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 and the research group. For everyone listening in, this should be obvious, but I think we're largely gonna focus on your efforts in CNS this morning. 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 where various programs stand.
Yeah, 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 nine years or so, and prior to that, I was at Sirna Merck in the same field of RNA therapeutics. It's been about 20 years or so working in this field, pretty much right from the beginning. At Alnylam, my efforts are focused on the technology of the conjugates and the extrahepatic delivery that we'll be talking about today. With that one, let's get into the CNS program, the portfolio at Alnylam. As you know, we have worked quite heavily on solving the liver delivery and came up with these two approaches.
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 nanoparticle, other the GalNAc-siRNA conjugates. With the GalNAc-siRNA conjugate-like platform, we were able to really optimize the siRNAs for metabolic stability, for in Vivo activity, and importantly, for recognition by the RISC, the RNA-Induced Silencing Complex utilized by the RNAi pathway. With this one, we are taking the lessons learned from this liver delivery with GalNAc conjugates and applying them for delivery to other tissues. The key here is we are not starting from very early kind of things here because we can really exploit the advances in the siRNA design.
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. With our partners at Regeneron, Alnylam has a growing CNS portfolio, which leverages our C16 conjugate platform, targeting the CNS indications. 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 a long duration of effect, which is an hallmark of the RNAi technology, and obviously while minimizing any potential safety concerns. 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 non-human 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, six months after a single injection, which suggest that it could be biannual or potentially annual treatment. With all of this, we decided to go with the ALN-APP or C16 siRNA conjugate targeting Amyloid Precursor Protein for Alzheimer's disease or the Cerebral Amyloid Angiopathy. 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. In addition to ALN-APP, and we'll talk more about that, I suppose, in the later part, we have these other programs that we're thinking about. Importantly with ALN-APP, and the data that we expect, if it is positive, we think this will really de-risk the C16 platform in humans.
Yeah.
open the path for.
Yeah.
for other targets.
Okay. Great overview. You published a really interesting paper at Alnylam a year or two ago looking at preclinical translatability from mice NHPs to humans for GalNAc.
Yeah.
It essentially showed in NHPs, I think it actually underestimates the potency as you go into humans. For CNS, I mean, in NHPs, right, you're seeing this huge knockdown after one dose. Why wouldn't you be able to recapitulate that in this LNP 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, I mean, that correlation is reasonably together. The other thing that we also see in this translation with the GalNAc siRNAs 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 these in terms of chemical modifications, all that. The delivery uptick mechanism or uptick agent, I would say is different. You know, we'll know soon. I don't want to speculate that the same thing.
Yeah
-would happen, but, fingers crossed.
When we think about this initial readout, Vasant, 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, you know, levels where seeing this kinda knockdown that you saw preclinically is actually feasible?
No, that's a very important point and question. You know, any time you go into a newer space with a newer platform, you do want to be very conservative. 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. Also, the screening that we are doing for the patients is critical here for the inclusion, exclusion criteria. I would say we're taking a very cautious approach. We're building the platform in a way for the translation.
Yeah.
A-and, and-
Right
... you know, you have to start at reasonably low doses to make sure that things are looking good and then, and go to the next one.
I guess, you know, investors, right, they always care about what's the catalyst, what's the data readout. Like, are you already past 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.
Yeah.
If it reaches to the point of showing the PD effect, that would be awesome. 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, I've spent a lot of time in looking at different Alzheimer's drugs. I'm sure you have as well.
Yeah.
The glaring question we've had when we've looked at this is just, is this target too 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?
No, it is an important point. I think let's look back at different approaches that have been tried, right? With the antibodies, with the clearance, with the BACE inhibitors, trying to reduce the Beta-amyloid. We think we're bringing a unique approach that hasn't really been tried before. 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. We believe that there is a potential to go after both of these and have an impact. Now, with ALN-APP, we have done 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. 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, the Rab5-positive ones, is increased. 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 functional effects in a way in the mouse models. Things are moving in the right direction on that front in the preclinical model data. Obviously, humans obviously is a completely different game.
Like, the tough thing with amyloid is that you can't easily measure these potentially toxic soluble Beta species, like oligomers and protofibrils, and then plaques are at the other end of the spectrum. I mean, are you looking at PET SUVr in the MAD portion of this study? Do you think that that's a reasonable biomarker for target engagement for this mechanism?
No, I, again, that's a good point. We do want to take a step by step, right?
I know, I know.
With the initial data. You know, the PET technology obviously has been very useful for the antibodies because the mechanism there is.
Right
Directly on the clearance. on this deposit of the plaques. In our case too, we would expect over time, as the source of these plaques is reducing, that the things will move or we will tip the balance from deposition towards the clearance.
Yeah.
The magnitude and the dynamics of this one compared to antibodies versus siRNAs might be different. 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 these TTR deposits. Based on the data that we have seen with our siRNAs reducing the TTR, it does. It's able to do that one. It is feasible that we'll see that as well and we'll have to use these kind of techniques to really look for those changes. To begin with, I mean, there are...
Another, I mean, great thing about this target, and the work that has been done for so long, I mean, there are so many biomarkers as well. We're looking quite a few of them in our initial studies with the fluid biomarkers as well as.
Yeah
... the imaging and also, the functional studies on cognition and all that. I would just say that those data won't be available when we release the initial data.
Understood
... the initial data will be all on, the safety and target engagement.
Is p-tau one of those biomarkers?
I believe tau is.
Yeah.
Yeah.
Okay. Okay. Interesting stuff. I think in Alzheimer's, right, the mechanism here is intuitive to a lot of the investor community who's followed the space. We thought when we did work in this program that this whole question of 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 you could sort of speak to that indication and why you thought it was a good one to pursue with this approach.
Yeah. As you were saying, right, with the CAA, the deposits in the vessels can weaken these vessels and can lead to the strokes. Both in CAA as well as, the Alzheimer's disease as such, I mean, the central figure here is amyloid deposits, right? We think by gaining the POC for reduction of these biomarkers, it should ultimately work for both. Our current trial is in early onset, we will as the data comes in, based on that, we will also have multiple dosing kind of arm on that one in future. 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're seeing. U ltimately our intention is also to move into the CAA, but obviously we'll talk about that later. it is obviously there.
Yeah. Yeah. Okay. Okay. We'll get this readout from the SAD soon.
Yeah.
That's favorable, you'll move to the MAD portion, and that MAD portion will, you know, maybe give us more information on PD, at least in Alzheimer's. Is that right?
Yeah. It will be in the early onset as well. I just want to clarify, it's multiple doses rather than MAD per se. It's multiple doses. From the first, the initial study, we should get an idea about what dose we are seeing.
Okay. You take forward that dose, and then it's multiple doses. It's not ascending again. Okay. I get it.
Yeah.
Okay. Okay. That's great. Makes sense. Do you wanna talk a little bit about beyond APP, what other assets here you may be excited about?
Yeah. you know, beyond APP, which, you know, 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. With that one, the next in our list is Huntington as a target. For the Huntington disease, I mean, inherited disease with 100% penetrant with this trinucleotide expansion. 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 for these very terrible diseases like having symptoms of ALS, Parkinson, Alzheimer all in together. On top of that, the competition and the data so far is not promising.
We think with our technology, as we have done with lowered targets with a guide like 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. With Huntington, this program is in preclinical development, obviously with our partner, Regeneron, with whom we have this alliance in the CNS and the ocular space. We are looking at variety of strategies to go after Huntington.
Just maybe a shout-out that, there's a CHDI conference on April 26, 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?
Yeah.
You know, did the Tominersen, not just failure, but dose-dependent underperformance of placebo diminish at all your enthusiasm for either HTT knockdown or, you know, the safety of reducing wild type Huntington? Like, what makes you still excited about that space despite that setback?
Yeah. I think that's where we're saying that, again, we'll talk more about that one, that there might be multiple ways of going after this one. Full-length exon- 1, SNP, many different approaches have been tried. With our platform, the ability to sort of titrate the knockdown, you know? I mean, we're showing about 80% or so in NHP for the APP, but all of this is dose dependent. We should be able to achieve more controlled level of knockdown and that. Overall, the safety of our sRNAs in general gives us the confidence that we should have a differentiating profile here. You know, it's a space with tremendous unmet medical need.
Yeah.
We've got to go in.
Yeah. Okay. Okay, great. 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. 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. This platform, in a way, is a combination of all our prior efforts. I won't really call it as our generation one kind of thing because it has all the bells and whistles and all the learnings that we have from the previous one. It's kind of in a pretty advanced stage already.
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. This initial data will be a milestone for this platform and will open up many other opportunities, as we discussed on HTT and SOD1, and the other ones that are coming. Watch out this space. That's all I would say about it.
Can I ask you one last question?
Sure.
You know, in this area, one of the things that we've been paying attention to are ways, better delivery methods besides intrathecal, right? I know your animal data actually supports you can go IT and get broad bio distribution, but, you know, companies like Denali, there's another private company looking at kinda antibody-drug conjugate-based delivery. There's, you know, devices where you could kind of implant here, kinda like what [Bomber and Dave with Brujeria]. Is that something that you're interested in trying to kinda find, you know, potentially better, safer, easier ways to access the CNS?
I mean, overcoming blood-brain barrier, right, would be great, and should 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 good safety profile, and very importantly, if it is infrequent dosing, we're not... I mean, this is where I think the durability really comes in picture. We're not talking about subcutaneous dosing here. This is IT dosing. If we can get to something like every six months or every one year, then we believe that is still a very attractive option. You know, as we have done previously, we have continued 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.
Yeah
thank you, Vasant, for taking the time. Super interesting stuff.
Well, thank you, Paul. Thank you for this opportunity.
Okay. Thanks, everyone, for listening in, and I'll hopefully see you on the next one. All right. Have a good rest of your day.