Everyone for joining us for the Alnylam Pharmaceuticals fireside chat, at the 43rd annual TD Cowen Conference. I'm covering analyst Ritu Baral. 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.
Pleasure.
Good to have you back.
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.
Yeah. First of all, good to see you, Ritu, and thanks to you and TD Cowen for inviting us here today. Really excited to be participating in the conference. Look, in terms of our ONPATTRO or patisiran review of the SNDA, you know, we announced, as we did on February 17th, that we'd 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. You know, there's always, in the context of a review, some back and forth that happens in terms of data clarifications, et cetera. In the context of the AdCom, we don't have any more information at this point.
Okay. 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, you know, 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, you know, always going to be facilitating the review. When issues are raised to us, we'll certainly address them.
Okay. you know, 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 then that you're then preparing around? Because usually most developers will just go straight to the review issues. What topics are you prepared around? How do you even start preparation if you don't have review issues to serve as the core of the conversation?
Yeah. I think maybe a couple points there. First of all, I think it's important to note that, you know, as part of FDA's armamentarium of things that they can do in terms of reviewing an application is, it's their prerogative to convene an advisory committee of independent experts to give them advice. That's part of the process. 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. You know, it's possible, while I don't have any specific information, that this may fall in the realm of efficacy. You know, you'll recall that the FDA issued guidance in 2019 on heart failure.
Yes.
As part of that was where they announced that both, you know, functional, measures like the six minute walk test, quality of life measures like the KCCQ, in the absence of outcomes could be registrable endpoints for heart failure. To our knowledge, patisiran would be the first drug, reviewed under that, under that guidance.
That guidance did not have any specified threshold for effect size for either of those two?
Not to our knowledge. We're waiting to see what the FDA brings forward, and they will, you know, raise in due course the, what the topics that they wanna cover. As far as we in our preparation, look, we're here to really facilitate the agency's review and the questions that the advisory committee panelists will wanna ask. We feel very good about the study that we've designed, conducted, executed, and the data that we have. 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. You know, design, conduct, safety, efficacy, statistics, clinical pharmacology, whatever it is, we'll be prepared to speak to that.
This would potentially be the first heart failure-related approval on six minute walk in Kansas City, KCCQ, correct?
To our knowledge. It would in the absence of the outcomes data.
Which would then present precedent for future applications for future developers.
Potentially.
Potentially.
Yeah. I don't speculate. Yeah.
Are you gonna be submitting 120-day safety data?
We will. We will be. You know, as part of our obligations is to provide a safety update to the agency, and so we'll be doing that, as you noted, 120 days roughly after the mark, we kinda do that update.
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 trying an SNDA, so I'm hoping you're telling me that you can tell me that there's a point of communication that you are expecting that's in PDUFA.
Yeah. you know, from our understanding, you know, 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, mid-cycle review meetings, et cetera. 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 two months before scheduling the meeting, before the scheduled date of the meeting.
Got it.
We'll look forward to hearing more from the agency. 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. How are you gearing up for the potential launch? I mean, 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 a seemingly smaller population. Are you going to be expanding call points, hiring additional reps? How are you thinking about that?
Let's talk about the patient population in a bit.
Yeah.
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.
Mm-hmm.
-or the patients with the cardiomyopathy of hATTR amyloidosis, in addition to the physicians that we see today. 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.
Mm-hmm.
Further granularity to that, it's a competitive space.
Sure.
We aren't going to get into, you know, 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. Really not building this from scratch.
Mm-hmm.
Rather, taking the knowledge and the relationships that we have established and being able to position ourselves well for that.
Well, is a cardiology call point, is a cardiology rep, a materially different higher than a rare neuro rep?
I think we're looking for general traits in a rep that are able to take a specialty call point.
Mm-hmm.
It's really taking new HCPs and new centers of excellence.
Mm-hmm.
That many of them have already been seeing patients, with hATTR amyloidosis with polyneuropathy at these centers of excellence. They see all the different forms.
I see.
of ATTR amyloidosis.
Okay. Yeah.
as we expand.
Mm-hmm.
Kind of potentially expand the label, there'll be many pieces of the existing footprint that we can leverage.
Got it.
They either have experience, these treating physicians may have experience with ONPATTRO for the treatment of the polyneuropathy manifestation of disease.
Mm-hmm.
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. There's a lot to leverage there.
Understood. I think I swore I had that. Any changes to the hub around this, and what do you think the profile of the ideal ONPATTRO ATTR cardiomyopathy patient is?
Sure. Nothing materially changes in the hub.
Mm-hmm.
It's kind of 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.
Mm-hmm.
Get the support that they need for treatment. When we're thinking about-
Sure.
The potential indication in ATTR amyloidosis with cardiomyopathy, the existing landscape is that these patients are experiencing disease progression or inadequate treatment.
Yeah.
There remains to be a significant unmet medical need in this population. 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.
Mm-hmm.
to therapy.
Sure.
Those are some examples of patient populations that might have the potential to benefit from ONPATTRO, should we get the approval in that indication.
What do you expect the approximate... I think this is independent of pricing, but with the price, Part B copay, for these patients?
Right. What the important piece is there is that the out-of-pocket copay and the.
Mm-hmm.
The payer dynamics are not cost-prohibitive for patients.
Mm-hmm.
to get access to it. Further details along that, it's still a little too early to discuss. 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.
The Part B copays do tend to be lower than the Part D copays, correct?
They do.
And-
In general.
In general. Would this really expand a real possibility for combination with the stabilizer, upon potential approval?
Again, it's early.
Right.
Without having a label and without, you know.
Hypothetically.
Approval, to be determined, right.
Mm-hmm.
We want the physician to make the decision based on the data.
Sure.
based on what the individual patient needs would be. those are.
Nothing in the statute says no, you couldn't.
A statute.
just in, like Medicaid, Medicare, there's no...
That would be, you know, based on the individual plans and the expectations for the individual patient.
Yeah.
It's theoretically possible.
Mm-hmm.
Again, label to be determined and things like that.
Of course. You're not pursuing the biannual treatment regimen anymore?
Right.
Has that had any impact to your internal models about how much ONPATTRO could sell for cardiomyopathy?
The biannual regimen is for vutrisiran.
Oh, yeah. I'm sorry.
Yeah.
On, for, AMVUTTRA could sell for cardiomyopathy.
Right. For AMVUTTRA. Let me, maybe review some of the rationale for
Mm-hmm.
Strategic decision to not further pursue the biannual dosing regimen at this time, and it's really three different reasons.
Mm-hmm.
-that have come together to lead us to this decision. The first is that the 25 mg quarterly regimen of AMVUTTRA has had a very, a very successful early launch. The first six months of that have been exceeded our expectations. We're really, really pleased with what we've seen there, and it's been essentially a game changer for this space.
Mm-hmm.
You have the efficacy, the safety, and the quarterly regimen that uptake from physicians and patients has been, we're very pleased to-
Mm-hmm.
to see the favorable results there. 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 non-inferior to the 25 mg regimen.
At nine months.
Essentially for two doses. Yes.
Mm-hmm.
It achieved its intended endpoint on the non-inferiority and the safety profile. What we did see was some return of the TTR reduction at the end of the biannual regimen, so towards the end of the six months.
Yes.
That's not aligned with the optimal target product profile that we would like to bring forward.
You want coverage. You want good coverage.
You want robust and sustained TTR knockdown. The third element that's really relevant to this decision is the TTRsc04 molecule.
Yeah.
that's right, behind and just started dosing in the phase I study. 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 molecule has the potential to provide, kind of led us to say, "Let's, let's streamline this, franchise development and focus on sc04 for that next molecule in the, in the line.
Were there potential IRA considerations into that strategy as well?
No. No, that was 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?
Yeah. Maybe a couple points there, right? HELIOS-B is our outcomes-based study for AMVUTTRA or vutrisiran in ATTR-CM. I think first and foremost, we're really encouraged because the APOLLO-B data that we talked about at the beginning of this discussion.
Mm-hmm.
really portends well, we believe, for HELIOS-B, right? 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. That, first of all, really helps us a lot in terms of thinking about all of those are important prognostic factors that relate to outcomes, right? HELIOS-B is, you know, roughly twice as large, and instead of being a 12-month study, goes out to 36 months, 30-36 months. It's considerably larger and longer. We feel very good about the design and conduct of the study. As you know, 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%. What's that?
You won't tell us what they are.
We have factored in that, you know, allowance of up to 50% was our operational target.
Mm-hmm.
in terms of percent of patients on baseline tafamidis. We've come in south of that. you know, the last we've spoke about, when we talked about taf drop-in, those rates have been low, and we've been comfortable with that as well. 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 2024.
Are you looking at the blinded event rate?
We have teams, you know, in any clinical trial that we're doing.
Mm-hmm.
We have teams looking, at the data, overall, primarily for study integrity purposes.
Right.
-to make sure that the study's 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 blind data and, you know, we're very comfortable with what they're seeing. We feel good, again, about the conduct of the study. It's also being reviewed by a data monitoring committee.
Mm-hmm.
They also continue to, you know. We feel good about the fact that their reviews have been uneventful. 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.
Yeah.
Hypothetically.
I think we are really committed to bringing forward this medicine to patients with this disease. It's obviously there's a huge unmet need, as Rena referred to. We wanna bring forward this medicine, and we're gonna do everything that we can to optimize our clinical trial to deliver that. Again, we feel good about what we've designed and what's being executed here.
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. Could you? Is it impossible?
I mean, it is, Ritu, so speculative.
Yeah.
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.
Mm-hmm.
we feel good about where we're at.
Okay. The next catalyst people are focused on ALN-APP.
Yeah.
You set the bar at 50% knockdown. Just to clarify for folks, this is the protein itself in the CSF, correct?
Not exactly. What we're looking at, maybe just as a, you know, zooming out for a moment.
Mm-hmm.
This is our first foray with an RNAi therapeutic into the CNS.
Mm-hmm.
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.
Mm-hmm.
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. 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, you know, to show safety and tolerability.
This is the first time delivering a drug into the CSF space, an RNA therapeutic, and also then knockdown. To your point.
Knockdown.
To your point around that, you know, we're not measuring APP directly, but we're measuring downstream cleavage products of that.
Mm-hmm.
which is soluble APP alpha and soluble APP beta. These are very good you know, these are proximal indicators of what level of knockdown that we're seeing.
Got it. It's the soluble APP alpha, soluble beta that you are expecting to hit that 50% threshold.
Yeah. 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.
When we talk about 50%, that's really a crude threshold from the context of when we've been asked, you know, what is the level of targeting that we'd like to see.
Mm-hmm.
Where we might expect to see therapeutic benefits in longer-term clinical trials, right?
Yeah.
That comes from genetic data, where we think that if we can get to about 50%, you know, 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.
Mm-hmm.
We're 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%.
Mm-hmm.
I will say that, you know, models here, preclinical data are limited, right?
Mm-hmm.
We have a strong therapeutic hypothesis that, you know, the antibodies have actually validated that, you know, the A Beta hypothesis that lowering amyloid can be beneficial. Certainly, there's a tremendous amount of residual unmet need.
Right.
I think all of us would believe, you know, want to see better therapies for patients with Alzheimer's disease. We think that by this mechanism, by going upstream, we can actually turn off the tap here in terms of amyloid production. Not only of full-length amyloid, but various oligomers and fragments that are developed, and not just extracellularly in the parenchyma of the brain...
Mm-hmm.
Actually intracellularly as well. 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. Again, in accordance with that, we think the genetic data would suggest that getting to about 50% knockdown.
Mm-hmm.
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? I mean, it's a disease of cognition.
Mm-hmm.
Of course, that tissue is easy to access. It's just the gray matter, essentially on the outside. Basically, if that occurs, if it's only knocked down on those tissues, sort of on the outside of the brain rather than the deep brain tissue.
Mm-hmm.
Would that have any implications to potential downstream clinical effects?
No, I think, you know, we do know that in Alzheimer's patients, certainly that there's amyloid that's deposited in multiple regions of the brain. You know, certainly, there's a lot of cortical involvement potentially.
Mm-hmm.
particularly in more advanced disease. We're, you know, we're going to be measuring the APP alpha and beta in the, in the cerebrospinal fluid.
Yeah.
which is really going to be coming from the total mass of the brain.
Mm-hmm. Got it. Is there any way to figure out if you're seeing knockdown in the deep brain structures?
There's no, you know, we're not directly measuring that.
Mm-hmm.
I mean, certainly what we've seen from non-human 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. We've shown data, now, looking at that-
Mm-hmm.
You can see, good difference.
What cell types?
Across, you know, neurons, astrocytes, glial cells, and into deeper structures in terms of striatum, thalamus, et cetera.
Okay.
A variety of cell types and tissues.
That's non-human primate brain?
That's non-human primate data.
Got it.
Yeah.
Okay. Any other biomarkers you're gonna be releasing with the top-line data? And if so, what do they mean and what kind of movement?
Yeah. I think the initial tranche of data will be focused primarily, as I said, on safety tolerability in soluble APP alpha and beta. 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, Aβ40 and 42, markers of inflammation, et cetera. We will also be doing neuroimaging through a variety of modalities, including volumetric MRI, et cetera.
Mm-hmm.
Those are gonna come in due course.
Not-
Those will not be the part of the initial tranche of data.
Got it. All right. Let's move to zilebesiran in the upcoming KARDIA-1 and KARDIA-2 readouts.
Yeah.
later this year. 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 two, the phase I/II on monotherapy.
Mm-hmm.
any reason to expect anything different in KARDIA-1?
zilebesiran, a very exciting program that can really fundamentally be transformational potentially for the treatment of hypertension and reducing cardiovascular disease. The ability to sort of tonically control blood pressure for prolonged periods of time, it's really very, very differentiated from anything that's come before and sort of addresses the fundamental problems we've had with blood pressure control. In the phase I study, what we saw was we took single doses up to 800mg , 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 20mm of mercury and lasting for up to six months.
Mm-hmm.
Really exciting profile and good safety and tolerability with that. The KARDIA-1 study is really trying to now expand on that experience. We're looking at a range of doses from 150mg- 600mg .
Mm-hmm.
regimens of every three months and every six months. Right. The goal here is to actually come up with the dose and regimen that will be used in pivotal trials.
Mm-hmm.
Any blood pressure reduction of 5mm diastolic is considered clinically significant. A 5mm systolic blood pressure reduction roughly associates or correlates with a 10% reduction in cardiovascular morbidity and mortality. It's quite clinically significant. I think based on the data that we saw in the phase I, we'll expect, you know, maybe even see something higher than that.
Even higher? Okay.
Than the five, yeah.
Than the five.
Yeah.
how should we think about KARDIA-2?
Yeah.
wrote that wrong. It's the combo therapy.
Yeah. Yeah, yeah.
You know, how will real-world use across larger centers and maybe better background control or maybe less good background control...
Yeah.
how should we be thinking about that magnitude of millimeter benefit?
Yeah. look, I think what we'll look to do there, I mean, both between KARDIA-1 and KARDIA-2, we're now expanding across them. We're gonna have almost 1,000 patients.
Mm-hmm.
in, you know, on this drug.
Mm-hmm.
I think that's gonna be really helpful to understand, and also patients with more cardiovascular risk factors or comorbidities.
Yeah.
We'll be exploring closer to the populations that we'll be studying in pivotal trials. You know, we're targeting this drug ultimately for patients with uncontrolled hypertension who are at high cardiovascular risk. Many of these patients are gonna be where there's a high unmet need.
Mm-hmm.
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.
Mm-hmm.
These patients are also now taking multiple medicines and polypharmacy is quite common in hypertension management. KARDIA-2 will really start to develop the data set about how does zilebesiran combine with other commonly used classes of medicines.
Yeah.
Diuretics, calcium channel blockers, and angiotensin receptor blockers. In terms of the magnitude of effect, you know, as you get on patients and you're using a therapy on top of one or two or other medicines, you often will expect to see that treatment effect may be somewhat lower.
Mm-hmm.
There's also synergies that happen. We know that RAS blockers combined with a diuretic can often have, you know, enhanced efficacy. 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.
Yeah.
We had some experience, both we've got pre-clinical data, but also phase I experience that says in, you know, in contrast to what may have been seen previously when you'd use two RAS blockers together, where there's really not additive efficacy. Again, in a very small cohort of patients, of about 12 patients, we saw about a 6.5mm increase or additive benefit of giving of combining the two agents. That's encouraging with no safety concerns emerging there. This will be a much larger experience of looking at that combination.
Mm-hmm.
It'll be quite interesting to see if there's additive efficacy and lack of safety concerns.
Just very quickly, you know, as we think about everything happening, KARDIA-1 and KARDIA-2 coming to fruition, APP at potential phase two start, and the potential ATTR-CM launch, how are you thinking about OpEx increases over the next three years as you know, as you reiterate a break even, I think, in 2025?
Mm-hmm.
Which was the important. Jeff finally put a year on it for so many years. Mid-term break even. 2025, break even. Is there gonna be a significant... Is he giving you a lot of money for that?
Um-
Money to anybody.
Jeff's been very kind to us, in development. look, I think we are very committed to our P to the fifth by 2025 goals, which includes profitability within the period. I think that really comes from two aspects. One is growing the top line.
Mm-hmm.
We've committed to, you know, an average of a 40% CAGR over the period. That's gonna be driven by all, you know, the existing products as well as what launches in hopefully cardiomyopathy. Then tempered and then balanced against that will be, continued investments in R&D and in the pipeline, and in OpEx overall. But maybe as an illustrative point, you know, in 2021, OpEx grew by about 16%. Last year was about 14%. Then the guidance, that Jeff just provided at our last earnings call, you know, we're forecasting the midpoint of the range of OpEx increase of about 13%.
Mm-hmm.
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 sort of meeting that profitability goal. That said, we have a very rich set of opportunities ahead of us. We have a very productive R&D engine, it's important that we continue to invest both in bringing more products forward, but also enhancing in our ability to bring medicines to patients in terms of investing in our AMVUTTRA field force, et cetera. We'll be working on all those things, but certainly you'll see a tempering.
Mm-hmm.
-of that and discipline around the OpEx, and the continued efforts on growing the top line. 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 for joining us.