Latest / CareTalk: Healthcare. Unfiltered. / How AI Is Helping The Fight Against Parkinson’s w/ Gene Mack, CEO, Gain Therapeutics

Transcript

How AI Is Helping The Fight Against Parkinson’s w/ Gene Mack, CEO, Gain Therapeutics · CareTalk: Healthcare. Unfiltered.

• 0:00
  David: Parkinson's disease affects nearly 1 million Americans, but treatments have been limited to managing symptoms rather than slowing the disease itself.
• 0:08
  David: Now, a clinical stage biotech company is using an AI powered drug discovery platform to take on one of neuroscience's greatest challenges.
• 0:17
  David: Its lead candidate is already showing signs that disease modification may be within reach.
• 0:29
  David: Hi everyone.
• 0:30
  David: I'm David Williams, president of Strategy consulting firm, health Business Group, and host of the Health Biz Podcast, where I interview top healthcare leaders about their lives and careers.
• 0:39
  David: My guest today is Gene Mack, CEO of Gain Therapeutics Under Gene's.
• 0:43
  David: Leadership Gain is advancing a potentially groundbreaking disease modifying therapy for Parkinson's, Parkinson's disease, while deploying its Magellan AI ML drug discovery platform to unlock additional treatments.
• 0:57
  David: Gene, welcome to the Health Biz Podcast.
• 0:59
  Gene: Thanks David.
• 1:00
  Gene: Thanks for having us.
• 1:02
  David: Now I understand you joined gain around, uh, 2024 as the CFO and then quickly switched over to, uh, running the company.
• 1:09
  David: And I, I think you said at that point, uh, you really didn't want anybody else in charge.
• 1:13
  David: So I'm wondering what was it about gain and the science and mission that made you so certain about that
• 1:19
  Gene: the.
• 1:20
  Gene: Company, um, wanted to take a more focused approach to, um, its, uh, capital market strategy, uh, and, and financing.
• 1:29
  Gene: And, um, they, in the process of bringing me on board, um, they, uh, you know, decided more and more responsibility.
• 1:39
  Gene: Um, and, you know, it's not something I've never, no one, I, I always say no one comes out of the womb wanting to be the CEO of a biotechnology company.
• 1:49
  Gene: I made it well, well, well, uh, known that my job was supposed to be second base for the Yankees, but I couldn't get there.
• 1:56
  Gene: Um.
• 1:57
  Gene: And so, you know, I, when, when, when I was joining Gain, um, you know, the, the role, they said the role may be in flux.
• 2:05
  Gene: Um, and they asked me about the CEO, you know, would, would you, would I ever see myself as a CEO?
• 2:10
  Gene: And I kind of said no.
• 2:11
  Gene: Um, I liked finance, I liked my lane, I liked what I did.
• 2:14
  Gene: I a lot of expertise, uh, you know, uh, for better, you know, I don't love, you know, dealing with a board is a separate job.
• 2:21
  Gene: You know what I mean?
• 2:21
  Gene: So, um, but they're lovely and they've been so supportive and they really made it a, a, a very, um, uh, really sort of, um, uh, gratifying experience.
• 2:32
  Gene: And I feel like I've grown and I've learned a lot in the last two years.
• 2:35
  Gene: Um, so I'm glad it all played out the way, the way it did.
• 2:38
  Gene: And yeah, you and I, and I, and I still believe that, that it got to the point where, you know, uh, I was an interim C cf CEO for about six months.
• 2:45
  Gene: Um, prior to them making it permanent, and by the end of that six months I was, I was really, uh, nervous that they would go in a different direction.
• 2:52
  Gene: Because by that point, you know, you're starting, you're starting to wrap your arms around everything that's problematic and you sort of see your way clear, uh, to a path and you're like, well, we bring in somebody new.
• 3:02
  Gene: Is that to all the things that we think we can have rolling?
• 3:05
  Gene: So, uh, ultimately it all, I think it all played out the ways it should have.
• 3:11
  David: Uh, Parkinson's patients and families are well aware of the limitations of current treatments.
• 3:16
  David: It's really just about managing symptoms, at least what I've seen, uh, thus far.
• 3:20
  David: And my belief is that gains approach is pretty different.
• 3:25
  David: Um, can you explain what it is that the drug does and why you think it could be the first disease modifying therapy for Parkinson's?
• 3:33
  Gene: Yeah.
• 3:33
  Gene: So, um, you're absolutely right.
• 3:35
  Gene: For decades now, the only, um, relief we've been able to offer to Parkinson's patients has been, uh, some kind of mask over their symptoms, and that wears off over time and the disease, the pathology, and the disease progresses.
• 3:48
  Gene: So what do you do to address that?
• 3:49
  Gene: What do you get to the underlying biology and you try to correct on a molecular level?
• 3:54
  Gene: What's happening, um, to create these symptoms.
• 3:57
  Gene: And we believe that GT 0 2 2 8 7 is going to be among the first, if not the first, uh, disease modifying, uh, therapeutics based on the data that we've seen so far, the preclinical, um, efficacy that we've seen of the preclinical mechanism, uh, that we've seen this drug, um, uh, uh, uh, work through.
• 4:15
  Gene: Um, suggest disease modification at every level.
• 4:18
  Gene: We have tested it at, um, including what we think is, you know, the phase one B in patients now Parkinson's, where we're seeing biomarker evidence.
• 4:27
  Gene: Um, these are the actual bio biological indicators.
• 4:30
  Gene: Of how the disease is, um, is progressing.
• 4:33
  Gene: We're seeing what we believe, uh, is some real impact there, uh, in the presence of GT 0 2 2 8 7.
• 4:39
  Gene: Um, and we believe it is being, it's linking to a clinical benefit early days in this study still, and we have low numbers of patients, but the signals are impossible to.
• 4:51
  Gene: Um, and that's what's really exciting about what Gains doing now.
• 4:54
  Gene: Um, we've just recently presented data at a, at a, a global conference in Copenhagen called the A DPD conference.
• 5:01
  Gene: Data was very well received there, and we think we've given, um, the field a lot to think about now in terms of how, what we're seeing in the biomarkers, and hopefully they're gonna do work that's similar to ours and, and help us understand it better based on, you know, the, the, the, uh, the drug development that they're doing.
• 5:19
  David: Great.
• 5:19
  David: So let's go, just go a little bit, uh, deeper in terms of how things work.
• 5:23
  David: And I'm just, uh, not an expert, but just looking at your materials and seeing that it appears that, uh, your drug is targeting a misfolded enzyme and works through an, I think, pronounced allosteric mechanism.
• 5:35
  David: It's not binding to the active site.
• 5:37
  David: Why, uh, does that matter?
• 5:40
  David: And what makes this kind of allosteric modulation potentially a better approach.
• 5:45
  David: So not just you're getting the clinical evidence, but you know what, why is it that you think that may be an underlying better way to go?
• 5:51
  Gene: Yeah.
• 5:52
  Gene: And that question is essential to what we're trying to achieve here too.
• 5:54
  Gene: So the allosteric binding, we're, that's a, what does that mean?
• 5:58
  Gene: So there's ways to, there's different ways to bind a, a target protein or enzyme.
• 6:02
  Gene: Um, typically if you bind it at the active site, um, you're looking to probably try to inhibit that particular enzyme.
• 6:08
  Gene: Maybe it's overactive or it's have to, it's, it's, it's, it's misfunctioning in a, in a hyperactivity way, right?
• 6:14
  Gene: So you wanna, you wanna, you wanna, you wanna, uh, disable some of that enzyme.
• 6:19
  Gene: Sometimes you can bind to the active site and actually enhance the activity too.
• 6:22
  Gene: It all depends on the binding kinetics and what's happening in that, that particular area of the molecule.
• 6:27
  Gene: What, what, how you're impacting it.
• 6:30
  Gene: Uh, based on that binding.
• 6:30
  Gene: Now what we do is we move further, mostly further away from the active site.
• 6:35
  Gene: We're looking to stabilize the enzyme.
• 6:37
  Gene: So if you remember from high school biology, the lock and key mechanism for proteins and enzymes, their, their, their, their function is determined mainly by their conformational shape.
• 6:46
  Gene: So if that gets disrupted either through genetic mutation or some sort of post, you know, some, some sort of post-translational modifications to the protein.
• 6:53
  Gene: So after it's transcribed and it's sitting in the cell, you know, if something comes along and disrupts it.
• 6:58
  Gene: Um, so what can you do in order to preserve.
• 7:01
  Gene: The function of an enzyme, um, uh, that might be, you know, genetically malformed or under assault some other way.
• 7:07
  Gene: Well, so we bind to an allosteric pocket on this enzyme, stabilize the confirmational shape of the protein, and chaperone that that enzyme through its traffic pattern in the cell and the particular target.
• 7:20
  Gene: GT 0 2 2 87 is an enzyme called glucose cerebro.
• 7:24
  Gene: It's a mouthful.
• 7:25
  Gene: We shorten it to G case.
• 7:27
  Gene: G case is a very well defined, very fairly well understood enzyme.
• 7:32
  Gene: Um, that is prominent in the pathophysiology of Gaucher in the periphery mainly.
• 7:37
  Gene: So that's another disease.
• 7:38
  Gene: Where, where this particular enzyme is not working properly.
• 7:42
  Gene: Um, but in Parkinson's patients, it also plays a role too, particularly if you have, uh, what's called the GBA one mutation and the gene that encodes.
• 7:51
  Gene: For glucose cerebritis, if that, if you're carrying a, um, uh, a mutation in that gene, uh, your enzyme function is going to be naturally lower than a normal individual or a person who has, uh, you know, uh, normal levels of G case activity.
• 8:04
  Gene: So we're trying to enhance that, that protein activity, enzymatic activity in Parkinson's patients, because that enzyme is responsible for clearing out toxic substrates that build up in the cell and create those symptoms over time.
• 8:18
  David: So you're talking about, uh, a genetic mutation, and my understanding is that the drug was originally designed for that subset of Parkinson's patients that had that mutation.
• 8:29
  David: But also I think maybe some of the excitement about their early data is saying, well, maybe it's actually a broader population that's that's relevant.
• 8:36
  David: Is that, is that a, is that the case and is that a big deal?
• 8:38
  David: If so?
• 8:39
  Gene: Yeah.
• 8:39
  Gene: So there, um, so the, the prevalence of the gene mutation, the GBA one mutation is about 10 to 15%, um, globally.
• 8:48
  Gene: Now, it depends regionally and ethnically.
• 8:51
  Gene: In a lot of cases there, there's some distribution of that, uh, percent.
• 8:55
  Gene: It's not, you know, for example, uh, for whatever reasons, Ashkenazi Jews have a much higher prevalence of a GBA one mutation than, uh, than other races do.
• 9:05
  Gene: There's a population of Northern Africans that also carry a higher, uh, prevalence of it as well.
• 9:11
  Gene: Um, not, not well understood why that is, but so some of that is, you know, so, so there are some certain populations that.
• 9:16
  Gene: Express this mutation more than others.
• 9:18
  Gene: Uh, but overall in the, if you look at all the literature, you find it's about 10 to 15% of the patients, which would maybe make it fall into sort of an orphan category.
• 9:26
  Gene: We're agnostic to orphan or, uh, otherwise, what we don't wanna do is leave any Parkinson's patients behind if you carry the mutation.
• 9:34
  Gene: Our hypothesis with GT 0 2 2 8 7 is you may respond better to, um, to, to, to our intervention.
• 9:41
  Gene: However, all patients.
• 9:44
  Gene: Parkinson's can benefit from an elevation of their G case activity because there's clearly a buildup of toxic substrate, genetically mu, you know, driven from a genetic mutation or otherwise.
• 9:55
  Gene: There's other things that can happen to proteins too, that are not related to a genetic mutation that may be occurring more in Parkinson's patients.
• 10:03
  Gene: Right?
• 10:03
  Gene: So outside influences and toxins.
• 10:05
  Gene: Things that get into the cellular microenvironment like pesticides.
• 10:09
  Gene: Those can drive Parkinson's.
• 10:11
  Gene: And even though G case is not mutated in that particular individual, they may benefit from a super dose of G case.
• 10:18
  Gene: Right?
• 10:19
  Gene: So we elevate their G case activity to overcome the other onslaught.
• 10:22
  Gene: And so we think that we can cover, uh, all Parkinson's patients with potentially differential responses among patients who have a genetic mutation.
• 10:31
  Gene: Those that are, you know, idiopathic instead, which is, you know, not, not a very ill-defined way.
• 10:36
  Gene: You know, there's no real.
• 10:37
  Gene: Uh, understanding of how the par, you know, there might be another genetic mutation or some other cause that we dunno about.
• 10:42
  Gene: Um, but, uh, but we think that both populations, uh, can benefit from GT 0 2 2 8 7.
• 10:49
  Gene: So for now, we're enrolling everybody to see if we can tease out how these different, um, uh, you know, patient phenotypes, how they present and they all present very differently how they all react to the drug so we can better understand how to address patients.
• 11:03
  David: So it sounds like a very interesting program.
• 11:05
  David: Uh, you also have a broader Magellan platform, and I've seen it described as a physics-based AI ml drug discovery engine.
• 11:14
  David: Now obviously AI is a, a place that we wanna be.
• 11:18
  David: Um, at the moment there's a lot of hype about it in drug development.
• 11:22
  David: I'm not saying it's it's for real, but I'm wondering, you know.
• 11:25
  David: Is Magellan for real?
• 11:27
  David: And is there something about this approach that you're taking that surpasses what a traditional approach would be able to accomplish?
• 11:35
  Gene: Yeah, so it's a, it was an earlier iteration of Magellan that actually led to GT 0 2 2 87.
• 11:41
  Gene: So we've actually been refining it and improving it along the way.
• 11:44
  Gene: Uh, we've actually, um, the, the backup series of compounds, the GT 0 2 2 8 7 were also, uh, developed using, uh, using Magellan.
• 11:52
  Gene: So we find it to be a very efficient platform.
• 11:54
  Gene: The thing about AI and drug development, at least the way we're deploying it, right, is that there are, in order to find novel binding sites on proteins, you have to understand.
• 12:04
  Gene: The, the, the binding and unbinding kinetics that molecules small molecule has to achieve in order to get into that binding pocket.
• 12:12
  Gene: And then you have to figure out whether or not something like that can be constructed if it's not already in the public domain.
• 12:17
  Gene: In other words, we're also trying to expand development with AI beyond what's in the public domain, to come up with molecules that may be never have been formulated before.
• 12:25
  Gene: Well, that's a lot of calculation and some of which that takes.
• 12:28
  Gene: It takes 10 minutes to conduct, right?
• 12:30
  Gene: You have to do that over billions and billions of iterations.
• 12:32
  Gene: You can see the time, right?
• 12:34
  Gene: So our, uh, sort of approach to this is to, to, to use proprietary physics-based calculations that are automated and can do all that in milliseconds.
• 12:43
  Gene: And so by constantly refining that through those binding, kinetic, um, iterations much, much faster and arrive at a molecule sooner.
• 12:51
  Gene: Now, the thing about AI is we can pump out, you know, theoretical molecules all day long.
• 12:55
  Gene: At some point you gotta get 'em into, yep.
• 12:57
  Gene: You have to pull up stakes, uh, and, and, and, and validate the platform through clinical development.
• 13:02
  Gene: And that's a much slower process that AI is going to.
• 13:06
  Gene: I don't, we could, we, we're gonna need to put a pin in how we deal with the human aspect of uh, uh, if there's any way that we can, you know.
• 13:14
  Gene: Bypass some of the human testing that's done by using ai.
• 13:17
  Gene: I think that's, that's gonna be a heavy lift.
• 13:19
  Gene: Um, but at some point you have to go through that, uh, that, that, that very, you know, well-defined, uh, and much more slow, slow moving path.
• 13:27
  Gene: And that's what we're doing now.
• 13:28
  Gene: So, you know, we, we, Magellan has gotten us to this point, but now we're a clinical stage.
• 13:33
  Gene: Pharmaceutical company developing clinical assets and we need to focus on those.
• 13:37
  Gene: Magellan continues to be refined.
• 13:39
  Gene: We believe there's a lot of value there.
• 13:41
  Gene: We can always go back to it for a new molecule, but right now our resources are tied up in what we have in the clinic.
• 13:47
  David: Got it.
• 13:47
  David: You know, we're getting to the point where with the help of AI, you can do a milliseconds, generate enough ideas that would take a lifetime to be able to actually test out.
• 13:56
  Gene: Yeah, that's, uh, yeah, we have to, yeah, exactly.
• 13:59
  David: So how do you go from, so I, I get the, uh, the shift and it's a, it's a big milestone to get to be a clinical stage company, and especially not just clinical stage, but also have something that's interesting and, you know, creating data and, and serving a, a population that may make the market size five times what you originally thought.
• 14:16
  David: So that's all good.
• 14:17
  David: How do you think about then, let's say, taking the next step and using the platform and its new, you know, AI based approach.
• 14:25
  David: Use it to, uh, you know, generate a pipeline versus being a one drug company, as exciting as that may be by itself.
• 14:34
  Gene: Yeah.
• 14:34
  Gene: So again, it comes down to target identification, going into the biology, looking for, you know, across diseases, looking for those bad actors.
• 14:42
  Gene: Uh, in our case it's, it's, it's, it's proteins that, um, need help are sick.
• 14:48
  Gene: And so which one of those proteins do we wanna put through the model to see if we can come up with an a, a novel molecule that we can then test in the clinic.
• 14:57
  Gene: But, you know, once you do that, there's a whole battery of IND.
• 15:01
  Gene: You know, you have to do a whole bunch of preclinical testing on it, so it's not, you just get right into the human being as well.
• 15:05
  Gene: So, building a pipeline with ai, it's still gonna be very, very labor intensive.
• 15:10
  Gene: You can get to a, at least the way we're deploying ai, we're getting to molecules that way we're not able to.
• 15:17
  Gene: Their early preclinical de uh.
• 15:25
  Gene: You could be up to 10 years away from a drug once AI done with it's, it's with its lift, right?
• 15:32
  Gene: I mean, it can still take that long.
• 15:33
  Gene: Now, hopefully it's more like three to five.
• 15:36
  Gene: Um, that's more or less what we're trying to achieve based on our, where, when, when we, um, uh, initiated the clinical development.
• 15:43
  Gene: But there's a lot of work that went on behind that, in front of that, that had not nothing to do with ai.
• 15:49
  David: When we started out this conversation, you talked about enjoying being on the finance side and, you know, not, not having to deal with some of the stuff that the, the CEO may do now.
• 15:59
  David: Not this, that the CEO doesn't have to to deal with this, but the capital markets have been pretty tough for biotech lately.
• 16:06
  David: Um, I, I guess that's an understatement, but how do you think about like where we are at the moment that would explain why it's so tough and how do you navigate in that type of environment?
• 16:18
  Gene: Yeah, I think there, oof, that's a, there's a lot to say there.
• 16:21
  Gene: I've been in this sector and around this sector for 30 years now, and I can tell you this has been going back to when things, uh, got difficult in biotech in terms of access to capital.
• 16:32
  Gene: That goes back to.
• 16:34
  Gene: Starting in the middle of 2021 and, and getting really bad towards the end of 2021 and then into 2022, it was completely frozen.
• 16:43
  Gene: Um, you know, this, uh, that, that has taken.
• 16:48
  Gene: Um, way longer than anybody had thought it would to kind of wash through a typical biotech bear market.
• 16:54
  Gene: And there's bubbles.
• 16:56
  Gene: I, I can recall off the top of my head at least three or four very significant ones, and the sector over the course of my career.
• 17:01
  Gene: With little ones in between, there's usually a much faster, the, the difference with this one is the snapback has been grueling least.
• 17:10
  Gene: So, I mean there are signs over the last six months or so that things are improving, but it is a very, very slow walk back to, um, uh, days where capital was accessed on a much more rational basis than it is today.
• 17:25
  Gene: Um, what's driving that all is combination of things.
• 17:28
  Gene: We, um, have a strange interest rate environment, um, an administration that's very difficult to predict.
• 17:34
  Gene: Um, and a global crisis that seemed to kind of wax and wane, uh, on a daily, weekly basis.
• 17:42
  Gene: That's the kind of uncertainty that the market, you know, it's hard enough to predict the things.
• 17:47
  Gene: That are already difficult to predict.
• 17:49
  Gene: And then, you know, layering on top of that a bunch of geopolitical and macroeconomic cri, you know, challenges and you've got a, you know, no one wants to invest in a company that's gonna be a liquid for three or four years.
• 18:01
  Gene: Well, they figure out if a drug works in a clinic.
• 18:03
  Gene: That's all this is.
• 18:04
  Gene: It's not even a testament to whether or not, you know, biotech is doing a good job of developing drugs.
• 18:09
  Gene: Biotech has not skipped a beat.
• 18:10
  Gene: We're still pumping out.
• 18:12
  Gene: Uh, new drugs and new drug applications.
• 18:15
  Gene: Um, but the access to capital for them, you know, it's, it's the investor's appetite for risk that's changed, not our ability to deliver and our appetite for risk right now is just really not very big.
• 18:28
  Gene: It is very small.
• 18:29
  Gene: Um, and they want, they want, you know, it's, they want de-risk opportunities and that's why we spend so much time in our phase 1D looking at the biomarkers.
• 18:38
  Gene: The biomarkers are meant to give people comfort.
• 18:40
  Gene: The field scientists, clinicians, investigators, investors, it's meant to give them comfort that we're on the right track and we have a much better shot being successful in a phase two study, which is larger and gonna be powered for statistical significance.
• 18:58
  Gene: Signals.
• 18:59
  Gene: We know are li or that we have a high degree of confidence are real and phase one B study.
• 19:05
  Gene: So we, we, we developed these, uh, we developed these objectives for early stage studies so we know we can de-risks the later stage studies and we think we've done that successfully, um, to address the markets requirement.
• 19:18
  Gene: Normally, we went back five years ago this, this drug where we wouldn't have even done a phase one B study per signal.
• 19:24
  Gene: We would've gone straight once.
• 19:25
  Gene: This was healthy.
• 19:26
  Gene: The healthy volunteer study, the study that we, the study that we conducted prior to this phase one B was a phase one A in healthy volunteers.
• 19:33
  Gene: So you have to first show it's healthy, and it's safe, and and healthy before you can move into a more fragile population like patients.
• 19:39
  Gene: In a healthy volunteer study, we saw a target engagement.
• 19:41
  Gene: We saw an increase in GK activity.
• 19:44
  Gene: And those healthy volunteers that were done.
• 19:45
  Gene: That's one of the reasons why also we moved out of the GBA one population.
• 19:49
  Gene: If we can elevate enzyme activity in healthy volunteers, let's go after all the Parkinson's patients first.
• 19:55
  Gene: And then if we unfortunately have to slim down the population, um, then, then we will do that.
• 20:01
  Gene: And let me be real clear here.
• 20:03
  Gene: This is not a commercial decision.
• 20:04
  Gene: It is a, it is.
• 20:05
  Gene: We part, the mission at gain is to improve patient outcomes.
• 20:10
  Gene: The application of small molecule, uh, protein enhancer.
• 20:14
  Gene: That's what our, that's our mission.
• 20:17
  Gene: Um, we can get to large commercial success, whether this is an orphan drug or it's a, uh, or it's, it's, it, it, it serves a much wider population.
• 20:30
  David: No, that's good.
• 20:30
  David: I was, I was wondering what you were gonna say about how.
• 20:33
  David: You discovered that it could go beyond the mutation?
• 20:35
  David: 'cause you wouldn't have discovered that in phase one B if you just recruited people with a mutation.
• 20:39
  David: That's right.
• 20:39
  David: So there was this phase one signal.
• 20:40
  David: That's phase one.
• 20:41
  David: A signal that gave you that.
• 20:42
  David: So yeah.
• 20:43
  Gene: Yeah.
• 20:43
  Gene: So and so outta curiosity and just out of, you know, you know, out of intellectual curiosity, we looked at, uh, because there's no reason to believe that we would activate G cases things, you know, enzymes work in a homeostatic environment.
• 20:55
  Gene: So if you, even, even if you transiently increase.
• 20:59
  Gene: A particular enzyme or something, there's probably some other feedback mechanism to compensate for that and bring it back down, uh, through some other mechanism.
• 21:07
  Gene: Um, we saw it in the healthy volunteers so that, that we changed our, uh, our, our, our view.
• 21:13
  Gene: Um, on, on a target population.
• 21:15
  Gene: Say, let's, let's, let's bring in all comers first and see, uh, and see how they, how, how, how they respond relative.
• 21:21
  Gene: It can also help the field understand more about GBA one, Parkinson's.
• 21:25
  Gene: What does idiopathic Parkinson's?
• 21:27
  Gene: We owe the field that as well.
• 21:29
  Gene: So we wanna, we wanna put this into all comers right now and really kind.
• 21:33
  Gene: Look individually based on patient characteristics, how they respond.
• 21:36
  David: Great.
• 21:36
  David: So let's talk about that upcoming phase two trial, which you mentioned of course is gonna be bigger.
• 21:41
  David: And I understand it's around, you know, a hundred to 200 patients, which should be a little easier, I guess, to enroll if you're, if you don't have to focus just on, on mutation.
• 21:50
  David: But given the earlier conversation about the funding environment, how do you pay for that?
• 21:56
  David: And is that different now than it would've been, you know, not during the, the long trough that we're in.
• 22:03
  Gene: Oh yeah.
• 22:03
  Gene: No, I mean, so four or five years ago.
• 22:05
  Gene: Okay.
• 22:05
  Gene: Yeah.
• 22:06
  Gene: I need to go back to the, where, where I was talking earlier.
• 22:08
  Gene: So three or four or five years ago, if we had demonstrated, um, safety and efficacy, uh, sorry, safety, if we, uh, uh, demonstrated safety and tolerability and healthy volunteers plus target engagement, I believe that would've been, we would've probably been able to raise a hundred to 150 million, uh, on that alone.
• 22:27
  Gene: That would've carried us easily through phase two instead.
• 22:31
  Gene: With risk appetite being so, um, so nauseous really, um, that, that, that we're taking little bites and more incremental steps because of the risk involved with a hundred million versus 20.
• 22:45
  Gene: So can there, can we do a half measure?
• 22:47
  Gene: It's not great for drug development.
• 22:49
  Gene: It's not ideal, but we've been making the best we've been, we've been, you know, making the best of it.
• 22:53
  Gene: And I think what we've, we've, we, we've been able to achieve.
• 22:56
  Gene: Some on, on on very little funding is Herculean.
• 22:59
  Gene: If you think of the characterization you can now put forth for GT 0 2 2 87 to bio evidence of biomark, multiple biomarkers that are moving in correlation with what we believe is a clinical benefit.
• 23:11
  Gene: That's, that's pretty good out of a phase one B study.
• 23:14
  Gene: Now, again, we have to prove that up with statistics in the phase two.
• 23:17
  Gene: Um, but the, but the totality of the signal that we're seeing among the patients in the phase one B studies.
• 23:23
  Gene: Just impossible to ignore.
• 23:25
  Gene: Um, so there's, there.
• 23:26
  Gene: So we think we would've been, we would've been much more efficient, uh, four or five years ago.
• 23:30
  Gene: Um, how are, we're gonna finance it now is, you know, we're, we're, we're talking with, um, with partners, potential partners from large pharma, large biotech, mid cap biotech.
• 23:39
  Gene: In fact, even too, we are agnostic to the type of, we just wanna get this to patients in the most efficient way possible.
• 23:45
  Gene: Is that in our hands?
• 23:46
  Gene: Is that in the hands of a partner?
• 23:47
  Gene: Is that co-development arrangement?
• 23:49
  Gene: We're happy to discuss all of that.
• 23:51
  Gene: We just don't wanna lose any time.
• 23:52
  Gene: We just wanna keep this drug on track so it gets out there as soon as possible.
• 23:57
  Gene: Um, while, you know, we're hand ringing over the right patients in the right way to go about doing things, we also have to focus on let's get this, let's get this done.
• 24:05
  Gene: Um.
• 24:06
  Gene: So we think, you know, by, by engaging with potential partners over the last couple years that we continue to interface with them on a regular basis.
• 24:13
  Gene: Um, we can come to some kind of a, uh, an arrangement there.
• 24:17
  Gene: Um, we're constantly evaluating capital markets and the, uh, uh, opportunities to finance with more diluted fund funding, um, or some combination of the two.
• 24:27
  Gene: Um, right now we have enough, uh, capital on our balance sheet to kind of finish the phase one B study.
• 24:32
  Gene: In the fourth quarter.
• 24:34
  Gene: Um, we think most of the data from that study is in the can at this point.
• 24:37
  Gene: So like we met with very good understanding of, um, the biomarker evidence of efficacy.
• 24:44
  Gene: Uh, with GT 0 2 2 8 7, we're seeing some, what we believe early signs of clinical benefit in these patients.
• 24:51
  Gene: Hopefully that remains durable over the course of the next three to six months while the phase one B completes.
• 24:58
  Gene: But we're gonna start the phase two study already.
• 25:00
  David: That sounds good.
• 25:01
  David: So.
• 25:02
  David: You mentioned before, I think, Gaucher, there's also some other potential, uh, applications for this drug.
• 25:08
  David: Dementia with Lewy bodies, Alzheimer's.
• 25:11
  David: And you have other assets too.
• 25:12
  David: How do you prioritize opportunities?
• 25:14
  David: Is it basically you just gotta go all in to get to phase two, do this phase two trial?
• 25:19
  David: Or how do you, how do you keep these balls, uh, in the air?
• 25:22
  David: Well,
• 25:23
  Gene: right, so due to Gaucher is also involving, uh, you know, that's a different patient population lot.
• 25:28
  Gene: Uh, children in that patient population.
• 25:30
  Gene: A lot more, uh, clinical testing that needs to be done in order to dose in younger patient populations.
• 25:36
  Gene: Those patients that are under 60.
• 25:40
  Gene: Um, that was not a practical route for us.
• 25:44
  Gene: First, um, the most practical route to establish the efficacy of, um, of uh, uh, GT 0 2 2 8 7 was in Parkinson's where there is nothing to treat, where the enzyme target is the same and very prominent in the disease process and where we could show delta, you know, clinical benefit with some reasonable timeframe.
• 26:05
  Gene: Um, so we chose to go there first hoping weekend.
• 26:08
  Gene: Um, uh, uh, commer, well, you know, get, get, get GT 0 2 2 8 7 approved on the back of that.
• 26:14
  Gene: And it becomes much easier to, to move it into other disease areas.
• 26:19
  Gene: Um, you know, for Gaucher, uh, dementia, Lewy Bodies, Alzheimer's, we have presented.
• 26:25
  Gene: Data suggesting that GT 0 2 2 87 reduces tau in an Alzheimer's model.
• 26:30
  Gene: So we are, you know, we've got eyes on that as well.
• 26:33
  Gene: Um, but, but for now, the decision, uh, on Parkinson's was the endpoint's very clear.
• 26:39
  Gene: It's, you know, part two on the MDS backed up by support from part three in that clinical scale for the FDA.
• 26:46
  Gene: Um.
• 26:46
  Gene: Field is trying to vi, uh, validate biomarkers that are predictive of that clinical benefit so that drug development can happen faster.
• 26:54
  Gene: And the FDA we're part of that effort with the biomarkers.
• 26:56
  Gene: We, um, what we, that we've discovered, um, moving, uh, in the right direction, uh, in association with GT 0 2 2 87.
• 27:05
  Gene: You know, we, we, we feel like we're part of that effort and maybe we can advance this biomarker forward for the field, uh, by, by continuing to pin it to a clinical benefit.
• 27:14
  Gene: And then the next sponsor who comes along, who's able to demonstrate these, the, the impact on the same two biomarkers, maybe their lives will be a little bit easier than ours, uh, with the regulatory agencies.
• 27:23
  Gene: And that's fine.
• 27:24
  Gene: That's what we wanna contribute to the field.
• 27:26
  David: What's the average age of the patient in your Parkinson's trials compared with the average age of a Parkinson's patient in the population?
• 27:34
  Gene: It's fairly similar.
• 27:35
  Gene: I believe the average age of the Parkinson's patients, I'm gonna have to go back and check, was somewhere between 35 and 45 in our, in our trial.
• 27:42
  Gene: So maybe a little bit on the earlier side.
• 27:44
  Gene: Um, typical Parkinson's patient is diagnosed in the forties or fifties.
• 27:48
  Gene: Um, most cases, but there are a lot of diagnosis in patients that are in their seventies.
• 27:52
  Gene: It's like this late onset type thing.
• 27:54
  Gene: Um, it can't be really, you know, uh, prominent folks have been diagnosed in their early thirties, so it's real wide spectrum, but they're typically older, older, older adults, well into their forties and fifties.
• 28:09
  David: Last main question is, you know, you emphasize that gains focus on the mission and having truly disease altering treatments going beyond the temporary symptom relief, incredibly important in Parkinson's in particular.
• 28:22
  David: So if the drug succeeds and realizing we're a long way from that in terms of number of patients trials and time, but let's just, let's just take the good case.
• 28:30
  David: We're
• 28:30
  Gene: getting closer.
• 28:30
  Gene: We're getting closer.
• 28:31
  David: Yeah, you're getting closer.
• 28:32
  David: I don't mean to, you don't need any.
• 28:33
  David: You know, dis persuasion.
• 28:34
  David: But I, for any patients out there listening to this, I, I, I wanna give the impression this is not tomorrow, but if the, if the drug succeeds, you know, what would it mean for neurogen neurodegenerative diseases?
• 28:47
  David: Including Parkinson's, but beyond Parkinson's two, what's like, what's the potential, what's the, what's the big kind of vision that you're shooting for?
• 28:54
  Gene: If the safety and efficacy profile that we are in early days of seeing continues to play out, I think what we will have done is contributed an entirely new backbone.
• 29:04
  Gene: Let's just talk about Parkinson's funding.
• 29:06
  Gene: This will, this will be the backbone therapy for Parkinson's patients until another disease modifying therapy comes along that may be better or additive.
• 29:15
  Gene: Or just different, um.
• 29:17
  Gene: This will be a new backbone of Parkinson's patients.
• 29:20
  Gene: And with the tolerability, a lot of clinicians aren't gonna care what our data looks like.
• 29:23
  Gene: They're gonna give their patients a shot on it, regardless of their genetic subtype or whatever.
• 29:28
  Gene: Um, that's just a fact.
• 29:29
  Gene: In the clinical community, they'll say, well, you know, using this in these patients, give it a shot.
• 29:34
  Gene: Give it a shot.
• 29:34
  Gene: If you feel like garbage on it, we'll take you right off.
• 29:37
  Gene: Uh, but let's give it a shot.
• 29:38
  Gene: So I think what we'll wind up doing is taking GT 0 2 2 8 7.
• 29:42
  Gene: It will form the backbone of any kind of symptomology that still exists in the patients once we've caught them with GT 0 2 2 8 7.
• 29:50
  Gene: So hopefully we.
• 29:51
  Gene: The progression of the symptoms where they are, those symptoms will still be there.
• 29:55
  Gene: But the L-DOPA that they use, the other supportive medication that they use, the deep brain stimulation that they may be using, that stuff may be less relied upon.
• 30:03
  Gene: And that's great for patients.
• 30:04
  Gene: Right.
• 30:05
  Gene: And then as the field gets more experienced with the drug, they'll probably move it earlier with or without our, our help with clinical studies, which we will do anyway.
• 30:13
  Gene: They'll move it earlier and earlier into patients with the ob, with the obvious objective of trying to halt their symptoms as soon as they see it.
• 30:21
  Gene: And if, and if there is some, you know, robust, uh, response to patients who have a GBA one mutation that we, um, uncover as we continue to develop and, and continue to, um, evaluate GT 0 2 2 8 7, then there will be a case to genetically test some patients to see what their status is, to get 'em on before symptoms even occur.
• 30:41
  David: Great.
• 30:42
  David: Well, that's it for another episode of the Health Biz Podcast.
• 30:45
  David: I'm David Williams, president of Health Business Group.
• 30:47
  David: My guest has been Gene Mack, he's president and CEO of Gain therapeutics.
• 30:52
  David: If you like what you heard, please subscribe on your favorite podcast platform and thank you Gene.
• 30:58
  Gene: Thank you, David.
• 30:58
  Gene: I appreciate your time.