Everybody. For those who don't know me, my name is Mike DiFiore. I'm one of the senior biotech analysts here at Evercore ISI. Welcome to our conference. In attendance right now, I have the pleasure of hosting Coya Therapeutics. Gentlemen, welcome, and thank you so much for making time for us. A lot going on at Coya. Before we get into the nitty-gritty questions, we'd love to have you provide maybe an overview of the story, maybe some business highlights, and then we could delve in.
Yes, soon. Actually, I'll have Howard tell our foundational story since he's our founder, and then I can take it from there.
Sure. Yeah. Well, the company was founded about four or five years ago, and it was based on the principle initially it was a personal story. My own father had cognitive loss, and I took my father in to see a top-rated physician. And it was at that meeting that I established a relationship with a gentleman by the name of Dr. Stanley Appel, and he's world-famous. And he showed me he said, "Look, come back next week. I want to show you something." I came back the following week. He showed me the incredible correlation between regulatory T- cells, Tregs, and neurodegeneration. So it was that relationship that started this process. Originally, we started as a cell therapy company, but since we've then evolved into biologics to enhance Tregs. So, Arun, you can say what we're doing with those.
Yeah. So that was the start of our company out of Houston Methodist. Coya is focused on neurodegenerative diseases, and we do this by fundamentally we try to address neuroinflammation. We believe that neuroinflammation really drives most of the neurodegenerative diseases. As Howard mentioned, we address it by regulating the Tregs, the regulatory T- cells. We believe that increasing the function, the suppressive function, and numbers of Tregs can resolve a lot of the issues associated with these diseases. How we do that, as Howard said, we started out being a cell therapy company, but subsequently we figured out there is a more efficient way to do it, which is we have a proprietary low-dose Interleukin-2. We use that to get the Treg numbers up as well as the suppressive function up. And then I'll talk a little bit more about how we keep that function higher.
We do that by combining, and we do believe that combinations is the way to treat neurodegenerative diseases, combining it with the CTLA-4 Ig. By doing this, we also keep the macrophages anti-inflammatory and the environment anti-inflammatory. This allows the Tregs to have sustained durability in function, and we also recognize that the function is better, the suppressive function is better. So that is our lead product. We call it Coya 302. Coya 301 is our proprietary IL-2. Right now, we are pursuing in the clinic, we are going to pursue ALS. We have clinical data in ALS as well as in Alzheimer's disease, but we're also looking at entering clinical trials in frontotemporal dementia as well as potentially Parkinson's disease.
Thank you for that, Arun. And to my knowledge, no one else is really doing this. I mean, you guys are I mean, Tregs have been around forever, but you guys have really kind of pioneered this secret sauce of kind of priming, if you will, with IL-2 and then treating with 302 afterwards. But is it really just simply about quelling inflammation from all different angles? How come no one has really kind of latched onto this pathway as much as you guys had before?
I'm going to let Howard add to that. But I mean, that's an interesting question. A lot of them have followed some of these paths for autoimmune diseases, Tregs. And we believe our modality will work there as well. Why people haven't pursued it in neuroscience, I'm curious, but maybe Howard has better insights on that.
The reason is that it's only recently that Tregs have become known to play such a central pivotal role in these diseases, in ALS, in Alzheimer's, in Parkinson's. We, and thanks to our relationship with Methodist, have been at the forefront to establish those relationships. This is relatively recent. We've known inflammation plays an important role in neurodegeneration, but the Tregs sit at the top of the pyramid. By regulating the Tregs, you also regulate multiple downstream pathways. That's why one pathway is not sufficient. One cytokine, IL-6, IL-1 beta, TNF alpha, probably not sufficient. We've taken a step up by not just regulating Tregs, but blocking the pathways that deactivate the Tregs. Combination approaches, that's sort of our claim to fame as well. Got it. Okay.
Before I get into questions on ALS and the other disease states, I mean, could you describe your what I assume is an autologous manufacturing process? Is it or no?
No. So we are not a cell therapy company anymore. That's how we started out. So we're out of the autologous process. What we're doing now is using biologics, and we're combining biologics to achieve the same or actually better outcomes and also drive down the cost significantly. So yes, that's the pivot we have made in the last 18, two months, two years or so.
Just looking back, now into questions about ALS, just looking back on your commentary from the beginning of the year, it seemed like the IND filing and phase two commencement was originally planned to have already occurred. Now it's expected to occur in Q2 of next year. What happened there? Why the delay?
Yeah. No, we obviously took a pretty aggressive path forward with the FDA. The feedback we got was that we need to complete an additional preclinical toxicology study. So we are in the process of doing that. And then we plan to resubmit in the second quarter. It's a very standard tox package, so we don't expect anything unusual. We use low doses of Interleukin-2, and we also use half the dose of the CTLA-4 Ig. So one wouldn't anticipate any surprises, but that's really it. But what is nice about it is that we now have clarity from the FDA on our path forward. We know exactly what we need to do to get through this Phase 2b study all the way to the end of the study. So we have a lot of clarity, which takes out some uncertainty for us.
Okay. Have you conducted any phase l studies with your contractor?
Yeah, so we haven't.
If you so, how does the safety look on that so far?
The safety looks good. It was an investigator-initiated trial, small, very small population of ALS patients. They came in at a baseline of 33.5 ALSFRS. What we saw was pretty remarkable, and I think you were talking about ALS with the previous speaker. We saw in six months in that small study a complete stop of progression, meaning it stayed the score at the end of six months was the same, which is remarkable. As you know, even a three-point decline in ALSFRS can be the difference between walking with a cane and being on a wheelchair. It's pretty dramatic, and in one year, we saw about a 1.7-point reduction in ALSFRS when you would normally anticipate about a 12-point reduction because the average ALS patient declines one point a month, and most of them die, as you know, within two to three years of diagnosis.
Okay, and just for folks less familiar with the story, can you give an overview of the proposed phase two design?
Yeah. Our phase ll design is going to be a double-blind randomized study. We're going to have two dose arms versus placebo. It's six-month endpoint for ALS FRS, six months because the FDA views that as the right endpoint. Also, ALS patients kind of becomes unethical to keep them on drug past six months when you can roll them to the open-label arm. So we will have an open-label extension that goes beyond it as well.
Got it. I remember speaking to you, gentlemen, earlier this year. You mentioned that this trial, this phase two trial, will exclude fast progressors due to their typical lack of response. That's what I had in my notes anyway. So how do you define such patients in terms of their ALSFRS trajectory in terms of fast progressors?
Yeah. I'll let Howard add to it. But what we want to do in our protocol is we have a criteria for what points per month is a patient declining in the last six months before they come into a trial. And we don't want that to be too rapid because then those patients are starting to progress a little too fast, and you start getting into those issues. And we don't want them progressing too slow either because then you really can't.
There's a sweet spot.
We're picking a sweet spot, but Howard, if you have something to add to that.
Yes. I don't think we've disclosed the exact numbers specifically above the threshold, but Arun's right. There is this window where you just have to get it right. But I do think that it's also important to treat patients above a certain ALSFRS. You don't want to treat patients that are too far declined on their score simply because their inflammation and a lot of damage has already been done. I think that's an important point. And are you just targeting a certain subgroups of patients like spinal versus bulbar or taking all comers?
No. All comers, genetic and sporadic as well.
Okay. Okay. Again, you conducted a four-patient academic study you mentioned too, where you showed success insofar as that there was no progression over six months. I guess how will the baseline characteristics in this trial compare to that? I mean, were there any kind of wonky characteristics in that small study that would not read across to this larger study?
No. I think it'll translate in that study. We had one patient with familial C9orf72 mutation. The other three were sporadic, which is kind of consistent with the numbers you see with ALS patients. About 10%-15% are genetic. The others are sporadic. So we don't expect our trial to be that different. We'll be recruiting similar patients.
I see. And just more broadly, how should we think about the potential for Treg exhaustion or durability of response? And will this phase two trial clarify this just given the limited study duration?
Yeah. I mean, that's a fascinating question. So there's a few answers to that. I don't think the biology of Treg senescence is fully known. It is clear, though, that when you put Tregs in an inflammatory environment, they start going bad. The FOXP3, which is the transcription factor, it starts, you see, the expression going down. That's what we actually saw in this last trial in Alzheimer's disease, that the IL-2 at a higher dose causes the FOXP3 to slowly decline. So the answer is the IL-2 and Abatacept, the CTLA-4, really provide an environment where it's like consolidative treatment where the Tregs stay healthier, more durable and longer and more suppressive over a long period of time.
It's almost as though the CTLA-4, by binding to the CD80 and CD86 and modifying the inflammatory milieu, keeps those Tregs healthier and prevents the sort of inflammatory damage or senescence on the Tregs. That's our hypothesis. Obviously, we want to prove that out in a longer-term study.
Got it. Got it. Another mechanism question. Low-dose IL-2 has Treg enhancing properties, whereas the high-dose IL-2 has Treg suppressive properties. So I guess my question is, is there lots of variability among patients whereby what may be considered low dose for one patient may actually be considered too high for another, and then you get a difference of response?
We don't have that level of patient data to know, but in our Alzheimer's study, the low-dose IL-2, we had two doses. We had once a month and every two weeks. So every two weeks is the higher dose. We did see a difference. As we expected, the once a month worked really well. We saw cognitive function improvements. We saw improvements in biomarkers like A beta 42 going up, which indicates plaque removal from the brain. We saw Treg function numbers all nicely line up. But in the every two-week dose, because now we're starting to push the IL-2 dose higher, not surprisingly, we saw FOXP3, we saw the Treg function come down. And then that translated into the clinical outcome as well. We did not see any difference within patients in those doses. So it was a 40-patient trial. So I think getting the dose right is important.
I don't think there's going to be that much variability within patients because IL-2 PK is not a very variable PK across people.
So it sounds like things are. There's nothing to worry about right now.
No. I think we found our dose. That was the goal of the dose-finding study. And to your previous question of safety and tolerability across both these studies, we have seen nothing unusual except for minor injection site reactions. And in the Alzheimer's trial, we wouldn't expect it with our mechanism, but we didn't see any ARIA either.
Got it. Last question on 302 and ALS. Just given the mechanism, should we expect an outside effect on NFL reduction? And as a color earlier, why might oxidative stress markers be more relevant than NFL here?
Yeah. So on the second question, so it's very interesting. We've done a study. We have a large longitudinal database of ALS patients where the patients have been tracked for many years from diagnosis all the way through to death. And we've looked at NfL, and we've looked at oxidative stress. And it's pretty remarkable. The data should be coming out early in the year in being able to predict survival and also rate of decline based on those two markers. It appears NfL is a reasonably good marker as everyone has determined, but 4-HNE and other oxidative stress markers are also very good. So that data should come out, and they play a role. We can talk about the biology and how oxidative stress, inflammation, NfL all interrelate, but it's also a temporal thing. The increases in NfL are slightly different than the increases in oxidative stress.
There may be temporal components that you use in these biomarker predictive capacity. Your first question was.
Hang on. What was my first question?
NFL.
Yeah. Basically, should we expect an outsized or any effect for that matter on NfL reduction just given?
I think so. I think what we saw in at least Alzheimer's is that low-dose IL-2 by itself actually almost fully stabilized NfL versus placebo, which went up in the CSF. So I think it's very possible that we do see some changes in the positive direction with NfL. We would hope so.
Okay. Obviously, you've done some work in Alzheimer's. Maybe just briefly recap what work has been done and what's next. Do you guys plan to start a larger phase two for 302 and Alzheimer's, or will you first test other combinations with 301?
Yeah. So we have had two small investigator-initiated trials done in Alzheimer's. One was an eight-patient open-label study. What we saw in that study was that cognitive function measured by Mini-Mental State Exam actually improved, and all the biomarkers and different functions moved right. So based on that study, the Gates Foundation and the Alzheimer's Association funded our next double-blind study, which was a 40-patient study in mild to moderate patients with Alzheimer's disease. I briefly told you the results before. What we saw there was that in the once-a-month dosing, ADAS-Cog, for example, cognitive measure, was numerically better at five months than at baseline. And more importantly, compared to placebo, we saw a delta of five, which is very clinically meaningful. Other measures as well, like CDR sum of boxes, all moved in the right direction. So we saw cognitive improvement.
We saw A beta 42 go up in the CSF, and we saw all the biomarkers move in the right direction, including NfL and so on. So this is very encouraging results for us. Number one, this study actually validates our approach of combining with Coya 302 and increases our confidence in our ALS trial as well because we've kind of seen that this mechanism works. So that's number one. And in frontotemporal dementia as well because those are very related. As far as our next steps in Alzheimer's, what we are actively doing is we're talking to potential strategic partners. And we see a lot of potential in a combination. As an example, combining our low-dose IL-2 with the beta amyloid could potentially provide a path forward to reducing the beta amyloid dose and reducing the ARIA associated with beta amyloids, just as an example.
But we're looking at other combinations as well, including we have filed intellectual property in combination with GLP-1 agonists for application in Alzheimer's disease and others. And there's a lot of data now on GLP-1s alone with positive impact on Alzheimer's, and we see some potentials there as well. So we will pursue it either with grants from big foundations or through a strategic partnership or a combination of both.
There's a thing just too up in the air regarding the future phase 2 trial. But interesting, you're testing mild to moderate patients. Is that because it has maybe less than a year or a year follow-up?
In Alzheimer's?
In Alzheimer's, yeah.
Yeah. Yeah. Most studies look at mild Alzheimer's, as you know, and the mild to moderate are typically faster progressing, and you get more rapid decline than in a mild patient. I think it's a better way to get an answer quicker than in going 18 months out in the mild. You need much larger patient cohorts in order to determine significance.
I see. Okay. Maybe, guys, in a minute we have less. You're also kind of doing some work with Coya 302 in FTD. Describe that a little bit.
Yeah. I mean, we're going to pursue it in frontotemporal dementia. We anticipate submitting that to the FDA sometime towards the later half of next year and starting the trial.
First in clinic, right? First of the phase one?
First, we have an investigator-initiated trial ongoing right now. We'll have results from that at some point in the early second half of 2025. Informed by that study, we will refine the protocol that we currently propose and move forward in frontotemporal dementia.
Phase two.
Phase two.
phase two. I see. I see. Last question from me. Current cash position and runway.
So what we last reported is pro forma. We have about $40 million. What we reported in our last earnings was $31 million, but we had subsequently raised a PIPE of $10 million. So it puts us around $40 million pro forma. And it'll take us into the second half of 2026. And we don't have. Yeah, we have a pretty clean cap table, as you can see.
Got it. Well, I think we're out of time, gentlemen. Thank you so much for joining us today. Wishing best of luck.
Yeah. Thank you, Mike.