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

Great. Thank you, and thanks, everyone, for continuing along to listen-in. It's my pleasure to be sitting here with Vasant Jadhav an SVP level rep of Alnylam in the research group. Just for everyone listening and this should be obvious, but I think we're largely going to focused on your efforts in CNS this morning. But Vasant, maybe you can just kind of give folks a little bit of background about yourself. And with that, maybe just a brief overview of Alnylam's efforts in CNS and more various programs stands.

Yes, absolutely. Well, first of all, thank you Paul for this opportunity. My name, Vasant Jadhav. I've been leading our RNAi platform efforts at Alnylam from last 9 years or so. And prior to that, I was at Sirna, Merck in the same field of RNAi therapeutics. It's been about 20 years or so working in this field, pretty much right from the beginning. And at Alnylam, my efforts are focused on the technology of the conjugates and the extra adding delivery that we'll be talking about today. So with that one, let's get into the CNS program, the portfolio at Alnylam. So as you know, we have worked quite heavily on solving the liver delivery and came up with these 2 approaches. And prior to that, Alnylam as a company was also working in many of different things, but really focused in the liver brought together maturation of these delivery technologies. One is lipid nanoparticles other the GalNAc-siRNA conjugates. Now with the GalNAc-siRNA conjugate-like platform, we were able to really optimize the siRNA for metabolic stability or -- in vivo activity and importantly, for recognition by the risk, the RNA induced silencing complex utilized by the RNAi pathway. So with this one, now we are taking the lessons learned from this liver delivery with GalNAc conjugates and applying them for delivery to other tissues. And the key here is we are not starting from a very early kind of things here because we can really exploit the advances in the siRNA design. And so with that one, with these optimized siRNA, we are now invented an internal C16 conjugate platform to allow delivery to multiple cell types in CNS, in eye and other tissues, we published this one in Nature Biotechnology last year. And with our partners at Regeneron, Alnylam has a growing CNS portfolio, which leverages our C16 conjugate platform targeting the CNS indications. Now our goal for the CNS platform is to come up with good distribution across the regions of the brain, all cell types with desired reduction of the target protein and the long duration of effect, which is a hallmark of the RNAi technology. And obviously, while minimizing any potential safety concerns. Now in preclinical studies, we've been able to demonstrate that C16 conjugates can achieve this kind of profile. We've shown that with intrathecal injection, we see good distribution and RNAi activity across CNS of nonhuman primates, obviously, also on the rodents in the brain, in spinal cord and across cell types. We also shown that the level of knockdown is 80% or more with the doses that we have used. And the duration is pretty durable. I mean, 6 months after a single injection would suggest that it could be biannual or potentially annual treatment. Now with all of this, we decided to go with the ALN-APP or C16 siRNA conjugate targeting amyloid precursor protein for Alzheimer's disease for the cerebral amyloid angiopathy. Now with this one this program is currently in Phase I in the early onset Alzheimer's disease. We expect the interim data from this one to come in second quarter coming soon then. And then in addition to ALN-APP, we'll talk more about that, I suppose, in the later part. We will have -- we have these other programs that we are thinking about. But importantly, with ALN-APP and the data that we expect, if it is positive, we think this will really derisk the C16 platform in tumors and open the path for other targets.

Okay. Great overview. So you published a really interesting paper at Alnylam a year or 2 ago. looking at preclinical translatability from mice NHPs to humans for GalNAc. Essentially showed NHPs, I think GalNAc actually -- actually underestimates the potency as you go into humans. For CNS, I mean, in HP you're seeing this huge knockdown after 1 dose. Why wouldn't you be able to recapitulate that in this ALN-APP study? Like is that kind of a realistic base case?

Well, I think as you look into our data that with the GalNAc siRNAs, we do see improvements going from NHP to the humans, especially at the lower doses, though, as you go on the higher doses at 80%, 90% of knockdown, that correlation is reasonably together. But the other thing that we also see in this translation with the GalNAc siRNA is going from lower to higher species all the way to humans, the durability increases from rodents to NHP to humans. Now obviously, liver being a different tissue versus CNS but the base siRNA is still the same within this in terms of chemical modifications, all that. The delivery uptick mechanism is -- or uptick agent, I would say, is different. So we'll know soon. I don't want to speculate that the same would happen, but fingers crossed.

Are you -- when we think about this initial readout, Vasant, are you -- because it's your first time in the brain, are these initial dose levels? Are you starting out at the more conservative end of the spectrum? Or do you think you'll be at levels where seeing this kind of knockdown that you saw preclinically is actually feasible?

No, that's a very important point and question. Anytime you go into a newer space, with the newer platform, you do want to be very conservative. And so that's the approach that we are taking. We're going very cautiously, methodically and making sure that this single ascending dose is moving in a very careful manner. And also the screening that we are doing for the patients is critical here for the inclusion and exclusion criteria. So I would say we've taken a very cautious approach. But we're building the platform innovate for the translation. And you have to start at reasonably low doses to make sure that things are looking good and then -- and go to the next one.

And are you -- but you already, I guess investors right they always care about what's the catalyst? What's the data readout? Like are you already passed those lower doses where now when we get this data update in 2Q, you should be at a level where 50% knockdown, 60% knockdown is feasible based on preclinical data. Is that the right way to think about it?

Again, I mean, our goal is in the first study, the primary goal is safety. And if it reaches to the point of showing the PD effect, that would be awesome, but really looking for the safety and the initial read on the pharmacology of these ones, whether it will be at what level, again, let's wait for that.

Okay. All right. Fair enough. As it relates to APP specifically, so I've spent a lot of time in looking at different Alzheimer's drugs, I'm sure you have got some knowledge, the glaring question we've had and we've looked at this is just is this target to upstream. What data do we have that shows that you can reduce APP and then lead to a downstream reduction in oligomers, protofibrils and plaques?

Yes. No, it's an important point. I think let's look back at different, different approaches that have been tried, right? So with the antibodies, with the clearance, with the base inhibitors trying to reduce the beta amyloid. So we think -- we're bringing an unique approach that hasn't really been tried before. So you're essentially reducing the concentration or the levels of disease-associated protein precursor in this case and ultimately, the fragments that would come from that, that are involved in deposits, either in brain or in the blood vessels in case of the CAA. And so there is -- we believe that there is a potential to go after both of these and have an impact. Now with ALN-APP, we have done a fair amount of preclinical studies. In the mouse model, we do see that with the treatment of the APP siRNA we can reduce the deposits. And then in the model where this was in the iPSC-derived cells, we can see that in this model, the size of the endosomes -- early endosomes Rab5 positive ones, is increased. And with the treatment with the APP siRNA, we can see the reduction of that one. There are other experiments as well looking at the behavior and the functional effects in a way in the mouse models. So things are moving in the right direction on that front in the preclinical model data. But obviously -- humans obviously is a completely different game.

So are you -- like the tough thing with amyloid is that you can't easily measure these potentially toxic soluble Abeta species like a oligomers and protofibrils and then plaques at the other end of the spectrum, are you looking at PET [indiscernible] in the MAD portion of the study? Do you think that that's a reasonable biomarker for target engagement for this mechanism?

No. Again, that's a good point. We do want to take a step by step, right? With the initial data -- and the PET technology, obviously, has been very useful for the antibodies because the mechanism there is directly on the clearance on these deposits of the plaque. In our case 2, we would expect over time as the source of these plaques is reducing that the things will move or we will keep the balance from deposition towards the clearance. But the magnitude and the dynamics of this one compared to antibodies versus siRNAs might be different. And I mean, I would kind of take the example of TTR in this case. I mean, when we started on this one, it wasn't clear that knocking down TTR would impact reduction of the TTR deposits. And based on the data that we have seen with our siRNAs reducing the TTR, it does -- is able to do that one. So it is feasible that we'll see that as well and we'll have to use these kind of techniques really look for those changes. But to begin with -- I mean there are another great thing about this target and the work that has been done for so long, and they have so many biomarkers as well. So, we are looking quite a few of them in our initial studies with the fluid biomarkers as well as the imaging and the functional studies on cognition and all that, but I would just say -- also say those data won't be available when we release the initial data, but usually will be all on the safety and target engagement.

Is p-tau one of those biomarkers?

I believe tau is, yes.

Interesting stuff. So I think in Alzheimer's, right, that the mechanism here is intuitive to a lot of the investor community who's following this space. Can you -- we thought we did work in this program that this whole question is APP too far upstream might be less salient in something like CAA where the monomers actually seem to be toxic. Is that the right way to think about the pathology of CAA? Maybe can you sort of speak to that indication and why you thought it was a good one to pursue with this approach?

But as you saying right, with the CAA, the deposits in the vessels can weaken these vessels and can lead to the strokes. But both in CAA as well as the Alzheimer's disease as such, I mean the central figure here is the amyloid deposits, right? So we think by gaining the POC for reduction of these biomarkers, this should ultimately work for both. So our current trial is an early onset and we will -- as the data comes in and based on that, we will also have multiple dosing kind of arm on that one in future. And that data will really help us figure out what should be the dosing regimen with these kind of molecules. What's kind of durability effect that we are seeing, and ultimately, our intention is also to move into the CAA, but obviously, we'll talk about that later. But it is obviously there.

Yes. Yes. Okay. Okay. So we'll get this readout from the SAD soon. Yes, that's favorable. You'll move to the MAD portion. And that MAD portion will -- maybe give us more information on PD, at least in Alzheimer's. Is that right?

Yes, it will be in the early onset as well. And I just want to clarify, it's a multiple doses rather than MAD per se, it's multiple doses. So from the first -- the initial study, we should get an idea about what dose we are seeing.

Okay. And then you take forward that dose and then it multiples, it's not ascending again. Okay. I got it. Okay. That's great. Makes sense. Do you want to talk a little bit about beyond APP, what other assets here you may be excited about?

Yes. Beyond APP, which kind of gives the wealth of biomarkers for target engagement and tracking the disease. CNS is also a place where there are many other genetically validated targets and the huge unmet medical need. And so with that one, the next in our list is Huntington as a target. So for the Huntington disease, I mean, inherited disease with 100% penetrant with this trinucleotide expansion. And with recent advances in the disease understanding, we think there are more ideas now how to target HTT. I mean as we know, currently, there are no cures very terrible diseases like having symptoms of ALS, Parkinson's and Alzheimer all in together. So on top of that, the competition and the data so far is not promising. So we think with our technology, as we have done with liver targets with the GalNAc siRNA, we should be able to come up with a differentiating profile of the extent of knockdown, duration of effect as well as the safety of our molecules with the double-stranded siRNAs pretty much showing the activity to its intended target. So with Huntington, this is -- this program is in preclinical development. Obviously, with our partner, Regeneron, with whom we have this alliance in the CNS and the ocular space. So we are looking at a variety of strategies to go after Huntington. And just maybe a shout out there is a conference, CHDI conference on April 26th, where we'll talk more about some of our data on the C16 siRNA platform against HTT and some of the approaches, including the comparisons with other approaches as well.

Can I ask you one question on Huntington's. Did the tominers and not just failure but dose-dependent underperformance of placebo diminish at all your enthusiasm for either HTT knockdown or the safety of reducing wild-type Huntington. Like what makes you still excited about that space despite that setback?

Yes. I think that's what we're saying that, again, we'll talk more about that when that -- there might be multiple ways of going after this one, full-length Exxon 1, S&P, so many different projects have been tried. And with our platform, the ability to sort of titrate the knockdown, I mean we're showing about 80% or so in NHP for the APP. But all of this is dose-dependent. And so we should be able to achieve a more controlled level of knockdown. And overall, the safety of our siRNAs in general, gives us the confidence that we should have a differentiating profile here. And is the space with tremendous unmet medical need. We got to go in.

Yes. Okay. Great. So what else would you like to highlight about this platform that maybe investors are overlooking or underappreciating?

No. I mean we are very excited. I think when we think about our C16 siRNA platform, we made a bet in CNS after sort of solving the delivery in liver. And while competition has looked into the other tissues, we decided this is the place to go. CNS with the unmet medical need and the targets there. And this platform, in a way, is a combination of all our prior efforts. So I won't really call it as our generation one kind of thing, we get all the bells and whistles and all the learnings that we have from the previous one. So it's kind of a pretty advanced stage already. And so based on our track record of what happens in NHP to the humans, obviously, all of that with the liver programs. We feel excited that this should happen in humans as well. And this initial data will be a milestone for this platform, and will open up many other opportunities, as we discussed on HTT and [ SAD1 ] and the other ones that are coming. So watch out this space. That's all I would say about it.

Can I ask you one last question. In this area, one of the things that we've been paying attention to our ways better delivery methods besides intrathecal, right? I know your animal data actually supports you can go IT and get broad biodistribution, but companies like [ Denali ] is another private company looking at kind of antibody drug conjugate-based delivery. There's devices where you could kind of implant here, kind of like BioMarin did with BRINEURA. Is that something that you're interested in trying to kind of find potentially better, safer, easier ways to access the CNS?

I mean it's overcoming blood-brain barrier, right, would be great. and all pursue that one. At the same time, when you look at the profile of the C16 platform as it currently stands, if the IT dosing is at sufficiently low dose, giving us a good safety profile and very importantly, if it is infrequent dosing, I mean, this is where I think the durability really comes in picture. We were not talking about subcu dosing here. This is IT dosing. So if we can get to something like every 6 months or every 1 year, then we believe that is still a very attractive option. And as we have done previously, we continue to innovate with our liver platforms, and we will be looking at these other approaches as well.

Great. Well, we look forward to the data coming very soon. So, thanks Vasant for taking the time, super interesting stuff.

Well, thank you, Paul. Thank you for this opportunity.

Okay. Thanks, everyone, for listening-in, and hopefully see you on the next one. All right, have a good rest of your day.