Alnylam Pharmaceuticals Inc at Stifel Virtual CNS Forum Summary

The following is excerpted from the question-and-answer section of the transcript.

Question: Paul Matteis - Stifel - Analyst : <_ALACRA_META_ABSTRACT>Great. Let's talk about APP as a target. I mean I think CAA, it's intuitive to me. I mean the monomers 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 mind around is, why isn't APP too far upstream, right? I think about someone Aimab that targeted monomers, very marginal benefit, right? You think about base inhibitors, right? And I guess in a world where amyloid starts accumulating 10 years before anyone has disease anyways like I feel like if you're not hitting APP when someone is 30, like are you really going to show a big effect? Obviously you guys have a sophisticated view on this. So what gets you excited?

Question: Paul Matteis - Stifel - Analyst : So how can you prove out this hypothesis? I mean before running a Phase 2/3 study with an 18 month cognitive endpoint within 500 patients, like walk us through the Phase 1/2 plan and when do you think we could expect to see something on P-tau or PET imaging or some sort of measure that kind of validates again that this isn't too far extreme, that this is having an impact on pathogenic amyloid species?

Question: Paul Matteis - Stifel - Analyst : People listen in what do you get when you measure amyloid beta 42, 40? What part of the pathway are you kind of --

Question: Paul Matteis - Stifel - Analyst : Monomers like what you're still talking about the early non-pathogenic subspecies. Is that right or is that wrong? REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. MARCH 18, 2025 / 7:00PM, ALNY.OQ - Alnylam Pharmaceuticals Inc at Stifel Virtual CNS Forum

Question: Paul Matteis - Stifel - Analyst : Any update for people listening in on the timing of when we can get that data on things like tau and pet?

Question: Paul Matteis - Stifel - Analyst : And what would be the duration of follow up by then of these patients?

Question: Paul Matteis - Stifel - Analyst : So 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.

Question: Paul Matteis - Stifel - Analyst : Do you want to talk a little about CAA? I mean I feel like this is overlooked. When we think about APP, right? It's this question of proximity to the pathogenic target is it's less salient, right, because the monomers are toxic. Maybe just give people a bit of a REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. MARCH 18, 2025 / 7:00PM, ALNY.OQ - Alnylam Pharmaceuticals Inc at Stifel Virtual CNS Forum background on the disease, the work you guys are doing there, and what are -- beyond biomarkers, what are the rights inputs to focus on?

Question: Paul Matteis - Stifel - Analyst : How prevalent do we think CAA actually is? It would seem like at least today, it's -- the diagnosis rate is probably very low. Is that fair?

Question: Paul Matteis - Stifel - Analyst : Anything else to add on CAA before we talk about Huntington's?

Question: Paul Matteis - Stifel - Analyst : Maybe give us an overview of you guys' efforts in Huntington's and yeah, look, from my perspective, right, I mean there's like I would love your perspective in Huntington's in general because on the one hand, right, it seems like 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 have this home and nursing failure which, the drug that Mivelsiran placebo on 6 endpoints, right? REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. MARCH 18, 2025 / 7:00PM, ALNY.OQ - Alnylam Pharmaceuticals Inc at Stifel Virtual CNS Forum 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?

Question: Paul Matteis - Stifel - Analyst : 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 1 fragment? Like where does this all kind of originate from and why isn't there like unequivocal agreement in space?

Question: Paul Matteis - Stifel - Analyst : Still an open question at all as to whether knocking down wildtech Huntington is safe. REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. MARCH 18, 2025 / 7:00PM, ALNY.OQ - Alnylam Pharmaceuticals Inc at Stifel Virtual CNS Forum

Question: Paul Matteis - Stifel - Analyst : What is the development that look like in Huntington's and beyond showing knockdown and 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?

Question: Paul Matteis - Stifel - Analyst : Well, maybe I'll turn it over to you. What else would you like to talk about in your CNS pipeline?

Question: Paul Matteis - Stifel - Analyst : Yeah. Tau's really exciting. Do you -- as you think about the relevance of tau model and like how important is the data from and so approach that's coming sometime next year? REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. MARCH 18, 2025 / 7:00PM, ALNY.OQ - Alnylam Pharmaceuticals Inc at Stifel Virtual CNS Forum

Question: Paul Matteis - Stifel - Analyst : Yeah.

Question: Paul Matteis - Stifel - Analyst : And as it relates to tau specifically, right, like what gives us confidence that targeting tau or targeting intercellular nuclei, like, is this going to be safe? I mean these -- like tau has a role, right, in normal brain development, neuronal cell integrity? What can we do to kind of diligence that question?

Question: Paul Matteis - Stifel - Analyst : As you think about your guys positioning longer term, do you guys have efforts internally? Are you looking externally at all at brain shuttle based approaches, right? I mean I think the interesting thing about what you guys have accomplished with your conjugation approaches you can get 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 the brain with transparent or something else via IV. Like is this something that Alnylam is going to be participating in?

Question: Paul Matteis - Stifel - Analyst : Kirk, I hope you don't mind. I'm going to 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 approval, and when are we going to get the next data readout from your program?

Question: Paul Matteis - Stifel - Analyst : Is there any reason to be concerned about the CSF assay with Huntington's? I mean I think with PTC, right, they -- correct me if I'm wrong, I think they're looking at peripheral Huntington, and then you know if you are right, they've had some noisy data. I know where seemed to have it figured out, and then of course that program was. So just like, yeah, your confidence in measuring Huntington. We can't measure the exon 1 fragment, right? So like what does biomarker data look?

Question: Paul Matteis - Stifel - Analyst : And you're comfortable that like the CSF assay is like reliable and has like a tight variance because I thought you had some issues. I don't know if it's the same assay.

Question: Paul Matteis - Stifel - Analyst : 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 drugs, these targets, and even for idiosyncratic talks are good predictors of human safety?

Question: Paul Matteis - Stifel - Analyst : Anything else to add before we wrap up, Kirk?

Question: Paul Matteis - Stifel - Analyst : 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.