Okay, great. We're back. We have Gain Therapeutics, ticker symbol G-A-N-X, Gene Mack, CEO, came in, took over, took over the reins, earlier, this year. Company is in the Parkinson's disease space, with its allosteric, allosteric modulator, that impacts GCase activity. Sounds complicated, it's really not. It could be a disease-modifying drug that has had some really interesting data in healthy subjects, just a few weeks ago at the Movement Disorders conference in Philadelphia. There's a Phase 1b in actual Parkinson's patients that's coming up. Really good time to be looking at Gain, if you're thinking about the Parkinson's disease space and opportunity there, so welcome, Gene. Thank you. I think this is our first fireside together. There's no fire, but, you know, whatever. It's a name that obviously we're very interested in, and I think it would be helpful for everybody if you introduce yourself and just give, as a high-level overview of Gain, and we'll kind of go from there. Yeah, sure. So I'm Gene Mack. Thank you, Jason, too, for hosting this event and inviting us to participate in it. We're really appreciative of the opportunity Maxim's giving us here. Yeah, my name's Gene Mack. I'm the Interim CEO and CFO of Gain Therapeutics. I joined the company back in April of this year, so not too long ago as the company's CFO. And then, in June, that role was expanded to include CEO as well. Prior to joining Gain, I was an operating CFO for ten years, public and private companies, everything from preclinical stage of development on up through commercial. And it also includes companies based in the U.S. and in Europe as well. Prior to that, much like yourself, I spent fifteen years as a senior publishing analyst covering the space for a number of Wall Street firms. Spent the majority of my career at Lazard, HSBC, and Mizuho Bank, and it was that long ago where only I think one of those banks still even has a capital markets desk to go with it, and my backgrounds in biochemistry, clinical neurology, and finance. So yeah, so let me tell you a bit about Gain and where we are, and we're at a very, very interesting time in our development, where we are now at the point where we can talk about actual human data, actual patient data, and we're all very excited about that because it was... It's been a bit of a tough ride in the capital markets the last several months, first half of this year. In particular, you know, telling folks, "We're gonna have this data, it's coming out, it's gonna be in humans, it's not preclinical anymore. We're a clinical stage company." We were getting pounded around a lot as a result of it taking us the time to get some clinical data together, so what Gain is endeavoring to do is develop what we think will be the first disease-modifying therapy in Parkinson's disease, and what we mean by that is, up to this point, there's been nothing but symptomatic approach to Parkinson's disease, things like L-DOPA, pramipexole. These types of drugs relieve the symptoms of Parkinson's disease temporarily, but the patients ultimately progress, their symptoms get worse, and the drugs become less effective over time. We are developing GT-02287 to get to the underlying mechanism of the disease, to truly halt the progression or slow the progression of Parkinson's disease in its tracks. The way we do that is by targeting an enzyme in the disease cascade that is responsible for multiple housekeeping roles inside the neuron. It is responsible for eliminating toxic substrates that develop in the cell, it's responsible for reducing stress in the endoplasmic reticulum, and it promotes mitochondrial health by promoting healthy electron transport. We think there's this cascade of things that GCase accomplishes that's important in every aspect in the cell. So we call GT-02287 a GCase modulator. It attaches and targets GCase at the point of its transcription, protects that protein from misfolding as it traffics through its pattern in the cell, and that includes out of the endoplasmic reticulum to the lysosome, where there's toxic substrates into the mitochondria, where, again, we need healthy electron transport. So GCase targeting Parkinson's disease really stems from a genetic mutation in Parkinson's disease patients, where the GCase enzyme, which is glucocerebrosidase, for those of you playing at home. The GCase enzyme is misfolded as a result of a genetic mutation in the GBA1 gene, so hence GBA1 Parkinson's disease. And in this particular subset of Parkinson's disease patients, the symptoms are much more harsh. There's earlier onset, and they get more severe. They progress faster in the disease pathology. So GBA1 Parkinson's disease patients face a worse prognosis than the idiopathic Parkinson's disease patients. But what we know is GCase is implicated in both patient populations. So we're excited that after the multiple ascending dose study in human volunteers, we demonstrated the ability to modulate GCase in healthy volunteers by a proportion that we did not expect to see. Simply because in a healthy state, you would assume the cell in homeostasis, even if you're able to elevate a certain enzyme, there are compensatory mechanisms that would bring that back into balance very quickly. But we were gratified to see that we could actually get evidence of GCase modulation from GT-02287 at the therapeutic range, at the doses that we predicted would be in the therapeutic range. And that's what we were all able to confirm with the multiple ascending dose study. And now it's on to proof of concept with actual patients. And I think that's probably why the stock has started to perform a bit better, is because it's on the heels of the data you mentioned, Jason, earlier at the MDS conference, which we just recently presented at, plus some additional data at the Society for Neuroscience conference about a week ago. And we're just rolling out another. We'll have another presentation at Michael J. Fox later this week. And we're rolling right into our proof-of-concept study by the end of the year, so that we can prepare to deliver our next data inflection point in the first half of next year. That was the big deal right now. Sorry, Chad. At the Movement Disorders conference, or even before it, we heard from investors, we heard from your feedback too, like it was targeting engagement. Yeah. Can you actually get it there? Does it actually engage its target? And so you've answered that question. So just could you talk about the importance of that aspect, and it kind of doesn't de-risk a Phase 1b because you haven't done the study yet, but it suggests that what you saw preclinically seems to mesh with what you're seeing clinically, at least in healthy subjects, and that sets the stage for that trial. Yeah. So when you activate GCase or modulate, I should say, GCase with a chaperone, such as GT-02287, not only do you see an increase in GCase activity, you see reduction of endoplasmic reticulum stress, because that protein being misfolded in the ER clogs it up and creates protein production problems in the ER. Right? It also, by modulating it and chaperoning it, you also get it to the mitochondria. So when we see activation of GCase, we're encouraged to see that for sure, 'cause we know we're going to get activity at the lysosome. But we also can at least feel better or more confident that we're actually going in humans like we were in the animal models, and promote mitochondrial health. So we're thinking by getting target engagement, we will get those other items as well. And that's what gives us broader confidence that the proof of concept study will reflect what we've done preclinically. But yeah, that target engagement piece, the importance of it though, which is interesting. Healthy volunteers, we thought we had a drug for GBA1 Parkinson's disease, and GBA1 Parkinson's disease was where we were going to see our effect. Because we're able to elevate GCase activity in healthy volunteers by 50% or more, we believe that we now have a compound that can address idiopathic Parkinson's disease along with GBA1 Parkinson's disease, because while not every Parkinson's disease patient has depressed activation of GCase, many of them do, and many of them have a significant decrease in GCase activity. It's not necessarily from the gene mutation or any gene mutation we know of yet, but it could be some other post-translational modification that's happening to the enzyme, some sort of insult in the cellular microenvironment that's creating another stressor. If we're able to impact those patients as well, it opens up our planning, which is why our Phase 1b now includes idiopathic patients with Parkinson's disease as well as GBA1 patients with Parkinson's disease. It's because we saw that piece in the healthy volunteers that we are now able to say, "Well, we need to see. We owe it to the Parkinson's disease patients, the idiopathic patients, to see how if we can benefit them as well. Can you talk about what level of GCase activity in Parkinson's patients you would need to see? What level that would translate into? Yeah ... clinical benefit? That is a great question, and a couple of us are working on it. So you have other companies that are working on GCase activators and, you know, they're very focused on the lysosome and alpha-synuclein substrate and other toxic substrates. Very focused there. Those other companies have correlated sort of a 50% threshold, which we see with our compound. But we're not sure. We think that's necessary, but not sufficient. In addition to getting the lysosome worked out, again, these other areas of cellular support need to be looked after. And those activators don't do that because they're only sending more activated GCase to the lysosome. But that doesn't tell us how well the rest of the cell is behaving, quite frankly. And we just haven't seen that data, so we can't correlate right now what level of activation you need in order to sort of get a threshold effect, where you're actually starting to impact the underlying mechanism of Parkinson's disease. What we're confident about is, we have demonstrated a 50% increase pretty consistently in animals and other sort of ex vivo models. And we've seen all these other clinical benefits. You know, we walk animals through wire hanging tests, beam walks, and we punish these animals with all sorts of cognitive and motor assessments after insulting them with a Parkinson's disease mimicked environment. And, you know, we get these therapeutic effects at the doses we used in the MAD study at levels that are probably around 50% of GCase activation, but could be lower. We don't know that you need a lot of GCase activation. What we do need to do is manage GCase's entire traffic pattern through the cell. Because if you're only at the lysosome, we think that's necessary, but not sufficient for broad neuroprotection. Is the baseline GCase activity different between GBA1 and idiopathic Parkinson's? Yeah. There's a lot of overlap with GCase activity in idiopathic patients with normal individuals, with you. Well, hopefully none of us have what GBA1 patients are. But our, assuming we all have healthy genetics with respect to GBA1, our levels of GCase in a normal distribution overlap that with Parkinson's disease. However, there are idiopathic Parkinson's disease patients that sit very, very low in that spectrum of GCase activity that is in line with a GBA1 mutation, but not due to the GBA1 mutation, and that's where we think our idiopathic sweet spot is. So the shorter answer to your question, you know, they, GBA1 Parkinson's disease patients, definitely with a mutation, their activation, if you're, you know, if you're heterozygous, your activation is 50% right off the bat. If you're homozygous or you have some sort of other sort of partial mutation, it could be lower than that. You know, normal individuals, there is a broad inter-patient variability in GCase, believe it or not. It's really the lower the base, we think the higher the increase we can get. We've seen that, so that's why, again, we were focused on GBA1, but again, those patients in idiopathic Parkinson's disease, they will start. There are some of them that will start from an almost identical base as the, as the mutated patients. So it's interesting, and it can get complicated, but if you just think of there's a basket of idiopathic Parkinson's disease patients that look like GBA1 patients for some reason or another, because of GCase activity that we can get to, but there's the GBA1 patient population is the low-hanging fruit. They are all starting off with a baseline of 50% or lower. But go ahead, Jason. I see you going. Yeah. Can you just elaborate on what differentiates GT-02287 from other allosteric GCase activators? Yes ... as well as gene therapies that are in development? Yeah, and this can sound philosophical in some respects, but there's allosteric activators of GCase, which we don't really know what that means, because if you're binding allosterically, and you're probably not, probably away from the activation site. Or sorry, yeah, you're away from the activation site, probably. So, I don't. It's hard to tease it out. We know we are a chaperone. We know that we reduce ER stress, we know that we improve mitochondrial health. We know that we're attaching to the protein. We all bind uniquely to GCase. Well, when I mean we, I mean all of the therapeutic approaches, small molecule therapeutic approaches at GCase all attach at different binding sites. We know ours attaches and stays with the compound, essentially, putting it almost in a cast to keep that conformational shape that's crucial to its function, in with integrity. And we don't think the others bind that way. We think the others bind in a way that direct GCase to the lysosome, improve activation there, but then dislodge or are not present in the mitochondria or the endoplasmic reticulum. And the reason why we make that as we're hypothesizing that is, we looked at one of these compounds, one of these allosteric activators, side by side with GCase, and we saw the lysosomal activity, but we didn't see the broad neuroprotection that we got. We reproduced those results too. So that's why we get to this. That's what leads us to believe that chaperoning the enzyme leads to a different potential efficacy outcome than simply activating it at the level of a lysosome. So is it kind of like, I mean, are you changing its, not its structure, its, its how it's folded a little bit? Or, or as... Because if you think about Vertex's drugs for, for CFTR, CFTR, channel, like their potentiators, their correctors, they, they do something, they kind of tweak things a little bit, just get it working better. Is it, is that maybe a better way to think about 2287? Yeah. Yeah, that's why we use the term modulator. Because if you think about that, it's, we're helping GCase do different things at different stops. So, we're simply getting it out of the endoplasmic reticulum in its correct conformational shape. So we think we get to GCase at the level of transcription, and are then able. And that's why we see a reduction in ER stress. And, you know, the markers of mitochondrial health improve, so we must be getting it there as well. We can't see that with just the activators. It is a chaperone effect. Because, like, if you think about alpha-synuclein, right? You guys, this all functions to deal with some of those toxic substrates that are there, right? Do you have to then be earlier in Parkinson's disease progression because the alpha-synuclein has to be internalized to more for those toxic aggregates to actually do anything damaging. So you don't wanna be too late, because it's maybe too little too late, and you wanna be earlier in disease with a modulator. Yeah, I mean, I think that may matter more for the activators, because they may want, that may be something where you wanna get to alpha-synuclein before it starts that toxic cycling, which builds up just more and more substrate, more and more substrate, more and more substrate, and then the horse is sort of out of the barn. We think it might be more important for activators, but because we saw the effect of our drug both when we. So there's a way to model GBA1 Parkinson's disease in mice. You use this compound called CBE, which covalently binds to GCase and knocks it out. And you add what are called alpha-synuclein preformed fibrils, basically the scaffolding of alpha-synuclein that you inject into the brain of the animal, and it starts to aggregate and collect and become plaque-like with Parkinson's. Now, that's idiopathic model of Parkinson's. When we add this other molecule, CBE, you're knocking down GCase and you're adding the fibrils. So when we see this activity in both, that's a broad. So we don't know that. I don't think it matters when you introduce GT-02287. I think what we'll find is that if you're at a point where there's certain neuronal degeneration, we won't regenerate any of that back, but we will stop the symptoms of Parkinson's at that point. And the earlier we go, probably the better results we will see longitudinally. That's gonna take years to find out, right? Because we have to do-- we first have to demonstrate efficacy in a patient population that will be optimized, you know, at a point in their disease process, and we think maybe that's within the first six months or so. At least that's what we're gonna look at now, where we can see change with a sort of practical dosing duration of, you know, maybe six to 12 months, somewhere in that range. That's, you know, sort of where we think we'll start to see efficacy. And I think if we see any material change in motor or cognitive improvement, I think clinician-- I mean, where wouldn't you use it? That's a very, very tolerable drug. In the MAD study, we saw nothing but Grade 2 nausea, some headache. These are very kind of sort of nonspecific types of GI effects that happen with a lot of. Yeah, I think just about everything's got nausea as a side effect. And it's good to see something because we know we're active. But with the tolerability profile we have, we think that probably GT-02287, until there's other things, if this is the first that, you know, we're successful, and this is the first thing that winds up becoming approved as a disease-modifying agent, I think it's, you know, you draw your own conclusions of what will happen in the hands of clinicians. Can you just quickly walk us through the upcoming Phase 1b, when it's gonna start, when we could expect data, and then, and maybe what's next after that? So, we've submitted the protocol for the Phase 1b to the Australian authorities. We've worked well with them in the past for our MAD study, so we don't anticipate any issues with the agency. We will probably start opening up centers definitely by year-end. Hopefully, screening patients as well by year-end. We'll dose the first patients as early as we can in the new year. You know, with Australia, we'll probably have a holiday issue, you know, through December and January. But we're gonna do the best we can to get patients screened. We also have to take lumbar punctures, right? Yeah, it's not around Christmas, you wanna get your spinal tap. That's gonna be a hard thing to get patients in to do. We'll do the best we can with the centers we have, enrolling, but we think we'll start dosing patients very, very early next year, definitely by the end of January, so we'll enroll 10-15 patients. It'll be a mix of GBA1 and idiopathic Parkinson's disease patients, based on what we've just talked about. We'll dose them for three months. But at the end of that trial, we may, because our tox data is now out beyond, starting to become out beyond three months, as we're enrolling patients and dosing them for three months, if we can get the six and 12-month tox data, by the time we dose some of those patients two months, we can put a protocol amendment in and just extend the study out and include some other geographies and roll into a Phase 2. Do you think you need to titrate? Because enzyme activity, as you know, is weird, right? It's not too high, too low. You gotta find, like, that right balance. Not that you have side effects, just that maybe just enough, just that right dose is maximal versus a max dose, whatever that might be. Yeah, so the way we're thinking about that is we saw Grade 2 nausea and headache in the MAD study with the human volunteers. Now, importantly, around 20% of those patients were over the age of 40, and that's important because you typically get younger patients in a healthy volunteer study. We were fortunate to get a significant population of patients that overlap with the same age demographic as most Parkinson's disease patients that are diagnosed, and what's good about that is you just get a better sense of, you know, how age, if there's any sort of correlation with age or there's none with our compounds, so that's good to see. You know, we're we wanna make sure that the Grade 2 nausea doesn't turn into a grade 3 with Parkinson's disease patients who might be a little more fragile or taking other medications, that sort of thing. We're starting the dose at pretty much where we left off in the MAD study, which was the top dose, 13.5 milligrams per kg. We are going to start with that dose in the proof of concept study. We can adjust, we'll adjust that dose maybe down a tick if patients have trouble tolerating it. But otherwise, we should be. We're in the therapeutic range from both our observations from the multiple ascending dose study and the back everything up. We think we found the right dose, but we'll learn more when we get into actual Parkinson's disease patients to make sure we're not pressing too hard. But we don't see much need for titration. We're working on a backup formulation as well, just, you know, for life cycle purposes. And we also have backup compounds, which in some cases are more potent. So we may have a fast follower situation too from our pipeline, which we're sorting through as well. But at this point, we think we're pretty good with dose. In fact, because of this, we had some very interesting data at the Society for Neuroscience conference just last week, where we went back to the preclinical models and looked at washout to see if there was a sustainable drug effect. And we ran three models: a beam walk test, a wire hanging test, and a cognitive test. It was nest building, which is a great test to run because you can really see the intersection of motor and cognitive sort of functionality in the animals, which closely mimics what human beings, you know, their activities of daily living. So that's probably a more complex test. And each one we know from our earlier studies, that we're able to rescue the animal's ability to perform the physical function, the motor function, or the cognitive function, once we treat them with GT-02287 in either an idiopathic model or GBA1 model of Parkinson's disease. We're able to rescue their ability to regain function. But what happens if we take the drug away? Does the benefit wash out immediately? Do we get any sustainable effect? And what we saw after treating animals for 20 days, is that when we took them off of GT-02287 for a period of a week, the sustainability, there was no change from the animals that we continued to treat. No significant change from the washout, which is very, very gratifying to see, because that's a little bit more evidence of a disease modification. If you're able to continue that effect on the cell is still healthy relative to what you started out with when you start treating the subject, that sustainability suggests you're getting underneath the disease mechanism. And so when you say titrate, we may actually, if things go really, really well and GT-02287 is as effective as we think it is, we may be able to be in a situation where we can wean some patients onto lower doses. Because if the effect is sustained, and then if there is any sort of funky nausea in some patients, so they have a little bit of issue tolerating early doses of it, maybe once they get through that period, they can come down on dose because the, you know, alpha-synuclein load is reduced, and the cell is functioning more healthful, more healthier. And they don't need as much drug. So that's something we'll have to answer in later studies though. Got it. So we're pretty much out of time, but Gain Therapeutics, GANX is the ticker. Gene, thanks for coming. Well, they checked a lot of boxes over the course of this year. It's been a bumpy ride in 2024, but with that Phase 1 healthy subject data, this cash runway, Phase 1b coming up- That is the key. Really good name to take a look at, and we've published that previously. So, Gene, thank you very much. Thank you, Jason. Thank you. Appreciate it. Thank you so much.