Good morning, everyone. My name is Boobalan Pachaiyappan. I'm Managing Director and Senior Biotech Analyst at ROTH Capital Partners. With me today is Gene Mack, who is the Chief Executive Officer of Gain Therapeutics. For those who are new to the story, Gain is focused on developing oral drugs for neurodegenerative diseases, including Parkinson's. Gene, welcome to the show.
Thank you, Boobalan. Thanks for having us. Thanks for having the conference where we can ring in spring, which is nice and good weather.
Yeah. I hope you're enjoying the West Coast weather.
It's a little better on the East Coast, that's for sure.
Yeah. I'm sure you have noticed that, you know, our conference is well-attended by both journalists as well as by healthcare-focused investors. Maybe for the sake of clarity, what we have decided to do is segment this fireside into five different topics. Right. First, we will touch upon a little bit on Parkinson's disease, unmet needs, and then we'll talk about the standard of care. Then we will move on to your Magellan platform and how this platform facilitated the discovery of 02287. Then after that, we will go over some of the clinical results that you've, you know, shown in both in healthy volunteers and in patients, especially the most recent results that you presented at ADPD. Then fourth, we will talk about what is next.
Fantastic.
In terms of what you're, you know, discussing with the FDA. Finally, if there is time, we can talk about your additional shots. I know GT-04686 is an interesting program.
It is, yes.
Maybe if you have time, we can touch upon it.
Sure.
Of course, your cash.
Sure.
That's the high level takeaway or high level outline for this. We'll start with the introduction first. Parkinson's disease, this is a decade-old disease and you know, there's approximately one million Americans have Parkinson's disease. Right. Tell us a little bit, you know, how Gain is approaching Parkinson's differently versus other companies, and what are some of the key unmet medical needs that are keeping you up at night?
Well, the key unmet medical need is to get to something or to discover and develop something that can get to the biology of Parkinson's disease and what's going on, what's going wrong. You know, right now, the only thing we can offer to patients is symptomatic relief, and that's through L-DOPA and its derivatives and some other symptomatic, you know, some symptomatic focused approaches. We're trying to peel back the onion on the biology, correct some of that, and prevent the neurodegeneration, the neurodegenerative process that's involved in Parkinson's. That's what Gain is aiming to do by targeting glucocerebrosidase.
All right. We have a bunch of drugs approved by FDA. We have carbidopa, L-DOPA-
Mm-hmm.
We also have monoamine oxidase inhibitors. We have COMT inhibitors as well. How are you thinking about it? What is the differentiation here? Is this something an incremental improvement in efficacy and better safety or better efficacy or equal safety? I just wanted to clarify this upfront.
I think what we were trying to achieve here is creating a backbone of therapy for Parkinson's patients that starts with the biology first.
Mm-hmm.
If we can do something that's disease modifying and symptomatic, then the symptomatic approach is gonna be that much more effective and useful and longer lasting. Problem with L-DOPA is eventually you're gonna need more. You're gonna have to up the dose and that's just a fact. If we can arrest the progression of the disease, then your L-DOPA, you won't think about changing it as soon. If we can start to move that and migrate it earlier in the disease process, you know, maybe we can catch patients before they even need it at all.
Okay. Maybe let's have a little refresher on GT-02287, but before that, let's talk about your Magellan platform.
Sure.
Now it is everywhere you go, there's always AI.
Yeah.
AI that. My fifth grade daughter, she talks about AI that puts me in embarrassment sometimes. Anyway, tell us, you know, how is Magellan platform differentiated versus rest of the computer-assisted drug design platforms, and how this led you to GT-02287? We can take things from there.
What we're trying to do with Magellan is automate these very complicated calculations that determine binding kinetics.
Mm-hmm.
When you are trying to fit a small molecule into a binding pocket of a target protein, right? You know, we're pretty clear about this. Like, we're not looking at the active site. We're not trying to inhibit proteins by binding with the active site. We're trying to stabilize and promote their activity, gain of function. That's the name of the company.
Mm-hmm.
Gain Therapeutics is based on the fact that we're looking to create small molecules that can bind to areas and proteins where they can stabilize and improve that function. Glucocerebrosidase is our first shot at it. We have backup compounds that also target GCase as well. But Magellan was specifically designed to get through these binding kinetic calculations very quickly. Things that take something that would take a normal computer 10 or 15 minutes to do, down to milliseconds, because they have to do that iteration billions of times. You need it down to milliseconds. That's the intellectual property that's being poured into our IP. Sorry, into our Magellan platform and the IP that surrounds that. It's the calculations that process.
Let's say you arrived at GT-02287, but what are some of the attributes of this molecule that led you to believe that this is the one you wanted to carry forward to the clinic?
Well, it stabilizes the enzyme target that we're going after. Glucocerebrosidase, which as you know, is prominent in the disease pathophysiology of Parkinson's, also Gaucher's, but Parkinson's as well. For patients that have a genetic mutation in their GBA1 gene where glucocerebrosidase is misfolded or dysfunctional, we're able to show that we can stabilize that protein and traffic it through it, and chaperone it through its traffic pattern in the cell. So that it can do multiple maintenance functions that it's meant to do in the lysosome, in the mitochondria. These are all. It's a very important enzyme and what we think we're able to do is make sure we're protecting it longer so it can perform more of its function in patients, you know, in folks that have Parkinson's and a deficiency there.
You don't just need the genetic mutation to have a decrease in glucocerebrosidase. Parkinson's patients, even in idiopathic state, could benefit from an increase in GCase activity. It is the enzyme that breaks down, you know, lipid substrates that lead to, you know, this toxic buildup of substrates creating the symptomology of Parkinson's and the neuronal and neurodegeneration.
Okay. You just came from ADPD.
Mm-hmm.
You met with a lot of doctors, potentially, and also other companies. What is the take on GCase as a potential target for Parkinson's? Obviously, we don't have any drugs for this particular target, so you are sort of at the frontier, which also, you know, gives this baggage, you know, whether to take your data seriously or, just being honest here. What are your thoughts on or what is that you're hearing from physicians about GCase?
It's not so much. When we recently presented at ADPD our full 90-day data set, which included the biomarker analysis that we had done. Looking at the biology, are we perturbing? If we're truly chaperoning GCase, what else is happening in these patients, right? We analyze the blood in CSF, and we're seeing markers of Parkinson's that are being affected by GT-02287. One particular lipid in the cerebrospinal fluid is coming down in these patients, and it is along that same disease pathway that starts with dysfunctional GCase.
If you don't have functional GCase, you cannot break down these lipids, one of which is, and this is a mouthful, but glucosylsphingosine in the CSF is a marker of Parkinson's. It's also a marker in other diseases as well. In Parkinson's, in the CSF, we know that elevated levels of this suggest a Parkinson's patient. If we can bring those down, then we're affecting the disease biology. That is what we were meant to do. That is what we are trying to show at GT-02287, and we have. We've shown that, and we've shown some correlative biomarker activity as well.
There's an enzyme, DOPA decarboxylase, that is responsible for breaking down patients' L-DOPA that they take into dopamine, usable dopamine, and that enzyme is elevated in patients with elevated levels of glucosylsphingosine in their CSF. Guess what? In the presence of GT-02287, that also comes down. Now, does that mean that patients are utilizing DOPA decarboxylase better? Maybe. They seem to be doing better clinically because the MDS-UPDRS scores that we've tracked in those patients that have high glucosylsphingosine seem to react quicker. Now, the field is skeptical.
Mm-hmm
Of clinical outcomes at this stage because we're only 90 days in or 180 days in. Like, we're not a year or two in, and Parkinson's is a slow-moving disease. The field is, you know, a little bit skeptical of the MDS-UPDRS scores, but they are for sure not skeptical a bout these biomarkers. They want to learn more. They wanna see more from us about the biomarkers 'cause that definitely made a difference at the ADPD conference.
Yeah. You jumped ahead of us, but-
Sorry
We'll take a step back and then we will.
Okay, okay.
Take one clinical
Apologies.
Trial at a time.
Yeah.
Obviously, you have mapped out your clinical journey. You started with healthy volunteer studies.
That's right.
After that's your I-A. After that, you moved to I-B, where you actually did this open label study involving actual Parkinson's patients, both with idiopathic characteristics as well as GBA1-PD. Interestingly, you had data cutoff for day 90, and then now you recently, you've released day 150, and hopefully there'll be day 270 at some point, right?
That's right.
Let's just talk about healthy volunteers. You put 20, 27 healthy volunteers for the first time. What is that you are looking for? Then especially.
Good question.
The safety.
Yes.
If you can tell a little bit about the safety of the molecule?
We were looking at safety, and the healthy volunteers gotta make sure that, you know, there's nothing of note there. You know, we were able to demonstrate safety and tolerability. Some nausea in healthy volunteers that did not appear in the actual patient population. For healthy volunteers, that was our concern, was that there was some nausea. That has not resurfaced. The other thing, we looked at GCase activation in the healthy volunteers because we were able to put those patients in a very controlled environment. GCase is a finicky enzyme. It is prone to circadian rhythms. It is also affected by diet. It is affected by the time of day. In a very tightly controlled environment, uniformly. Do that in healthy volunteers, m uch because they come in at different times of the day.
We can't control for everything that they eat, especially over, you know, over a 14-day study with healthy volunteers, it's easy to control. Over, you know, a three-month study with Parkinson's patients, there's only so much you can demand that they do, you know, after a lumbar puncture and take this every day, and by the way, this is should be your diet, that sort of thing. However, we are able to see the downstream effects of a gain of function.
Mm-hmm
In glucocerebrosidase by noting the decrease in glucosylsphingosine, which is an important downstream marker. You cannot get there, you can ask any lipid biologist, you cannot get a reduction there unless GCase is working more properly.
Target engagement is achieved?
We have demonstrated central target engagement from multiple perspectives, and the UPDRS scores are there.
Mm-hmm.
Let's see if they hold up. That is the gold standard. That is what the FDA wants you to deliver in order to have a therapeutic that's approved. You've got to improve patients clinically. I don't care about the biology so much unless you can link it to clinical improvement, and that's what we're hoping to do. It's still early days, but I'll tell you, Boobalan, the study is doing exactly what it was designed to do. We've got our central target engagement. We've got downstream.
Mm-hmm
Downstream evidence of central target engagement. We've got stability in UPDRS scores. We have a differential, potentially a differential response based on levels of glucosylsphingosine in the CSF. We just have to let that all play out. I mean, yeah, look, we just need stability and durability in those scores. The biomarkers speak for themselves.
Okay. This is very good. I just wanted to touch on nausea a little bit. What is the nausea rate in Parkinson's patients currently on standard of care?
Yeah.
Meaning this population is already vulnerable, right? They are, they're very old, and then they have Parkinson's. Not that, you know, they are going to have any comorbid symptom or anything. Is nausea going to be a concern in the future, especially in your day 270 data?
No, no. Nausea is not a concern. In healthy volunteers, it's more likely if you take a healthy person, they're gonna notice any slight disturbance.
Mm-hmm
... Pretty quickly and then it's gonna be notable for them. Parkinson's patients are soldiers. They're taking all kinds of different medications, and they've got. You know, you have Parkinson's patients with diabetes. You have Parkinson's patients with all s orts of other comorbidities. They're taking. Most of them are taking lots of medication, and they probably feel pretty miserable on a daily basis. Adding GT-02287 didn't move the needle for them in that regard.
Okay.
What we hope we can do is maybe take off some of those other medications if GT-02287 promises to do what we think it's doing. Then if we can, we can actually make them feel better. The nausea is not showing up for Parkinson's patients, and that's something that is not hard to understand because, you know, healthy volunteers, they're gonna be more sensitive to any kind of disturbance in their GI or their normal sort of pattern of feeling, right? Our Parkinson's patients are dealing with a lot. They're swallowing a lot of medication. They probably won't even notice extra nausea if they.
Okay. Let's set expectations for day 270 data.
Okay.
Right? This is going to come out sometime in H2 of this year.
That's right.
Right. All right. In terms of efficacy, what do you need to show that you have not shown previously? Do you want it to show more UPDRS stabilization, or will there be any new biomarker analysis or, like, revisiting some of the glucosylsphingosine levels?
Right.
For the sake of simplicity?
The first thing I wanna do is remind everyone that this is not a phase III trial.
Right.
This was a signal finding study. The goal of this study was to find biological evidence that we were hitting the GCase pathway, and we achieved that. The next best thing we can hope to do is show that the biological, you know, the biology that we're impacting leads to clinical improvement. That will unfold with the UPDRS scores. You know, what we're hoping to show is that the patients aren't getting any worse. We cannot repair dead brain tissue. That is just a scientific fact. You can't resurrect dead neurons. What we can do is stop the assault.
Mm-hmm.
Stop the progression. Stop the UPDRS decline, if you will, right? Really, that's what we're aiming to do. Now, for some patients, GT-02287 may offer a sort of quick alleviation of the chronic or acute attack on the brain, right? If we calm that storm down. The neurons that were sick, but viable and could be repaired, do so, and there's your UPDRS improvement, right? Just from that. We need to carry that through. It needs to be durable. We need to show that the protection we're offering patients with GT-02287 is sustainable and durable, and we're doing that, but it's not a flashy show. It doesn't come with big numbers. It comes with, they're not getting any worse.
Yeah.
That, in effect, is them getting better.
In other words, a reduction in disease slowing.
I think that's the best we can hope to achieve right now. You know what I mean? You start forming a new backbone in Parkinson's therapy, where you're putting disease modifying therapies on top of the symptomatic stuff, and these patients will feel better.
Okay. Sorry, a reduction in disease progression. All right. Let's talk about the next steps because we got, like, five or eight minutes now.
Sorry.
To wrap up. Obviously you are in talks with the FDA. Your next step would be a full-blown phase II study. Potentially, this could involve.
That's right.
US patients, right. Tell us, you know, the overall design, and most importantly, what's your inclusion and exclusion criteria? Because now that you have done some biomarker analysis and people are going to bombard you with questions like, are you going to focus more on Gaucher's? A t the same time, this is going to narrow your Parkinson's population to a subset of, or, so to speak, you know. How are you thinking about that? And of course, touch a little bit on endpoints.
Yeah. You know, there's some trade-offs we have to think about. You know, we're trying to keep everything on the table still.
Okay.
You know, companies do. That's what. That's our job. We wanna keep everything on the table.
Mm-hmm.
We wanna treat all the patients. For right now, I think the best thing that we can say is that we have this very, very interesting biomarker that seems to crop up in high propensity. There was about half of the patients where we had good cerebrospinal fluid samples from, about half of them, they had elevated levels of glucosylsphingosine. That is not insignificant. That's half of them. We think, you know, we can still enroll an all-comers trial.
Mm-hmm.
We don't have to pre-select. The reason why I say that is pre-selecting patients on the basis of their level of glucosylsphingosine in CSF requires lumbar puncture. That's not a great diagnostic approach 'cause it punishes the patient. We wanna try and find something we can analyze in the blood that leads to that, and then we just have to keep looking. However, we can analyze the CSF, and we can find out if they have high glucosylsphingosine or low glucosylsphingosine, and maybe they preferentially respond to GT-02287.
We're gonna take all comers for now, enroll all those folks. We'll stratify based on who has high and who has low, and we'll see if the UPDRS scores, you know, duplicate what we have seen early here in phase I-B. We have to look at other stuff as well, and we have to analyze CSF fluid because we do have to do the alpha-synuclein seeding assay for these patients to confirm their diagnosis, to make sure that they truly do have Parkinson's.
Mm-hmm.
We get the benefit of CSF fluid. We'll have more samples, more patients. We understand more about the drug at this point and inasmuch as, like, we know that there's this high glucosylsphingosine, low glucosylsphingosine dynamic that we need to look at. How does that even tie into GBA1.
Mm-hmm.
Genetic profile? We don't quite have a handle on that yet, too. This is like, that's all gonna be phase II, but we're getting there. Like, the drug is doing what we asked it to do.
What about the endpoints?
The endpoint for the phase II study will be UPDRS, MDS-UPDRS part two and part three, but really part three. Sorry, part two is the one that is the, you know, the gold standard for approval. It needs to be supported by part three, which is the clinical. You know, part two is the patient-reported clinical outcome. Part three is the clinician-reported outcome, clinical outcome, functional outcome. Part two needs to be clinically meaningful and significant and needs to be supported by part three. We think we'll get there 'cause that's what we're seeing in the phase I-B study. Low numbers, we can talk about the statistics.
Mm-hmm.
As far as the population that we've enrolled, they seem to be doing well.
Okay.
The biomarkers are lining up. The phase II, the logical extension of that is to power up a phase II study for UPDRS and hope that the biomarker evidence we see now plays through in that.
Does this population will have both GBA1-PD.
Yes.
And IPD? If so, what would be the approximate breakdown?
We're, you know, 10%-15% of patients have GBA1 mutation, and that's kind of what we saw in the phase I-B study.
Mm-hmm.
Now we're gonna enroll over 100 patients in phase II. We're gonna try to push for a disproportionate number of GBA1 patients, so we'll use patient advocacy groups, the groups that profile Parkinson's genetic profiles and try to push some more of those patients into this study so we can enrich for that. But yeah, at this point, I think the three questions that people are most interested in us answering in phase II is How do truly GBA1 patients react to this drug. How do patients with elevated levels of glucosylsphingosine react to this drug. Is there a tie-in with their GBA1 status. And what's the clinical improvement. I think we're gonna have good answers for all of those.
When do you expect to start the phase II study, and what are the limiting factors for the initiation?
We expect to hear shortly from FDA on our IND application, which we-
End of this year, maybe?
No, it should be sooner than that.
Sooner?
We've had a really good dialogue with FDA got disrupted a little bit earlier this year. There was a government shutdown, and then our reviewer, we swapped out reviewers, all with respect to the agency's internal things, you know. We feel like we're making really good progress with the FDA. They asked us for additional data on our preclinical toxicology package, so we sent that over to them.
Mm-hmm.
Earlier this month, we expect to hear back from them in a couple weeks. You know, our expectation is we'll be able to go to phase II in the third quarter of this year, and we'll be able to open up US centers.
Okay. Maybe at the last segment, maybe in a minute or so, can you describe your follow-on program, which is GT-04686?
There is.
What is the m otivation to suddenly push this molecule into the limelight?
Well, there's a couple of things, right? We think GT-02287 has an excellent profile and a fully viable commercial profile. You know, the work continues, right? There are, you know, we think there are things about our backup molecules which all target GCase but are all structurally distinct that may offer advantages, you know, in terms of response characteristics or in terms of potency, and we need to continue to develop these molecules. Yeah, we have something behind GT-02287 that, you know, could potentially be more potent, a little bit more convenient to deliver potentially as a result of that, more effective. Yeah, that's all part of life cycle management.
Absolutely. Thank you very much again for speaking with us. This has been great.
Thank you, Boobalan.
All right. As a disclosure, I cover Gain Therapeutics. The recommendation for the stock is a buy rating and $10 price target. In order to see the risks and disclosures, see our most recent research report. Thank you.