Good morning, everyone. I want to welcome you to the Gain Therapeutics Parkinson's Disease IOL event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. Before we begin, I would like to remind you that Gain Therapeutics management may be making certain forward-looking statements in their presentation today. Please refer to this slide about forward-looking statements, which describe disclaimers and risk factors related to such statements, and consult Gain Therapeutics' public filings made with the Securities and Exchange Commission that can be found on Gain Therapeutics' website or at www.sec.gov. Now, I'll turn it over to Gene Mack, President and CEO of Gain Therapeutics, for opening comments.
Thanks, Tara. Hello, everyone. Welcome, and thank you so much for taking the time to join us today, where we will provide additional detail on the exciting biomarker evidence further elucidating GT-02287's therapeutic potential that we have observed in part 1, or the first 90 days, of our ongoing phase 1b study. As we announced earlier this morning, patients who completed the first 90 days of treatment experienced an average improvement of 2.2 points on the MDS-UPDRS Part 2 and Part 3 combined scores. Previously, we reported a slightly greater improvement from the first nine patients that completed 90 days. However, the 2.2-point improvement in MDS-UPDRS scores from the 15 patients available from the total cohort is more in line with what we would expect at this stage, given GT-02287's mechanism of action.
It is important at this point to keep in mind that Parkinson's is a slow-moving assault on the brain that remains persistently on the attack for decades after symptoms begin. Over a course of a year, the bar for a clinically meaningful improvement on the combined MDS-UPDRS score is approximately six points versus placebo or no intervention. We believe at the 90-day mark in our phase 1b study, we are witnessing the manifestation of GT-02287 weakening and halting that attack over time, leading to a significant clinical improvement in those scores over the duration of treatment. Our confidence in this outcome is far greater, given the biomarker evidence we are about to explain in further detail today and this stabilization of MDS-UPDRS that we appear to be beginning to witness.
Before I review the agenda, we hope you will take away from this discussion a better understanding of what we believe is clear evidence that GT-02287 does indeed modulate GCase activity in the brain, with now new, never-before-produced evidence that GCase modulation in the brain leads to a downstream effect and a reduction of an important substrate, glucosylsphingosine, that is highly implicated in the pathophysiology of Parkinson's, as well as Gaucher's, which is not currently a part of our clinical development plans, but remains another potential route to expanding the clinical development of GT-02287.
Given the stabilization of MDS-UPDRS scores that we are achieving at 90 days with no changes in dopamine administration for any of the subjects, we believe the biomarker evidence around glucosylsphingosine supports our hypothesis that GT-02287 will lead to a significant and clinically meaningful stabilization of Parkinson's progression that will continue to mature through the duration of the phase 1b study. We have a packed agenda today, so here's a quick look at what's ahead. We'll start off with a quick introduction for our speakers. I'll give a quick overview of Parkinson's disease and the breakdown between GBA and idiopathic Parkinson's. And then after that, we'll share a high-level look at the design of the phase 1b study, and I'll mention a little bit more about the MDS-UPDRS scores. And then we'll get to hear from Dr.
Roy Alcalay, who will walk us through the importance of glucosylsphingosine in Parkinson's disease. And then next, Dr. Peter Lansbury will discuss the utility of glucosylsphingosine in Parkinson's and its implication, along with other GCase substrates in Parkinson's disease biology and broader drug development. From there, we'll dive into some of our recent phase 1b biomarker data with Roy and Peter's context in mind. And finally, we'll open up for a live Q&A with our covering analysts and submit questions if time permits. So let's start with a quick introduction of our speakers. We are thrilled to be joined by Dr. Roy Alcalay, Chief of the Movement Disorders Division at Tel Aviv Sourasky Medical Center and a Professor of Neurology at Tel Aviv University. He previously spent many years at Columbia University, where he continues to be involved in research and education.
His work focuses on the genetics and biomarkers of Parkinson's disease, and he plays a leading role in major initiatives, including the Michael J. Fox Foundation's PPMI study and the Parkinson's Foundation PD GENEration Program. Also with us is Dr. Peter Lansbury, a Harvard neurologist who spent over 30 years studying what goes wrong in neurodegenerative diseases like Alzheimer's, Parkinson's, and ALS, and how to turn those insights into real treatments. His lab was the first to work out key properties of alpha-synuclein, and he's led several major Parkinson's research centers at Brigham and Women's Hospital. Alongside his academic work, he's also founded and led biotech companies that were later acquired by AstraZeneca and Bial. Before we dive into the science, let's just take a quick overview of the Parkinson's disease landscape.
As you may or may not know, just to set everybody's market knowledge of Parkinson's, Parkinson's remains the second most prevalent neurodegenerative disease in the United States, with about a million patients nationwide. Approximately 15% of those patients carry a GBA1 mutation, which we think has special significance for GT-02287's development pathway, given its targeting of glucocerebrosidase, which is the enzyme coded for by the GBA1 gene. And now just a quick overview of the phase 1b. So again, this was a fairly involved trial design. We started off with a 90-day treatment duration and then a voluntary open-label extension beyond the 90-day treatment course so we could continue to follow patients, those patients who choose to stay on therapy and be able to continue to watch their progress on GT-02287.
What you'll hear today is exclusively from the part 1, which we completed in November 2025, a portion of the phase 1b study, so those first 90 days, 21 patients enrolled in that trial. We had 15 of those patients opt to move over to the extension phase. With that, I'm going to just go into a little more detail about today's press release. Again, a total of 19 patient participants completed the first 90-day administration of GT-02287. Four participants were excluded from the MDS-UPDRS analysis: two patients that were alpha-synuclein negative at baseline and another two that were measured in their off-state, which means the time in which dopamine is, or the time at which they have no symptomatic support.
The average improvement that we saw in that 90 days, as it applies to Part 2 and Part 3 of the MDS-UPDRS scores, we saw an improvement of 0.6 on Part 2 and an improvement of 1.6 in Part 3 for a combined improved score of 2.2 points. However, there are, among 13 of the 15 evaluable patients, we saw a much better improvement of around four points. So there are two patients in that cohort that could potentially be outliers that we're continuing to watch and monitor. But for the most part, the majority of those patients have maintained the benefit that they achieved or have been able to maintain the benefit that they achieved over 90 days. So with that being said, let's turn things over to Roy, and he'll walk through the role of glucosylsphingosine and the GCase metabolic pathway. Thanks, Roy.
Thank you for having me. As Gene said, I'm not going to talk about specifically the Gain product, but rather about the glucocerebrosidase metabolic pathway. To highlight what's my, I think, independent opinion about how important glucosylsphingosine is as a biomarker in the GBA pathway. This is my disclosures, just to highlight those in addition to what Gene said. Just a brief overview, glucocerebrosidase or GBA1 is a lysosomal enzyme that breaks down lipids. Now, it is almost universally thought that the association between the gene and Parkinson's is because of reduced GBA activity. Glucocerebrosidase is the enzyme, GCase activity. The reason to think, there are multiple reasons to think this way.
The most obvious one is that multiple, multiple mutations in GBA have been associated with Parkinson's, and all are associated with loss of function, with loss of the GCase hydrolase function. What is the function that we refer to when we say loss of function? It's the breakdown of lipids into smaller lipids, into so it's either glucosylceramide to ceramide or glucosylsphingosine that is not as abundant but is more toxic to sphingosine, and in both cases with glucose. So because ceramide, glucosylceramide is the more abundant is the most abundant lipid that GCase breaks down, a lot of focus has been put on glucosylceramide. Specifically, I would like to show this data, this published data in Lancet Neurology by the group from Sanofi.
I'm a co-author, where we showed that venglustat is a molecule that did not reach clinical meaningfulness but showed a great target engagement in the GCase pathway. This is showing the target engagement. So venglustat is not activating the GCase enzyme, but rather inhibiting the counter enzyme, the enzyme that is supposed to synthesize those glucosylceramide and glucosylsphingosine. And we can see on the left that with venglustat, the level of glucosylceramide in plasma significantly goes down. These two graphs clearly are different between placebo and control. And the same when you measure glucosylceramide in CSF. So glucosylceramide is a great biomarker to test whether the product works. However, when they, this is the same study again, the published data of looking at the effect of the drug on the UPDRS, on the MDS UPDRS Part 2 and 3. So these are the clinical markers of Parkinson's.
Two is mostly a questionnaire. Three is most essentially a neurological exam. We see that in purple is the group that is treated in a dotted line, the group that was receiving placebo. We see that among those who had GBA severe mutations, the graphs are completely similar. And with the people with the mild mutations, those with placebo, if anything, did a little bit better than the group of those who were treated. Take-home message is that glucosylceramide, the most abundant lipid that the GBA enzyme, GCase metabolizes, is not really associated with outcomes that you're looking for if you would like to treat Parkinson's. And therefore, it makes a lot of sense to look at the next, at the more toxic, less abundant lipid, glucosylsphingosine.
Indeed, in studies of Gaucher disease, when Gaucher doctors would like to monitor how much of the drugs they administer, they should administer, they use glucosylsphingosine as a biomarker. They don't use glucosylceramide because its levels can fluctuate, and they're not necessarily correlated with severity of Gaucher disease. In Gaucher disease, there's no, or there's severely diminished GCase activity. Now, glucosylsphingosine is so toxic that its levels are very low, and it's previously hard to measure it. That is why it wasn't reported in the study in Lancet Neurology of venglustat. But more recent technology is able to measure it both in plasma and in CSF. I'm showing here data from my cohort at Columbia that, again, published data in the Journal of Movement Disorders, where we tested multiple lipids.
But at the top left, we can see glucosylsphingosine, and we can see that the levels in GBA carriers are higher than the levels in non-carriers. And we don't have that same association with glucosylceramide. And at the bottom right, at the most right point in the graph, we see the levels in Gaucher patients. And again, you see that in glucosylsphingosine, the levels are tenfold higher in people with Gaucher disease compared to GBA carriers, heterozygous carriers, and non-carriers with and without PD, while within the Gaucher patients do have some overlap with non-Gaucher patients with regards to glucosylsphingosine, glucosylceramide. So in summary, GBA, the gene that has been associated with Parkinson's in over 10% of the patients, encodes an enzyme that breaks down lipids, GCase. This enzyme breaks down two key lipids, glucosylceramide and glucosylsphingosine.
We've learned from the Venglustat study that the glucosylceramide levels are not correlated with disease severity or with any clinical markers of Parkinson's. And therefore, I think the money is in glucosylsphingosine. And that is something that I would say for all drugs that target this pathway. Thanks.
Thanks. Thanks so much, Roy. Next, let's turn it over to Dr. Peter Lansbury to talk about glucosylsphingosine, the utility of glucosylsphingosine compared to glucosylceramide and its role in the alpha-synuclein aggregation.
Yeah, just to sort of retread some of the things that Roy said, I've shown the reaction here on the left, but I've shown it in this context, which is the biological, the metabolic context of the enzyme. To emphasize, one thing I think is really important here is that these metabolite levels are markers of traffic through a pathway, right? They are not necessarily themselves so important as the entire pathway is important. The way I think about this is it's traffic, right? So what you want to make sure is that traffic is flowing smoothly through here. When traffic is not smoothly, as we see in the Venglustat study, when you disrupt this, you can reduce the amount of metabolites in the pathway, but that has a negative effect because the effect you're looking for is to normalize the pathway.
It's like saying, "I'm going to solve New York traffic by closing all the bridges," right? That'll surely reduce the traffic in New York City, but it won't have the desired effect, the reason the traffic was there in the first place. So that's what I think a big difference is between glucosylceramide and glucosylsphingosine. Glucosylsphingosine is a side product. It's only formed in a case where there's not enough GCase enzyme activity. So on the next slide, I just show some data. Here's some published data showing the levels of glucosylceramide don't correlate with the amount of GCase in the brain. So you would think that the higher GCase activity would be the lower glucosylceramide. You don't see that clearly in the brain, right? And when you look at patients versus controls, also, you don't see these large differences in glucosylceramide.
Glucer has a way, that pathway has a way of normalizing itself. The problem becomes when that pathway, when there's really not enough GCase, and now you have not enough GCase to process this glucer to convert it into ceramide, but on the far left, you see now it takes a turn, a wrong turn. This is like a dead-end alley that if the traffic's bad, you may be tempted to take it, and your car is just going to sit there, and glucer just sits there, and when it sits there, it does bad things to a lysosome and has potentially a lot of toxic effects, so this is a big difference. Glucer only shows up. It's only there when there's an abnormality. That abnormality in this case is low GCase activity.
So when you increase GCase activity, the glucosylceramide can naturally be processed and removed from the cell, and that's what I think is what we're seeing here, so I'll show you some data to support this idea. So as Roy said, patients with Gaucher disease have very low GCase, and this is showing the level of glucosylceramide. This is in blood, but you see they have very, very high levels of glucosylceramide. Patients who are GBA carriers, meaning they have one mutant gene, who have GBA PD, have elevated levels of glucosylceramide relative to normals, so that elevation is not linear. This is a severe traffic jam. This is just a slowdown that causes some traffic to accumulate in certain places. This other paper shows the same type of thing, that is, glucosylceramide seems to accumulate in brain of PD patients.
This is postmortem brain, and that accumulation is correlated in some way to the accumulation of synuclein, which is something else that you may be familiar with as a marker of Parkinson's disease. So I think the important thing here is glucosylceramide is a signal that something's wrong. If you right that wrong, then you should remove glucosylceramide, and the pathway can operate normally, and all the things subsequent that depend on the pathway, like synuclein metabolism, can be normalized.
Great. Thank you so much, Peter, for that. Now, just to put everyone, I'll tie this all in a nice bow with our data. Jonas Hannestad will go through phase 1b biomarker data and what we know as of right now. Go ahead, Jonas.
Thank you, Gene. I just wanted to first pick up a bit where Gene was talking about the study earlier. If we can go to the next slide, I'm supposed to move the slide. Sorry. The study has two parts. This is a phase 1b open-label safety and tolerability study in people with Parkinson's. In part one, as Gene said before, people dose for 90 days open-label. Everyone gets active GT-02287. Then after completing part one, they have the option of continuing into part two, where they would get the same dose for another nine months and for a total of 12 months. Here you can see the number. We screened 27 people. We enrolled 21 of those, and 19 completed part one. Part 1 completed back in November of last year.
The two people who discontinued were for a variety of adverse events as shown here at the bottom of the slide. Of the 19 who completed part one, 15 of them chose to continue into part two. Three of them did not want to go into part two, and one of them wanted to, but he had some extensive travel planned, so he wasn't able to participate in part two. We will not discuss part two further here. That's an ongoing study. It'll read out around September of this year when all those 15 patients complete part two. What we'll focus on today are some of the both clinical data and biomarker data from part one. So if you go again, sorry, I'm used to other people moving the slides for me. Sorry about that. So picking up again where Gene was talking about the UPDRS score.
So just to contextualize this a little bit, because I think this is something I encounter frequently, a bit of misunderstanding. So in Parkinson's disease, you have kind of two big buckets of trials. You can have trials of symptomatic treatments, which affect dopamine in some way, and that have very rapid effects. And then you have trials of disease-modifying treatments, which require much longer duration because, as Gene said again, Parkinson's is, in general, a very slowly progressing disease. So just to give you two examples, on the right here, we have a trial of Tavapadon, which is a dopamine D1/D5 receptor agonist. So this one will activate the dopamine system in people, in this case, in people who are not on any dopaminergic treatment. And that leads to a rapid symptomatic effect.
As you can see here, UPDRS scores in both the active arms drop significantly, which means an improvement, whereas the placebo worsens a bit, stays mostly stable over 26 weeks, so pretty short study. This is symptomatic effect. Now, in Parkinson's, we have a lot of symptomatic treatments, and those are very important, obviously, for these patients. However, these symptomatic treatments do not stop the underlying progression, so even if they treat the symptoms and do it well for several years, the underlying biology and the disease progresses, and over time, they will get worse, so what is really needed is a medication that can slow disease progression, and that's what was attempted in that middle graph with Exenatide, which is the GLP-1 agonist. This was a phase three study. They failed to show that it slowed disease progression, but the design is what you need.
So basically here, if you look at the horizontal scale here, the time here is almost two years. So this was a, I think, 90-week study where they compared placebo and Exenatide. And as you can see, those two lines, they barely diverge. What you want to see is that they diverge so that the placebo gets worse over time and the active gets less worse over time. But with a disease-modifying treatment, you do not expect an acute benefit, as you see with the Tavapadon or other dopaminergic agents. So just putting that for context. So our drug, GT-02287, from what we know, falls into the category of Exenatide. We think it has disease-modifying potential if dosed over a long period of time, which is why we don't expect to see an acute symptomatic treatment.
That is, as you can see in the graph here, again, on the left, in our 90-day study, there was perhaps a slight improvement in UPDRS scores, but obviously nothing like a symptomatic treatment, right? We don't expect that. To test the hypothesis that this drug is disease-modifying, after the current study, we will have to go into a much longer study, 12 months, potentially 18 months, kind of like the Exenatide study, to show that the placebo and the active arm diverge over time. That's just some background on the UPDRS. Now, what we can get from this short study is biomarker evidence that the drug has the intended biological effects. That you can measure much faster than changes in UPDRS. Again, to summarize what both Dr. Lansbury and Alcalay were talking about, this, my slide, is a bit simpler than theirs.
This is how I conceptualize it, so when you have reduced GCase activity, you cause this traffic jam that Peter was talking about. You have an increase in, you have accumulation of glucosylceramides in the cell, and then some of that glucosylceramide is then eventually, when you reach a certain excess, it's converted to glucosylsphingosine, and glucosylsphingosine doesn't really have a physiological role in the cell as far as we know. It's kind of a toxic byproduct that shouldn't be there. When it accumulates in the cell, first of all, it's difficult to get rid of because GCase can convert glucosylsphingosine to sphingosine, but it's not very efficient at doing that, unlike converting glucosylceramides to ceramide, so when it accumulates, it has these toxic effects. It impairs mitochondrial function. It impairs lysosomal function, and it increases the aggregation of alpha-synuclein.
And as you know, in Parkinson's disease, all of these three pathways are thought to be implicated in pathobiology, basically, right? So mitochondrial dysfunction, lysosomal dysfunction, and aggregation of alpha-synuclein. So it's very possible that then glucosylsphingosine accumulation in the brain, and specifically in dopaminergic neurons, will lead to those neurons not functioning well and thus to symptoms of Parkinson's disease and progression, right? Now, what we will show in the next slide is that our drug appears to decrease glucosylsphingosine, which we assume is due to an increase in GCase activity. So we're increasing GCase activity. We're unclogging. We're emptying this bathtub full of glucosylceramide so that we have less glucosylceramide being converted into glucosylsphingosine. And then eventually, this is catabolized and gotten rid of, and you have less glucosylsphingosine. So that's, we think, will have a therapeutic effect in the long term.
But then I want to point out also what Dr. Alcalay was talking about before is that glucosylsphingosine is a much better biomarker of this biological effect than glucosylceramide for the various reasons stated. And in Gaucher disease, glucosylsphingosine in plasma is used both as a marker for disease activity and treatment response. Now, Gaucher disease, at least type one Gaucher disease, is in essence a peripheral disease. It affects your liver, your spleen, your bone marrow, but there's very little implication in the brain, right? So measuring something in plasma makes sense when the disease is peripheral. However, Parkinson's is a brain disease. So you have to measure something ideally in the brain, which you can't do. So CSF is kind of the closest you get. And that's why we have focused on measuring glucosylsphingosine in CSF, and I'll get to it in a second.
So what measuring glucosylsphingosine does is, one, it's a biomarker for a treatment response, and two, it's an indication that you're getting rid of a toxic substrate that could lead to clinical benefit over time. So just to reiterate the point that measuring something peripherally in a CNS disease like Parkinson's may not be useful. So here's the correlation between plasma and CSF glucosylsphingosine in our data. And this has been also extensively published, and this is well known, but they don't correlate. So whatever's happening in peripheral organs doesn't track what happens in the brain. Therefore, measuring something in plasma is generally not a good indication of what's happening in the brain. So when you're doing CNS drug development, you want to get closer to the brain, and hence you want to measure things in CSF.
And when we do that, we see that in CSF, in people who have an elevated level of glucosylsphingosine, so this toxic metabolite that's a biomarker for GCase activity, when you have high levels of that, it decreases after 90 days of treatments. 90 days of treatment, too short for UPDRS scores, but it's long enough to show this biological effect. So you can see here, every subject who had elevated levels at baseline decreased substantially. The people who had lower levels in what we presume is the normal range didn't have any change because they have levels that are presumably sort of within the physiological range, and there's no need to decrease those levels. So what does this mean? So it means two things again. One, it's a biomarker of an effect.
So this means that the glucosylsphingosine that we measure in CSF presumably correlates with glucosylsphingosine in the brain. So it shows that glucosylsphingosine in the brain has decreased, which means that we've unclogged that traffic jam, those New York bridges that Peter was talking about, by increasing GCase activity. So the biomarker of a central, of a CNS target engagement effect, right? Two, if you reduce glucosylsphingosine in CSF, presumably it means that you have reduced glucosylsphingosine in the brain. So you have less of this toxic substrate that interferes with mitochondrial function, lysosomal function, and that increased aggregation of alpha-synuclein. So in people with Parkinson's, those effects could have long-term benefit if you continue dosing. And that's what we're hoping that this biological effect over a longer period of time, the 90 days, will lead to clinical improvement or rather clinical slowing of progression.
Then I also want to measure, though, that from a sort of a biological point of view, we see a similar effect in blood. And we don't think that what's happening in the blood is not a reflection of what happens in the brain, but it is a reflection of what the drug is doing, right? So the drug may be doing the same thing in brain and peripheral organs. The peripheral organs, it's not very important in Parkinson's, but it could be important in, say, Gaucher disease if that's a disease that we Gain Therapeutics wanted to pursue in the future. But what we see is the same thing is that glucosylsphingosine in the blood also goes down in cases where levels are elevated.
There's one exception to this, and this is interesting from sort of a scientific point of view, is this is a certain mutation that is believed not to be responsive to this mechanism of our drug. And that one does not change, whereas the other mutations do change. So that's an interesting fact that we'll explore further. Now, lastly, just going back to the UPDRS scores again, as I said, we don't expect much change over a 90-day period because it's not a symptomatic effect. But we do see that there appears to be a correlation, again, small numbers, but there appears to be a correlation between changes in the UPDRS scores, so improvement in UPDRS scores, and decreases in glucosylsphingosine in the brain.
So the people who had decrease in glucosylsphingosine in CSF, rather, which indicates the brain, had improvements in UPDRS scores, and the ones who didn't have decrease in glucosylsphingosine in CSF did not have improvements in UPDRS scores. So does that mean that this is a symptomatic effect? No, it's probably more likely that this is that this unclogging and reduction of this toxic substrate may have a slight sort of short-term benefit on the function of these neurons, right? That is a possibility. But I think this is something that we'll have to wait and see as part two of the study continues, we'll have to follow these patients longer and see if this potentially promising finding holds up that the glucosylsphingosine level actually do predict and correlate with improvements or less worsening of the UPDRS over time.
Thanks so much, Jonas. So with that backdrop, what we're hoping that you can start to appreciate is that we have very, very, what we believe, solid biomarker evidence of a biological effect that GT02287 is having in the brain via the GCase metabolic pathway or the GBA metabolic pathway. We are excited to watch this play out and are looking forward to continuing to follow the patients in our phase 1b study. Over the next year, what you can expect out of GAIN is continued analysis of the phase 1b study extension. And we are going to continue to look at safety tolerability. We'll continue to find other evidence of target engagement and biomarker activity. But importantly, we're looking forward to seeing the evidence of disease stabilization that is already, in our view, beginning to materialize.
The final results from the phase 1b study are expected in the second half, probably around September, so likely towards the end of the third quarter, beginning of the fourth quarter, but we will be able to hopefully provide updates throughout the year. We have filed our IND with the FDA and have begun a very productive dialogue with the agency already, so we're looking forward to putting in place all of the commitments that we need to initiate a phase II study, hopefully in the second half, early part of the third quarter of this year, and again, looking forward to more insights from the mechanism of action and the continued clinical development. We also will have some news from our pipeline as well as we're expecting to make some progress there, so stay tuned.
Gain is expecting to achieve a lot in 2026 and move GT02287 into phase II. So I think with that, if I'm not missing anything off the agenda, Tara, maybe we can open it up to questions.
Awesome. Yes, thanks, Gene. So at this time, we'll be conducting a question-and-answer session with our speakers. Please hold for a brief moment while we pull for questions. So our first question comes from Jay Olson at Oppenheimer. Please go ahead, Jay.
Oh, hey, congrats on these impressive results. And thank you for providing this exciting update. Can you talk about the correlation between glucosylsphingosine reduction and UPDRS stabilization or improvement at the patient level?
To Jonas, maybe.
Yes. Yeah. Thanks, Jay, for the question. So I think, as I said in the previous slide, these are small numbers. So I think we have to be very cautious about drawing any conclusions.
But it appears that people who had a reduction in glucosylsphingosine in CSF also had symptom improvement on the UPDRS, and the people who didn't, didn't. So whether that holds up in a larger sample size and over time, we don't know, but it could indicate that there are some sort of subacute effects of benefits of clearing glucosylsphingosine in the brain that helps these dopaminergic neurons function better, potentially.
Okay. Understood. Thank you for that. And then I guess, how should we think about variations for baseline glucosylsphingosine levels in Parkinson's patients? And do baseline levels correlate with disease severity and GCase activity? And then maybe a related question is, would you expect Parkinson's patients with elevated glucosylsphingosine to gain more benefit from treatment? And would you use that as a biomarker for future clinical trials?
Yeah. So again, excellent question.
So that's something we have obviously thought a lot about after seeing these results, right? And I think the challenge is that there is very limited data on glucosylsphingosine levels in CSF because, as Dr. Alcalay pointed out earlier, the methods to measure very low levels in CSF have just been developed in the last five years or so. Before that, it wasn't even possible. So we don't really know much about glucosylsphingosine levels in CSF. The Michael J. Fox Foundation and their PPMI dataset are currently measuring that. So we'll have much more data. And then we'll be able to look at correlations between levels and baseline characteristics, disease progression, etc. And our dataset is too small for that.
But I think if these data hold up, it is possible that we, in a future study, would have to select patients who have a certain level of glucosylsphingosine in CSF at baseline because those patients may be more likely to respond to this specific mechanism, this drug, right? So then it would be kind of a companion diagnostic or a stratification marker.
Okay. Makes sense. And maybe if we could just a few more questions from us.
But so Jay, I just wanted to add one more quick point to what Jonas said, and that you asked about GCase's activity correlation with glucosylsphingosine. And I just wanted to highlight that I think that glucosylsphingosine is a better, but would be, we don't know yet, but is expected to be a better marker than GCase's activity just because GCase's is a lysosomal enzyme.
In CSF, the pH is 7, so it doesn't work in CSF. That's why I anticipate that GCase's activity in CSF is not going to be as useful as glucosylsphingosine. That's like if it's a promising biomarker.
Okay. That's super helpful. Thank you for that. Maybe as a follow-up, is it safe for us to think that these reduced levels of glucosylsphingosine would support a disease-modifying benefit for 2287?
I mean, insofar as levels of glucosylsphingosine are detrimental in the brains of these people with Parkinson's and that over time, reducing those levels will slow disease progression, then yes. But again, this is sort of cutting-edge biology. We won't know until we do the actual phase II experiment.
Okay. All right. Understood. Maybe if I could thank you for taking all these questions. Maybe if I could just ask one more.
Based on these encouraging data that we've seen so far, can you just talk about your target product profile for 2287? And I guess, what's the ideal patient population that you'd like to treat with 2287?
Yeah. So I think in an ideal world, if we could treat anybody with Parkinson's, regardless of GBA variants or glucosylsphingosine levels, that would be beneficial for the largest group of people. But I think as we characterize this drug more, we may find ourselves in a situation where we realize that the benefits are likely to be larger in certain subpopulations. And this could be GBA1 carriers. It could be people with high levels of glucosylsphingosine independent of any genetics, right, or a combination there. And we're just starting to develop those different development pathways as we speak.
Excellent. Well, this is extremely encouraging.
And thank you again for providing this update and taking all of our questions.
Great. Thanks for the questions, Jay. Our next question comes from Ram Selvaraju at H.C. Wainwright. Please go ahead, Ram.
Thanks so much for taking our questions. And congratulations on all this progress as well as this important information divulged on today's call. I wanted to ask the company how you expect to proceed with regard to regulatory interaction and obtaining regulatory feedback, if any, regarding the use of potential surrogate biomarkers in the evaluation of GT-02287 in Parkinson's disease going forward and how this is going to dovetail with the purported registrational path in this indication.
I also wanted to see whether there was any expert opinion on the likeliest patients to show a response to the drug based not just on the levels of a specific biomarker in the CSF, but also on the degree of deterioration that has occurred in the course of the pathophysiology of the disease. Because one might expect that 02287 would be particularly helpful in those patients who retain some degree of dopaminergic neuronal architecture in the Substantia nigra, as opposed to those patients with Parkinson's disease who have already deteriorated beyond a certain point. So I was just wondering what the evidence indicates would represent the ideal context for a drug like 02287 to be applied. Thank you.
Okay. So there's a lot there.
I think the first part of that question was what we can maybe expect or what we can maybe try to forecast in terms of our interaction with the FDA around biomarkers. So I don't know, Jonas, if you want to take that. I mean, it's possible that glucosylsphingosine becomes a much more important biomarker if our efficacy continues to be durable. I think you'll find other sponsors start chasing down what their compounds do in terms of glucosylsphingosine in the CSF now that there's the ability to assay that and also peripherally. So you may see the emergence of this biomarker more rapidly now that if GT-02287 is successful at validating it. Jonas, maybe you can add or avoid or.
Yeah.
I mean, I think, as you know, the question of surrogate biomarkers is something that FDA is pretty clear that to agree to a surrogate biomarker, you have to show that it correlates with or predicts clinical outcomes, right? And typically, you can only do that when you do a large phase II or phase III study. So until such time, my expectation is that FDA at this point would not agree for us to use glucosylsphingosine or any other biomarker as the a surrogate endpoint for the purpose of approval, right? It may be that as we get more data in, say, in phase II, they may be open to a conversation at that point that we could get accelerated approval based on that biomarker. But I think it's very early to say. In my experience, they're generally fairly conservative.
In Parkinson's specifically, they haven't agreed to use other biomarkers such as dopamine transporter imaging or alpha-synuclein in CSF, which we don't really know yet, as surrogate markers. So I think from a development planning point of view, we are expecting at this time that we will have to do sort of the traditional UPDRS-based phase III studies to get approval for this product. And then the other part of your question was about what stage of progression in Parkinson's we want to target. And I think, again, in general, as you pointed out basically in your question, is that the more neurons you have left in your brain, the better off you are, presumably. So treating people as early as possible in neurodegeneration in general is viewed as better. Now, would this compound specifically have an effect when people are farther progressed? It's possible. We don't know.
It might be worth actually hearing from Peter and Roy what their opinion would be on how much evidence the FDA might need in order to validate a biomarker like glucosylsphingosine. Roy, you care to take a shot at that?
I can't imagine anyone doing nowadays a study on Parkinson's with GBA without measuring glucosylsphingosine in plasma and in CSF. I think it's especially after the data are strong. Peter would agree with me that glucosylceramide is not a good biomarker for the pathway. Or at least we know that modifying glucosylceramide isn't a promising way of looking at modifying PD.
Yeah. I agree with everything Roy said there. But as to whether the FDA would accept it as a surrogate marker, I think we're in early days.
I think if the Fox Foundation goes after their entire PPMI database and some correlations emerge that are interesting and that can be followed up on, I could imagine potentially this would be used. But I think you guys are the icebreakers here. I'm not sure that will happen in the time course that it would be useful for you.
Now, however, I always feel like the FDA looks at data. If you have data that clearly shows there's an effect of glucosylsphingosine level on response in a large trial, I don't think they're going to ignore it. So I don't think they will conditionally approve a drug if there's no clinical benefit based on that yet. But I do think that it should be obtained and you should because I do think there'll be an explosion of measuring. I know that there are a bunch of companies looking now to measure glucosylsphingosine in CSF. I know it's a big active area.
And it's something that we can get back to you about whether glucosylsphingosine is already used in Gaucher trials. I think it is. It is at different levels of glucosylsphingosine, but if that's the case, I can imagine that it'll be easier for the FDA to consider it because at least it shows that there is a reliability and validity across labs in measuring glucosylsphingosine.
Yes, and so, Ram, just to summarize, we're off to a really good start with glucosylsphingosine. The likely consequence of that being sort of first here is that while we might go a long way towards establishing it, it's probably likely others or maybe in our earlier stage pipeline that will receive.
Thank you.
Thanks for the questions, Ram.
Our next question comes from Tom Shrader at BTIG. Please go ahead, Tom.
Hi, everybody. Thanks for all the detail. I thought with all the brainpower, I'd ask some philosophy questions. What is the best data that GK you could back someone out of established Parkinson's disease? And the question is really motivated by Alzheimer's, where removing plaque was much more profound in its treatment effect than it turned out to be in humans. Are you comfortable the models are better? What's the best data that's driving the biology hypothesis?
I think I can take a stab at the question. When we look at the rate of progression of, and this is like I kind of hinted to it, but I didn't say it in these specific words.
When you look even in the Venglustat study on the rate of progression of people with mild mutations in GBA to those with severe mutations in GBA, it's very clear that those with severe mutations progress faster. So the hypothesis is that it's not just that the GBA, whatever pathophysiology is just causing PD, it's also once it happens, it also contributes to faster progression. So if you can modify that and bring the severe mutations to the mild mutations and the mild mutations to bring them to non-carriers, you have modified the progression of PD in a way that you can see even in a one-year study.
So you don't really need to back someone out to have a drug. You could simply just stop them from progressing. The bar is maybe lower.
Right. I think to talk about reversing, I think it's a little early, right?
We're not where this is a, but there's not a great epidemiological data to support reversing. But I say that even rate of progression, the people mentioned earlier, the motor progression and which stage of the disease should be affected. People with Parkinson's that have motor symptoms still have quality of life. If you can prevent the cognitive deterioration that happens more frequently with GBA mutations, that will be huge. That is actually that will be amazing. Even if you don't reverse the motor symptoms or the progression is slower and you were able to develop an intervention that prevents cognition or cognitive impairment, that would be great.
Then a quick follow-up. Do you think this program is directly competitive with LRRK2 activation? Or do you think LRRK2 activation only works in the presence of robust GCase activity?
I didn't understand what you meant when you said initially competitive. Because it's much easier to do GBA drug targets than LRRK2 just because there's such a larger population and patients do worse with GBA mutations. So they're much more likely to participate in clinical trials. There is a very small subset of people who are dual carriers of GBA and LRRK2. And the data out there is controversial to whether it doesn't look like there is synergy, which means if both are deleterious in a similar path, you would expect that one plus one will be three. But it doesn't look like this. It doesn't look like those who are dual carriers progress worse than carriers of only LRRK2 or only GBA. Some studies actually say that the dual carriers do better than GBA carriers without LRRK2.
So I think it's too early to think of a combination therapy of a LRRK2 inhibitor with a GCase enhancer. And I think the low-hanging fruit is targeting the GBA pathway just because it's so much more abundantly affected in PD.
Okay. Great. Thanks for the thoughts.
Thanks for the questions, Tom. Our next question comes from Jason McCarthy at Maxim Group. Please go ahead, Jason.
Hi, guys. Thanks for taking the questions. Nice job on the study outcome. A couple of forward-thinking questions. One, is there any imaging potential for glucosylsphingosine given that ceramides are bioactive sphingosines? They've been used by MRI or modern MRI, if you would, for things like cognitive impairment and surrogates for drug activity?
I'd be willing to give that one a shot because I looked very hard for a few years.
I think it's very unlikely that there will be an imaging agent for glucocerebrosidase activity in brain. I think I would say it's ever possible, but very unlikely in the next five, eight years. It's very difficult. As for directly imaging glucosylsphingosine in the brain, you would have to use MRI for that, and I'm not aware of a signal that I've seen that one could attribute to that particular substrate. It's going to be very difficult because it's such a low-abundant substrate that even if it had a unique sometimes you get a unique proton signal that you can key on, it's going to be very low abundance, and it's going to vanish into the forest of other protons from other related molecules, so I think that CSF is probably the best we're going to do.
But I did mention in my slides, there is this nice postmortem brain studies that seem to sort of roughly correlate with CSF. So I do think that CSF is probably a pretty good correlate for what's going on in brain. The best we're going to do. Did you want to add to that? I think that, yeah, I agree with Peter that imaging glucosylsphingosine in the brain is probably very difficult because it's present at such low levels. But there has been a lot of progress in imaging alpha-synuclein. So once that is ready, insofar as reducing glucosylsphingosine will reduce aggregation of alpha-synuclein, you could use that as a sort of a proxy imaging biomarker for an effect on glucosylsphingosine.
Okay. And in terms of the next study, the phase II glucosylsphingosine, I'm assuming in CSF would be part of your enrollment criteria.
That's something you may discuss with FDA. But also, you had mentioned there are certain mutation types that popped up where the drug might not be as effective in terms of lowering those levels. So do you need to screen for these certain mutation types? Is that part of the plan to really try to concentrate your patient population that could potentially benefit from drug?
Yeah. So in the planned phase II study, we're not going to exclude people based on these characteristics, but we're going to measure them so that because I think the data we have at hand is too small. The sample size is too small to conclude anything, right? So what we want to do in phase II is we will get CSF at baseline.
We'll measure the glucosylsphingosine, and we'll have some pre-specified hypotheses about high levels of glucosylsphingosine in CSF may do better on XYZ. Similarly, we are genetically characterizing all these patients also at baseline. We will include everybody, but then we may have some pre-specified hypotheses about such and such mutation in GBA1 may respond better or worse to this mechanism. Then we'll see how that pans out in the phase II study. Just really quick, and I might have missed it, so I apologize. For the 15 evaluable patients for glucosylsphingosine levels, were all 15 elevated at baseline, or was there a subset of them only? It was all 15? No, no, no. So I think there was about six or seven who had elevated levels at baseline in CSF, and that came down.
The others were so the other half or a little bit more than half, they had sort of "normal" levels.
Got it. Thank you, guys.
Thanks, Jason. Tara, do we have time for one more or two more?
Yes, we do. We have Manasa Sangeetha from Roth MKM. So Manasa, please go ahead.
Hi, guys. Thank you so much for taking the questions, and congratulations on the progress. So my first question is, so based on the data that was presented today, are you seeing evidence that GT-02287 serves not only as a GCase activator, but is participating in downstream events, including restoring mitochondrial function and neuronal survival? So what do you think about that?
So we have seen, not in this study, obviously, but we have seen in vitro and in vivo mouse models a lot of evidence supporting that.
GT02287 does not activate GCase directly, unlike some of our competitors. It's a chaperone. It helps GCase and the endoplasmic reticulum fold better so that there's less misfolding. And that then helps the correctly folded GCase to get to lysosomes where it has its activity. We have also seen in vitro, especially, that GT02287 has effects on mitochondrial function, so improving mitochondrial function. Now, whether that is mediated through GCase and glucosylsphingosine potentially, or it's a more direct effect, we don't know because GCase also has been shown recently to have an effect in stabilizing complex I in mitochondria.
Thank you. I have just one more. Do you think the ongoing phase 1 open-label extension will reveal details about key CSF biomarkers such as alpha-synuclein and NfL? Do you have any thoughts on that?
Yeah.
So those are biomarkers that, again, we think you need longer studies to detect the change, right? So for NfL, if there is a disease-modifying effect here, we would expect NfL levels to increase at a slower pace in a long-duration study like a year. So we may see some of that in our extension. And when we dose these patients for a whole year, that NfL levels decrease. Again, the challenge here is we don't have a placebo arm, right? So we'd have to compare to historical controls. But in our phase II study, we will definitely look at both NfL and alpha-synuclein, so seeding amplification species in CSF.
Okay. Thank you so much. And congratulations again.
T hanks, Manasa.
Yes. Thanks for the questions, Manasa. So this concludes today's Q&A session. I'll now turn it back over to Eugene for closing remarks.
Thanks so much.
So I hope everyone is gaining a better appreciation of how GT-02287's mechanism is being elucidated. And it is very exciting to see the evidence supporting our hypothesis. We know now that we are seeing multiple points at which GT-02287 is aiding in the GBA metabolic pathway. And we expect that to play out in stabilization of these UPDRS scores and significant clinical benefit for our patients upon continued dosing of GT-02287. So with that, we'll close the call. Thank you all for your time and attention and interest. Please feel free to follow up with the company if there's anything we weren't able to address on this call. We're happy to follow up individually or via teleconference. And look forward to talking to some of you in the future and over the next couple of weeks, potentially on the. In San Francisco.