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

Great. Thanks very much. It's my pleasure to be on a panel with Akshay for -- I don't know how many of these we've done together, Akshay, but it's always fun. So thank you so much for attending. And for those listening, this is always, I think, a unique experience to talk more about what Alnylam is doing in neurology as that often gets overlooked, but it's now progressing pretty quickly towards going into patients. So with that, Akshay, I just want to thank you again.

And maybe just to start, could you sort of set the stage on your efforts in neuro and the status of your first couple of candidates?

Yes. Let's kick off by saying our efforts in neuro started a long time ago, actually, because the peripheral nervous system is part of the nervous system, as we all know. And with hATTR amyloidosis peripheral neuropathy and the approval of ONPATTRO, we were delighted that, that was our first foray into helping patients with neurological disease. Again, although it's not a disease primarily of the brain, hATTR amyloidosis causes a severe peripheral neuropathy effect in both motor and sensory function. People end up in wheelchairs and in their bed and a severe autonomic neuropathy. So that's kind of what we've accomplished. And the recent data for vutrisiran, which we shared in January, and we'll follow-up at AAN with the fuller data set in that population, I think, very exciting. So we have both intravenous and hopefully soon in subcutaneous TTR drug to offer patients in that space. So that's where we started. Now of course, a couple of years ago, we announced that we had delivery to central nervous system. And as we did in the liver, we built a variety of conjugates for delivery to the nervous system as in the brain and the spinal cord now, albeit intrathecal delivery. And we're delighted that we've shown knockdown against a wide range of targets in a wide range of cell types, all in animal models. And broadly speaking, some characteristics to keep in mind that we're excited about is as we deliver infrequent dosing, so it looks like we can -- when we get to the clinic, we hope to be able to find once every 6 months, once every 12 months intrathecal injections, which would be important for patients, and a degree of knockdown which, I think, would be better than anything achieved by any other oligo-based therapeutics based on the animal work we've done side by side. And also in terms of not just potency and durability but by distribution, so the neurodegenerative disorders encompass a large range of nuclei and foci in the brain, and we won't be able to get to all of them, it looks like we can achieve that including deep brain structures. So these are very differentiating features of our technology and what we're finding with our CNS conjugates relative to other oligo approaches, and I'm sure you'll be helping me get into some of those areas as we go on. But that's where it stands. And the first IND is coming up middle of this year. We're on track for that, a drug we call ALN-APP that will be going towards the Alzheimer's space and the cerebral amyloid angiopathy space. So that's the intro, really. You're muted, Paul.

My God. Great. All right. So biodistribution is actually something I really wanted to talk about because I think we have no idea, but there's been speculation in the investment community and the medical community on the recent failure of tominersen in Huntington's given that mutant HTT theoretically is an awesome genetically validated target. And if I do some guessing, it feels like biodistribution could be a culprit. And so with ASOs, we really don't see as much knockdown in the deep brain. And kind of all of the biodistribution work when we have CSF data is triangulated off of smaller animal brains. So can you talk about the work you've done and anything you can kind of point to quantitatively on biodistribution in different areas that affirms your confidence at going into whole brain diseases like your first indication and maybe even like Huntington's eventually, too?

Yes. I think there are 2 aspects to discuss, Paul. One is on the pharmacodynamic side, and hopefully, that would then translate to the clinical efficacy side. On the pharmacodynamic side, you've got both the potency of the oligo approach you're using as well as the biodistribution. And so to achieve optimal PD in a disease like, say, Huntington's, you want intrathecal injections. You want probably north of 50% knockdown in key foci like the basal ganglia, which are the striatum, substantia nigra, et cetera, in deep brain, right in there. And we've been able to show both in small animals like mice and rats as well as in nonhuman primates that we get 50% or greater knockdown basically in all areas of the brain from a single intrathecal injection. And that knockdown will last of the order of 6 to 12 months, we believe, once we get to humans based on the animal data. Clearly, we've got to get to humans and show all that. And -- but the animal work in the past has translated very well for us when we look at our liver portfolio going from animals to humans. And so we're very optimistic about doing that with our lead program, ALN-APP. And then hopefully, that would presage well for these follow-on programs like Huntington's. So I think that data is in hand. We shared it at R&D Day last year. We've shared it in other forums. And people can go on our website and look at those data. We're going to start publishing it as well. So I think that's really important. And that's a kind of pharmacodynamic threshold in terms of potency and biodistribution that's not been seen with other technologies. And the reason for it, I think, is probably largely to do with, a, the intrinsic potency of RNAi versus other oligo approaches; and b, the delivery systems that we use. So recall that other oligo approaches to date have not used any kind of facilitated delivery mechanism. And so generally, that's -- if you look at other parts of the body, that's ended up being an inefficient way to get an oligonucleotide into a cell. We always chose to have a delivery system for our sRNAs, and it worked well in the liver, as we've all seen. The same approach now for the central nervous system. And so we have more efficient uptake. We get broader biodistribution and uptake. And I think that accounts for what we're seeing, intrinsic potency and delivery mechanism. And then the other side, from the pharmacodynamics/clinical efficacy is [ to go to ] safety. And of course, exposure is important, and the recent work of antisense oligonucleotide companies like Ionis and Wave is very important. And of course, the groundbreaking work in SPINRAZA was fantastic by our Ionis colleagues and the investigators that worked there. But I don't know if they can get the same level of knockdown in higher brain structures. The Huntington's data would suggest not. The other concern, of course, is they've pushed dose. They saw NfL elevations and signs of neuro-inflammation. And to date, we haven't seen that in animal systems, right? And so we're going to have to show that again in the clinic. So both from a potency, durability, biodistribution, which should give good pharmacodynamics, including in deep brain structures as well as the safety, neuro-inflammation side, we think we've got a technology that can serve patients well. And the ALN-APP will be the start of our journey, and the biomarker data and safety data will be very important in that regard.

Awesome. Great. So can you talk about this initial indication and what's exciting about it? How genetically validated is your target? And do we have a good understanding of what a goal knockdown level would be that can impart clinical benefit?

Yes. So the initial forays with ALN-APP amyloid precursor protein, I think most in the audience will be familiar that this is a genetically validated target, and anyone that follows Alnylam knows that we're always very interested in genetically validated targets. That's worked well for us. And there are people with APP duplications and triplications that are predisposed to Alzheimer's. There are APP mutations that are predisposed to Alzheimer's. So there are a number of autosomal dominant forms of Alzheimer's that -- where the dementia starts earlier in life as opposed to later in age, in 60s and 70s. And so this is truly, we think, a genetically validated target. So we're very interested to start in a so-called autosomal dominant Alzheimer's disease, ADAD, population. And so the Phase I, we'll focus in. You can't do these kinds of Phase Is in healthy volunteers for good reasons. So we'll be focusing on the disease population that can hopefully get some benefit as well. And look, in animal models, we've seen well north of 50% knockdown of the relevant APP and Abeta-related biomarkers in the cerebrospinal fluid. So we hope to recapitulate that. Obviously, we'll have to carefully dose-ascend and document that. Again, there's lots of room for optimism because translating from animal to human has been quite predictive for us in the past. And so that's kind of the initial foray with ALN-APP into the ADAD space. Now I would also add that APP is a very important pathogenic protein in human disease. And there are forms of Abeta -- mutant forms of Abeta that also cause a very specific vascular deposition in the cerebral vasculature and lead to so-called cerebral amyloid angiopathy, which is a distinction from Alzheimer's disease. And it's got that A word in there, amyloidosis. So we're interested in that. And we really do believe that if you -- just as we did in hATTR amyloidosis, if we turn off the tap and reduce the levels of APP, then when we're reducing the amount of amyloid protein depositing in those vessels. And hopefully, those folks can benefit from their major problem, which is the vascular deposition of Abeta leads to micro bleeds and then major cerebral hemorrhages. And there's both an inherent -- just as in Alzheimer's, I spoke about ADAD and the sporadic Alzheimer's, in cerebral amyloid angiopathy space, there's an inherited form, which is very rare. But a very large fraction of patients with CAA have sporadic disease, and there are hundreds of thousands of those in the U.S. alone. So we see a very good application of our strategy of starting with genetically validated targets, starting with well-defined genetic populations and going to the broader population. Initial goal will obviously be safety and biomarker knockdown.

Yes. Okay. That's great. Well, in this initial study, I don't know how much you can say yet about the design of it. If you can speak to it, I think that would be great. But beyond showing knockdown in the CSF, is this a type of study where we could get a sense of clinical benefit or even something in between where you show knockdown of your target and then also show maybe a favorable change in neurofilament that could be corroborated?

Yes. I mean it is early to call. We haven't filed the IND/CTA yet. So once we file that, we'll be showing a lot more about the study design. And given that patients are participating and willing to take an intrathecal injection, it's obviously important that we do everything we can to characterize the drug from a safety PK and also, hopefully, from an efficacy perspective. And there are a number of things beyond the pharmacodynamic biomarkers related with APP and Abeta that can be measured. You've mentioned one, NfL. There could be others, and we will share that when the time comes. But we should all be very clear, right, that this is the first IND/CTA for our CNS programs. It's our first journey into that space. So yes, demonstrating safety, PK, is the target being engaged, is it not. And these are the primary early goals. And then we'll see beyond that what we can achieve. But we'll obviously try and do best for the drug and for the patients to not just characterize it but see if we can help these patients.

Yes, yes. Okay. Great. Well, let's talk about one more CNS indication, and that is Huntington's. And you spoke to biodistribution as an advantage, and maybe that's a [ culprit of tominersen ] but -- of that failure. But what else is kind of different about your Huntington's program? And I know you've also talked about finding a target that inhibits full length in the exon 1 fragment. And so maybe speak to why, based on your work, you guys think that that's a compelling approach?

Yes. I mean historically, the field has been built on the idea that knockdown of full length will -- there's an autosomal dominant disorder where 1 of the 2 genes is mutated. And allele-specific approach is -- they may be possible using an RNAi approach, but there are also some challenges there. But conversely, the field has been built on the idea that if we knock down full length and take down the wild type, which is probably participating in the disease, but there's a debate around that as well as the immune allele messenger RNA, then that should translate to efficacy. And there's certainly animal data to support that. We and others have generated that in the past. So that's one important approach, and we believe in that, and we are studying that. And let's keep that in mind that the field is very supportive of that. Now more recently, in the last few years, there's been increasing interest on the exon 1 transcript from the mutant allele. And it seems that there may be truncated forms of exon 1 transcript that are not full length.

Yes.

That those truncated exon 1 transcripts maybe contribute to the pathophysiology, either at the transcript level or truncated protein level. And so there's great interest in thinking about that as well. And we believe those data. We like those data. And so in parallel to a full-length effort, we're also intensively exploring an exon 1-based effort. And there are a number of options. So one could go with a full length and test that hypothesis. We could just go with the exon 1-specific approach. You could even imagine what we call BIS, which is you try and take down both. We're working through all that right now, Paul, and we'll obviously update folks as we get closer to the definition of the product we're going to take into the clinic. But I think the recent events -- and it is very sad that a number of these programs obviously were stopped last week. And there's an area of enormous unmet need, and I think one feels for the patients here. And hopefully, we can help and make up for some of the setbacks that field had experienced. But we'll look at both approaches, and our technology is certainly enabling us to take one or both those approaches.

Yes, yes. Okay. Great. One more CNS question before maybe I throw in there this vutrisiran update in the spirit of AAN and then talk a little bit about opto and neuromuscular. And that is on the CNS side, you alluded to your peer in the ASO space in neuro pushing the dose and maybe that leading to tox. Is there anything you can say about the dose levels where you think you're going to get robust target engagement and kind of your broader confidence in a therapeutic index?

I mean I don't know...

Sorry, I didn't mean to put you on...

No, no, no. I'm just trying to get my thoughts together how best to answer this. So for us, to date, the CNS journey really has been very encouraging from a safety perspective. So it looks like we've got a wide margin. Now our experience is much more limited. And I want to be sure that Ionis and other colleagues have done fantastic work in the CNS space. There's an approved drug, SPINRAZA, which is helping patients. That's great. We've got to do all that, right? But so far, at least in our preclinical work with ALN-APP and other programs, we're seeing very encouraging window from a toxicology perspective. So I don't feel like we're necessarily constrained in terms of an upper bound right now. We'll -- again, when we share the ALN-APP Phase I design and the dose range, we'll share why we're going in that dose range, why we think the upper dose limit is what it is and why we've set it and so forth. But we feel really good about that so far, and hopefully, that translates. Now again, the liver stuff translated very well. And if we do translate them, that's great because I think there are these 2 major disease areas we spoke in Alzheimer's, HTT that we can try and make some impact soon.

Yes, yes. Okay. Great. Maybe just quickly on vutrisiran. I think -- I'm sure anyone who's listening here knows this program, your TTR franchise extremely well. But as we kind of get ahead of this AAN presentation, any couple of things that you'd like to highlight? And I guess my one question would really just be, I think everyone is going to rush and try to take these data and superimpose them onto the APOLLO-A data. Is that a reasonable way to contextualize it?

Yes. I mean look, at the highest level, some expectations we had for vutrisiran that others, I'm sure, also shared and you'll be able to examine the data for is as far as the neuropathy is concerned and the primary goal is the neuropathy, do you get mNIS changes that are of a similar magnitude? Do they do the percentage of patients that improve with the drug that similar to APOLLO? After all, the study was designed to closely mimic APOLLO. We think we kind of achieved that. But again, most people on this call know that comparing between studies is fraught with certain challenges, and you can never do exactly the same study twice. But as we shared at a high level in January, we're pretty pleased. We think that we've seen an impressive recapitulation, by and large, of the APOLLO data. And we're going to be excited to show that at AAN. And obviously, there will be now more details of the mNIS, and the mNIS is the primary endpoint for the neuropathy. MNIS changes over time, proportions improving, 10-meter walk test, the quality of life. We really think that this is going to be -- got to get through the regulatory process, of course. But once pending that -- all of that being done, we think this is a wonderful, at the very least, equivalent opportunity to ONPATTRO for patients, if not better in certain regards. So that's a pretty important contribution for these patients, I think, and to be able to take them once every 3 and then 6 months because we're going to be now studying q6 monthly dosing with vutrisiran and having ONPATTRO-like efficacy both in terms of the neuropathy but also some of these other areas we're interested in, that's what we hope to offer patients. And I think the AAN presentation will give people a good insight into that and be allowed to conclude for themselves whether what I'm saying now is something they agree with or not. But that's our sense of debate.

Yes, yes. Okay. Biannual dosing, does your confidence in that come from animal data? Or does it come from actual human data where someone has only gotten one dose and then you've just seen TTR lowering persist?

Yes. So both. So we have enormous amounts of animal data and pharmacology modeling we do on the animal data that allows us to, for the liver compartment, predict very nicely doses and regimens we want to go forward with in humans. So that all points to q6 monthly of 50 milligrams doing the trick, so to speak. And then in the Phase I itself for vutrisiran, there are data there that -- well, smaller numbers because it's a Phase I study. But when we model that, we, again, came to the same conclusion that we could go to 6 monthly. And so there's a combination of both human and animal data. And of course, at this 9-month time point with HELIOS-A, there was an additional data tranche that's further validated our belief that this can really be done effectively for patients and achieve similar clinical outcomes and not just pharmacodynamic outcomes. So we feel pretty good about that. There's a good amount of science behind that, both from animals and human setting.

Great. Awesome. A couple of last questions, Akshay, and that is you talked about your work in TTR as you work in neuromuscular. What's your view on some of these next-gen conjugation approaches for neuromuscular? It looks like there's some promising animal data in the space, and it seems like a very logical area for Alnylam to play at some point.

Yes, yes. I mean -- and I guess in this regard, you're talking about further expansion of the conjugate space with...

Peptide conjugates, yes, right? And then in NHPs, you're seeing like a meaningful improvement in therapeutic index.

Yes. I -- look, I just think this decade is going to be so exciting because Alnylam was started with the promise of any gene in the genome. And I kind of, over the years, in my mind have expanded to, hopefully, any disease in the body. That really means getting to every tissue, right? If you look at the work we've done in the liver and now the emerging work in the CNS and the eye, which is animal-based so far, I think this modality, as John Maraganore, our CEO, said, this is a new class of medicines. And to realize its full potential, we're going to have to get to all these different tissues. I think the data we're seeing from us and others with respect to other tissues like muscle is real. And I think it depends what oligo platform you're using for optimal results. I obviously think RNAi is the best way to go if you're going to deliver to these other tissues. But we have a sizable effort beyond liver, CNS, eye. We've talked about lung at R&D Day. There are other tissues we're working on. And there's a full range of modalities that we're also exploring in terms of delivery technologies to get to the dream we started with any gene in the genome, any disease in the body. So I think this decade is going to see a massive expansion of the range of tissues that oligo-based therapeutics will get to. And I do still retain the hope, based on data, that the most promising and powerful technology will be RNAi as opposed to all the oligo-based technology because it's an intrinsic powerful mechanism that we're harnessing. So you'll see from us in the coming months and years additional data on new tissues.

Yes. Okay. Okay. Great. Anything you want to just finish with on your efforts in the eye? I mean that's an area that some oligos have played in before. What's unique about what Alnylam is doing and could offer there?

Yes. I mean I think the eye is another -- look, it's great fun planning with Regeneron for CNS and eye. There are 2 very important things for the eye, of course, is that they are experts in the eye. And secondly, they have a range of genetically validated targets to do with the eye that are both the anterior chamber and the posterior chamber. So there's a lot to do there. We are grateful that we've been able to show the potency of RNAi, at least in the animal setting, with knockdown in the microgram injection range. I mean we've seen fantastic knockdown in the 5- to 10-microgram per eye range in animals -- large animals. That's impressive. And so we're busy translating that to development candidates. And in the coming years now, you're going to start seeing IND/CTAs from Regeneron because they're the ones that will develop it once we hand it off to them for the eye. And it won't just be -- my prediction is that it won't just be for retinal disorders. It will be for a range of ocular diseases and for some really super well-validated genetic targets. So that's exciting.

Awesome. All right. Great. Well, look forward to AAN and everything else that you guys have going on in this year and the other years to come. So thank you so much, Akshay. It's always a pleasure.

Thanks very much, Paul. It was fun. See you soon.

You, too.