Hey, welcome back, everybody. Day three of our healthcare virtual summit, and we're gonna kick things off this morning with Inhibikase Therapeutics. Dr. Milton Werner joins us, CEO of the company. A lot of big news for this company just in the last week or so. Raised a significant amount of capital to support its program in pulmonary arterial hypertension. Developing two drugs, we don't wanna lose sight, of course, of Risvo in Parkinson's disease. That's the brain-penetrant c-Abl inhibitor, and also IKT-001, or we just call it Pro. That's the drug that's gonna go into PAH, also very important. So welcome, Milton. Obviously a busy week, number of directions we can go, all positive. So, I think a good place to start would be maybe from your view, a top-down look at the company, and we'll kind of see where things go from there. Sure. So thank you for having us. Appreciate it, inviting us to talk a little bit about what's transpired in Inhibikase. We have worked in the last number of years on two clinical assets, both of which are going into late stage. Risvodetinib, which is a novel c-Abl inhibitor that's brain penetrant, that's been validated in a variety of preclinical models, of which we were partly developers of in both MSA and in Parkinson's disease, and show that it had rather interesting properties of both recovery of function and protection of loss of neurons, along with clearing of the underlying protein pathology. And IKT-001 Pro, which is a prodrug of the anti-cancer agent imatinib, and its history is quite interesting. It goes back to the earliest days of the company, when we were trying to understand how do we mitigate on-dosing side effects related to oral therapy-enabled inhibitors. Drugs like Gleevec or imatinib mesylate, now in a generic form, have a common problem. They make people feel sick all the time, they have some persistent side effects, not just in the GI, but also with periorbital edema and other effects in the blood system. And so we were looking to see how to mitigate that and develop this prodrug technology, which had unexpected properties. So our entry into PAH was relatively recent, until the last year, only because we were really looking for a way, how do we monetize an asset that we think has very interesting properties that we validated, we showed in people that it may actually have the same properties we saw in preclinical models? And then last week happened, so, which has been quite unexpected. I think what the driver is, is that imatinib had proven in the twenty tens to be a very potent agent, as good as sotatercept, the recently approved, Winrevair from Merck. And, but it's an oral therapy that you would take at home, rather than a subcutaneous injection therapy that you have to learn how to administer. It's also true that because of the mechanism of action of such drugs like sotatercept and imatinib, they are likely to be complementary in mechanism. That complementarity might lead to synergy, something that we will test directly in our upcoming trials, and if that synergy is there, that really could be a transformative moment for patients. Because people with PAH are, you know, literally dying during the trial. It predominantly affects women between the ages of 30 and 60. It's not clear what the gender preference is of that disease, but it's a really interesting opportunity, and because the FDA was willing to view IKT-001 Pro or an imatinib prodrug as a new molecular entity, that opened the opportunity to have a commercially viable drug product that should have improved properties and mitigate some of the things that were seen fifteen years ago in what was known as the IMPRESS trial with imatinib mesylate. That disqualified the drug at that time from being approved. So we're quite excited, and as you see, so did half the healthcare investors on the street, which is, to me, very, very unexpected. How could you not be excited about that? And so maybe talk about that, because... And we discussed this before the call. It's you never know. They came in, it seems, for PAH, right? Right. But it's blue chip, all the biotech funds that you know support that are important, right? So maybe just talk about that transaction as a kind of a model of- Sure What happened, for these You know, it was an unusual circumstance. I literally woke up in the middle of the night in between Christmas and New Year's in December, and said: "Can I just get this asset properly monetized? We don't really want to push it down the direction of a cancer indication, go into a cancer patient population for a slightly better generic. We think it has more value than that, and we think it could have a broader application in patients." So we made the query out loud. We talked about it internally to the company at that time. Then we had, through a transaction effort, met Soleus, the lead investor in the transaction. They had a long history in PAH, got very interested in this. Then come June, with the Aerovate failure, or at least the disappointing results in their phase two, three trials, that really sparked a moment. Many people in the field, including many people on the buy side, had believed strongly in the results of the IMPRESS trial and were puzzled why no one had been able to find a proper solution to take that forward. And so... Sorry, I'm in a conference today in Parkinson's disease, and so there is some background noise. So when that happened, I went out to talk to many of the institutional investors who had been in the space. They were all pretty receptive. And then through a set of discussions between roughly early July and early September, this transaction took shape. Many people got very excited about the company, the asset, the indication, and you know, it led to what was announced last week, which is a really remarkable deal. I mean, certainly for a company of, you know, well, what I would say had been much more substance, but from Wall Street didn't see, you know, the value yet that we were trying to demonstrate to the buy side around our Parkinson assets. And now I think what people have hopefully will see is that this very science-driven company that has late-stage clinical assets across multiple therapeutic areas, all focused around Abelson tyrosine kinase inhibition, really has a lot to offer and something to bring to patients that we think are gonna be transformative in multiple disease indications. And I think that's ultimately what the investors have bought into. Obviously, there's a lot of early discussion around the PAH work as we can move it forward into the clinic and take it into the clinic. In three to four weeks, there'll be the outcomes of the 201 trial in Parkinson's disease. We're looking forward to that outcome. We'll get unblinded very soon, and I think once again, what I expect we'll see is, again, the very science-driven focus of the company will have a really exciting outcome and drive movement of that asset also into later-stage trials for the benefit of patients. Can you talk about what pro is as a pro-drug, and also what happened in the Aerovate trial? Because it's in the obviously the same class medicine. Yeah. So it's, you know, there was a theory that was put forward by both Gossamer and Aerovate, and it's not a theory I'm critical of that was trying to address the observations made in IMPRESS, which was the trial of Novartis' Gleevec in PAH. And what happened in the PAH trial was concerning to the FDA, concerning to patients. You had a disproportionate occurrence of about 2%-4% in subdural hematoma. That was almost entirely due to the fact that patients at that time were taking warfarin and related anticoagulants, which were known to be incompatible with imatinib. But because they were standard of care, they couldn't be removed from those patients to see what happens with imatinib therapy. You had a lack of experience, to some degree, of clinical investigators with the side effects of imatinib, periorbital edema, some anemia, some fatigue, that looks like worsening PAH, and I think those two events really sort of tied themselves together to make it a diminishing interest at that time. In the years since, what's happened is that standard of care has changed. Patients are doing better with a combination of an endothelin receptor antagonist inhibitor, and PDE5 inhibitor, like Viagra or Cialis, and that combination really touches on the symptoms of the disease, but not the underlying causes. The underlying causes are really related to just a loss of proper balance in signaling between proliferation and dilation of these microvasculature in the lungs. And so that's where sotatercept was focused on one side, on the side of the endothelial cells that can proliferate inside the lumen of these small arteries, and where imatinib can play a role, which plays a role in modulating the effects, the activities of the smooth muscle cell walls of those vessels. And when those two drugs act in concert, and we think that's what's going to happen, although that's unknown still, we think that's gonna mitigate a lot of the underlying side effects that are coming from the disease, and really try to bring those signaling things back in balance. And so what we hope will happen here is that we can bring a drug forward whose active ingredient has already been validated in late-stage trials as being very statistically meaningful and clinically meaningful, and mitigate that with a pro form. What the pro form does, what it was built for, was primarily trying to suppress the GI and other on-dosing adverse events. Mm-hmm. Now, the way we evaluated whether such things were happening was using non-human primate toxicology models. People used to study Gleevec in dog toxicology models, but dogs are completely intolerant to drugs in that class. Non-human primates are very sensitive, and one of the unique sensitivities is that they have no excess water. So if they have persistent diarrhea or persistent vomiting, they're going to die very rapidly. And so we thought that model would be very interesting to be able to evaluate: Did the prodrug mitigate these on-dosing side effects in the GI? And that's what the studies appeared to show. The what's called the no adverse event level, was much higher for prodrug imatinib, relative to what had previously been measured for imatinib itself. Now, when you measure the no adverse event level, it doesn't measure just one side effect, it measures everything at once. So the fact that it was over threefold higher in exposure before you saw an adverse event suggested, but doesn't prove in humans, that we actually may have mitigated many of these side effects that are linked to imatinib early in the course of disease. Drugs in this class are known to be well adapted by people. So if you start taking the drug, you have some side effects that diminish over the first two or four weeks. Here, what may be happening is the prodrug is actually taking you to that adapted state earlier or more quickly, and if that's what's happening, we'd expect to see a more favorable side effect profile in people. Certainly, that was true in the bioequivalent studies we made with healthy volunteers, what was known as the 501 trial, that we were putting news out last year and early this year. And now we'll find out, hopefully middle of... beginning, middle of next year, roughly, what's gonna happen in these critically ill patients when we now add imatinib therapy as a pro drug onto the standard of care, which is an endothelin receptor antagonist, or ERA, in combination with a PDE5 inhibitor, like Cialis or Viagra. Yeah. So do you... Oh, sorry, Joanne. Because the standard of care has changed, right, with PDE5s and ... I missed the other one, the endothelin receptor antagonist, right? So do you have to consider drug-drug interactions even with an imatinib that's been in this setting but before the standard of care had changed? So the ERA plus PDE5 has been used for long anticoagulant therapy and multiple anti-prostacyclins. Today, you have an ERA plus PDE5 inhibitor, and typically just one anti-prostacyclin. So that's antiplatelet therapy, and no anticoagulants. So if you look back at the IMPRESS trial, and this was published in 2015, you can see that there's no negative drug-drug interaction potential between imatinib and standard of care. So that's clear. You see a modest increase, 20%-40%, in the steady state concentration of an ERA or a PDE5 inhibitor in the presence of a therapeutic dose of imatinib, but that's not a concern. If you saw a fivefold increase, you'd get concerned. And so, because we already know about that issue, we're far less concerned about that. The real problem in the past was you cannot take imatinib with an anticoagulant like warfarin, and today, at least to my knowledge, anticoagulant therapy is almost never used. Antiplatelet therapy, like a prostacyclin, is fairly common. About half of all patients take one. Got it. And, you know, you completed the hERG study, and earlier in May, you also received encouraging feedback from the FDA at the pre-IND meeting, regarding pro for PH. Now you're gearing up for the phase 2 702 study. So could you just share some highlights from that meeting, particularly, you know, regarding the NME designation, yet remaining on the 505(b)(2) pathway? Right. So that was the idea that was born in the middle of the night when I was frustrated with the market and had to think of a new way to raise additional capital. And I said, "Couldn't you have a branded drug and an indication that does not have an approval for that drug? But because of all the prior knowledge, wouldn't it still be eligible for at least consideration of a 505(b)(2) path approval?" So when we had our pre-IND meeting, which was on April fifth of this year with the FDA, that's what we put forward. We actually went one step further. We believe that imatinib, as the active ingredient, should be eligible for breakthrough designation already based on the IMPRESS results. And we asked all three of these questions, and many more, of the agency when we had this discussion, because we needed to know, with some confidence, whether the FDA's position is favorable to at least allow us to evaluate this, which is as far as they ever will tell you. And more importantly, do they think we should be doing this? Which is a question they don't normally answer, but in this case, gave us a positive response. So with the ability to have new molecular entity status and using 505(b)(2), that opens the door for full patent exclusivity. We don't know whether that's what will be granted. You don't know that until you file an NDA. The FDA won't evaluate before then, but we have 20 years plus in front of us. Compositions of matter IP through 2033. We have standard extensions of that IP will go to 2039, and then we have use IP, which we just filed in April of this year, and that full twenty-year window, so to 2044. If we are successful, complete this trial, which we think could be adequate for approval, that's not known, but we think that's possible, and if that's adequate for approval in three years' time, roughly three years' time, I should say, then we'll have 17 years in front of us. For a 30-year-old drug substance that's been reformulated with a new way of delivery in a critical patient population, for which it's already been shown to be successful. I think that's the combination that got so many of the marquee institutional investors excited, and as you saw, we've added a number of really high-profile individuals from the industry onto our board, who will be formally joining on Monday, when the close of the transaction occurs. So I think there has been this coalescing around a lot of really just exciting elements that piece together very nicely to make a really cogent story. In the trial itself, it's planned to be a phase 2b trial, formally. It's a phase 2 trial because the primary endpoint is planned to be what's called pulmonary vascular resistance. So this is the back pressure that occurs, that you can actually measure with a device from a company that used to be called CardioMEMS. Grew up in Atlanta, right down the street from me, when I started in Amicus way back when. That back pressure can be cause right heart enlargement and left heart deterioration. And that's an easier endpoint to reach. Imatinib was extremely active in heart health, heart hemodynamics, and was also very beneficial overall in the functional analysis of what's called the change in six-minute walking score, comparable to or better than sildenafil, which is a very well-tolerated drug. One of the things that occurred in the past was that imatinib therapy wasn't very well tolerated. We think prodrug should mitigate a lot of that. And we think that tolerance also had to do with the drug-drug interaction with other standard of care medications. I think the combination of everything that's going on here will be quite compelling, and if we don't see significant dropout, we may reach statistical significance for both PVR, or pulmonary vascular resistance, as well as the change in 6-minute walk distance, which is the primary determinant for approval in this field. And if we reach statistical significance in both, I see no reason why the FDA wouldn't grant at least a conditional approval with a post-market obligation, given the past history, and that we know so much about this drug substance and long-term administration across a large variety of patients. What would, what would be the timeline for getting that trial going, and- Well- - Enrollment times? We're hoping to get. If you look at recent trials, you can look at the Keros trial, you can look at the trial for sotatercept. You can enroll roughly 100 to 125 people in a year from 50 to 80 centers. And so in our case, we're planning on roughly 60 centers, predominantly U.S., EU, and U.K. There may be some additional geographic locations, where there have been very productive centers in Israel and in the East. It depends on how our enrollment plays out. We hope to have first patient dosing in next summer. I think that's probably a reasonable timeframe. There's a lot of infrastructure build-up because of the way we run trial work. That needs to be done on the PAH side. That previously was just centered around looking at bioequivalence, so it was very simple work in the past. I think that's roughly the timeline. If that all comes to pass, the trial's gonna have a number of internal metrics, the first of which is gonna be a safety evaluation when 60 of the 150 planned patients complete 12 weeks, so the middle point of the evaluation. We'll make sure with the Data Safety Monitoring Committee whether there are any safety concerns that have emerged. We should be able to see those concerns if they are present by 12 weeks, because for Abl kinase inhibitors, most things that are gonna be harmful are seen in three months' time. Then we'll also have a fertility analysis at 24 weeks, when half the patients, or 75 people, have completed the 24-week stage. One of the challenges in this field, which is more acute than others, is that you have to keep everybody on drug. It's life-saving in most cases. You may not withdraw the drug from individuals while you're waiting to find out whether it's truly beneficial. So if there isn't any harm, everybody has to go into an extension study, typically for years, because it takes usually a few years to finish a trial, finish your analysis, do the work for an NDA filing, et cetera. So it's a long-term commitment for the company to go down this path. We think that it's a very worthwhile commitment because just as we've done for Risodetinib, we believe it's... That we have a capacity for real innovation and finding real solutions for human beings for the long run. And I think, given what we know about imatinib's efficacy in this space, there's every reason to believe, but still has to be proven, that we're gonna have a safe and well-tolerated drug as an excellent add-on therapy and complement to sotatercept and other drugs that are being developed. But like sotatercept, Keros is a company that's doing something like that, alongside a TKI inhibitor, which is not an inhaled one. As we know, the inhaled inhibitors have not proven to be clinically meaningful. So the funds that came for the amount of capital that you raised, right? This is really to go down the PAH road. Is that to get you potentially to an accelerated approval? How far does that get you on the PAH side? That first close will fund everything, all the way through the end of that trial. Okay. In our opinion. And that's not all of the cash that we raised. So, while the raise was predominantly focused around prodrug and PAH, I believe it'll support, although this is still part of our internal discussion, some of the next intermediate steps as we complete the trial, the 201 trial readout, and what's gonna happen next with risodetinib in Parkinson's disease. And then that work will be, like any other program, funded when it's in a manner that's appropriate for it. And, we believe that the outcome of the 201 trial will be very motivating and support next steps, and next steps will come with adding additional capital for that purpose. Given the healthcare investors that are now involved, and we've all had this internal discussion, while we don't know this, and I don't think they know this, everybody wants to see those outcomes to evaluate whether they will just be the obvious supporters of what happens next with Risvodetinib. There's no intent to abandon it anytime soon, at all, because of what we've already established. Mm-hmm. Sort of switching gears over to the Parkinson's side. Mm-hmm ... I... I wanted to ask, how does risodetinib, the c-Abl inhibitor, also imatinib, also address the underlying pathways of Parkinson's? And sort of what are the implications for its potential role in modifying disease progression? Risvodetinib is a completely novel agent. It's a selective inhibitor of just the cytoplasmic members of a family, Abl-1 and Abl-2, and unlike imatinib, it does not hit the receptor tyrosine kinase. It's known as KIT, PDGFR alpha, and PDGFR beta. It's for that reason that risvodetinib has had such a favorable side effect profile in Parkinson's patients, whether they're on symptomatic therapy or not. We published, beginning in 2022, in Movement Disorders, and then in 2023 in Science Translational Medicine, just how effective therapeutic administration of risvodetinib can be. It both blocks disease progression, it clears underlying alpha-synuclein aggregate formation in the affected neurons, it restores and preserves neurons from degrading, restores loss function, restores motor function, suppresses neuroinflammation. Most of those features have been characterized in detail and reviewed in the paper in Movement Disorders, which you can pull from our website from twenty twenty-two. That was authored by myself and Warren Olanow. And then you can see the demonstration of that in inherited and sporadic models of human disease, in the paper in Science Translational Medicine. In people, we'll find out, do we see clearance of Alpha-synuclein aggregate formation in the organs of disease? We're measuring that directly in skin and in spinal fluid, although spinal fluid measures are limited because that's usually a gating factor for enrollment, particularly for untreated disease, so you don't get very many volunteers to do that. But for skin biopsy, we get a lot, and that's a very well-validated measurement tool. We're doing the same thing for functional parameters in the brain.... autonomic nervous system activity and for GI activity. So it was a very comprehensive evaluation in the 201 trial that was primarily based on safety, with a whole series of secondary endpoints for different analyses of motor and non-motor features of disease, activities of daily life, et cetera, and we're encouraged by what we've seen in a blinded case, but of course, we don't know what it means. Since unblinding is gonna happen within the next two weeks, three or four weeks from now, we should know the answer, and I think, I hope we'll have a very supportive outcome to drive what's gonna happen next, both for an extension study of the risvodetinib participants in the 201 trial, and then for the planning of a next stage study, which we would imagine would be phase 3. Can you just- Mm ... at a high level, mention the importance of where alpha-synuclein is causing issues, and why Risvo being an Abl 1 and 2 cytoplasmic-focused drug seems to make a difference- Sure -versus other drugs out there? So in Inhibikase, along with a whole group of other academic researchers, principally Ted Dawson at Johns Hopkins University, carried out a series of studies where we evaluated what is the driver of synuclein aggregate disease initiation and progression. And what we believe happens is that alpha-synuclein aggregates are internalized by the affected neurons. When they are internalized, that activates c-Abl, 'cause the role of c-Abl in the disease, in a mature neuron or a mature cell, is to drive cell death whenever the cell senses a toxicity. So alpha-synuclein aggregate internalization can be viewed as a form of something unusual or foreign. The cell's response, the neuron's response, is to kill itself to protect its neighbors. So very egalitarian community of organs in your brain and everywhere else in the body. So when c-Abl's activated, two things happen: you chemically modify a specific tyrosine, tyrosine 39, of alpha-synuclein. That gives us a marker for pathology that we can trace. We now have novel antibody to actually trace that in biological tissues and fluids, something we've telegraphed a little bit about this year. And you also have phosphorylation of a protein known as parkin, which is formerly known as ubiquitin E3 ligase, and plays a significant role, along with PINK1, in mitochondrial integrity and biogenesis. And so two things happen. The alpha-synuclein aggregates affect gene expression, they affect vesicular trafficking, they affect mitochondrial function directly. That effect on mitochondrial function turns on what's known as PARP, PARP-mediated apoptosis, or parthanatosis, as it's been termed. And what happens in parthanatosis is a kind of double-stranded DNA in the nucleus activity that degrades nuclear genetic information, leads to degradation of the nucleus, degradation of the neuron in subsequent steps. When you inhibit Abl, you block the formation of synuclein aggregates that are being phosphorylated, and so at any point in which you do that, you can both block further effects on, of alpha-synuclein within the neurons that already contain it, and because you've blocked Abl, you... as you turn over parkin and parkin becomes reactivated, you restore the loss of mitochondrial function. And so what we've seen in cells and in neurons and in living organisms is that we start rescuing function that hasn't been fully lost, because the rate of degradation is very slow. And as you rescue function and you block the spread of synuclein aggregates, they have nowhere to go. And so endogenous activities, predominantly through the ubiquitin proteasome system, because parkin is reactivated as a ubiquitin ligase, and potentially also autophagic mechanisms through the lysosome, can drive clearance. And so in living organisms, we saw a response to therapy in the brain and in the GI tract, that synuclein aggregates are being cleared in response to therapy. Even though the disease was established for weeks in these animals, you see that disease being cleared. We're now making similar measurements in human beings. We'll find out whether, in fact, we're clearing synuclein aggregates from human beings in response to therapy. Obviously, if we were to see that in a therapeutic setting, it is one of those pieces of therapeutic response one has tried to achieve for many decades. It was tried initially to be done with antibody therapy and did not have any benefit, because at least in the Inhibikase view, antibody therapy is really only affecting aggregates that are outside of the affected neurons. The disease process is internal, and antibodies cannot penetrate into the neurons. You have to attack the disease process and that pathology from within the affected neurons. If you can do that, and those neurons have not fully lost function, you at least have the opportunity to preserve function that's not fully lost. So that's what we think is gonna happen. We have no idea until it's unblinded, so a few weeks away. We have about thirty seconds or so. Can you just quickly run us through the next events for the company investors can look towards the next six months? Sure, so you're gonna have a number of announcements for key hires in the company to support the PH and the Parkinson's programs. On the medical side, particularly, we're gonna have the advancement of the PH trial work moving forward, and we should see results from the 201 trial in Parkinson's, and the next steps that are coming from, as a consequence of those results. I think those are the things we're gonna see in the next six months, and probably at the end of that six-to-eight-month period, we may even have the first patient dosed in PH. It really depends on the logistical setup of all of the pieces of the puzzle we have to put into place. But it's an exciting time, and fortunately, we have quite a lot of capital and the opportunity to raise more as needed to support these diverse programs and Abl kinase inhibition, which is what Inhibikase is all about. Thanks, Milton, for coming on, but congratulations on everything. You guys- Thank you very much. last week or so. Thank you very much. Appreciate it. Thanks for your time. Have a great day. Bye-bye.