Conference Transcript - GANX 2026-02-25

Jay Olson, Analyst — Oppenheimer

Hello, everyone, and welcome to Oppenheimer's 36th Annual Life Science Conference. I'm Jay Olson, one of the biotech analysts here at Oppenheimer, and it's a pleasure to welcome you to our discussion with Gain Therapeutics. And it's an honor to introduce Gene Mack, the CEO of Gain Therapeutics. And I want to thank you so much, Gene, for joining us here today. With that, I'll turn it over to you for a few slides before we begin our fireside chat.

Gene Mack, CEO

Yeah, and thanks so much for having us, Jay. We're really pleased to be here. to get an opportunity to talk about our progress at Gain Therapeutics. So I'm just going to dive right in. So Gain Therapeutics, just to give folks an idea who are not familiar with the company, was established in 2017 and went public in 2021. We've got about 25 employees, and they are scattered through three locations, Bethesda, Maryland, Lugano, Switzerland, and Barcelona. Spain. Gain Therapeutics is engaged in developing what we call allosteric modulators of proteins. So instead of trying to design molecules that will target an active site of an enzyme or protein, we are looking away from that active site more so to provide a gain of function by stabilizing proteins and stabilizing enzymes rather than trying to inhibit them. We think our lead program, GT02287, is special in that we believe the biomarker evidence from our preclinical and now early clinical work is demonstrating disease-modifying properties, which would make GT02287 among, if not the first, disease-modifying treatment for Parkinson's We'll talk more about that in a bit. We are interacting with the FDA at the moment to clear an IND, and we'll hopefully have some news on that shortly because we are initiating a Phase II study with GT02287 in the third quarter. And while we are wrapping up, the current Phase I-B extension study that is completing, and I'll talk more about that in a bit. We have full worldwide rights to GT02287, including Composition of Matter Patent Protection that goes through 2038 without any provisions under the Hatch-Waxman designation. And we have early support from all of the interested Parkinson's patient advocacy groups. Here's another look at our pipeline, but really the focus today is on GT02287. We do have multiple earlier stage molecules. we also have backup compounds to GT02287 that all target this enzyme glucocerebrosidase. That is the target of GT02287. It is an enzyme that is prominent in the pathophysiology of Parkinson's disease as well as other diseases such as what is displayed here like Gaucher's, dementia, Lewy bodies and Alzheimer's. These are all areas where we believe GT02287 development can be expanded later on in its development. A bit of background on Parkinson's disease. It's the second most prevalent neurodegenerative disease next to Alzheimer's in the U.S. It has about a million patients. Approximately 10 to 15 percent of those patients carry a genetic marker, genetic mutation, sorry, in their GBA1 gene. This is the gene that encodes glucocerebrosidase, or G-Case, the natural target of GT02287. So you can imagine the mutation creates disruption in this enzyme, and with the properties that GT02287 exhibits, stabilizes that enzyme and promotes its function. So as we're getting into the mechanism of GT02287, just as a step back, it is a novel mechanism. Again, we're binding allosterically to stabilize this important enzyme so it can perform multiple functions that we'll walk through in a second. in the cell, particularly in the neuron. We believe that its disease modification stems from its restoring G-case activity and the downstream biomarker activity that we're going to show you sort of supports that thesis and that hypothesis. We have completed a 90-day Phase I-B study, 90-day dosing trial, where we'll present the full results of that study at the ADPD next month. ADPD meeting next month in Copenhagen. I'm going to preview a little bit about what we're going to talk about there. But the Phase 1B study, its initial 90-day dosing period has ended, and we have moved it into an open-label extension. We got exciting participation in that open-label extension from the main study, and we'll talk about that in a minute as well. We have demonstrated safety and tolerability through Phase 1B, and we anticipate the Phase 2A again in the third quarter of this year, while we continue to analyze data from the Phase I-B study, which will complete in September of this year with data availability probably in the fourth quarter. So what is GT02287 doing in the cell? So what we're seeing happen is GT02287 engages with GKs as it is transcribed. It's important that it stabilize the enzyme at this point so that it can get out of the endoplasmic reticulum, otherwise it will create stress in that cellular compartment. G-Case has to then travel to the lysosome where it's responsible for disaggregating toxic substrates and cleaning out waste. And then in the mitochondria, we're learning over the last three to five years, there's a very important role G-Case plays in stabilizing electron transport one, electron transport in the mitochondria for energy production. So all three of these, it's correct transcription, it's traffic pattern around the cell has to be maintained so it can perform multiple functions. Or you're going to get a breakdown in the lysosome, you're going to get reactive oxygen species buildup from the mitochondria, and things are going to go wrong and the neuron's going to die. We see with GT02287 that we're able to restore G-case activity, that we're able to restore lysosomal function, that we are seeing toxic substrate depletion. This one's slightly highlighted because this is important to our biomarker analysis from the phase 1D study. This glucosylceramide levels in this particular illustration demonstrate that when an animal has Parkinson's-like symptoms or is induced in a Parkinson's-like state with the addition of GT02287, we can reduce this substrate and it's important it's going to come up in a few slides we also see reduction of er stress mitochondrial function improving alpha synuclein depletion these are all things that have to be maintained in the cell for it to be healthy and overall neuronal survival and this is an amalgam of all the preclinical studies we've done we're going to skip over that today in the interest of time so we can get straight to the clinical data but what we've seen in our first initial human experience with GT02287 in a single ascending and multiple ascending safety study was that the compound was safe and well-tolerated. We saw 32% nausea in that particular study, but that has not shown up in any of the patient studies, so we think it's something that was unique to the healthy volunteers, so a very safety, very clean safety profile at the moment. We achieved therapeutic levels, and we had evidence of target engagement by showing that G-CASE in healthy volunteers is increased, G-CASE activity is increased in the presence of GT02287 by a statistically significant, meaningful amount of 53%. We saw that in healthy volunteers. That gives us an idea that we're safe, and we're on target. We've got targeted engagement, G-Case is being, the G-Case cascade is being perturbed by GT02287. So from the Healthy Volunteers Study, we moved into the Phase 1B. This is a summary of that design. Again, we had a 90-day initial Part 1 to this study, 90-day daily oral dosing of GT02287. We completed that in November, and the final results of that particular part of the study will be presented in full at the ADPD meeting in Copenhagen next month. But we are additionally rolling a Phase 1D extension study for any patients who wanted to maintain on study if they felt like they were benefiting. And I can tell you that of the 19 patients that completed Part 1, 16 have elected to stay in the study in Part 2. So we're really encouraged by that alone, just based on the fact that these patients in an open-label study are maintaining a perception of benefit. The study was conducted all in Australia in seven centers, again, for the phase two, which is one of the reasons why we are discussing an IND with the FDA. We will move development to the U.S. We'll keep Australia as well and potentially open up some European centers and make it a global study. But that is our planning for phase two. But in phase 1B, we kept the study in Australia. The objective was safety and tolerability, but again, we were looking at a host of biomarkers here to see further evidence of GT02287 affecting this Gcase pathway in a beneficial way. So what did the Phase 1B study show us in summary? Well, we demonstrated that GT02287 was safe and well-tolerated. Again, 16 of the 19 patients that completed the Part 1 of the study stayed on for part two. We noticed some very interesting biomarker evidence of activity further down from G-Case, which is important and related to the glucosylceramide data that I showed you in the previous slide. We saw that patients with an elevated level of glucosyl sphingazine, this is a related lipid, and I will draw the correlation, I will make the relationship clear in a second, patients that had baseline levels of elevated glucosylisphengazine in their CSF had a significant, experienced a significant rapid reduction of that glucosylisphengazine by about 81% on average down to levels that looked more normal or were perceived as being more normal. Those patients also were ones that demonstrated a a more robust functional improvement on the MDS-UPDRS score scale, and I'm going to go through that data in a second. But GT02287 was well tolerated. We have conducted additional biomarker evidence that we're going to show you today and also add on to at the ADPD meeting, and our Phase 2A study is being planned in earnest with a Q3 start date targeted. So going back to glucosyl sphingazine and its relationship to glucosylceramide and G-case and how this all hangs together. So as a result of increasing G-case activity, we know we have more enzyme to process glucosylceramide. Glucosylceramide is a ubiquitous lipid that accumulates in the body. And if it spills over, if it tips over a particular threshold, it becomes glucosyl sphingazine. Glucosyl sphingazine is known as this sort of dead-end lipid. It doesn't perform any sort of maintenance or functional role in the cell that we can identify. However, it does lead to mitochondrial dysfunction, lysosomal dysfunction, and the aggregation of alpha-synuclein. It goes back to this cascade that we showed earlier, where if you're not able to chaperone G-Case throughout its traffic pattern in the cell, not just activate it, but protect it through its traffic pattern in the cell, you're not going to get broad neuroprotection. You may improve the function of the lysosome or the mitochondria selectively, but without all these compartments functioning normally, you're not going to have a healthy cell. you're not going to have a healthy neuron. So when glucosylisphengazine builds up, we know that that leads to that mitochondrial lysosomal and increase in alpha-synuclein. When patients entered our study, those that had high baseline levels of glucosylisphengazine demonstrated in these green, in this green spaghetti chart here, these green lines, those were all the patients that are considered above even Parkinson's-type levels of glucosylisphengazine in the CSF. Every single one of those patients came down to what we would characterize as more normal levels. Normal levels for Parkinson's disease and healthy individuals is still a matter of debate, and there's not much difference or daylight between those two levels. For a normal individual, I think that the experts suggest that 20 to 30 picograms per ml is a more normal-ish level for maybe the people listening to this call and you or me if we don't have Parkinson's. If you have Parkinson's, it's above 50, and it gets above that level depending on the

Jay Olson, Analyst — Oppenheimer

type of Parkinson's, and we're still trying to understand those different types of patients.

Gene Mack, CEO

But what is clear to us is when you have the high baseline levels of lupus sphingazine, evident in the CSF, you will respond to GT02287. And as a result of that, your UPDRS scores, based on our Phase I-B evidence, are likely to move quicker and potentially more dramatically in the early days of treatment. So what we see from the overall population of patients that we had CSF samples of glucosylosfingazine and UPDRS scores of both. So we needed a clean CSF sample to be included in this cohort, and you needed to have MDS-UPDRS scores recorded. Of the 13 patients in the overall population, we saw pretty good results after 90 days. You would expect to see not much movement after 90 days. After about a year, a clinically significant movement in UPDRS for the Part 2 and Part 3 that we've summed up in this furthest to the right column here, that number should be around 5 or 6, and that takes about a year. We're seeing some movement in the overall population after a couple of months. That's good to see. We hope that these scores are durable. We're not looking to repair dead neurons. We can't do that. So UPDRS scores that have improved dramatically over time and continue to improve, that's a goal we're still looking to achieve. But right now, we're trying to slow and stop the progression of Parkinson's, which means no further erosion of function, no further increase in UPDRS scores. And you're seeing that we're getting good stability in the overall population. When we take the patients with low baseline glucosylisphengazine, they don't do as well as the patients with high baseline glucosylisphengazine. And we think this is driving the majority of that UPDRS improvement over the 90 days. That's fine to see. That's great. We have to figure out ways to stratify our patient population and hopefully find another marker so that we're not testing CSF in these patients who are in population. I'm sure we'll talk more about that in Q&A. So from there, we have also, I'm sorry, we've also identified additional biomarkers. And at the ADPD meeting next month, we've correlated this particular biomarker with DOPA decarboxylase. So there'll be some interesting data presented at ADPD in relation to this data that you're seeing with further evidence of biomarker improvement. Our phase 2A study is summarized here. We're looking to enroll about 111 patients. We'll do two doses. We will stratify for GBA1 mutation. We'll stratify for high and low levels of baseline gluposyl sphingazine and CSF, and we'll do other stratifications based on what we are learning from the Phase I-B study. But just in summary, we know that the mechanism of GT02287 is as a allosteric modulator and chaperone to protect the enzyme through its traffic pattern in the cell. We restore GK's function. We are completing the Phase I-B study in September, but we've shown statistically significant improvement on pre-specified biomarkers biomarkers of Parkinson's, such as glucosylsphengazine, and we're seeing additional evidence of biomarker improvement as well. And I expect to have, again, more of that elaborated on at the ADPD meeting next month. The company has enough cash on hand as of December to complete the phase 1b study and get through all of 2026. Our goal with GT02287 is to either finance the phase 2 study on our own or to partner or license GT02287 in a co-development arrangement with large pharma biotech and those conversations are going on in earnest in real time. So that is pretty much Cain Therapeutics where we are now. I would urge investors to stay tuned and follow us during the ADPD conference. We'll have additional data there on some exciting, we think exciting

Jay Olson, Analyst — Oppenheimer

activity for G202287 on display. Excellent. Thank you, Gene. Appreciate the update and definitely looking forward to ADPD. I guess maybe just to kick things off on 2287 and the recent phase 1B data. Thanks for providing that analysis of the biomarker data. Since you've announced your top line results back in December, it's been a couple of months and you've had some time to engage with KOLs. Can you just share with us any feedback you've received on that initial data and what are the key themes that are emerging from those discussions? Yeah, it's interesting. We've talked

Gene Mack, CEO

to a couple of lipid specialists regarding glucosylisphengazine, glucosylceramide, their relationship and our impact on glucosylisphengazine, and they immediately wanted to stop talking about G-case activity in the CSF. It's difficult to measure because the pH destabilizes the enzyme, so we have not clear signal there. They've all moved past that. The KOLs have all moved past that. There's no way, in their view, for us to be reducing glucosyl sphingosine in the CSF without increasing activity of G-case in the neuron. We won't see that in the CSF based on the pH imbalance. Okay, understood. And you're very excited by this, and they think it's closer

Jay Olson, Analyst — Oppenheimer

to the toxic impact of low G-case function. Okay, that makes sense. And you had a nice slide on the importance of glucosyl sphingosine in Parkinson's pathogenesis. Can you talk about why glucosyl sphingosine has not been more broadly tested and studied before in Parkinson's

Gene Mack, CEO

research? So we know glucosyl sphingosine real well from gauches. It is the marker in the plasma for disease activity there. In the CSF, it's been difficult to measure and the technology hasn't there until just recently. So it's hard to, there's not, there's nothing really to compare our data with. We believe that if the importance of gluposyl sphingosine holds up through our studies, it's going to be something that everybody's going to have to start looking at now.

Jay Olson, Analyst — Oppenheimer

Okay. That makes sense. And it's good, it's good to be a pioneer. I guess based on the data that is available. How does the level of glucosyl sphingosine correlate with Parkinson's disease progression and prognosis? And is there anything we can learn from Gaucher's?

Gene Mack, CEO

So again, so it's the marker for Gaucher's and plasma. The correlation in CSF is more difficult. And I think it's too early for us because right now the logical thing for us to do is identify if glucosylspingazine is elevated in the plasma among Parkinson's patients, can we select for that? Our numbers are too low to suggest that we have that plasma marker. We're going to have to look at that at phase two with larger numbers. It'd be irresponsible for us to say we've got it, not with 13 patients. We're going to have to see a larger study to understand if we can draw it out that way. But that would be the best thing we could learn from glucosylsphengazine is that it has a marker for patient selection. As far as the disease pathology in the CSF, stay tuned. We're just learning. So we're going to run it back again in phase two. We'll have CSF samples from those patients. There'll be more of them. You saw the propensity of those that entered our study with high levels of glucosylsphengazine. Hopefully that plays out in the general population. and we'll get a nice stratification there and some clear signal.

Jay Olson, Analyst — Oppenheimer

Okay. Understood. And does the GBA1 mutation correlate with elevated glucosylsphengosine, or is there some other predictor?

Gene Mack, CEO

So our numbers are, again, our numbers are low. So we do know that carriers of the GBA mutation have higher levels of glucosylsphengosine in a plasma baseline. We need to know more. We've seen it, we've had three GBA1 patients in this particular study. We have one patient that's up, one patient that's down, one patient that's in the middle. So it's hard to say, you know, there's no correlation there. Yeah, I mean, with three patients, it's just difficult. Let's stick a pin in that one. Let's get more GBA patients enrolled in the phase two and understand that correlation a little bit better. But what we do know is there's, based on the phase 1b, there's a significant patient population that have elevated glucosyl sphingosine at baseline that need to be addressed. And I think we found a way to do that.

Jay Olson, Analyst — Oppenheimer

Okay. And that makes sense. And then, I guess, besides glucosyl sphingosine, are there any other biomarkers that you would expect to have an influence on with 2287? And maybe what are some of the data points we should pay attention to at ADPD?

Gene Mack, CEO

Yeah, so there's another marker that we've seen that we will present at ADPD that has interesting correlation, and that's with dopa decarboxylase. So dopa decarboxylase, or DDC, that is an enzyme that's responsible for converting L-DOPA into dopamine in the brain, Correlating those levels with what's happening with elevated levels of glucosylsingazine and lower levels of glucosylsingazine and then our treatment on top of that has yielded some interesting correlative evidence that we will show at ADPD, but we're under embargo, so you understand. But you can conclude, if it's interesting, it's probably in favor of our hypothesis, right? So, but stay tuned, we'll have that for peer review next month.

Jay Olson, Analyst — Oppenheimer

Okay, got it. We'll look forward to that. And then you did say that having an improvement in UPDRS scores in a short period of time is not typically seen. You saw a movement in a couple of months. Could you maybe contextualize the significance of that and what would you have expected to see in a patient population similar to those that you enrolled in your study?

Gene Mack, CEO

So we expected the 90-day MDS-UPDRS scores to be a big snooze. Like it just wasn't going to show much. Maybe some erosion of, you know, how fast can GT02287 get on top of Parkinson's progression? It's a progressive disease. How fast can we get on top of progression while these patients are maybe three, four, five years into their disease? So we wouldn't expect to see much movement whatsoever. Where we think we'll see incremental improvement in MDSG-PDRS is those neurons that are under attack but viable. And if we can take that acute attack off, that doesn't mean we're bringing back neurons that have already gone the way. But if we can take what's already under attack, there might be sort of a step up in terms of improvement. And maybe we're seeing that preferentially in patients that have high levels of baseline gluposyl sphingazine. And if that's the case, then we need to think about that. And we need to think about that in terms of the direction that we're going to go in clinical development. So we need to do one, we need to bear that out in the phase two.

Jay Olson, Analyst — Oppenheimer

Okay, makes sense. And then since you have the opportunity to enrich your study population for patients with elevated glucosyl sphingosine, and it looks like you're going to be stratifying patients, what is the best stratification? How do you define high versus low glucosylusingazine? And it seems like half of your patients had higher levels. Is that something you expect to see in a larger Parkinson's population?

Gene Mack, CEO

Yeah, I think, you know, so, and it goes back to MDS-UPRS a little bit too. So the levels of glucosylosaphingazine, we think, reach importance in terms of Parkinson's, above 50 picograms per ml. We could argue, is it 30? Is it 50? I don't know if any of us knows enough yet about glucosylosaphingazine and its levels associated with the burden on the brain. I think, you know, once we get above 50, those are the patients we're going to start looking at more closely. to see if they come down again and repeat this result. So as you get above 50 picograms per ml, I think we're in territory where you're at high levels of glucosylosphengizine. This does not correlate with MDSU-PTRS at baseline either, though, Jay, just to further confuse everyone. So what you saw in those glucosylosphengizine, so the driving that we saw, so when we went and showed this data here, This negative 6.17, that's significant, that was in all the high glucosyl sphingazine patients, but they didn't necessarily have high levels of, they didn't necessarily have, they were all over the place baseline MDS, UPDRS. There wasn't, they didn't have inordinately high UPDRS scores at baseline, which is interesting. And getting back to, well, what did you expect to see and what do we think and what's so you know the clinical a clinically meaningful movement on part two and part three together is six points whether that's over six months nine months a year it doesn't matter but you typically wouldn't see something like that until a year maybe drugs can make it happen faster we'll see maybe gt02287 is one of them um but over the span of a year if you can achieve a six point difference and i'm not saying improvement necessarily the difference from your control, because they're going to be getting worse, you've got a clinically meaningful improvement there overall in those patients. So we're hoping to see that over here and durability, Jay. So these MDSU-PDRS scores, we don't necessarily want them to move anywhere anymore. Just stay where you are. That's a good result. That means that your disease is not progressing. And if we get you earlier, you can draw that line where if we can move it earlier, earlier, earlier, then we're stopping symptoms at very, very early stages.

Jay Olson, Analyst — Oppenheimer

Okay, excellent. So you've given us a really good idea of what to look for, and I guess since most patients have rolled over to part two of the phase 1B study for an additional nine months of treatment, can you remind us how many patients remain in the study to date? Yeah, all 16 patients are still in. Oh, okay. Understood. Yep. Okay.

Gene Mack, CEO

We'll be able to update their UPDRS scores. I think we have the next UPDRS readout we have is in a couple of months. And we'll be able to continue to update that. We also have optional CSF lumbar puncture draws. Now, who's lining up to get a lumbar puncture? You know, it was per protocol in part one, so they had to do it. We left it optional because we punished these patients enough already. So, you know, we want to be kind. But if they'll give us their CSF, we'll take it. We don't know how many of those patients. We haven't had them rolling off yet. We'll see. We're not expecting a whole lot, but maybe we can generate additional analysis that way. But right now we're really starting to turn our attention to phase two design.

Jay Olson, Analyst — Oppenheimer

Okay, that makes sense. So, yeah, let's shift gears to your Phase II study starting in the second half of the year. Since you'll have some U.S. study sites, can you just talk about any regulatory discussions or interactions with the FDA? And do you think the FDA is going to want to see the Part II data from Phase I-B before you start the Phase II study?

Gene Mack, CEO

No, we don't think so. So our interactions with the FDA got interrupted slightly by the, there's a partial shutdown that impacted us, and then one of the folks went out on maternity leave. So we're sort of moving along that path, and hopefully we'll be able to say something soon about the IND. But we're having very productive conversations with the FDA. Right now, there's no reason to believe that they want to see the Phase 1B data before we start the – they know when we're starting the Phase 2 study. So, then they have not, as yet, passed for any of that data.

Jay Olson, Analyst — Oppenheimer

Okay, got it. And I apologize, we're running a little short on time, so I'm going to try to ask you a few questions tied together. So I guess for your Phase II study, is that something that you would like to fully run to completion independently, or would you consider partnering, or do you want to wait to partner until after you have Phase II data? And then since you also mentioned several additional opportunities beyond Parkinson's disease, including Gaucher's, how are you thinking about those opportunities and whether not you would do those alone or with a partner? Yeah, so right now we're focused on Parkinson's.

Gene Mack, CEO

We can conduct the phase two study all on our own. Would it be more efficient with a partner? Depends on the partner. And we're talking, I mean, there's large pharma, there's large biotech, there's mid-cap biotech companies and some small cap biotech companies, all thinking through some interesting ways to co-promote or co-develop. And we just have to have those conversations. um we can do it on our own we'd be more efficient with a partner um i think we're you know ambivalent as to how that happens as long as we get the phase two started and we think q3 um i forgot the rest of that question though um yeah just in terms of gauches or all right so so for us though parkinson's we i don't think we would move expand development uh beyond parkinson's until we're in a pivotal study for Parkinson's. Now, if a partner comes along and they want to have that Gaucher's dementia lewy bodies or something else sooner, we're happy to go.

Jay Olson, Analyst — Oppenheimer

Okay, got it. All right. I know there's a lot more we could talk about, and I'm sorry we've run out of time, so we'll wrap things up there. Gene, it's always a pleasure catching up with you. Thank you so much for making time for us today and sharing the impressive progress that you're making on behalf of Parkinson's patients.

Gene Mack, CEO

Thanks, Shay. I hope everybody joins us at the ADPD conference for some additional data. All right. We'll look forward to that. Thanks, Shay. Thanks, Gene. Thanks, everybody.