Alnylam at Stifel’s 2025 CNS Forum: Advances in RNAi for Neurological Diseases

On Tuesday, 18 March 2025, Alnylam Pharmaceuticals (NASDAQ: ALNY) presented its strategic initiatives at Stifel’s 2025 Virtual CNS Forum. The company highlighted its RNAi-based therapeutic approaches targeting neurological diseases. While Alnylam is optimistic about its innovative C16 platform, challenges remain in navigating regulatory environments and ensuring effective delivery methods.

Key Takeaways

• Alnylam is advancing its CNS portfolio with RNAi-based therapies for diseases like Alzheimer’s, Huntington’s, and ALS.
• The company’s C16 platform focuses on intrathecal delivery to target mRNA, aiming to address downstream disease-causing protein aggregates.
• Phase 1 trials are ongoing for Alzheimer’s, CAA, and Huntington’s, with plans to expand to Parkinson’s.
• Future data readouts are expected later in the year, with a focus on biomarkers and imaging.
• Alnylam collaborates with Regeneron on the SOD1 ALS program.

Operational Updates

• Alnylam’s CNS portfolio leverages the C16 platform for drug delivery to the brain.
• MiBelseran, a lead program, is in Phase 1 for Alzheimer’s and Phase 2 for CAA.
• The Capricorn study is in Phase 2, assessing CAA’s hemorrhagic and non-hemorrhagic forms.
• An exon 1 targeting strategy is employed in the Huntington’s program.
• The SOD1 ALS program, in partnership with Regeneron, is in Phase 1.

Future Outlook

• Alnylam plans additional data readouts on its Alzheimer’s program later this year.
• A 36-month open-label extension will provide long-term data on various biomarkers.
• The company is exploring systemic RNAi delivery to the CNS, with promising early results in non-human primates.
• Alnylam aims to optimize blood-brain barrier delivery, working internally and with partners.

Q&A Highlights

• Questions arose about the appropriateness of APP as a target for Alzheimer’s.
• Concerns were discussed regarding the CSF asset in Huntington’s.
• The regulatory environment and potential for accelerated drug approval were addressed.
• The reliability of preclinical models as predictors of human safety was questioned.

In conclusion, Alnylam’s presentation at Stifel’s 2025 CNS Forum underscores its commitment to advancing RNAi therapies for neurological diseases. For more detailed insights, readers are encouraged to refer to the full transcript.

Full transcript - Stifel’s 2025 Virtual CNS Forum:

Paul, Moderator: Great. Thanks, everybody. It’s my pleasure to be moderating this panel with Kirk Brown, who runs CNS Research at Elmylam. I’m gonna mention this to people now so they don’t just ping me the questions if this is a neuroscience focused chat with Alnal. I mean, I’m not I’m not gonna be bugging them about the TTR PDUFA.

But, but with that, Kirk, thank you for taking the time. And, you know, maybe just set the stage for people and give know, a brief overview of Alnaim’s efforts in neuroscience, the different programs you guys have in the clinic and late preclinical, and then we’ll we’ll dive into each. So I appreciate it.

Kirk Brown, Runs CNS Research, Elmylam: Sounds good. Thanks, Paul, for having me on. I appreciate it. So little on the CNS portfolio at Alnylam briefly. So the sRNA platform for CNS is built off a foundation of sRNA developments and innovations, targeting the liver, essentially focusing on making an sRNA more potent and durable and more specific.

So we’ve applied all those learnings to our C16 platform, which enables the delivery to the CNS and multiple cell types across the CNS. With our partners at Regeneron, now NYLIM has now a growing portfolio which leverages the C16 platform. And it does utilize intrathecal administration, which we’ve seen fantastic distribution across the spinal cord, the brain and into the deep brain. For programs, MiBelseran is our lead program in the CNS. It targets amyloid precursor protein or APP for the potential treatments of Alzheimer’s disease as well as cerebral amyloid angiopathy.

This program is currently in a phase one study in early onset Alzheimer’s disease, where we shared initial data from both the single ascending dose and multiple dose parts of the phase one. And we’ve demonstrated potent reduction in the biomarkers of target engagements as well as encouraging safety profile in the early studies to date. And the Phase II is planned for later this year. My Belstra is actually also concurrently in a Phase II in cerebral amyloid angiopathy, which is a major cause of intracerebral hemorrhage, which is the most severe form of stroke. HCT is another program of high interest to us and high end net need for the treatment of Huntington’s disease and this program is currently in phase one in enrolling patients.

Then we have Regeneron who is leading the SOD1 ALS program And we have numerous preclinical programs and developments such as MAPT for tau and tauopathies as well as alpha synuclein for Parkinson’s disease. And we recently shared at R and D Day, a brief update on the delivery progress of our sRNA platform, sRNA platform, and we’ve shown that we can deliver across the blood brain barrier to nonhuman primates. So really, we’re particularly excited about what we’re seeing in the platform, both with our c sixteen platform and clinic and also what’s to come in the future with the sRNA delivery in the CNS.

Paul, Moderator: Great. Let’s talk about APP as a target. You know, I mean, I think CAA, it’s it’s intuitive to me. I mean, the monitors are toxic and you’re one step away. I mean, the analog to TTR, I think, is really good.

I think for Alzheimer’s, the question we’ve been trying to wrap our minds around is, you know, why isn’t APP too far upstream? Right? I think about somonizumab that targeted monomers, very marginal benefit. Right? You think about base inhibitors.

Right? And and I guess, you know, in a world where amyloid starts accumulating ten years before anyone has disease anyways, like, I I feel like if you’re not hitting APP when someone is 30, like, are you really gonna show a big effect? Obviously, you guys have a sophisticated view on this. So what gets you excited?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. Yeah. Great question. I mean, you know, first and foremost, APP is a genetically validated target for AD and CAA. Right?

We know the mutations in APP itself, as well as the enzymes that process it, drive early onset AD and autosomal dominant AD as well as CAA. We also know that duplications or even trisomy twenty one in Down syndrome also produce early onset AD and CAA. So APP is attracted to us for many reasons. There are clear biomarkers of target engagement, which can be measured in phase one. It’s cleaved into multiple soluble products, such as soluble APP alpha and beta, which are measurable in the CSM.

What we know from other approaches, such as antibody based approaches, is that they’ve targeted a variety, as you mentioned, of amyloid states and assembly states, monomers, oligomers, and others, and have had little success halting the disease progression. Honestly, we feel like targeting far upstream at the mRNA level, that’s something that others cannot, which are addressing all downstream products and assembly states of the amyloid as it accumulates and into plaques or in CAA aggregates along the vasculature. Importantly, RNAi can do things that antibody based approach cannot do. It works well both intracellularly and extracellularly and addresses those manifestations of the disease, particularly, intercellular toxicities that are come to know from neuronal health. So we’re excited by that.

Regarding BACE and and gamma secretase inhibitors, I mean, they’re targeting APP production, but at an enzyme, responsible for processing where, you know, they’re not, potentially the most specific or sole substrate of those agents. Whereas, with an sRNA, it’s it’s truly ultra specific, right? The substrate or target in their case is a complementary messenger RNA sequence of APP. So it is incredibly specific to that messenger RNA, therefore allowing us to have confidence in all reductions of downstream amyloid, both in the plaques and in the aggregates, as you said, along the vasculature. And we’ve seen that pre clinically.

We’ve shown preclinically that you can lower APP messenger RNA and see changes in both francima, as well as aggregates along the vasculature and preclinical models of CAA and AD.

Paul, Moderator: Yeah. Yeah.

Paul, Moderator: Okay. So how can you prove out this hypothesis? I mean, before running a phase two, three, you know, study with an eighteen month cognitive endpoint within 500 patients, like, walk us through the phase one, two plan. And when do you think we could expect to see something on, you know, p tau or pet imaging or some sort of measure that kind of validates again that this that this isn’t too far extreme that this is having an impact on pathogenic amyloid species?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. Great question. I mean, you know, we know from at least the early biomarker assessments of amyloid beta forty two and forty that we are similar to soluble APP alpha and beta reducing them in the CSF. We’re seeing clear target engagement. We see dose responsive effect.

Paul, Moderator: People listening in, where is what what do you get when you measure amyloid beta forty two forty? What part of the pathway are you kind of

Kirk Brown, Runs CNS Research, Elmylam: What part of the pathway? Where where is that g?

Paul, Moderator: Monomers, like, what what again, you’re still talking about the early non pathogenic subspecies. Is that right or is that wrong?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. That’s a that’s a fantastic question. I mean, that that it’s a really the critical question of, like, what is the source of the amyloid, right? Is it coming from plaques? Is there natural turnover?

Because we’re not aggressively targeting the plaque for clearance, which also potentially protects us from some, potential, ARIA like effects. But we are seeing those clear reductions, both of amyloid beta forty and forty two. But to the question of, when do we expect to see, we are collecting important disease progression biomarkers. We’re looking at amyloid PET as well as exploratory biomarkers. And we’ve just recently, modified the study to include an extension to capture longer term knockdown over the course of thirty six months, which will give us a pretty good clue into what’s happening both on exploratory biomarker front, pet imaging and also on biomarkers such as tau and neurofilaments and others.

And we’re very encouraged by the safety signal we’ve seen so far, right? I mean, after both single and multiple doses, we see essentially no impact on neuroinflammation, no changes in CSF protein or white counts. And importantly, neurofilament is holding even after multiple doses, which is quite encouraging, for our first foray into this space with CNS.

Paul, Moderator: Right. Okay. Any any update for people listening in on the timing of when we could get that data on things like tau and pet?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. So we’re planning some additional data readouts, later in this year. Okay. Stay tuned for the second vaccine.

Paul, Moderator: And what would be the duration of follow-up by then, these patients?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. So, as I said, we’ve expanded the scope. The open label extension now multidose will go out through, thirty six months. So that’s So

Paul, Moderator: you’ll have patients out beyond a year. Like, basically, I’m just trying to like, it’ll be long enough to really be able to get an answer on these things.

Paul, Moderator: Yeah. Okay. Yeah. We’ll have yep. Yep.

Good.

Paul, Moderator: Okay. Great. Do you want to talk

Paul, Moderator: a little bit about CAA? I mean, I feel like this is overlooked. When you think about APP, right, it’s this question of proximity to the pathogenic target is less salient, right, because the monomers are toxics. So maybe just give people a little bit of background on the disease, the work you guys are doing there. And, you know, what are beyond biomarkers, what are the right influence to focus on?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. So as I said, we started a phase two, the Capricorn study, looking at efficacy, safety, and pharmacology in CAA, both sporadic CAA, which is much more prevalent, as well as a rare Dutch type CAA, which is the genetic sort of ultra rare population, which affects folks at a much younger age, where they see recurrent strokes in the ages of 40 and fifties. And so, we’ll be looking at both, and maybe to your question, both hemorrhagic and non hemorrhagic manifestations of the disease. We have those two cohorts that I described, which will be randomized in the double blinds versus, my Belstrand or placebo for twenty four months. And then we have an open label extension there for eighteen months to assess additional safety and efficacy.

To your question around CAA, yes, it’s certainly under recognized cause of stroke, you know, but the CAA pathology itself is quite common. You know, it’s been argued that CAA pathology is seen upwards of twenty percent of the population and actually higher so in those individuals with Alzheimer’s disease and those comorbidities. And really only a subset will have imaging abnormalities.

Paul, Moderator: Yes. Okay. How prevalent do

Paul, Moderator: we think CA actually is? It would seem like, at least today, it’s the diagnosis rate is is probably very low. Is that fair?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. I think it’s I think it’s improving. Right? I mean, there’s the the Boston criteria two point o. But there’s certainly an unmet need for patients, with CA’s to reduce, stroke.

So, I mean, it’s the second most common cause of intracerebral hemorrhage, after hypertension. And, you know, there’s approximately eighty thousand or so new, or recurrent cases of ICH each year, which, you know, significant number of those will have CAA or driven by CAA.

Paul, Moderator: Yep. Okay. Anything else to add on CAA before we talk about Huntington’s?

Kirk Brown, Runs CNS Research, Elmylam: No. I think that’s good. Thank you.

Paul, Moderator: Okay. Yeah. Maybe give us, give us an overview of you guys’ efforts in in Huntington’s and yeah. Look, from my perspective, right, I mean, there’s

Paul, Moderator: like, I would love your perspective on

Paul, Moderator: just Huntington’s in general because, you know, on the one hand, right, it seems like there’s so much there’s so much to be excited about, like, biologically. Right? Like, it’s autosomal dominant. We understand the bad actor. On the other hand, right, it’s been really challenging.

I mean, you know, you have this Tomanirsen failure, which, you know, the drug that worsened placebo in six endpoints. Right? Like, there’s been challenges with the CSF assay with Huntington. Like, I feel like it’s I feel like there’s truly two sides of the coin here. And so in the backdrop of that, why is this an indication that Alnylam decided to pursue?

Kirk Brown, Runs CNS Research, Elmylam: I mean, you touched on I mean, it’s an attractive target for genetic medicine. Right? It’s a high unmet need patient population, and we know that we’re able to deliver well, to the brain and the deep brain. So Huntington’s is an attractive potential place for us to have disease modifying therapy. And we’re really excited about our Huntington’s program for a variety of reasons.

And you mentioned some of the other, you know, players or or failed programs. Our approach is quite differentiated from those. We’re including what’s known as an Exxon one targeting strategy, which is a toxic fragment that is produced from the expanded repeat, the greater the expansion, the greater the propensity of this alternate splice variance, exon one, a toxic peptide to be produced, in addition to the toxicity that’s associated with the mutant Huntington itself. Secondly, we know that we were able to hit Huntington’s quite well and deeply. We’ve seen, that we can show very robust silencing both in the brain and in the deep brain, and we can do so using our C sixteen platform, which is incredibly, encouraging with what we’ve seen so far in clinic as far as the emerging safety profile, as well as the duration of activity we’ve seen with APP lowering, we think it’s likely that it would be something around Q6M or even less frequent dosing in clinic.

So fewer intrathecal administrations, potentially, even a better safety profile there for patients with HDT.

Paul, Moderator: Okay. Why is there why is there such a controversy in this space around the right isoform? Or what is the actual driver of the toxicity? Like, is it full length? Is it the exon one fragment?

Like, where does this all kind of originate from? And why isn’t there, like, unequivocal agreement in the space?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. I mean, it’s a fantastic question. I mean, the there’s a growing body of evidence now supporting both from preclinical models through multiple preclinical models showing you that the somatic instability that occurs in in HTT with this expansion of the c a g repeat, does produce a much greater propensity of that shorter isoform. Preclinical models, longer CAG repeats correlate with increased expression of the one a fragment, and that shorter one a fragment is highly aggregation prone and therefore highly toxic in these rodent models of disease. And so multiple labs now have shown that lowering Huntington using the shorter exome 1a targeting approach, prevents the protein aggregation and other Huntington’s phenotypes much more so than just lowering the wild type or the mutant Huntington itself.

So literally addressing this aggregation prone effect much more directly by targeting the exon one fragment. But our approach, and just to clarify, we are not exclusively targeting the shorter 1a fragment, right? We’re also targeting the full length mutant fragment. So we should have this likely potential to address this question quite directly, the combination of lowering both the one a fragment as well as mutant Huntington, potentially to have some benefit here.

Paul, Moderator: Is it still an open question at all as to whether knocking down wild type Huntington is safe?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. You know, it’s it has been around for a bit, but I I’ve grown more and more confident with our preclinical work leading up to the to the program heading to clinic. We’ve shown both in in single and multi dose nonhuman primate studies that we can lower the wild type hungsten protein in the brain and deep brain striatum caudate, to the levels of 80 to 90% at the protein level and and, no adverse events or or toxicity noted. So we’re and these are long term studies, not just one month or two month studies and not in your primate. Long duration of silencing of Huntington’s protein in the brain and deep brain, in our preclinical workup.

So, you

Paul, Moderator: know, I

Kirk Brown, Runs CNS Research, Elmylam: think if we were to see something with, I mean, 90% knockdown is is quite robust. Right. Yeah. Okay.

Paul, Moderator: What does the development path look like in Huntington’s? And, you know, beyond showing knockdown in the CSF, what do you see as the clearest or easiest way to prove that there’s some downstream clinical benefit? Is it neurofilament? Is it something else? I mean,

Kirk Brown, Runs CNS Research, Elmylam: yes, fantastic question. I mean, the initial study we’re looking at PKPD and widespread engagements. We’re going to look at biomarkers of target engagements in the CSF. We are going to look at neurofilament in the HD population, which has been shown to elevate over time. The thinking there is we should be able to to hold it in in place or level that off, which should give us some confidence that we’re seeing at least, preserve health of the neurons as as the disease progresses.

Paul, Moderator: Yeah. Okay. Okay. Well, maybe I’ll turn it over

Paul, Moderator: to you. What else would you like to talk about in your CNS pipeline?

Kirk Brown, Runs CNS Research, Elmylam: I mean, we’re excited by a lot of the different programs that are coming down the line. We have, as I said, the SOD1 program that is run by Regeneron, currently in phase one dosing patients now. And I would really direct you to them for specific details on the study and and readouts. And we also have a partner program with them targeting alpha synuclein for Parkinson’s disease. A little bit, shortly following behind these are the c 16 targeting map t for tau lowering, which we believe has broad utility across a wide range of primary and secondary tauopathies, Alzheimer’s disease, PSP, dementia, and others.

I mean, tau is a pretty high profile target of interest in AD space, and and we believe, a genetic approach like ours has a potential to have great impact, both intracellular tau as well as extracellular.

Paul, Moderator: Yeah. Tau is really exciting. Do you, as we think about the relevance down line on, like, how important is the data from an ASO approach that’s coming, you know, sometime next year?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. It is important. I mean, I think, you know, it’s, they’ve shown that you can lower tau to a certain level, in the CSF and in in the brain. It’ll be interesting to see what’s, they’re able to share with everyone as it’s the first half of next year. Yeah.

Paul, Moderator: Okay.

Kirk Brown, Runs CNS Research, Elmylam: Yeah. We are following that program.

Paul, Moderator: Yeah. Okay. And as

Paul, Moderator: it relates to TAO specifically, right, like, what you know, what gives us confidence that targeting tau or, you know, targeting intracellular synuclein? Like, is this gonna be safe? I mean, these like, tau has a role, right, in normal brain development, neuronal cell integrity. And what can we do to kind of diligence that question?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. It’s a fair question. I mean, you know, none of these treatments are are are knockouts. Right? They’re not, permanent changes.

Right? And we can track a dose responsive change in in in in TAU both in the CSF and you can visualize it through the imaging, and we will obviously track safety biomarkers in these these trials as well.

Paul, Moderator: Yeah. Okay. As we think about your guys’ positioning longer term, do you guys have efforts internally or are you looking externally at all at, you know, branch shuttle based approaches? Right? I mean, I think the interesting thing about what you guys have accomplished with, you know, with your with your conjugation approach is you can get, you know, broader biodistribution, deep brain delivery, which is great.

IT is still not ideal. And it feels like we could be on the cusp, right, of delivering to the brain with Transparent or something else via IV. Like, is this something that Alnylam is gonna be participating in?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. Great question. I mean, I do think first, I wanna say that we’re pretty thrilled with what we’ve seen so far with our first generation c 16 platform in in clinic. Right? The beauty of this platform is that it’s both modular, reproducible.

We can drop on any sequence to the C sixteen technology and know that we can confidently deliver to the spine and the brain through a wide variety of cell types. And that’s an important distinction with the C sixteen profile. Right? It’s quite cell type agnostic. But we also believe that there’s gonna be a future where systemic delivery, of sirenates to the CNS is also something that should be an option depending on the indication.

And we’re gonna take this approach sort of as a CNS, target indication dependent decision. But we’re certainly playing in this space. My colleague, Vasant Jada, at r and d day, shared some early data from us, a few weeks back showing that we’re able to show a pretty robust silencing across the bbb, in nonhuman primates, which showed nice distribution both to the cortex, which is common with IT dosing, but also to the deep brain at comparable doses. So we’re encouraged by what we’re seeing there. But we also are planning it, somewhat as a biding our time wanting to have essentially the best in class approach, to BBB delivery, which, includes a variety of different targeting approaches that we’re exploring both internally and through partners.

Paul, Moderator: Yeah. Okay. Kirk, I hope you don’t mind. I’m gonna ask you one question that came in. I have filtered out any TTR questions.

So, even though I thought it’d be funny to ask one naively. But as it relates to Huntington’s, what do you guys think about the regulatory environment, the potential for accelerated approval and when are we going to get the next data readout from your program?

Kirk Brown, Runs CNS Research, Elmylam: A great question. I mean, I think, we’ll try to move as as quickly as we can, but we’re gonna let the data guide us, right? We wanna make data driven decisions. I mean, if we see encouraging knockdown and and potential, like I said, the the biomarkers of neurofilament, we see some some halting progression of neurofilament elevations over time. We’ll try to move it as as quickly as as we can.

But again, this first step is is safety, tolerability and and target engagement.

Paul, Moderator: Is there any reason to be concerned about the CSF asset with Huntington’s? I mean, I think with PTC, right, they correct me for wrong, I think they’re looking at peripheral Huntington. And then, UniCare, right, they’ve had some noisy data. I know Roche Hyona seemed to have it figured out and then, of course, that program was, you know, so just like, yeah, your confidence in measuring Huntington. We can’t measure the exon one fragment.

Right? So, like, what does biomarker data look

Kirk Brown, Runs CNS Research, Elmylam: Yeah. Biomarker data, at least in the phase one, will be mutant, Huntington, and the CSF. Yeah. It’s the c sixteen platform is unlikely to see changes of any sort of biomarker of Huntington in in the Huntington target Yeah.

Paul, Moderator: Plasma or something. So you’re comfortable that, like, the CSF assay is, like, reliable and has, like, a tight a tight variance? I I because I thought I thought you had some issues. I don’t know if it’s the same assay.

Kirk Brown, Runs CNS Research, Elmylam: Yes. I mean, it’s a fair question. Is it as tight as some of the biomarker assays we have for APP? Potentially not, but I think it’s engaged it shows enough target engagement and confidence that we’ve seen at least in assay optimization to date to to believe in it. So we’re confident moving forward with the mutant Huntington assay and CSF.

It’s a good question.

Paul, Moderator: Yeah. Okay. Okay. And then one other question that just came in, and I guess, you know, for Huntington’s or for tau, can we be comfortable that preclinical models for these for these drugs, these targets, and even for idiosyncratic talks are good predictors of human safety?

Kirk Brown, Runs CNS Research, Elmylam: Yeah. I mean, the preclinical models are often very exaggerated states. Right? I mean, whether it’s APP or Huntington or or tauopathies, but we have certainly in tau shown that we can reduce, aggregates in tau. We can see reduction of aggregates in in amyloid accumulation in preclinical, models of AD.

And same goes for, the exaggerated settings of the repeats of HTT. But as far as, you know, safety is concerned and engagement, we’re able to show that in in non human primates and are confident with that moving forward.

Paul, Moderator: Great. Anything else to add before we wrap up, Kirk?

Kirk Brown, Runs CNS Research, Elmylam: No. Thanks. This has been fantastic. I appreciate you having me on.

Paul, Moderator: Yeah. Thanks, man. I love to talk about neuroscience. So I appreciate it. And, thanks everybody for joining.

Yeah. We’ll see you on the next one.

Kirk Brown, Runs CNS Research, Elmylam: Thanks, sir. Take care. Thanks,

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