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

Good afternoon, and welcome to this special topic discussion RNA interference, strategies for success outside the liver. My name is Keay Nakae, and I'm one of the senior health care analysts here at Chardan. Joining me for this discussion is Dr. Pushkal Garg, Chief Medical Officer at Alnylam Pharmaceuticals. Dr. Garg is an influential thought leader in the area of siRNA therapeutics. Dr. Garg joined Alnylam in 2014 with 15 years of experience in clinical drug development. At Alnylam, he oversees all clinical development activities. He also serves on the Board of Directors at SQZ Biotechnologies. Pushkal, welcome, and thank you for being with us today.

Thanks, Keay. Delighted to be here. Thanks for inviting me.

[Operator Instructions] So Pushkal, clearly, we've hit an inflection point in terms of investor confidence regarding the ability to effectively deliver siRNAs to the liver. Alnylam's ONPATTRO was the first FDA-approved RNAi therapeutic. GIVLAARI is your first-approved RNAi using a GalNAc-conjugated ligand delivery approach. FDA approvals for inclisiran and lumasiran are expected by the end of this year. While there are still plenty of attractive targets in the liver, all of the RNAi-focused companies are looking to expand their therapeutics to targets beyond the liver. So the goal of this discussion is to better understand what is required for RNAi therapeutics to replicate the success outside the liver. So to start, let's take a step back. As a pioneer in advancing RNAi therapeutics as a whole new class of medicines, by definition, forces you to try some unproven things. However, this provides you an advantage in being able to learn from both your successes and maybe more importantly, your failures. So can you tell us what you know now that you didn't know back in 2010? When I first picked up coverage of names in this space, about 3 critical components in the playbook for success going forward. I know these are all interrelated. But first, let's talk about pursuing validated targets; second, strategic use of stabilization chemistries; and third, delivery technology. So let's talk first about pursuing validated targets.

Sure. Yes. No, as you point out, Keay, the field of RNAi therapeutics has advanced quite a bit in the last 10 years. So I think if you think about the validated targets aspect, in 2011, we actually announced our 5x15 strategy with the goal of having 5 investigational RNAi therapeutics in the clinic by 2015. And in fact, we exceeded that goal, and many of the molecules that you see now, either approved or in a late-stage pipeline, are products of that initial 5x15 strategy. A critical aspect of that strategy was that we were going to focus our efforts on genetically validated targets, and that has been a really critical aspect of our success. So looking in the literature, looking in databases for molecules where there was potentially gain-of-function or loss-of-function mutation that we could then take advantage of to understand what the impact of an RNAi silencing approach would be both from an efficacy and safety perspective. As I said, that's really led to where we are in terms of our pipeline. We also coupled that with making sure that in our development programs, there were active biomarkers that we could follow. So we could look at early stage whether there was knockdown of a target protein and ideally, a disease-related biomarker that would give us confidence moving forward. All of that has really led to what you may have seen at our last R&D Day, which is really a remarkable amount of productivity or success in advancing molecules through the pipeline. So our success rate of going from IND to a positive Phase III is about 50%, which far exceeds the industry averages, which are under 10% probability of success. So I think this real focus on human genetics as a way for target selection and a biomarker have been critical to our success and something we're going to continue to capitalize and leverage upon going forward.

Yes. Great. I know that's one of the favorite slides that investors like to see or hear about. It's just an impressive track record there. So let's talk about stabilization chemistries. Now obviously, we've got backbone modifications. We've got 2 prime carbon modifications. And while we know about them, tell us how important it is to know how to strategically employ them.

Yes. So I think -- as you point out, we are fundamentally a platform company. And so we are always working on the underlying platform technology to learn from our experiences both preclinically and clinically and then to continue to make improvements in advance. I think if you kind of look back, the first GalNAc-conjugate that we took into the clinic was revusiran, which also targeted TTR, required about 500 milligrams weekly to suppress TTR. We're now advancing, and that was based on our STC, or standard template chemistry. We've now advanced to next generations of our underlying backbone to what's called ESC, Enhanced Stabilization Chemistry. And what that included was a series of modifications to actually reduce the vulnerability of the siRNA to endo- and exonucleases. As an example, vutrisiran, which also targets TTR and is in the clinic and is a GalNAc-conjugate, actually has doses of 25 milligrams once a quarter. So 100 milligrams total over the course of a year as opposed to about 26 grams for revusiran. So it can show you what these modifications have really enabled us to do both in terms of reducing the amount of drug that's needed as well as increasing the potency and durability of these molecules over time. And so that really allows us to go after -- improve sort of the accessibility of a broader range of indications when you have that kind of a dosing administration profile as well as tolerability profile. And we've since, and I know we'll talk about this in a bit, made further modifications to even go to ESC+, and that further enhances the therapeutic window of these molecules.

Well, while we're on that topic, let's just stay there. So you did go from ESC to advanced ESC, and now you're at ESC+. So what is that looking to do -- how is that looking to advance the science and the performance of the sequences?

Yes. So when we were taking our ESC molecules into the clinic, as I said, we were seeing increasingly that we were able to increase the potency and durability of these molecules. We did see that certain molecules on a sequence-specific basis were associated with a low incidence, about 2% to 3%, of liver transaminase elevations, ALT elevations, typically. These were typically mild, asymptomatic and reversible. Well, we undertook a pretty detailed investigative science approach to understanding what was going on. And what we understood is that some of these sequences, by virtue of their seed region or the specific sequence there, were hybridizing to off-target transcripts and that was perturbing the transcriptome. Most of the time, that's a silent event. But in certain instances, we think that, that sort of effect on off-target transcripts was actually contributing to the transaminase elevations that we've seen. The way we address that is through our ESC+ technology. And what that does is it introduces a sort of a thermodynamic instability in the siRNA, sometimes, for example, by including a GNA, or glycol nucleic acid. And what that does is it preserves the potency or affinity for the target transcript, but it actually reduces the affinity for the off-target transcript. And so as a result, the therapeutic window widens. And so we are able to show preclinically that, that was able to aggregate some of these LFT elevations that we're seeing. And likewise, we've now shown and presented publicly data from 2 molecules, our alpha-1 antitrypsin molecule and as well as one targeting hepatitis B, that inclusion of these ESC+ chemistries actually can improve the therapeutic window with RNAi therapeutics. And so that is something that we -- is also in our toolbox that we can reach into as we screen for new molecules going forward against different targets.

And so maybe just to sum up the use of the chemistries, you also selectively use [ flooring ] substitutions. And you're trying to achieve a balance between -- you certainly want to have the payloads be immunogenic. You don't want to interfere with the risk process. You don't want to diminish that in any way. And then you talked about the off-target [ effection ] you're trying to avoid. So if you were to sum up, where are we at in terms of our understanding of how to play with all those chemistries and optimize them? Are we 90% there, more, less? How would you characterize that?

I guess -- I don't know if we're 90% there because the goalpost always keeps changing and moving away from us. And that's, I think, the process of innovation, advancing. What I will say though is that, as I think hopefully we've talked about here and you can see from the pipeline, we've now developed an understanding of this platform technology that we can actually go into broader and broader indications of patients. So for example, we now have RNAi therapeutics in diseases like hypercholesterolemia against hepatitis B in the clinic. At Alnylam, we're leading a program in hypertension. So this shows that the profile of these molecules allows us to address really broad based, highly prevalent diseases in the population. So really indicates both from a potency, durability, safety, tolerability, et cetera, that we actually have a very remarkable profile that's now developed. On top of that, we recently announced, I think just yesterday, the day before, top line data from taking an RNAi therapeutic into infants and children with primary hyperoxaluria type 1 and had a very well-tolerated safety profile there as well as good knockdown. And so I think the fact that now this technology has been derisked to the point where we feel comfortable that we can take this into prevalent diseases into the most vulnerable of vulnerable populations, children with disease, I think really shows how far it's come. But I think innovation is going to continue, and we'll continue to advance the field. [indiscernible] these into other tissues, which I know we'll talk about as well, these same platform modifications on the backbone.

Right. And so the last leg of that stool, if you will, was the use of the conjugated ligand. We started out having to protect our payloads with an LNP. ONPATTRO is protected by an LNP. It works. But certainly, the knowledge of the stabilization chemistry has allowed you to go to a GalNAc. High specificity for a specific receptor on the hepatocyte cells, ASGP. That's something that is -- it presents broadly. It recycles quickly. You get a very high uptake into the cell. Some might argue that, that is a confluence of rare events and that, that pairing is a unicorn. So is that true or not? Are there other targeting ligand, moiety, receptor pairings that are out there?

Okay. As you point out, the -- sort of focusing on hepatic delivery, I mean, delivery has been something that, as a company, we've been focused on for 18 years. Other companies in the field have really been focused on how you do deliver the insights in terms of LNPs. And then as you point out, the GalNAc-conjugate utilizing the ASGPR mechanism to target the liver really afforded a huge breakthrough in the field and something that we've been able to use now to bring forward a whole host of medicines and build out a robust pipeline. And it also helps that the liver is kind of a powerhouse in terms of protein production. So there's a lot of diseases where there's key proteins that are produced in liver that we could target. What I would say is that we are leveraging our insights in terms of ligand conjugates to think about other organs that we're going into. We haven't revealed anything at this point in what terms of specific ligands. But I think suffice it to say that we utilize those kinds of approaches in going into, for instance, the CNS. And we've announced that we have a -- we had insights about 2 years ago about how to deliver into the CNS in the eye using conjugated siRNAs and use that as a basis for a large collaboration with Regeneron. And we've announced and shown that in preclinical studies in the CNS that we're able to actually get very good knockdown of target proteins in the spinal cord, but impressively, in other parts -- throughout the brain as well, when you get to the cerebrum, the cortex, the cerebellum and the basal ganglia and as well across a whole host of cell types: astrocytes, neurons, glial cells. And so that's all very, very important as we now try and address other diseases of high unmet need in the CNS.

So yes, with the CNS, especially if we compare the liver, again, everything's a confluence of positive events, beyond everything we talked about, highly perfused. Now we're thinking about the CNS and maybe perhaps using intrathecal delivery. Talk about the challenges there that you need to overcome, again, with the goal of trying to get the siRNA into targets deep into the brain and how are you addressing them.

Yes. So as I mentioned, we are using intrathecal administration and in our preclinical data have seen really good, broad distribution of the siRNAs throughout the brain in these preclinical models and across a whole host of cell types. And I think if you think about the types of diseases we're going to be going after, these are going to be -- these are diseases of tremendous unmet need, very debilitating diseases, neurodegenerative diseases like Alzheimer's disease, like hereditary cerebral amyloid angiopathy, like Huntington's disease, et cetera, where intrathecal administration would be entirely acceptable if you had a effective therapeutic. So that's good, and we'll be doing that. That said, I think the other thing that is quite -- and intrathecal administration is certainly not uncommon. That said, intrathecal administration can -- is going to be burdensome [ if it has ]. And so this is where, I think, having -- leveraging some of our insights in terms of durable knockdown are going to be quite important because what that allows us to do is to space out the dosing, right? So now you can imagine quite a big difference if you have a therapeutic that has to be given every month intrathecally versus now if we can leverage our insights and learnings from the liver and have conjugated siRNAs that can be given once every 3 months or once every 6 months for these debilitating disorders. And that can only enhance sort of the acceptability and tolerability of those molecules, reduce the rate of infection and other things. So we're very encouraged by the emerging profile, and that durability will be important as we think about some of these targets in the brain.

For CNS, you are targeting amyloid precursor protein, or APP. Why is this a first -- a good first choice?

Yes. So APP, as you point out, is the first CNS target that we've announced. We're doing that in collaboration with Regeneron as part of the large neuro and CNS and ocular collaboration we have with them. And I think several reasons that it emerged at the top. First of all, it also is -- there's genetic validation for this target, as we've talked about, an important part of our strategy. For example, in the disease hereditary cerebral amyloid angiopathy where there are known mutations there that lead to -- it's an upstream protein that ultimately leads to beta-amyloid precursors. In the case of HCAA, they deposit in the vascular wall. We also know that there's genetic associations with forms of Alzheimer's disease, particularly autosomal-dominant Alzheimer's disease as well. So it's a genetically validated target upstream that we can turn -- that we can address. Second of all, I think it plays into something that we know that RNAi therapeutics do very well, which is turn off production of a disease-causing protein, right, amyloidotic protein. And so this is something as well that makes it a good target. It's a very high unmet need disease, and it has -- and this also serves as a gateway potentially because we can start in something like HCAA, but then we can go into autosomal-dominant Alzheimer's disease or even more common non-familial Alzheimer's disease as we advance this molecule. So it becomes a gateway to even larger and larger indications.

So for APP, you have presented nonhuman primate data. What are you most encouraged about, about what you've observed so far?

Yes. A couple of things. I think, first of all, the biology is compelling. The unmet need is enormous. The nonhuman primate data that we have already shared suggest that we can have something that could actually knock down APP for up to 6 months. And that's very encouraging to have that kind of a profile of a molecule with high levels of knockdown that's quite durable. I'm also really excited just by the mechanism. This is a molecule that works upstream and as a result, can have an impact on production of beta-amyloid both extracellularly, but also intracellularly. And that's quite a differentiated approach to treating some of these CNS disorders, and so I think the opportunity to really have an encouraging therapeutic effect and hopefully address this disease -- these diseases.

Okay. You also have mentioned Huntington's as a target. Again, back -- many years ago, the company did have an early program for Huntington's. I'm sure this one's a lot different, but tell me about your ability to target the exon 1 fragment. In addition to the full-length transcript, exon 1 appears to also have a significant impact on the disease.

Yes. So Keay, you're right to point out, another target that we are working on is Huntington's and that there is a fair amount of emerging science now that suggests that it's not only the full-length transcript, but that this exon 1 fragment may actually be responsible for the accumulating disease phenotype that patients experience. Obviously, Huntington's disease with the basal ganglia where people have a [ few ] movement disorders, and the exon 1 fragment, which heretofore hasn't been really addressed, isn't being addressed by other therapeutics that are being advanced, may be important and causative in disease. So our efforts are very much directed towards actually looking for an siRNA that can not only target the full-length transcript, but also exon 1. And we think that, that approach may be the most effective in tackling this very serious disorder. So that's what our teams are working aggressively on along with our collaborators at Regeneron and hope to advance something shortly.

Okay. And then the other general area you've talked about pursuing is the eye. So a lot of, obviously, good targets for inherited retinal diseases. Just give me the broad strokes of why that's an attractive place to go early on as well.

Yes. Well, I think you pointed out a couple of things. One, it's an accessible organ. Intravitreal administration is possible, and we can use other conjugated approaches to make sure that the siRNA gets into the cells and tissues of interest. But it's an accessible organ. As you point out, there are a series of inherited ocular disorders where the genetics are well understood that sort of provide a right set of potential targets. And three, I think that, again, drugs that are given via intravitreal injection but where the administration can be done on an infrequent basis, every 3 months, every 6 months, provides a pretty important therapeutic advantage for patients as well. If you think about what's happening, for example, in the AMD space where sort of spacing out the frequency of administration from monthly to every 6 weeks or every 8 weeks is a major therapeutic advance, imagine if you could now have a drug that could be given every 3 months or every 6 months. And so there's a lot of opportunity both because of the target space, the serious unmet needs of the diseases that are all well suited to the unique pharmacology profiles of RNAi therapeutics that we're developing. So it's an area we're very excited about and working closely with Regeneron.

So final question for you. As we look for siRNA to go outside the liver, people are targeting CNS, the eye, muscle, the lungs. 5 years from now, where are we in terms of our confidence of achieving success for an siRNA outside of the liver?

Oh, I think I'm quite confident. I think we've gotten a lot of insights. Others are working as well in this field. But I think now that we really understand about the RNAi backbone, all of our learnings from the liver, I think, can really enhance our probability of success. So building on what we talked about earlier, which has been a encouraging probability of success, I think we can take advantage of all that. So I'm really excited about the opportunities in the brain, for instance, and in the eye and the opportunity to really have a tractable approach to some of these diseases. So I think we'll see some real movement in those spaces in the next several years.

Okay. Well, we've reached the end here. I really want to thank you for joining us today, along with all of our audience participants. So with that, thank you, and have a good rest of your day.

Thank you, Keay. I really enjoyed it, and have a good day to you as well.