Hello, my name is Ram Selvaraju, I'm a Managing Director and Senior Healthcare Equity Research Analyst here at H.C. Wainwright. It's my pleasure to welcome you to another in a series of fireside chats here at Wainwright's Neuro Perspectives Conference. The next company is Gain Therapeutics, ticker GANX on the Nasdaq. We cover Gain with a buy rating and 12-month price target of $8 per share. Joining me today is Gain's Chief Executive Officer, Gene Mack. Gene, it's a pleasure to have you with us. Thanks, Ram. It's always good to be with you. Thanks for having us. For those in our audience who are not already aware, Gain Therapeutics is a next-gen emerging biopharmaceutical company focusing on the development of novel molecules, particularly allosteric modulators, and its lead asset is GT-02287, an orally bioavailable brain penetrant modulator of glucocerebrosidase, or GCase, activity for the treatment of, among other things, Parkinson's disease. At this juncture, I think it would probably be best for me to give you the floor, Gene, and have you walk us through the salient features of the GT-02287 clinical development program and the most important key clinical data that has been generated and released from this program to date. Of course, correct me if I'm wrong, at this juncture, you are already studying this molecule in Parkinson's disease patients. You have already generated meaningful proof of concept clinical activity data with this molecule. Yes. That's right. Thanks, Ram. Gain Therapeutics' lead product is GT-02287. We developed this product using our own AI-driven discovery and development platform called Magellan. This molecule has now been through its first-in-man studies, demonstrating safety and tolerability, of course. It was there that we were able to see for the first time target engagement. We know that GT-02287 is perturbing the GCase pathway, going back to healthy volunteers, where we saw increase in GCase activity in the presence of GT-02287 in those individuals, while testing for safety and tolerability. That was in 2024. We moved from healthy volunteers to a phase I-B study, that we began enrolling in March of 2025 with Parkinson's patients, trying to collect both idiopathic Parkinson's patients and patients with a genetic mutation in the GBA1 gene, which is the gene that encodes for the target of GT-02287. GT-02287 is designed to bind to, stabilize, and chaperone an enzyme called glucocerebrosidase, or GCase for short. This is an enzyme that fits prominently in the pathophysiology of Parkinson's disease as well as other diseases such as Gaucher. It is more well-known there, but in the brain, it can be very highly associated with Parkinson's and a very aggressive form of Parkinson's disease. In addition to enrolling a phase I-B study, we were able to expand that trial to an open label extension. We had a 30-day run-in with that phase I-B, and then some longer-term follow-up data, which we'll talk about probably throughout this conversation. Having followed up on the phase I-A with target engagement, we are now compiling additional biomarker evidence of efficacy that is cropping up now in the phase I-B Parkinson's population that we've enrolled in Australia, in seven centers. It was a 21-patient study. 19 completed the first 90 days, 16 have rolled over to the open label extension. Where are we going next? Upon completion, we'll get into some of that data, I'm sure, Ram, in our conversation. From here, we are looking to have an IND cleared by the FDA this quarter. We expect that by the end of the month. We're going to move to phase II clinical testing next quarter. We'll have the final results of the phase I-B, including that open label extension that I mentioned to you, in the fourth quarter of this year. We're excited that we are going to be moving along one of our pipeline candidates into IND-enabling studies now that we're moving to phase II with GT-02287, and we can talk a bit about that as well. We own all the intellectual property for GT-02287. We have a backup series of compounds, one of which I just mentioned, that are all structurally distinct, offering unique composition of matter patent protection on all those. We're very much looking forward to the start of the phase II study in the third quarter. Let's talk a little bit about the 02287 clinical data. In particular, I think it would be helpful for you to delineate for us on the biomarker side, the impact of GT-02287 clinical activity on glucosylsphingosine, especially of course, in the cerebrospinal fluid. Also the impact that you saw in particular, but not exclusively, at the 150-day time point in your phase I-B trial, as this pertains to indications that 02287 might be directly impacting core symptoms of Parkinson's disease, stabilizing the disease, and perhaps even reversing certain clinical features of the condition. Which of course, as we all know, so far with clinic, commercially available Parkinson's disease therapeutics is simply not something that we see. Parkinson's disease is widely known to be a relentlessly progressive, ultimately highly debilitating, and eventually fatal neurodegenerative condition, typically associated with a decline in dopaminergic function, selective death, and ablation of dopaminergic neurons in the brain, particularly in an area called the substantia nigra, and of course, is historically treated with levodopa, but which ultimately always loses its efficacy, and that doesn't at any point stop the progression of the disease or reverse its symptoms. Ultimately, if you are able to achieve these kinds of impacts with 02287, it really would constitute nothing less than a sea change for Parkinson's disease patients. Is that correct? Yeah, that's a really good point, and one I kind of glossed over just earlier. Yeah, the very key feature of GT-02287 is we believe this will be the first, or if not among the first, disease-modifying drugs that are available for Parkinson's if we are successful. Again, getting to the biology that is creating the symptom progression of Parkinson's disease, not just trying to address those symptoms, but getting to the biological roots of what's going on and then trying to correct that. That's what we think we're doing with GT-02287's interaction with glucocerebrosidase. This is sort of a confusing cartoon, but let me just walk you through the key aspects of it. You see one big box there, with a label, "GluCer accumulated due to insufficient GCase activity." GluCer is a lipid that is used for several cellular maintenance functions. There are good aspects of GluCer. There are some aspects that are a little bit not well understood, but we know that glucocerebrosidase keeps the glucosylceramides in metabolic homeostasis, for lack of a better word. If GCase is impacted or if it's impaired, if its function is impaired, that reservoir of GluCer will build up. You see there's a red bar across the top. That's indicating a trouble zone. If GluCer builds up too much, it spills over and converts into another very toxic lipid called glucosylsphingosine. Glucosylsphingosine is associated more directly with mitochondrial dysfunction, lysosomal dysfunction, and the accumulation of aggregated alpha-synuclein. Alpha-synuclein is that protein hallmark of disease that each neurodegenerative disease has their own kind of bad actor protein. In Alzheimer's, it's beta-amyloid, and there's tauopathies, that sort of thing. Alpha-synuclein's our bad guy, or is the evidence of the bad guy, in Parkinson's disease. The problem with glucocerebrosidase or GCase is it can't really metabolize glucosylsphingosine. You get this propagation effect where the glucosylceramides keep converting into sphingosine, and the sphingosine can't be metabolized by GCase. What are we doing? What GT-02287 does, I don't have a very good representation of it here, is it binds to and stabilizes the GCase enzyme so it can perform more of its tasks around the cell, and it includes multiple cellular compartments, the endoplasmic reticulum, the mitochondria, and the lysosome, where most of the activity is concentrated. What we're finding that in the presence of GT-02287, patients that have baseline elevations of glucosylsphingosine in their cerebrospinal fluid. We sample these patients' cerebrospinal fluid to understand what the lipid concentrations were in those samples, and to better get an insight of what the lipid concentrations are in the brain. We saw that about half of the patients that we had good samples from, there were some significant increases in baseline glucosylsphingosine in their CSF. This is a troubling signal. After 90 days of treatment with GT-02287, you can see that virtually all of them came back down to what would be regarded as more normal levels. We took all the patients that were elevated, and they have come down to closer to normal levels, while none of the normal patients escaped or increased during the initial 90-day treatment period. This is a very encouraging signal because from a biochemical perspective, from a biology perspective, and from a disease pathology perspective, we know we are keying in on GCase and its activity because we're seeing more downstream evidence of improvement in the presence of GT-02287 and GCase activity. As a result of that, from a clinical perspective, or I don't know, Ram, if you want to jump in. That's one of the biomarkers. We can talk about DDC as well, or talk about some of the clinical aspects of what we're seeing and then get into those. I think it's perhaps most important to delineate, now that we've gone through the glucosylsphingosine aspect of the story, the key clinical impact that you're seeing of 02287 on core symptoms of Parkinson's disease, especially when you think about things like loss of taste and loss of smell, as well as correction of abnormal gait, because these are obviously things that are likely to resonate very clearly, both from a clinical and a commercial standpoint. Yeah. What is the benchmark clinical rating scale for Parkinson's disease progression? That is recognized by the FDA, and is the scale you need to apply in order to demonstrate efficacy for approval of any drugs addressing Parkinson's disease. This scale is the MDS-UPDRS scale. It's the Unified Parkinson's Disease Rating Scale, created by the Movement Disorder Society. It's a very elaborate scale. It's got four parts to it. The FDA and most clinicians focus on two parts of this scale. The Part II test, this is a patient-reported assessment of their general wellbeing, and some symptomology, some motor symptoms, some cognitive things as well. Then the Part III is the physician's rating scale of how the patient is doing. Their assessment, based on a series of tests and exercises that they put the patient through, they score them on the Part III assessment. Patient does their own assessment on the Part II, then we look for what's clinically meaningful on these scales. Over time, a Parkinson's patient can expect to have a decline in their UPDRS, or actually, it's actually an increase in the score, but the decline in their functioning motor ability of about two points per year on Part II, and about four to five points on Part III. Most endpoints, assessing Parkinson's clinical efficacy, will look to improve patient scores by about six points on the two scores together. You want to see something like that over a period of a year. That can happen in multiple ways. If you're able to keep patients stabilized where their disease does not progress anymore, as a natural consequence to that, anybody who's not on drug will continue to get worse, you can see an improvement based on treated patients not getting any worse while a control group does. That's also a very favorable result in Parkinson's disease. Again, these are patients that have had neurodegeneration. It's very difficult, if not impossible, to bring back regions of the brain that are more or less non-functional or have a high degree of neurodegeneration. Those neural networks are difficult to reignite. If we can stabilize patients there so that they don't get any worse, we can continue to move GT-02287 earlier and earlier in disease progression, where the symptoms are very, very light or maybe not noticeable at all. Let's talk about what happened in the phase I-B, what our experience was on the MDS-UPDRS score, and how we think this ties in with glucosylsphingosine. Just showed how we demonstrated a big reduction in patients that had significant levels of glucosylsphingosine in their CSF, down to more normal levels. How did that translate on the score? We looked at patients that had low levels of glucosylsphingosine in the CSF, and those that had high levels of glucosylsphingosine in the CSF, then we compared that to all patients. All patients is the row at the top of this particular slide. You saw we see some benefit. Negative numbers on the UPDRS means that severity is coming down, so that's a good outcome. We had some improvement when you talk about all patients after 90 days. Six points in a year, it doesn't move very much. The scales don't move very much in a year, which is why we need biomarkers, we can get faster indication or more predictive markers of efficacy. In the top row there, you can see that all patients seem to be benefiting at some point. That's a very good result. If we can hold that positioning for about a year, the patients don't do any worse, then that's efficacy. In the second row there, those are the patients with low baseline glucosylsphingosine. You can see they have not done as well as those patients with the high levels right below them. It seems that the patients with high levels of glucosylsphingosine in their CSF are driving a lot of the improvement that we're seeing across the population. We're still happy with the low glucosylsphingosine patients as well and think we can benefit them. We don't want to lose any patients, but we want to pay attention to these high glucosylsphingosine patients because we may be seeing a differential response there. Embedded in these MDS-UPDRS scores, Ram, as you pointed out, were some other aspects of the disease that came across multiple centers, so not just at one center. We had seven centers and all patients in Australia. We heard from multiple centers anecdotal improvements such as return of taste, return of smell. Those to us are important markers because a loss of smell early in Parkinson's disease can be a predictor of a worse cognitive outcome. There are different aspects of Parkinson's disease. There's motor, there's cognitive, there's digestive, there's all kinds of other peripheral things. Smell seems to be associated with cognition, improving that to us is really, really material. We've seen improved taste and smell or the return of those senses, improved gait, some reports of improved concentration. That's a little bit more general. These other things we're hearing have led to us to put in some secondary endpoints in our phase II study, such as wearables to better measure this gait improvement. We're going to include a smell test to see if we can really understand better the anecdotal evidence that we're getting, that sense is impacted by this particular pathway. We're excited to see those results when we start the phase II study. This was the 90-day data, and we took another look at 150 days. While some of that benefit looks like it might be lessening, we think if you just look at the bottom row there, the -3 points, for us, movement around three to six points is not very material. We want to keep them in that band. We don't want to see them getting worse by six points or more in any regard. We're hoping to maintain that for at least a year or longer. Again, we still think that this is good stabilization of the disease. In a control group, we would expect. Now again, all the patients you see before you are being treated. We don't have a placebo group in here at all. What we would expect after about a half a year or so, is that the patients that were not treated would be probably falling off by about three points. Whereas we're still maintaining a three-point benefit. There's about a six-point gap there. We still think this is in the range of what is clinically meaningful, and we achieved that result early on. We just need to preserve it by making sure the patients don't get any worse or progress any worse. Just a couple of follow-ups there. Firstly, as you've been talking through the design of the phase II study with regulators, how does this fit into the overall clinical development paradigm for this molecule? Ultimately, how could positive data from the phase II, A, build upon what you saw in phase I-B, and B, inform the potential design of a registrational program? Secondly, I wanted to delineate something that I think from a competitive landscape perspective is very important. There is another GCase allosteric modulator out there, VQ-101, that has generated data demonstrating the impact on the biological target. That, unlike 02287, has not demonstrated meaningful impact on disease symptomatology or aspects, as you said, of the key validated efficacy outcome measure, which is the MDS-UPDRS. I would venture to say that at this juncture, so far, 02287 is squarely in pole position. Now as you look to move it into phase II aggressively well before the end of this year, it looks as though you're well-positioned to maintain that leadership position within the GCase allosteric modulation drug class. Is that correct? Yeah. It's right on the money, Ram. Just getting back to the phase II study, what are we hoping to achieve? Well, we want to see, the primary endpoint is going to be improvement in MDS-UPDRS score, squarely in line with what the FDA requires for regulatory guidance for approval. However, we want to validate those biomarkers. Well, right now, and this could change, but right now our thinking, as we continue with the phase I-B extension, right now our thinking is we don't want to only enroll certain phenotypes of Parkinson's. We still want to do an all-comers trial. We want to stratify for high glucosylsphingosine and CSF. We also want to stratify for GBA1 mutation. We think those could be very important distinctions in Parkinson's, but we have to see how that plays out in the phase II study. If the results we're seeing in phase I-B continue, we may have a validated biomarker that we can continue to use for Parkinson's, that is a predictor of efficacy. That would be phenomenal for the field, not just Gain, but for the field in general. We're really hopeful that we'll be able to validate that. That's the phase II study. As far as the competitive positioning, there were two closely related molecules, closely related in the sense that they target GCase, similar to us. They are direct activators of GCase. Vanqua or VQ-101 is one of those. VQ-101 is in a phase I-B study like ours. They have conducted their open label extension out to three months. We've gone out to a year, but they're out to three months, so they have very good PK data on how their drug is working in the first 90 days, compared with ours. You're correct. What they're showing is very, very good activation of GCase in the peripheral blood, which is great. You sort of want to see that. We see that with our drug as well. We want to see GCase active. That means the drug is on target in the periphery. In the brain, behind that blood-brain barrier, things get different. It doesn't always work the same way. What they saw when they looked at glucosylsphingosine in the CSF, and I don't want to speak for their data at all, but they didn't see any declines in cerebrospinal fluid of glucosylsphingosine like ours. To be fair, they didn't see elevations at baseline like we did either. It might have been just differences in the patient population, maybe differences in the assays that were used between the two of us, but they didn't see any decrease. They did see it in the peripheral blood. We saw it in both places. Now, as far as the clinical aspects of their approach, we don't know. They have not reported that. It's not to say they don't have a clinical improvement, they just haven't reported that data out yet. They may follow up in some subsequent presentations with that. You could argue that looking at 90-day clinical evidence is a little bit premature in Parkinson's. We're fine with that argument. We're curious, so we look anyway. Even out six months could still be a bit early. It doesn't say much one way or the other that we haven't seen their clinical evidence. What we know from their biomarker evidence is that they don't see reductions in glucosylsphingosine. They did see some slight reductions in some inflammatory markers, which is encouraging. We haven't looked too much at those. We're looking more closely to what the actual glucosylsphingosine, I'm sorry, the GCase cascade. That compound is in phase I-B, moving towards phase II like ours. There's another compound that Bial was developing up until yesterday, where they discontinued development because they did not see signs of efficacy in their phase II study, with their molecule, which is also a GCase activator. We think we understand why that is. We did side-by-side analysis with our drug and Bial's, and we saw improvements in the lysosome, that they were able to demonstrate, but we couldn't see neuroprotection there. There's the other compartments of the cell. The difference here, we think, is our drug chaperones GCase. It doesn't just work at the lysosome. There's mitochondrial implications for GCase, and there's also ER stress implications related to GCase. If you don't address the enzyme, we think, throughout the traffic pattern, you may be able to fix some lysosomal aspects, but that's necessary but not sufficient to drive broader neuroprotection. We think that's what played out there, unfortunately. We think this approach, which covers GCase for more of its activity and more of its mechanism, is more likely to drive efficacy, and we hope we're seeing that. Just very quickly before we close, Gene, I was wondering if you could comment on, A, the company's current cash runway. How does this operational runway compare to the length of time that you expect you will need to complete phase II development with 02287? Secondly, if you can offer us any kind of high-level strategic thoughts regarding when or if you might look to seek a partner for 02287. Would that be upon release of top-line data from the phase II, or potentially even earlier? How are you thinking about that in the context of optimizing the intrinsic value of the compound? Yeah. There are a lot of startup activities that we'll conduct in the third quarter. This data is new to us, and to the field, so we are giving potential partners time to answer their questions and go through diligence and things like that. We are also, obviously, always looking at capital markets opportunities, like every other biotech company. We're constantly evaluating and trying to be opportunistic there. We think over the next quarter or so, we're either going to finance the phase II study on our own, or partner, or some combination of the two. The current cash position that we have is, at the end of the last quarter, we reported about $16 million on the balance sheet. That's sufficient to get us now into the second quarter of next year. We have plenty of time to sort out the financing or any sort of potential partnering strategies that we might want to deploy. In the meantime, though, we're really just doing a big education campaign at this point. Gene, thank you so much for walking us through the salient features of the Gain Therapeutics story. I'm sure our audience will agree that 02287 is clearly a compound to watch in the highly dynamic and potentially very lucrative Parkinson's disease space. Thank you, Gene, and thank you to our audience for their participation. Thanks so much, Ram. I really appreciate your time. Thanks so much for the platform.