Right Target, Small Effect? Rethinking CNS - COYA THERAPEUTICS INC

Okay, we're ready to start this next session. In this one, we want to kind of continue our discussion on neurodegenerative diseases. In this session, we are going to focus on ALS. My name is Kane Akai. I'm the Director of Research and one of the senior biotech analysts at Chardon. me for this discussion is Dr. Fred Grossman, President and CMO of Koya, and Dr. Asa Bailovich, the CEO of Leo. So gentlemen, thank you so much for joining us. ALS, you know, the first, well, we've, you know, it's kind of been slow progress. A lot of failures here as well. Darabom was approved. would say, kind of limited to maybe best for early-stage patients, less effective for the broader ALS patient population. In 2023, we had the approval of Tefersen. I think notable in terms of a different approach, but obviously a much smaller class of patients with the SAD1 mutation, but also notably an accelerated approval based on a biomarker, NFL. So I think that was a nice milestone for the field. But again, I think we need better solutions for a broader population of patients with ALS. So let's dive into that with the two companies here. Maybe Asa, let me start with you. You know, in your case, you have an approach where you're looking to address the generation of the sphingoid livets and the ceramides. And so how do we keep that from becoming a problem and propagating progression of the disease? So maybe talk about your platform and how you're doing that, especially with your ASOs. Yeah, no, thanks so much. No, we're really, really excited about where we're at now in the clinic in patients with ALS. So Leal Therapeutics is focused on basically the intersection between metabolic disease and CNS disease. And we basically go after really well-characterized, deeply validated metabolic enzymes and pathways with brain penetrant drugs. And so case in point here, LTX002 targets an enzyme that's involved in the synthesis of ceramide sphingolipids. And it's really based on human genetics. So there's people with disinhibiting gain-of-function mutations in this specific enzyme that's the first in rate-limited enzyme to generate ceramide single lipids, this class of lipids that's known to be potentially toxic. And that is enough to cause ALS. It causes early onset severe ALS or ALS and FTD in people. But what's really exciting about the story is that when we went on to look, it's a fairly robust literature that ceramide sphingolipids are generally increased in sporadic disease as well. And people had shown, and we now have shown as well, that inhibiting this pathway is protective. It's anti-inflammatory. it also suppresses a lot of the kinds of pathology that you see in ALS. So I think what's been missing to an extent in ALС is a treatment that's genetically validated where there's robust biomarkers with a deep understanding as well, but that can help sporadic disease. to your point, the one thing that we now know is that ASOs can work in ALS. There's Tofersen, but as you know, also in the last couple of weeks, really exciting data for the FUS program. Again, NFL validated. And then we're just missing something for the other 98, 97, 98% that don't have those mutations. So here, what's exciting is we can go after both the rare genetic mutations, Again, there's rare individuals that have exactly this mutation that causes disinhibition genetically in excessive ceramide sphingolibase. But again, a lot of data that this is relevant in sporadic ALS as well. And then finally, we're now in the clinic and progressing well. So maybe highlight some of the key observations from your preclinical data for 002. Yeah, so we built particularly strong capability in Worcester, Mass., with just expertise in developing intrathecal nucleic acid therapies like ASOs, but also capability in BBB shuttle transport so that we could ultimately use peripheral delivery. So that's a transferrin-based approach, and we can talk about that as well. But with the, so ultimately we generated LTX002, we could show readily then in NHP that this reduced the level of this enzyme, it could suppress the production of ceramides, vingalopids, and it could do this safely and effectively. You can't 100% turn this pathway off, but we see a very broad safety margin, basically. So, and ultimately, we even have long-term data that supports taking this to open-label extension, and we actually are in that process now. So, yeah, so basically, ultimately, you know, after extensive other work, we, you know, in NHP, we could show that we could effectively and safely reduce the enzyme, and reduce the ceramide sphingolipids. And that allowed us to move forward. Separate from that, we do also have an oral small molecule that targets the same enzyme. It's the first-class brain penetrant oral small-molecule. There have been tool compounds for over a decade. They are effective in models of ALS. Other people have shown that models that do, that have this mutation, but also models that have other mutation, they suppress TDP43 pathology. this is upstream of TDP43 pathology because inhibiting it suppresses TDP 43 pathology, whereas knock-in mice, and this is work at the NIH, not our pre-clinical work, but at the NIH, people have shown that knock-on mice that have this mutation get typical TDP-43 pathologies, they get increased NFL, they get motor findings that can be suppressed with tool compounds. what's been missing is drugs that can actually help patients and get into the CNS. So we do also have oral small molecules, and we've shown that they are effective, again, across other models of ALS. So in your first in-human trial here, I know you're currently enrolling patients in Europe. Maybe just give us a sense for what you're assessing and when you first report interim data, what will you report on? Yeah. So, you know, huge upside to looking at a well-charitized metabolic enzyme. We can directly measure the product. So we can look at ceramide, sphingolipids, and show we engage targeted programs. We Can also actually measure the enzyme, SPTLC1, the subunit in CSF. We can measure that. So We can look it at PKPD very directly. But most exciting is NFL. Again, That's what's really enabled the Tofersen program, the FUS program. And we have a lot of data, and again, published data also, other people's data, that this pathway directly is upstream of NFL, upstream of TDP43 pathology. And then, of course, we'll get ALS, FRS, the ALS rating scale data, as well as other motor and clinical endpoints okay well great well I'll come back here also with some other programs that you have under development in your in your shuttle delivery but Fred let's let's shift to what you're doing at Koya you know basically addressing the the inflammation and the problem that that causes in the propagation of the disease using recombinant low-dose il-2 so tell Tell us how that works and impacts Tregs and then your initial compound, 302, is a combination of that and CTLA-4. So, you know, start with the Modos IL-2 and then the combination and the synergies that that's affecting. Sure. ALS is a disease of inflammation, you've heard that before, and we know that the inflammatory activity is quite high in ALS. The cornerstone of this inflammation, we believe, are regulatory T cells. It's been shown time and time again that regulatory T-cells are dysfunctional in ALS as well as other neurodegenerative diseases. The reason for that is that, obviously, in a healthy body, when there is a foreign invader, the innate inflammatory system increases, and you need something to hold it back. Otherwise, it'll continue to destroy itself. And that's where regulatory T cells come in. Now, the problem is it's very hard to harness something that can affect regulatory T-cells as a single agent. We know that low-dose IL-2 can raise regulatory T cell number and suppressive function, which is really the goal here. And at Koya, we believe in combination therapies because the immune system is very complex and redundant. We don't think a single agent is going to be effective. So we're really focusing on combination therapy. So let's go back again to regulatory T cells and ALS. In ALS, regulatory T-cells are dysfunctional. They're lower in number and lower in suppressive function. low dose IL-2, and by low dose, extremely low dose can increase regulatory T cells as well as increase suppressive function, and that's great. However, in the inflammatory environment, when you have a highly inflamed environment, regulatory T-cells can become dysfunctional again. So what we've found is that combining low dose IL-2 with CTLA-4 that tamps down the effector T cells, you can have prolonged elevation of regulatory T cell in number and suppressive function. And that's the basis of COIA-302, which is combination therapy in ALS. So the goal that we have is not to reverse or cure ALS, It's to take individuals who have just been diagnosed, who have some deficits, but a good quality of life, and hopefully initiate this therapy and stop the continued reduction in ALSFRS or the continued progression so that they can continue to have a good quantity of life. And by the way, that is associated with survival. So that's the initial goal that we have. We can talk about data if you want. Yeah, so obviously you're in a pivotal study right now, but before you got there, maybe highlight some of the key observations from your preclinical data, but maybe also, importantly, you also have some actual human data from disease patients from an IIT conducted by Dr. Appel. So maybe start with the key findings in the preclin and then the validation of that in Dr.Appel's patient. Sure. Well, most of our data are, in fact, in humans and come from human cells and human studies. Much of that work, as mentioned, is by DrAppel at Houston Methodist. But also our scientific board has Shimon Segaguchi, who won the Nobel Prize in Medicine last year for establishing and understanding regulatory T cells. So that's our focus as a company. No matter what disease we've looked at, whether it's through IITs at Houston Methodist, whether it'S Alzheimer's, FTD, and others, we find that this combination mechanistically does exactly what we want it to do, meaning that it increases regulatory T cell number and function in a sustained way. And in small numbers of patients, in fact, there is, in the case of FTD, there were nine patients. And in fact there was a stability in the MOCA and cognitive tests. However, we did find, importantly, increase in regulatory T cell number and function. So let's get back to ALS. this combination of low-dose IL-2 and CTLA-4 were given to four patients with ALS. These patients came in with an ALS-FRS score that averaged around 33-34, which is typically what you would see when someone is first diagnosed with ALS. And over a six-month period, remarkably, there was little change, little to no change in the ALS-FRS. Now, we know that in ALS, there's typically a reduction as the disease progresses of one point per month. So after six months, you would expect a reduction of six points on the ALF-FRs. And by the way, six points is significant. You know, that may be the difference between a patient who's walking and someone who winds up in a wheelchair. Well, we found flat lines in the ALS-FRS over six months. There were really no changes in that six-month period. Now, that's eye-opening, but it's only for patients. Continued those patients for another six months, 12 months, and at the end, found very little difference in the AlS-FRS. So we have a clinical observation here where patients who should have had a reduction of even 12 points had barely any change in over a year period. But it's only four patients. So importantly, we looked at the key variables mechanistically. And in fact, within a few weeks of therapy, regulatory T cell number went up. regulatory T-cell suppression went up, and it maintained through the course of the illness. So in those four patients, we see a clinical finding that was, I mean, quite frankly, eye-opening, but only four patients and biologic confirmation mechanistically of what we wanted to see. There were no safety concerns because the dose of IL-2 is extremely low. And even CTLA-4 is half the dose that's typically given. And importantly, the formulation is sub-Q. It means that if this will eventually get approved based on data, this can be self-administered by patients and their caregivers. So that was the basis of moving forward. OK, so you're currently enrolling in the All-Stars Phase 2. So maybe briefly highlight the design, but maybe more importantly, in doing your design, how did you incorporate your learning from your own studies but also the failures of other studies to increase or handicap your chances of success there? So this is a controlled study that consists of three groups. One group is the combination at the dose sequence sequence that was giving given to those four patients the second dosing group is half that dose given once a month versus twice per month and placebo so it's placebo control it's powered well over about 80 percent 120 patients which are full which have been enrolled already however there are patients in our screening period and we're allowing them to move through so it'll be a higher than 120 patients. The primary endpoint is a six-month endpoint, and it's the difference in the ALS-FRS. Of course, we have secondary NFL endpoint as well. And then we have a very interesting second half to the study. So the six-month period will be the primary endpoint, and quite frankly, if it's very positive, then we will be in discussions with the FDA to submit a file. The second six months are blinded, and so we have three groups, two treatment groups, one placebo. The treatment groups will continue blinded on their sequence therapy, but the placebo group will be re-randomized to one of those other two groups. And why is that interesting? Well, we just said before a six-point reduction in the ALS-FRS is significant, and you would expect that placebo group that most of the patients will have had that reduction so now we'll be able to test when they go on the either of the two doses whether it can stabilize even the more severe patients with ALS and we were going to complete the study after 12 months but there was really a lot of pushback patients wanted to continue and we don't it's blinded at this point. We haven't locked the database yet. Patients wanted to continue and PIs were requesting it, so we did add an open label extension at the end of that study, so if patients choose they can continue on that. The other innovative thing we did was to stratify by NFL, and we'll talk about that in a moment. NFL surely is an established biomarker, but it's not a a great biomarker, quite frankly. It's just a marker of axonal injury. And so it doesn't track with the ALS very well. And we can talk about data that we've done in 100 patients where it showed that it did not track. But we used NFL to stratify across the three groups. Why? Because in prior studies, they did not do that. And in fact, it's possible that some groups may have had a very high NFL, which would mean that they probably have had so much damage already that no intervention would be helpful. So stratifying was something that we did. We also had the entry criteria to ensure that we get the majority of patients who are reducing their ALS-FRS by history by just .5 to 1.5, because the fast progressors are likely not going to have enough time to to respond to your treatment we have an entry level of 35 on the ALS FRS which again is getting at those patients at that sweet spot when they're first diagnosed because again we're not looking to reverse ALS we're looking to stabilize it so patients and people you know can live a good quality of life so those are some of the things that we've we've done based on prior studies okay well great well you're on track to report the data top-line data in q2 so we'll look forward to that also let me come back to you because the the idea of the problems that excess ceramide sphingolyte lipids it it's not just ALS it can apply to other neuro neuro degenerative disorders but also an enabling technology that maybe is going going to allow you to proceed to addressing those others is your delivery technology and your conjugate to, as a shuttle, as you call it, to get more across the blood-brain barrier. Can you describe what you're doing on that? Yeah, no, I think this is a tremendously exciting time in CNS right now in that shuttle technology, which has been around to some extent for a couple of decades, is really maturing. And we've worked on this for the past four or five years. uh really trying to optimize different aspects we've looked at different kinds of shuttles these are antibody-like shuttles and and um we as some others have ended up focusing on transferrin receptor uh binding uh antibodies like uh like shuttle um we've we've uh iteratively really uh optimized these in terms of their affinities we've had to actually have bespoke different in shuttles to deliver sRNAs versus delivering antibodies. And what's really exciting is that we have two that are now in NHP and really getting lined up. One, a MAPTOW program where we selected a candidate actually delivering an sRNA as well as an APOE program. And particularly with the MAP-TOW, this is with subcutaneous injection of this conjugate subcutaneous injection, which ultimately could be every few weeks, we believe, maybe even up to even three months. Remarkably, we get better knockdown and quite deep knockdown in the CNS across the brain than we get in the liver peripherally. So, and again, that's taken a lot of optimization in terms of the nucleic acid, including the linker, and in terms of the affinities involved. And even looking head to head at some of the other shuttles, we do have a strong case that this could be best in class as a shuttle to deliver nucleic acids. So really excited, we've seen very clean tar ability and moving that forward now. We'll have NHP data this quarter actually and then very soon we'll start to push that into IND-enabling studies to get to the clinic. We do also have a shuttle, again, that can deliver antibodies, like A-beta antibodies, and that we now have, we just completed an in vivo study that's reading out to select a definitive candidate, and there also we're particularly excited because we believe we have optimized to avoid some of the off-target issues, as you know. With respect to delivering antibodies, one of the very active issues is how do you avoid toxicity? Because you typically do want to have an active FC. You wanna have an antibody that'll promote phagocytosis. But if that's excessive, if the FCA activity is excessive, or if it's polarized incorrectly, you can get toxicity, particularly reticulocyte drops, because these transferrin antibodies will also end up binding to reticulocytes. So just optimizing this has been really rewarding, and we really do think we have something that's potentially a bit more optimized than what we see out there. Again, we'll have the in vivo candidate selection completed this quarter and also pushing that forward. Okay, and Fred, maybe I'll squeeze in a final question about your pipeline. Obviously, 302, a lot of versatility. Give us a status update on 302 for FTD. Yeah, so we have FDA approval to move forward in FTD because like ALS, FTD is a highly inflammatory disorder, and we have some preliminary data I mentioned before where this combination can be useful. We will be initiating the FTD trial in 2027, and of course you can imagine if some of this data continues to come in positive, we'll be moving into other neurodegenerative diseases with this combination. Okay, ma'am, you had a question? Yeah, so in the non-human primate, particularly, for instance, with the tau or APOE, we have a really pretty deep understanding at this point in the field that tau plays a key role. We know how much we want to reduce it. We know that even we can reduce it in active disease from a lot of models so so really what we're doing in the NHP is showing first of all safety that's that's critical and and and second of all deep target engagement and getting a clear sense of the PK PD just to be clear so we're not so an NHP we're not modeling the disease per se this is really validating but but there's a a strong argument with targets like MAPTAL and APOE that there's so much human genetic, human biomarker, and preclinical data, and such a deep understanding that the more critical aspect is really showing target engagement and showing that you can do it in a tolerable way. All right, well, great. Go ahead, ma'am. Yeah. Yeah, yeah, yeah. No, it's very efficient, to your point. and absolutely i mean i think the same way the liver targeting uh you know was hugely beneficial safety-wise no question the targeting uh absolutely looks you know it looks looks well tolerated i think where people have run into trouble um is is with delivering with active f f with fully active fc um there uh and there are a couple different ways to to work that but um other than that the doses are with the targeting the doses are lower and and they're much better it's absolutely you don't run into some of the issues that you see with the untargeted sure . That question's to me. Yeah. Yeah, so, so. . Yes, so I can just answer it very easily. Remember, this mechanism is agnostic to whether it's familial or sporadic. It doesn't matter because we're reducing inflammation. It also doesn't mater what treatment they're on, so they can be on any treatment when they come in. So effectively, if they have high inflammation, which they will, and they meet our criteria, this combination can be effective. We're also looking at oxidative stress markers. We don't have time to talk about that, But that's something we're looking at also that may be a little more sensitive than NFL. All right. Well, great. Thank you so much for joining us for this session. Thank you.