Alnylam Pharmaceuticals Inc at Canaccord Genuity Genetic Medicine for Generalists (Virtual) Transcript

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

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Definitely. Definitely. Excellent. No, thank you again for joining us today, and you are the perfect person to be having this conversation with today, I think. And I should also say for everyone on the line, we will start high level, as I said, and kind of drill down into the details as we go with a focus on the CNS pipeline. So I forgot to come up with like a HELIOS-B joke at the beginning, but assume I did, ha, ha, ha, laugh. Now we're moving over and focusing it on the CNS stuff because we are very excited about this as kind of the next area of the platform, as I know a lot of people are as well. So with that, as I said, taking it all the way back to the basics, what is RNAi interference? How does it work if you were kind of some of these brand-new -- what is this cool new thing we've been talking about?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : I like the analogy a lot. I love a good analogy. That's excellent. Okay. And so you mentioned it to turn off the faucet, it's kind of modulating kind of the expression of some of these genes. How does it do that? It's like binding to the RNA copy and then -- or not, explain to us how that works.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Got it. That's really interesting. And I guess, are all silencing RNAs or RNAi's, or RNA's sorry, that kind of turned down the faucet created equally? Are there different ways to go about this? And I guess what's kind of -- what's the special sauce, I suppose, about the way that Alnylam does it?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Okay. That's helpful. So as you just described, you have these modified RNAs, which maybe are not really RNAs anymore, but modified kind of to do their job, you're adding this ligand, I kind of like to think of it as like a tag or maybe a key, you're attaching to the molecule.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Yes, like an address, yes. Okay. So in the liver, that's GalNAc, and you all have made a lot of progress there -- progress there in that front. So yes, talk to us about the CNS. And I guess, maybe let's start off with in terms of the modifications that you make to the RNA itself. Are there -- is it the same modifications, do you kind of have to like start all over when you think about targeting the CNS or different organ systems as you go along the way?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Got it. Okay. That's helpful. And another really like taking it back to the basic type question for me before I turn it over to Joohwan on my team who's the expert to dig into the weeds a little bit further. But why is getting stuff into the brain so difficult?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Got it. Okay. Super helpful. I think I'm going to turn it over to Joohwan now to dig into maybe that [fat]. I think you mentioned attached to the molecules.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Excellent. So yes, that was a really helpful kind of introduction, I think, to how to think about APP. And you mentioned -- you talked a little bit about what goes wrong, but before we get there, I guess, what do we know about the APP protein. What does it normally do in patients who don't have an issue, I suppose, and then we'll kind of dive in a little bit more to what happens when they do. 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 25, 2024 / 5:00PM, ALNY.OQ - Alnylam Pharmaceuticals Inc at Canaccord Genuity Genetic Medicine for Generalists (Virtual)

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Helpful. And then, I guess, relative to CAA, you kind of just mentioned it, but in Alzheimer's, so you're saying the plaques or the clogging up of these proteins happen in the brain in the neurons themselves, but as you alluded to in CAA, it's happening -- same thing happening, but just in different cell types in the blood vessels. Is that right?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Got it. Got it. Okay. That's helpful. Once again, this is sounding a little like TTR to me. And like there, we were talking about heart versus neurons and maybe some patients have mixed disease. Here, it's sort of the same, but all on the CNS, that is interesting...

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Yes. Yes. Okay. That is helpful. And it seems like a fairly straightforward problem, I guess, as you set it up, related to APP, but has one that a problem that's been hard to solve so far, at least from an antibody approach perspective. So I guess, can you talk us -- talk to us a little bit more about kind of what makes this disease hard to target from an antibody perspective. You touched on it a little bit in the sense of kind of your approach is shutting off the faucet versus trying to, I don't know, chew up the hair clog maybe, but there's different antibody approaches as well. So can you help us understand maybe just where are the challenges and why maybe your approach which sounds to me like kind of going further upstream maybe is the better way to do it.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Got it. That's helpful. And a related audience question here. How is your mechanism different from BACE inhibition.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Interesting. Interesting. Okay. Okay. So just so I understand, and I am a little bit fuzzy on -- or I have not studied BACE inhibitors, let me say that. But so BACE inhibiting or BACE inhibition is sort of preventing the cleavage to prevent the fragments performing. Is that right?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Some of the fragments performing. Yes, yes. Okay. And you're kind of silencing APP would just be preventing the production of the thing that gets cleaved to begin with.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Yes, yes, yes. Yes. Okay. So that makes sense, as you said, kind of even further upstream. Got it. Okay. And then I guess, what's different about the Alnylam APP approach versus maybe other silencing or ASO approaches for this disease?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Definitely, definitely. Okay. Perfect. That's helpful. All right. So we kind of have talked about figuring out delivery. We've talked about APP itself, which kind of brings us to ALN-APP. What is the target product profile of this as you all set out to develop this program?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : So I'm getting myself because there's some beeping in the background, Apologies if you can hear that. So that sounds good. So you -- as you said, you're in a single dose study, and you mentioned this a little bit in terms of what you're...

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : True, true, true. Fair, fair. Yes. Fair points. You have progressed. But thinking about the single ascending dose setting, kind of what you were looking for headed into that. And you touched on this a little bit, but the alpha fragment, the beta fragment, 42 versus 40 for somebody, again, who's kind of newer to the space, like what are all of these different pieces? And what do they tell you maybe alpha versus beta 40 versus 42.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Okay. That's easy, that's easy.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Okay. Perfect. And then kind of going back to sort of the genetic validation of the target that you mentioned earlier, are there patients like can you go too far, I guess, can you -- if you turn the faucet all the way off, is that a problem here?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Got it, got it. Okay. That's helpful. All right. So kind of going back to then what you did see though in terms of knockdown after a single dose, and you alluded to this earlier, but you were seeing kind of remind us, I'll let you talk about it, but significant percent knockdown at the different doses for a certain period of time. And that all kind of met your expectations or at least check the boxes as you move forward into the next phases.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Okay. That's helpful. And then you mentioned Neurofilament Light Chain. So let's dive into it a little bit because it does -- like we hear about it a lot. You mentioned it in the context of safety, but can you tell us a little bit about what that is? You mentioned it's kind of a measure of the health of neurons. But what do we learn from that? What do you learn from that, more importantly? And is it just safety? Or is there an efficacy.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Got you. Okay. That makes sense. All right. And then moving over to the ongoing clinical trial and in particular, related to some recent our recent announcement related to the FDA lifting the clinical hold, allowing you to initiate in the U.S. at least multiple dosing in the Part B. Can you remind us, again, for people who may not be familiar, kind of what caused that hold in the first place? And how did you convince the FDA to move past it?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Got it. Okay. That makes a lot of sense. So yes, you are in multi-ascending doses, as you said. So as you move there, what new are you looking for, I guess, as you move from the single ascending dose, you're looking for knockdown and kind of duration. What's the next question as you move to multiple doses?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Got it. Okay. That's helpful. And you mentioned you're doing some imaging work as well. and maybe kind of going back to something we didn't actually talk about, but the early onset Alzheimer's population and kind of what the baseline image of their brains looks like and the potential time course of any changes there. I guess, can you talk us through that? And should there be an expectation that maybe you'll see something positive from a multi -- this current multi-dose study?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : That's fair. That's fair. Okay. So if you turn off the faucet, but the unknown is still like how big the hair clog is how fast the existing puddle is draining, so that's okay, okay. That makes sense. And understood. All right. That's really helpful. And then, I guess, the ongoing study is in the early onset Alzheimer's patients, as you mentioned. What are the next steps or plans in CAA? 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 25, 2024 / 5:00PM, ALNY.OQ - Alnylam Pharmaceuticals Inc at Canaccord Genuity Genetic Medicine for Generalists (Virtual)

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : And to follow up on that point on the safety side, and you touched on this a little bit, but why shouldn't we be worried about ARIA here, just because of the natural clearing process happening versus...

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Got you. Got you. Okay. Which I can imagine this is particularly important in the in the CAA patients, in particular, as you said. Okay. And so in terms of next steps, you are planning to -- well, actually, I should say, because you mentioned some Alzheimer's patients have plague in their blood vessels. Are there any -- do you have any hints, I guess, of CAA like early looks at CAA, I suppose, from your Alzheimer's patients, or do you expect to based on the enrollment in the ongoing.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Got it. Okay. That's helpful. All right. And then as you move into studies here, is there any reason -- or do you -- are you targeting any different level of knockdown or anything like that in this form of the disease, I suppose.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Very similar. Okay. So the dosing work that's happening on the Alzheimer's side is pretty reads through directly to CAA.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Okay. Excellent. Excellent. Okay. Really interesting stuff. I guess, as -- again, having solved delivery presumably and kind of starting to get some preclinical -- sorry, clinical data from the Alzheimer's side, as you said, how much in your mind, does that derisk the rest of CNS. So is it like, all right, as we talked about, we figured out C16 we now have shown it works in Alzheimer's. So now we're just off to the races in CNS? Or are there any kind of new technical or platform challenges as you move from target to target.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Okay. That's helpful. And you've talked about 2 new INDs by 2025, I believe. And as you just said, you kind of highlighted the SOD1, ALS as well as Huntington's as being IND enabling. So are those the 2 we should be thinking about, or are there others?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : That makes a lot of sense. And just to be clear, for the SOD1 and HTT programs, are both of those kind of plug and play in the sense that they are also C16, or have you talked about that?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Okay. Okay. All right. And just going back to something you alluded to earlier, all of these are kind of direct to the CNS dosing, but you talked about looking at our kind of continuing to work towards systemic dosing to target on CNS. So -- and you talked about kind of antibody conjugates in that regard? Have you guys laid out time lines, or I guess how much of focus is the systemic dosing to reach the CNS for you.

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : That makes a lot of sense. Okay, perfect. And maybe just a bonus question at the end, thinking about other tissue targets, and you sort of highlighted some of this at your R&D Day as well. But CNS is just one additional tissue target, and you're working towards some others. So can you remind us, where else are you focused for the -- in the nearer term, I can imagine you're probably looking everywhere, but for the nearer term. And kind of how are you thinking about accessing those from a technology standpoint?

Question: Whitney Glad Ijem - Canaccord Genuity Corp., Research Division - Analyst : Very interesting stuff. Perfect. All right. Well, this has been really interesting. I learned a lot. I think we -- as I said at the beginning, we're very excited about the CNS and the additional tissue types, as you mentioned as kind of the next wave of where this platform could go. Let me not -- we are also excited about HELIOS-B, and so we look forward to seeing those results in due course. But I think the minute that, that news is behind us. We'll all be talking more about what's next. And so we really appreciate you taking the time to walk through this side of the platform with us, and thank you all for joining us as well. We'll be talking to you all soon in our next installment of the series tomorrow. So thank you again, Kevin.