So I thank the initial tranche of data will be focused primarily, as I said, on safety, tolerability, and soluble APP alpha and beta. But in the context of the study, we are measuring a number of other parameters. There's other CSF and plasma biomarkers that relate to target engagement at beta 40 and 42 markers of inflammation, et cetera. And we will also be doing neuroimaging through a variety of modalities, including volumetric MRI, et cetera. But those are going to come in due course. Those will not be on the part of the initial tranche of data.

Got it. All right. Let's move to zilebesiran and the upcoming KARDIA-1 and KARDIA-2 readouts later this year. What should we -- what should people's expectations for the milligrams of mercury improvement be for -- let's start with KARDIA-1 monotherapy on its own? No background treatment. Remind us what you saw in the Phase I/II on monotherapy and any reason to expect anything different in KARDIA-1?

Yes. So zilebesiran, a very exciting program that can really fundamentally be transformational potentially for the treatment of hypertension and reducing cardiovascular disease, the ability to tonically control blood pressure for long periods of time is really very, very differentiated from anything that's come before and addresses the fundamental problems we've had with blood pressure control. So in the Phase I study what we saw was we took single doses up to 800 milligrams, and we saw dose-related decreases in angiotensinogen and in blood pressure. We saw systolic blood pressure reductions at the highest dose of up to 20 millimeters of mercury and lasting for up to 6 months. So really exciting profile and good safety and tolerability with that. The Phase -- the KARDIA-1 study is really trying to now expand on that experience. So we're looking at a range of doses from 150 to 600 milligrams and regimens of every 3 months and every 6 months. And the goal here is to actually come up with the dosing regimen that will be used in pivotal trials. Any blood pressure reduction of 5 millimeters systolic is considered clinically significant. A 5-millimeter systolic blood pressure reduction roughly associates or correlates with a 10% reduction in cardiovascular morbidity and mortality, so it's quite clinically significant. I think based on the data that we saw in the Phase I, we'll expect maybe even see something higher than that.

Even higher, okay.

Than the 5.

Than the 5. And then how should we think about KARDIA-2, I wrote that wrong. It's the combo therapy study. How will real-world use across larger centers and maybe better background control or maybe less good background control. How should we be thinking of that magnitude of millimeter benefit?

Yes. So, look, I think what we're -- what we'll look to do there, both between KARDIA-1 and KARDIA-2, we're now expanding across them. We're going to have almost 1,000 patients on this drug. And I think that's going to be really helpful to understand and also patients with more cardiovascular risk factors or comorbidities. So we'll be exploring closer to the populations that we'll be studying in, in pivotal trials. We're targeting this drug ultimately for patients with uncontrolled hypertension who are at high cardiovascular risk. And many of these patients are going to be [ taken whether ] there's a high unmet need and an urgency to treat those patients and get their blood pressure controlled. For example, patients have a stroke or an MI, they have uncontrolled hypertension, you know if you don't bring that blood pressure down, they will be at higher risk for having a recurrent event. But these patients are also now taking multiple medicines and polypharmacy is quite common in hypertension management. And so KARDIA-2 will really start to develop the data set about how does zilebesiran combine with other commonly used classes of medicines, diuretics, calcium channel blockers and angiotensin receptor blockers. In terms of the magnitude of effect, as you get on patients and you're using a therapy on top of 1 or 2 other medicines, you often will expect to see that treatment effect may be somewhat lower, but there's also synergies that happen. We know that RAS blockers combined with the diuretic can often have enhanced efficacy. So I think we're looking -- we're very excited to see what that data set looks like. I think another interesting aspect of the data set will be how does it combine with an angiotensin receptor blocker. We had some experience. We've got preclinical data but also Phase I experience that says, in contrast to what may have been seen previously when you use 2 RAS blockers together where there's really not additive efficacy, again, in a very small cohort of patients of about a dozen patients, we saw about a 6.5 millimeter increase or additive benefit of giving -- of combining the 2 agents. So that's encouraging with no safety concerns emerging there. This will be a much larger experience of looking at that combination. It will be quite interesting to see if there's additive efficacy and lack of safety concerns for the patients.

Okay. And then just very quickly, as we think about everything happening, KARDIA-1 and KARDIA-2 coming to fruition, APP and potential Phase II start and the potential ATTR-CM launch, how are you thinking about OpEx increases over the next 3 years as you reiterate breakeven, I think, in 2025, which was the important, Jeff finally put a year on it after so many years, midterm breakeven, 2025 breakeven? Is there going to be a significant -- is it letting you -- is it giving you a lot of money for that?

Jeff has been very kind to us in development. So look, I think we are very committed to our P^5x25 goals, which includes profitability within the period. And I think that really comes from 2 aspects: one is growing the top line, and we've committed to an average of a 40% CAGR over the period. And so that's going to be driven by all the existing products as well as the launches and hopefully cardiomyopathy. And then tempered -- and then balanced against that will be continued investments in R&D and in the pipeline and in OpEx overall. And -- but maybe as an illustrative point, in 2021, OpEx grew by about 16%. Last year it was about 14%. And then the guidance that Jeff just provided in our last earnings call, we're forecasting the midpoint of the range of OpEx increase will be about 13%. So we really are trying to temper that growth as we get to be a larger and more mature company because we are very committed to meeting that profitability goal. But that said, we have a very rich set of opportunities ahead of us. We have a very productive R&D engine. And so it's important that we continue to invest both in bringing more products forward but also enhancing our ability to bring medicines to patients in terms of investing in our AMVUTTRA field force, et cetera. So there's -- we will be working on all those things. But certainly, you'll see a tempering of that and discipline around the OpEx and the continued efforts on growing the top line, but we will be investing in the company.

Great. Well, thank you, Pushkal. Thanks, Rena, for joining us and for the insight. Appreciate it.

Thank you, Ritu.