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

Great. Thanks so much. It's my pleasure to be hosting a panel with Kirk Brown, who runs CNS Research at Alnylam. We just made this joke offline, but I'll say it online. This panel will not include 10 nuanced statistical questions on HELIOS-B -- but I am doing a dinner with Alnylam with Pushkal soon, so contact me if you're interested in that. But anyways, I'm really excited to talk about CNS because you guys have done some super cool stuff here. And this APP program is really under the radar, but it's kind of coming to a head soon with some longer-term data and so maybe some downstream biomarkers that I want to talk about. So Kirk, thank you. Do you want to just give like a brief background on sort of your -- what you oversee at Alnylam and the overarching efforts in CNS?

Absolutely. First, [indiscernible] Paul, I really appreciate it. I'm really happy to be here. So yes, so my role here, I oversee the CNS Research Group, which focuses on target biology as well as sRNA delivery approaches, which we -- some of that work back in nature of biotechnology in 2022. And essentially, that work applies the lessons that we learned from delivering to the liver. So that foundation of innovation that brought us chemical modifications that improved stability, potency and specificity and give us that durable planned pharmacology that we see in liver we've now incorporated into our C16 conjugates for the delivery to the CNS which, as we've shown, very nicely delivers up to the spinal cord and into the brain and even deep regions of the brain following a lumbar puncture intrathecal administration. And importantly, as it gets to the brain, we also see good distribution to a wide variety of cell types, including neurons, microglia, astrocytes and oligodendrocytes, which gives us somewhat of an agnostic approach and delivery approach, excuse me, to all the different cell types with this initial distribution delivery enhancement that we got. And so we're very excited about that. So my team then, in partnership with Regeneron, has been growing a CNS portfolio, which leverages this C16 conjugate platform delivery. And then you didn't mention about the ALN-APP program. I also serve as research lead on that program and oversee part of it of the ongoing research in that space. It is our lead program in CNS that targets amyloid precursor protein or APP, but the potential treatment of Alzheimer's disease as well as cerebral amyloid angiopathy or CAA. It's currently in Phase I [indiscernible] when we reported positive interim results last year in 2023, which as far as a research focus to see that clinical translation last year where we saw deep and durable knockdown of APP as well as the amyloid biomarkers, amyloid beta 42 and 40, which are the ones implicated in Alzheimer's disease and CAA. To see that movements relatively rapidly, consistent with what we had seen in preclinic species was particularly exciting to us.

Yes. Yes. Go ahead. Sorry.

And we've now initiated the multi-dose Part B. This is ongoing in Canada, where the majority of our Part A patients are enrolled and in addition to the Netherlands and U.K. We've actually now received clearance from the FDA to proceed with multiple dosing -- dose levels that include and exceed those that we have plans to evaluate [indiscernible]. And so with that, in totality, we believe these positive results do derisk our C16 [indiscernible] technology to provide us additional confidence as we look to enable many more CNS or preclinical targets for CNS. A couple of those will be HCT. It's another target of high interest to us for the treatment of Huntington's disease. This program is growing in ID-enabling studies as well as pursuing SB-1, targeting SB-1, a specific subset of ALS. Also occurred in -- yes. So last couple of targets I'll mention on preclinical spaces, we have programs that are ongoing, which I think I shared some of that data back in our D-day in December, targeting MAPT [indiscernible] tauopathies as well as [indiscernible] Parkinson's. And there we shared, in my mind, extremely exciting data, where we were able to treat and lower tau aggregates with a single dose part of the MAPT and those enabled improvements both in clearance as well as [indiscernible] benefit in those animals and also likely in the synuclein model disease, whether we treat pre or post treatment with the alpha-synuclein aggregates, we're able to clear those aggregates and also [indiscernible] benefit in that model. So -- what we find here is we've got essentially a modular platform, very consistent [indiscernible] in line with what we see in the liver now just focused on CNS and CS we couldn't really be more excited with [indiscernible].

Yes. Awesome. It's a great overview. So let's talk about APP as a target because I feel like the clinical data you've shown and the knockdown data you've shown, like there's not much to dig into. It's pretty, for better or worse, uncontroversial, which is great. So APP, I mean the main question we've had, especially for Alzheimer's is why isn't this too far upstream? And why isn't this functionally a retest of the BACE inhibitor hypothesis that ultimately didn't really show much on pet and I know base might have its own idiosyncratic tox issues, but at least from an efficacy perspective, like it wasn't even really close. Why is that kind of a misunderstanding at least in your view?

Yes. Yes. I mean it's a great question. I mean, the answer is we don't know because no one has ever really tried this specific approach before, right? No one has ever used a therapeutic to knock down messenger RNA [indiscernible] models. And what we can take away from the amyloid work -- amyloid antibody work, excuse me, is that they have moved the needle some, but haven't really been able to halt the disease progression. So -- we're trying this unique approach, which is targeting the messenger level, which is, importantly, in our minds, upstream of all of those downstream events. And in so doing, we actually reduced all AB amyloid isoforms as well as APP drive peptides, in particular, peptides that work intracell like the beta C-terminal driver. And so I will have -- we've gained confidence in the potential of this approach with preclinical models, one of which some of that data we shared, I believe in RNA [indiscernible] where a mouse model may be where we showed reductions in amyloid deposition with a knockdown. And importantly, the single dose, which was importantly durable in that study as well, reduce amyloid deposits in the brain, reduced inflammation and resulted [indiscernible] in certain behavioral phenotypes. And so we've seen that with the APP messenger RNA targeting approach, we are still clearing extracellular amyloid in a more natural manner, but also addressing the intracellular manifestation of the disease, some of which include endosomal lysosomal applications, trafficking issues within the cell. And so we're able to address all of those upstream amyloid fragments that are driving some of those intracellular manifestation of the disease, which the antibodies certainly would not be able to touch. And so we believe we have a unique and differentiated approach here. And I was going to plug in, so Len Deng from my group is a talented scientist who works a patient-derived stem cell space, recently shared a poster at ADPD and I would think we have that now up on our telesite for those looking in more detail. Here she used APP-targeting sRNA in the presenilin patient-derived neuron. And to your question of what else are we doing outside of the amyloid clearance, we see a correction of Rab5-positive endzone enlargement, which is common AD lines and in patient's brain samples. And importantly, in addition to the Rab5, we see also Rab7 reductions and, actually, which is one remarkable piece of data that came out of that, we see that using a multi-electrode array following treatment with APP messenger RNA, we're able to, when compared to healthy controls and a control sRNA, we restored the role of connectivity and synchronicity following sRNA treatment, which is essentially a functional correction of neuronal health roughly 3 weeks after a single administration of sRNA. So we're doing something functionally different and unique within the cell in addition to what would likely be an outcome of natural clearance of amyloid flats in the brand. So that's one of the many reasons why we're very excited. So I would definitely recommend those who [indiscernible] to take a look at that poster that was just shared with ADP for more details on that, it's pretty exciting.

Okay. Great. So as it relates to progressing forward in the Phase I study and looking at multiple ascending doses in Alzheimer's patients, do you want to talk about where you are there? And I guess our view has been that in a MAD study, you can look at things like p-tau, I'm not sure if you're doing PET scans, but maybe tell me if you are. But at the very least, you can look at some downstream pharmacodynamic biomarkers and have a better sense if you're having at least a preliminary impact on the more pathogenic amyloid species. Is that a fair characterization? Maybe you can expound upon that.

No, that is a fair question, yes. So as a reminder, part B, is our open-label multi-dose course in the Phase I. We're evaluating patients previously enrolled in Part A. And so the still -- obviously still looking at safety, tolerability and pharmacology. Our hope is, as you've mentioned, with multiple doses, we will be able to maintain this robust [indiscernible] APP alpha and beta reduction, our target engagement biomarkers throughout a full 12-month period and a follow-up period, but in addition to our standard target engagement biomarkers, the safety evaluations, we are embedding a comprehensive set of exploratory fluid, cognitive and neuroimaging biomarkers in that Part B study. So we believe this will allow us to explore how we're using APP protein reduction and prolongs planned pharmacology with multidoses will give us some glimpse into what might be a disease progression biomarkers. And just as a reminder, with 50 and 75-milligram single dose, we saw really robust target engagement in the range of 84%, 90% knockdown, so I believe the alpha and beta we shared last summer. And remarkably, even with a single dose, we see sustained pharmacology with 30% to 40% [indiscernible] biomarkers now to 10 months. So we are -- have the expectation that in second dose, 6 months time, we'll provide that even more robust new planned pharmacology to speak to some of these questions that you're asking, what are going on with the fluid biomarkers that are more exploratory, what's going on with cognitive assessments as well as the neuro imaging biomarkers, which are particularly important to us. I mean, as I said, we do have confidence in the cell and the body's natural ability to clear. We have seen that in AD models of disease. Just with single doses, we were able to produce amyloid burden in the animals after several months of treatment. There is some expectation that we would see some occur.

Okay. So when might we get that data, Kirk?

Yes. So the plan is to continue to report out data throughout this year and -- at various conferences and updates. I don't have confirmed dates to share.

Okay. But that's the MAPT data and that's some of this downstream biomarker data that we should be getting in the next 12 months or so. Is that fair?

Yes. That is fair.

Okay. Okay. Do you think -- what's your view on -- so I think like p-tau181 makes a lot of sense. Do you have a view on neurofilament and whether that is something we could expect to move in Alzheimer's?

Yes. I mean it's a great question. We are evaluating neurofilament and others as safety biomarkers, but also as important biomarkers of disease impact in neuronal health. And so it is something we are keeping an eye on here, it's on our list as a...

Okay. And just in terms of pursuing Alzheimer's, like I think you guys have talked about [indiscernible], Alzheimer's for this approach versus familial versus this kind of early onset population. Like to what degree are these like overlapping? And what is your sort of -- how would you kind of tier your focus here?

Yes, it's a great question. I mean, our -- the mechanism of action is likely to be successful in many AD patient populations. We started with the early onset patient population as a starting point. But you're right, numerous other AD populations certainly would be amenable to this type of treatment depending on how the results come from this first study.

Okay. Okay. And sorry, the first set is early onset Alzheimer's?

That's what we're looking at now, early onset.

And who is that? Like is that a more genetic population? Or is it like a little bit kind of grayer, right? I'm assuming these patients are probably, more likely than not, a carrier for at least 184 allele, but like what else sort of differentiates them from your run-of-the-mill Alzheimer's patient?

Yes, there are patients that are showing signs of AD at a much earlier age, and so we're going out to them. We're -- but as of the sanction, this is not an AD AD-patient population. We're not going after ABP direct mutation carriers.

Understood. Okay. What is the thought that this population is like more enriched than a later onset pop or a typical onset population?

More enriched for...

Potential for the drug to work.

I think our expectation is that the drug we have would be likely to work in early onset AD [indiscernible] and potentially spread.

Okay. Okay. Okay. Got it. Do you want to talk a little bit about CAA? I mean my thought has been that, look, Alzheimer's is hard, right? We'll have to kind of see how these questions related to knocking down APP and then the downstream impact on the ligamers and flags plays out. Everything you say sounds promising, right? But in the meantime, for CAA, like knocking down APP, you're much more proximal to the biology, given that monomers themselves are toxic. Like is that the right way to think about it? And I guess, maybe just can you speak a little bit more about CAA, the biology and the phenotype there?

Absolutely, yes. Yes. I mean, in some ways, you can think of CAA as someone analogous to ATTR amyloidosis and that the accumulation of analog deposits themselves are directly indicated in [indiscernible]. The difference here is that while ATTR amyloid deposits causes damage in the peripheral layers in the heart, here CAA deposits means cerebrovasculature cause vascular damage that leads to strokes and other bleeding events. Given the potential of our approach to shut the faucet off way upstream, we're moving aggressively here with [indiscernible] develop into CAA. So we do plan to initiate Phase II in CAA in the first half of this year. I believe we shared that.

Okay. Great. And maybe just CAA a little bit more on that is like a disease and the phenotype and natural history?

Yes. Yes. Yes. I mean, similar to AD, APP is a genetically validated target for CAA. For example, they are well-characterized autosomal dominant forms known as HCA or hereditary CA most notable, but that's type CAA. Here where mutations result in [indiscernible] vessels, which quite young age, 30s, 40s and 50s. Here, again, the accumulation of amyloid deposits can drive wild type CAA. Speaking generally, it starts with a like larger group of patients much relative to this patient population. Biomarkers here, which we report clinical development include measures of target engagement, similar to what we have [indiscernible] vascular activity to assess disease progression. We do believe this represents an important complementary disease opportunity [indiscernible] APP, our mechanism of action, to serve as potentially disease-modifying therapy which is particularly high in that patient case.

Yes. Okay. How do you plan on selecting patients with this? And in Alzheimer's, right, there's been kind of a long-standing establishment of at least where we think the window intervention is, right? You have to go early. Like with APP what might the ideal trial population look like?

Yes. No, it's a great question. I mean it is, I would say, somewhat under-diagnosed -- under-recognized cause of stroke. CAA pathology is actually quite common, especially in older individuals, moderate-to-severe CAA probably seen 20% of the population we need higher [indiscernible]. So only a subset will have the imaging abnormalities that would enable the clinical diagnosis of CAA. I mean, we believe the most significant unmet need here is patients with CAA to reduce the risk of stroke. It's the second most common cause of ICA during cerebral hemorrhage, after hypertension. CAA and ICAs have significant increase in [indiscernible] recurrence. So diagnosis of CAA is typically accomplished through neural imaging and, to your question, which has been increasing with obviously a disease where [indiscernible] diagnosed, which is a small fraction of them formally diagnosed. Underlying inclusive CAA includes hemorrhages and micro bleed that we see in the neuro imaging zone.

Yes. Okay. Makes sense. On the stroke side, so do you have a benchmark of like -- like can you run a Phase II study that is powered for showing a difference on the rate of strokes? Like how regularly are these events happening?

Yes. That's a good question. I'd have to divert some of some of clinical colleagues for a more specific around stroke occurrence.

Okay. Okay. No worries.

I would make the comments, we are confident and I can speak to my preclinical experience in models of CAA where a single administration of ABB-targeting sRNA in a rat model of CAA didn't reduce both [indiscernible] so it's a question of clearance, but also importantly, vascular accumulation of amyloid around the vessels. And importantly, what we learned from that study, 6 months after a single dose that we saw a clear difference in the amount of micro bleeds in those same animal group [indiscernible] clearance [indiscernible]. This gives us an incredible amount of confidence then in that mechanism of accident targeting APP upstream, reducing the amyloid production also reduces the amount that will impact the vessels, but also allow the vessels to clear those, compared to control animals, which have a much more significant amyloid beta 40 burden on the vasculature and less healthy vessels in study [indiscernible].

Got it. Okay. On the safety side, where are things out with resolving the clinical holds in the U.S.? And do you expect, as you do CAA Phase II, MAD to be generating data in the U.S.?

Yes. No, it's a great question. So just to remind everyone that they didn't place a partial clinical hold on the Part B multidose portion of our Phase I last year, this would be defining observed prior nonclinical product studies, which were done at very high, very frequent doses, much higher and more frequent than workers use in a clinic. However, as announced in our recent Q4 call, the FDA has confirmed a multiple dose can proceed at doses up to 180 milligrams given every 6 months. This covers all the dose regimens planned to be explored in Part B. But I would say, however, given the robust and durable efficacy seen with our 75 mg single dose in Part A, we think it's very unlikely we'll need to dose higher than the group [indiscernible] or certainly more frequently, given our ability [indiscernible] -- so we couldn't be more thrilled with this outcome, as it means we'll be able to proceed with our Phase I multiple dose studies at levels up to and exceeding what we've dosed previously in Part A. And we've seen great target engagement with as little as 50 and 75 milligrams. We're confident we'll be able to get our full appreciation for what's durable class [indiscernible] multiple doses. And just as a reminder, this has already been approved -- received with multiple doses in Canada, the U.K. and the Netherlands [indiscernible] study.

Great. Okay. Maybe to round things out on a technology perspective, you guys have this collaboration with PeptiDream. There's a lot of buzz in the CNS space around the use of transparent receptor. Without myeloma, I mean, you guys have been at the forefront of conjugation, where the kind of efforts here stand with the peptides? And any view on like looking at antibody conjugates or things like that?

Yes. No, I think you're absolutely right. I mean we've been thrilled with our C16 platform to date, demonstrating the potent and durable silencing, both through preclinical species and now clinical translation. This quite unprecedented, he does bode well for exploring systemic delivery doses across the blood-brain barrier. It's very little drug. It goes a very long way in the CNS, right? So that bar is relatively low with the amount [indiscernible] injected dose actually needs to get to the brain to see this amount of silence. And my colleague, [indiscernible] at R&D Day in December, did present some initial data with antibody SI conjugate, which I believe we showed up to 50% silencing across various brain regions with a single administration. So I think it's highly likely we'll be able to apply this technology to some of our CNS pipeline program. We've got quite a bit of work ongoing, full list of targets and approaches here, including and not limited to, antibody conjugates [indiscernible]. Yes, I think it's an exciting space and an incredible opportunity, given what we've learned so far with our pharmacology safety profile with RNA [indiscernible].

Yes. Okay. Great. Well, we're up against time. Anything that we didn't cover that you'd like to add, Kirk?

No, I'm thrilled with what we've seen so far being part of this program research from earliest days. Happy to see it progress as much as it has. [indiscernible] therapeutics for patients with [indiscernible] generate these diseases. It's just extremely exciting time.

Yes. Okay. Very good. Well, thank you for taking the time this morning. We appreciate it and look forward to more data.

Thanks so much. Thanks again for having me, Paul.

Okay. Awesome.