Targeting Neuroinflammation to Treat ALS

Regulatory T cells target systemic inflammation and neuroinflammation, but when they fail to function properly, they can drive serious health conditions including neurodegenerative, metabolic, and autoimmune diseases. Coya Therapeutics is developing a pipeline of therapies designed to restore the ability of Tregs to modulate the immune system and reduce inflammation. The company’s lead experimental therapy is a combination of two biologics designed to treat ALS by boosting anti-inflammatory Tregs while suppressing other immune cells that drive inflammation. We spoke to Howard Berman, chairman and CEO of Coya, about the role of inflammation in neurodegenerative conditions, Tregs, and the company’s experimental therapy to treat ALS.

Daniel Levine: Howard, thanks for joining us.

Howard Berman: Thank you for having me. It’s a pleasure.

Daniel Levine: We’re going to talk about Coya Therapeutics, the neurodegenerative disease ALS, and your combination therapy in development designed to address an underlying inflammatory response that drives this condition. Let’s start with ALS. For people not familiar with it, what is it?

Howard Berman: ALS is a neurologic disease of the motor neurons, and unfortunately, what is the result of this disease is the muscles begin to stop working, and that includes muscles in the periphery. It also includes muscles near your lungs. And unfortunately, and ultimately, patients are unable to breathe towards the end of life. And that’s the way that some patients die from the disease. But it’s a progressive neurodegenerative disease of the motor neurons. The neurons get into trouble, unfortunately, and inflammation plays a very important role in the process of this disease.

Daniel Levine: Well, how is it treated today and what’s the prognosis for someone with the condition?

Howard Berman: So, unfortunately, there’s not a lot of treatments out there that are successful. Most patients are either given a regimen of supportive care, and then the newly approved drug, there’s a drug called Relyvrio, which is a combination of two different types of drugs, but it only slows progression in a very small manner relative to what they would traditionally decline it. And there’s another drug called Radicava, which has been approved by a company called Mitsubishi. We believe that’s a free radical scavenger, but again, like Relyvrio, it only slows progression very, very slowly. So, the ultimate result is that patients unfortunately last only two to five years. And the interesting thing about the disease is that it’s heterogeneous. Some patients may live for quite a long time, like you know about Stephen Hawking. Other patients die much quicker. Lou Gehrig died very quickly. But the average decline, the average longevity of these patients is between two to five years.

Daniel Levine: There was actually an interesting academic study about 10 years ago that suggested Lou Gehrig didn’t have ALS, but had CET.

Howard Berman: Yeah, I saw that. And I would of course have Dr. Appel and other experts weigh on that. But, you know, that’s the characterized definition of what he had. So, I don’t think a true answer will ever be known about him, but he did certainly die quite quickly. And I guess from what I’ve heard is some of the symptoms that he had were consistent.

Daniel Levine: There has been growing activity around ALS and a growing pipeline of therapies to treat neurodegenerative conditions more broadly. At the same time, there’s been some controversy around the FDA’s use of accelerated approval in these conditions and the level of proof required to demonstrate efficacy. What’s your sense of how the FDA is approaching these conditions and have any of these controversies appeared to change FDA’s approach?

Howard Berman: Yeah, I think that there is much more openness on the part of the FDA, and we’re very grateful for that. They realize and recognize that there are not a lot of treatments for this patient for this disease. Patients are in decline and they just unfortunately don’t have much other option. So, this sentiment by FDA is conducive to something called regulatory flexibility. And what it allows the FDA is to take a look at a study and use their discretion in terms of the requirements that that the sponsor will need in order to get an approval. And if you saw recently, there was a drug called tofersen by a company called Biogen. And that was for a SOD mutation. Well, the study was not a successful drug in terms of the traditional outcome of ALS-FRS, but ultimately it was approved because they were able to show changes in certain biomarkers. something called neurofilament light. It’s a marker of neurodegeneration. So there is regulatory flexibility. They do really look for drugs that are providing meaningful differences in benefits, and they’re looking for more objective biomarkers, more objective markers of the progression of the disease or the treatments that are modifying those markers. And that’s what we’re working on at Coya, is not just neurofilament light, but we’ve got a series of biomarkers, which are forthcoming, which we’re very excited about that really give some strong insight into the disease process.

Daniel Levine: There are a few challenges conducting clinical trials for these conditions with other therapies in development for ALS. Are you concerned there’ll be any challenge with regards to enrolling patients in studies?

Howard Berman: You know, we have put together a group of some of the top experts. We just brought on Merit Cudkowicz from Mass Gen, and we’ve got other key opinion leaders and we don’t anticipate, and neither do our experts, the inability to enroll. I think the data that we’ve shown in terms of the ability to potentially significantly slow or even stop the progression is exciting. And patients will be very compelled to participate in our forthcoming trial. But I will tell you that there are certain designs that people will appreciate more. If it’s, for example, a two-to-one randomization inactive in favor of the active, those studies will probably enroll better than if you’re one-to-one randomized. And of course, all studies have what’s called, or at least they’re expected to in ALS, to have an open label extension where the placebo arm crosses over to the active arm. Just to get back to your point, no, I don’t think we’re going to have an issue in enrollment.

Daniel Levine: At the same time, how important is patient selection with regards to where someone is in terms of the progress of the disease? Is there a sweet spot between a patient being far enough along to show the impact of the disease, but not too far along so that the benefit of the drug can be demonstrated?

Howard Berman: That’s an excellent question. And there’s multiple components that one has to consider when enrolling a patient. One has to consider the burden of disease. So, the score that the patient has in terms of their ALS before entering into the study, as well as the rate of decline prior to treatment. You don’t want patients who are progressing too rapidly and you don’t want patients who are not progressing at all because then the data could be biased in some capacity. So, there is a sweet spot in terms of the disease progression. Now, I will tell you there’s reasons for that and we’ve found this, if you look at the level of inflammation, oxidative stress in patients that are much further along in the disease process, you will find that the levels are significantly higher. And so we believe, and the mechanistic reasons are that the more inflammation that the patient has, the more difficult it is to intervene with the appropriate therapies.

Daniel Levine: Let’s talk about inflammation. Coya among other companies are increasingly looking at inflammation with regards to not only ALS, but other neurodegenerative diseases. What role does the inflammatory process play in ALS and how linked is that to the process of decline in patients?

Howard Berman: Yeah. Well, inflammation is a very broad category that includes many different aspects to it. There are multiple cytokines, there’s multiple cellular types that are associated with inflammation. So, it’s a broad category that everyone uses. Other companies are targeting, for example, different components of the immune system. They’re targeting the IL-6 and the complement pathway and the IL-1β and TNF-α. But those are just individual cytokines and unfortunately, the immune system is redundant. So, our approach, and I’m going to get to specifically why I think our approach to inflammation is important in ALS, but our approach targets multiple aspects of the inflammatory cascade. We target the regulatory T-cells. Why the regulatory T-cells? Well, we discovered, Dr. Appel did, and he looked at large numbers of patients, that the degree of dysfunction of the Tregs corresponds to not just the degree of decline of the patients, but the survival. So, if a patient is having, for example, a dysfunctional Treg—so the Tregs are not 40 or 50 percent as functional as, for example, another ALS patient, those patients will likely be dead sooner than the patients who had a functional Treg. And so, Tregs were elucidated to play a critical role, and they’re the master regulatory cell of the immune system. So, we know to prop up the Tregs, which cover many different pathways downstream, but we also hit other inflammatory pathways with our other component of the 302, which is CTLA-4, and that reduces the myeloid cells and the macrophages, which play another important role in causing Tregs to become dysfunctional. And they also play a role in ALS. So, by doing that, we actually go above and beyond what other people are doing in the inflammatory pathway. And let me just talk to you about why inflammation’s important. It turns out that the motor neurons at the periphery, in terms of the neuromuscular junction outside of the blood-brain barrier, are until very late stage disease usually anatomically intact, but they’re functionally intact. So, we believe that the immune system and the myeloid cells and the macrophages may play an important role in that functional dysfunction at the motor neuron. And if you can remove that functional block, just that block of immune cells, you can actually have the muscles working better and the signals firing between the neuron and the muscles. And so that’s why we think that the attacking inflammation and the associated oxidative stress is a critical function of intervening and having disease modifying capability.

Daniel Levine: Can you measure that in a patient? Can you see it on imaging or use blood or CNS fluid to determine the inflammatory activity and the health of the Tregs?

Howard Berman: Absolutely, yes. That’s all the things that we’ve done in our proof of concept clinical study. You can actually quantify the regulatory T-cell function, so you can see how functional or dysfunctional those Tregs are. You can also measure the Treg numbers and raw numbers and see how that’s impacted. And then you can actually measure inflammatory pathways. You can do proteomics and you can do immunoassays, and you can look at various cytokines that are going up and down. And then you have the ability to look at oxidative stress. That is also a very important process associated with ALS. So, you do all of that and it becomes a much more objective way beyond just looking at the ALS-FRS score, which is the functional scale.

Daniel Levine: So, within the world of ALS therapies today, how unique is Coya’s approach?

Howard Berman: Well, we have always been talking at the top of the banister that the regulatory T-cells are an important target for ALS and we’ll continue doing so. And so, we started off with cell therapy and we quickly went to biologics to enhance Tregs. So, we’ve been unique all the way from the beginning and leading the way on regulatory T-cell enhancement. But the novel discoveries are that if you synergize two drugs together, you can get a beneficial effect above and beyond the single drugs like they’ve discovered in oncology, and like they’ve discovered in HIV and AIDS. So, in that capacity, we’re very unique, we’re very differentiated, and we in fact modify biomarkers, blood biomarkers, and we haven’t published these data yet, but I think when that comes out, that’s also going to be a separation and uniqueness than others who have been really looking for more objective manners of modifying these objective blood or serum markers.

Daniel Levine: Let’s talk about your experimental therapy COYA 302, which you mentioned is a combination of two biologics. What are the components and how is this prepared and delivered?

Howard Berman: Sure. Our therapy, COYA 302, is two different biologics. The first biologic is low dose interleukin 2, and it has been prepared in a very low dose format and in a way that you can deliver it in its cutaneous injection, which makes this much easier to do. So, imagine the patient goes home, we give them these syringes or a vial, typically syringes. The patient can be injected by their caregiver or even themselves much like an insulin injection, and they do it over a given period of time on a daily basis. The other drug is the CTLA-4 Ig, which is the biosimilar of Abatacept, which we licensed from Dr. Reddy’s. And that drug is also a subcutaneous injection, which can also be administered in the home setting as well. So, these are very easily administered. It overcomes lots of challenges by patients having to go to the physician’s office or even to the hospital setting. It’s subcutaneous injections. It requires no CSF administration, intrathecal administration, like many of these other drugs where they’re just trying to have multiple injections through the spinal cord. And that’s just not a very convenient, and it’s a very painful way to deliver drugs. Our method is, I think, more streamlined and achieves the results that we’re aiming to achieve.

Daniel Levine: So, as you noted, combination therapies are not unusual to see in areas like cancer, certainly in certain infectious diseases. What’s the case for using it with a neurodegeneration like ALS?

Howard Berman: Much like cancers, it involves, as I mentioned before, the immune system [which] plays a critical role. And as we’ve learned in cancer, the immune system is redundant. So, if you target and attack one component of the immune system, another one can take over and it results in resistance to those chemotherapies or those targeted therapies. So, the only way to attack that is to block various aspects. So, there’s the innate immune system, and there’s the adaptive immune system, and that’s what these cancer drugs are targeting to actually do the exact opposite of what we’re doing. It actually ramps up the inflammation. You want to block the Tregs, you want to block the other aspects of the immune system to actually enhance components of the immune system. We’re doing the exact opposite. We are ramping up the Tregs so that you block the inflammatory process, but like oncology, you do that, you get the dysfunctions and other aspects of the immune system, which are not handled exclusively by the Tregs. And so, we have simply discovered other pathways that when you combine with the Treg enhancement, provide synergistic results in terms of the clinical and the combination, the potential benefit.

Daniel Levine: And is the expectation that this would slow progression? Could it halt progression or even reverse it?

Howard Berman: Well, from what we’ve seen in our small, in our open label clinical trial in patients, it stopped the progression out to six months. And this was in a population of patients who were progressing prior to treatment. So, our goal is to halt progression, but we are designing our trial not with the expectation that it will do so. But we want to be more conservative so we’re planning it that it will slow progression, but of course, if we can hold progression and have patients live much longer and this be more chronic disease and patients just can live with live with this the disease like HIV and AIDS, that’s really where we want to target.

Daniel Levine: What else is known about COYA 302 from the studies that have been done to date?

Howard Berman: Well, it appears to be safe and well tolerated. The main side effects were injection site reactions, which are simply, and you see this a lot with any injection, any subcutaneous injection, but it’s resolved just by taking Advil or Tylenol. We don’t see any blood abnormalities, any EKG abnormalities, any liver dysfunction, any infection, higher risk of infections to date. The toxicology work that we’ve done on the drugs in rats also looks very clean. So, from a safety and tolerability standpoint, we’re very confident. From the clinical efficacy, it looks to be very promising. As I mentioned, what we did in terms of these patients, and of course, the only way to really validate this and quantify the true benefit is to run a large double-blind randomized, well-controlled trial and to do it at multiple sites so that we can get hopefully a statistically significant difference at the desired endpoint.

Daniel Levine: Coya is a public company. You became CEO following the merger between Coya and Nicoya Health. The company was a rare small biotech IPO in 2023, it raised $15.25 million. Given the size of the offering, why did you decide to go public in this environment?

Howard Berman: Right. So, it was a very challenging year last year. Everyone knows it, but believe it or not, it was harder for private companies to remain private than for public companies to access capital. And that’s the unfortunate reality. A lot of these funds are investors, both in private and public. So, we had existing investors who invested in our company, both in the IPO as well as the series A investment. And they were very supportive of our company and they said, look, we will re-up the investment if you go public. And if you are able to have a tradable marketable security and set yourself an evaluation that was reasonable where people can make money long term. Because we didn’t have a lot of paid in capital going into the deal, we weren’t one of these companies who had to set a valuation that was so unreasonable that you couldn’t attract investors. So, we were in a more opportune situation to go public at a valuation that was decent for investors. And we were all investors in the deal. And that also helped our cause. People saw that we were putting our own money into the deal, skin in the game. And ultimately that, combined with the science and the clinical data that we’ve generated to date, it was a convincing factor for our investors. And so we made it happen.

Daniel Levine: And what’s the plan to raise funding to carry you forward? How much runway do you have right now and what are you thinking in terms of additional financing?

Howard Berman: Right. So, we are, and all the guidance as we said, is we are good through the second quarter of 2024, and into the second quarter of 24. And I can tell you, though, that we are in vigorous discussions, I’ll use that word, with strategic partnerships and I’ll leave it at that. But we are bullish on the process and we’re excited about starting our clinical trial next year.

Daniel Levine: Howard Berman, chairman and CEO of Coya Therapeutics. Howard, thanks so much for your time today.

Howard Berman: Thank you. It’s a pleasure.

This transcript has been edited for clarity and readability.