Good afternoon, everyone. I want to welcome you this afternoon to Gain Therapeutics' Parkinson's disease KOL event: biomarkers, clinical endpoints, and the path to disease modification, contextualizing the emerging data from GT-02287. Before we begin, I would like to remind you that Gain Therapeutics management may be making forward-looking statements in their presentation today. Please refer to this slide about forward-looking statements, which describe the 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 so much, Tara. And good afternoon, everyone, or good morning, wherever it may be. Good evening. And welcome. Thank you for joining us today for Gain Therapeutics' Parkinson's KOL event. What we'd like to do here is talk about some of the biomarkers that are best understood in Parkinson's disease and some of the clinical endpoints that will be relevant to our lead program, GT-02287, in Parkinson's disease. Before we get into introductions for the folks that are on the phone and joining us for the call today, let me just give you a brief overview. We're going to talk through Parkinson's disease, some general aspects of Parkinson's disease in the context, again, of GT-02287. I will describe for you a bit about the phase I-B study that is currently ongoing in Australia for GT-02287 in Parkinson's patients.
Then we're going to have one of our KOLs, Dr. Ken Marek, discuss the evolution of biomarkers and where we are now in terms of our understanding. And then next, we'll have Karl Kieburtz who'll talk about the clinical endpoints from the study that we will be focusing on, particularly with emphasis on MDS-UPDRS. And then we will, from there, talk through some of the preliminary or early observations we have from our phase I-B study, and then we'll go through some of the call to some questions. So with that, I'd like to first introduce, so I'm Gene Mack. I'm the Chief Executive Officer of Gain Therapeutics. I'm joined today with our CMO, our Chief Medical Officer, Jonas Hannestad. And we are also very thrilled to be joined by Dr. Ken Marek and Dr. Karl Kieburtz.
Dr. Ken Marek is currently the President and Senior Scientist at the Institute for Neurodegenerative Disorders. Ken is a global leader in biomarker discovery for Parkinson's and related neurodegenerative diseases. He leads several major international studies, most notably the Parkinson's Progression Markers Initiative, PPMI, or otherwise known as PPMI, and serves as a Scientific Advisor to the Michael J. Fox Foundation. He's also the Co-founder of Molecular NeuroImaging and XingImaging, two companies supporting clinical neuroimaging research, and we're also pleased to have with us Karl Kieburtz. He's the Co-founder of Clintrex and a board member at BlueRidge Life Sciences. Karl is a part-time professor of neurology at the University of Rochester, and over his career, he's led more than two dozen global trials in Parkinson's and related disorders.
He's worked closely with the VA and NIH and several research foundations and is deeply involved in optimizing trial design and endpoint selection. Okay, so before we dive into biomarkers and endpoints, just give a broad overview of Parkinson's disease and in the context of GT-02287. So as you may or may not know, Parkinson's disease is the second most prevalent neurodegenerative disease in the United States, for sure, with about a million patients. Approximately 10%-15% of these patients have a genetic mutation in the GBA1 gene. The relevance of this GBA1 gene is it encodes the specific enzyme target of GT-02287. So a malfunction in this genetic code creates a malfunction in this particular enzyme, and that is the target of GT-02287. The unfortunate reality for patients with a GBA1 mutation is that their symptoms of Parkinson's are likely to emerge earlier in life.
They tend to move faster, and it's generally accepted to be a more aggressive form of Parkinson's disease. So how does GT-02287 address this? In the cell, in the neuron, the enzyme target of GT-02287, glucocerebrosidase, or GCase for short, is transcribed in the endoplasmic reticulum. From there, it has to travel to the lysosome, where it's responsible for clearing out toxic substrates that accumulate in the lysosome as a general housekeeping function of the cell. From there, more recently, we're learning that there is an important role in GT-02287, or sorry, GCase plays in the mitochondria in support of complex I electron transport. It's an important energy support for the mitochondria and overall mitochondrial health. What we believe from the preclinical data that we've assembled for GT-02287 is that GT-02287 engages early in the transcription and translation of GCase.
It stabilizes the enzyme and chaperones that enzyme throughout its traffic pattern in the cell, helping it get to all the places it's meant to be, all the compartments that it's meant to be in the cell with its structural integrity kept intact. And for those of you who are new to enzymes, how they work, it's that conformational shape that really confers its function. So that stability in its shape is very important. And we believe GT-02287 stabilizes that conformational shape. And again, I mentioned the clinical data that we've assembled is how we got to this hypothesis on the mechanism of action, given the improvements we've seen in animal models of Parkinson's disease with GT-02287 demonstrating broad neural protection, which is evident by its activation of GCase.
The improvement in lysosomal function, mitochondrial function, the reduction of stress, and these other markers, also alpha-synuclein, which we will talk a lot about with the help of Ken today. And all of these aspects, all of these biological markers are highly implicated in the pathophysiology of Parkinson's disease, and we believe are addressed by GT-02287's interaction with glucocerebrosidase. So just a bit about the phase I-B study. We had initiated a 90-day dosing study of GT-02287 in patients with Parkinson's disease. Jonas can reveal a little bit more later on with some of the baseline characteristics of these patients, but they were more or less patients diagnosed up to seven years with Parkinson's, stable dose of dopamine, stable dose of background medication.
We treated these patients for 90 days at 13.5 mg/kg , which is the dose level that is predicted by our animal models to be in the therapeutic index for human beings. And upon the end of 90 days, and just recently, we have extended the open-label study to include an additional nine months of dosing for patients who are interested in staying on study, and I'm happy to report that as of September, oh, sorry, as of June 30th, we had 16 patients enrolled. Those patients completed their 90 days. More than half of those patients have already entered the extension phase of the study with more coming. We believe 80%-90% of the full patient enrollment from the 90-day portion will roll over to the extension phase. So we're gratified that the patients are having an experience such that they want to stay on medication.
So the main objectives of the phase I-B study, of course, still safety and tolerability. We demonstrated this in our healthy volunteers study in 2024. Additionally, we saw target engagement in that study with an increase in GCase activity of about 53%. And we are further demonstrating, and Jonas will talk more about the safety and tolerability profile observed from the phase I-B study, but that was the main objective here. And we're very happy with the safety profile that is emerging. We do have exploratory end points. Some of the reason why we're having this KOL call this afternoon is to discuss things like GCase activity and other biomarkers that we will be evaluating and the impact GT-02287 is having on these biomarkers.
So with that, I'm going to hand over the conversation to Dr. Ken Marek to discuss some of the biomarkers and where our current thinking is around some of these things.
Can you hear me?
Yeah.
Thank you, Gene, so much. And thanks. It's a pleasure to be here this afternoon and have an opportunity to discuss biomarkers as they relate to Parkinson's disease for a few minutes. It's actually a very exciting moment in the Parkinson's disease research field because we have been seeking to have adequate biomarkers to understand and treat and develop new therapies for Parkinson's disease for many years. We're not quite there yet, but we now are beginning to see some light at the end of the tunnel, which I'm delighted to tell you a little bit about in the next few minutes. So let me. Oops. There we go. So what is a biomarker? A biomarker is simply any objective measure of disease. It's defined very broadly. And of course, we're all familiar with biomarkers. Cholesterol is a biomarker. Blood pressure is a biomarker for stroke. PSA for prostate cancer.
And of course, we in the neurology field have sought to have biomarkers that help us to define, diagnose, and understand disease. It's a little bit more challenging because with regard to brain disorders, it's harder to identify biomarkers and sort of access the brain. But nonetheless, there's been enormous progress in the field of neurodegenerative diseases and more recently in Parkinson's disease. Why do we need biomarkers? Of course, there are many reasons. We need an objective measure of biology so that we can understand and track disease. Biomarkers may be present prior to the onset of any symptoms at all, and that affords us an opportunity potentially to identify who might develop a disease and potentially prevent disease. There may be subsets of individuals who have specific biomarkers which can be treated by targeted therapies.
And again, the ultimate reason is that for clinical drug development, biomarkers enable us to reduce sample size and potentially shorten the time it takes to detect a therapeutic effect. This is particularly important in neurodegenerative disorders, which are clinically heterogeneous. And really, heterogeneity is sort of the death knell to clinical trials. And so we really want to use biomarkers to create a more homogeneous sample set to be studied. When you think about a biomarker, one should think about what are you using that biomarker for? What's the context of use? And typically, there isn't a single biomarker for a disease, but there would be several required to potentially measure disease onset, disease progression, subtypes, and response to therapy. And of course, there are also biomarkers which are particularly focused on drug development, identifying target engagement for a drug or the pharmacokinetics or pharmacodynamics of the drug. Oops.
So as I mentioned, in Parkinson's disease, we have had an exciting last couple of years because we have finally been able to identify a biomarker for the key underlying pathology in Parkinson's disease. This is the aggregation of the protein called synuclein. So this is an assay which was developed a few years ago, which enables us to detect aggregated synuclein and is now widely used to help us to understand who might have the disease. It is currently a biomarker which is only available in cerebrospinal fluid and has the limitations that it is a yes/no biomarker. It's not a quantitative biomarker, although there is a lot of energy and effort to try to improve our ability to not only detect synuclein through the seed amplification assay, but to try to quantify that as well.
Synuclein now, in association with the ability to detect the downstream effects that occur in Parkinson's disease on dopamine degeneration, which have been noted for decades, again, really affords us an opportunity to develop a sort of a biomarker tandem that can define this disease biologically, and which we have now sort of termed neuronal synuclein disease or NSD. We are using that term NSD for a couple of reasons. One is to emphasize that this is a biologic definition, but more importantly, because we believe now this can encompass other phenotypes that arise from synucleinopathy, in particular, diffuse Lewy body disease known as DLB, so Parkinson's disease, DLB may have different phenotypes, but their biology is identical, and so NSD encompasses this range of disorders.
So this really enables us in Parkinson's disease to be able to now, for the first time, understand the disease more effectively prior to the onset of symptoms. This is a slide which is simply meant to show the natural history of Parkinson's disease. This bright white area is sort of the area prior to diagnosis, which has really been a black box. But now, as we have been able to understand and measure synuclein in life using the Seed Amplification Assay, we can begin to sort of paint the picture of what's happening in this white box. So it's important also to know that we have this additional benefit of nature that synuclein is highly associated with a simple test that we can use to detect individuals who might have a positive synuclein Seed Amplification Assay, and that's abnormal olfaction or smell.
It's been known for years that people with Parkinson's disease are likely to have a reduction in the sense of smell, but now we have further associated this loss of smell with the development of alpha-synuclein can be easily tested with scratch and sniff tests such as illustrated in this slide, so scratch and sniff tests tell us who has alpha-synuclein. Ultimately, some of those people will go on to develop dopamine deficit that can be detected using brain imaging. Ultimately, some of those people will go on to develop clinical symptoms, and this enables us now to begin to utilize this strategy to identify individuals at the earliest stages of disease more effectively. This is just the beginning. As we recognize that there are many other pathways involved in some individuals with Parkinson's disease, some of which are listed here. Gene mentioned a few as well.
So immune function, mitochondrial function, lysosomal function can all be affected. And we now need to be able to examine whether these are subsets of individuals with synuclein, whether they occur before synuclein. And these are all based on identifying appropriate objective markers which we can detect in blood or CSF or using brain imaging to help us to understand better the onset and progression of disease. This is all, of course, embedded in this is the importance of genetics. And certainly, that's very relevant to today's discussion as that may well sort of be the quarterback that determines how people respond to all these biomarkers. I'll just mention, as Gene did, that I have the honor of leading the Parkinson's Progression Markers Initiative, a study sponsored by the Michael J. Fox Foundation, which has been ongoing for 15 years to identify biomarkers in Parkinson's disease.
It's this study which this commitment to this long-term effort has enabled us to validate the Seed Amplification Assay. We are now in the process of expanding this dramatically to identify a variety of other fluid biomarkers, some of which are listed here that we think may be important in both influencing synuclein or perhaps determining whether synuclein goes on to develop disease in these individuals. I'm not going to go through the details here, but just to point out that there is really a robust effort to identify biomarkers, single analytes, as well as using multiplex systems. As well as using brain imaging, of course, it's been a key goal in the area in Parkinson's disease to identify a PET tracer that can target synuclein, just as we have PET tracers that target amyloid and tau for amyloid for Alzheimer's disease, which has really helped move that field forward.
We're getting, I think, closer to having the synuclein tracer that we seek. In fact, there are now, as you can see on this slide, several groups that have identified compounds that have the characteristics that might enable us to predict these can be synuclein tracers. They're not here yet, but we think 2026 may well be the year when we begin to identify tracers that can detect signal in Parkinson's disease that would be complementary to the fluid biomarkers in Parkinson's disease, just as they now are in Alzheimer's disease. We think this is sort of a tipping point in Parkinson's disease where we can really move the information we have about biomarkers forward more rapidly.
And so we expect over the next months and years to improve our ability to define the clinical and biologic characteristics that would really now enable us to have real precision targeted therapeutic trials. This is the trial we're talking about today is an example of a precision targeted trial focusing on genetics. But in addition to that, we want to be able to use the biology of disease, other key determinants and modifiers of neurodegeneration. And we want to also know how these determinants of neurodegeneration change over time so that we know what stage of disease we want to target as well. So what we need to do. That are additional biomarkers to understand both the genetics and the biochemistry and imaging, digital biomarkers.
I think all these are coming, and so we think this is an exciting moment in Parkinson's disease, and we're just sort of at the start of a process. I'm going to stop there and hand it over to my colleague, Karl Kieburtz, who's going to talk a little bit more about some of the clinical scales that we are utilizing in Parkinson's disease.
Yeah, and just thank you so much, Gene. Just before Karl starts, I just want to remind all the listeners from a timing perspective, so we will be analyzing biomarker data throughout the next couple of months, and it will be available from our study later in the Q4. We're very excited to see how GT-02287 will be impacting things such as particularly alpha-synuclein. That will come and be available to us later in the Q4. Karl's going to review some of the clinical outward manifestations that these toxic substrates create in patients and how we are observing those changes in our phase I-B study. So I just wanted to provide some timing insight there. Thank you so much, Ken. And Karl, please go ahead.
Thanks, Gene. Yeah, Ken's really described some of the very exciting things that are happening in being able to describe the disease processes down at a molecular level and the imaging tools that we're starting to develop to be able to have insights into them as well as the biofluid biomarkers. In contrast, clinical measures may sound a little bit more antiquated. Of course, clinical measures have to do with the outward manifestations of individuals affected with these intrinsic disease processes and what we see in them as human beings and we can measure as other human beings. And I'll talk about a key one of these measures. There's a lot of initials up here, MDS, UPDRS. MDS stands for Movement Disorder Society, which is the International Society concerned primarily with Parkinson's disease, but also other movement disorders.
And UPDRS is the initials of the Unified Parkinson's Disease Rating Scale. There was an initial one developed just about 40 years ago. The way rating scales were developed at that time, four guys went into a room in Bermuda and wrote up a scale about what they thought was important. They were smart guys. They were knowledgeable. But it was very much from the expert clinician's perspective that this UPDRS scale was developed.
And it had idiosyncrasies, but it also had operating characteristics that made it useful. And it was used for many of the approvals of the drugs we have in Parkinson's disease, particularly if you look back historically, parts two and three. And in the old UPDRS, those were assessments of activities of daily living and a motor examination, both of those things done by a clinician. The new UPDRS, which has only been developed this millennia, is along the same lines, but is different. And what you can see here is that there are four domains of it, and they're called parts, parts one through four. And usually, the first three parts are the ones that are most frequently used. And they are, in this circumstance, done by different kinds of raters. The first two elements of the UPDRS are actually primarily self-report by an individual and/or their caregiver.
And the first section is about experiences of daily living that have to do with non-motor features of Parkinson's disease: pain, apathy, cognitive problems. And 13 items asking people about how those experiences impact their function. The second part is the same idea: experiences of daily living as reported by a person about how things like tremor, rigidity, and motor features impact their daily function. The third piece, and the one you'll hear the most about later from Jonas, has to do with an examination done at a specific point in time by a clinician, which will rate things by their severity, things like tremor, how much a person is shaking, or how fast people can do things like tap their fingers or open their hand. So it's an impairment scale that is done at a moment in time. I would think of that as like today's temperature.
And the other two things are like what season it is because they reflect experiences reported by the patient over the last week, whereas the examination is done at a point in time. And in this particular study, the examination that was done at a point in time took into account when people took their last medication if they were on medication. So if people have not taken medication overnight, that's called an off examination, meaning you're off your medications. You're in a practically defined unmedicated state or practically defined off state. So you'll hear this language. And that has to do with the motor examination. What about the regulatory significance of these things? What has traction with regulators? In the past, Part 3, the examination, carried a lot of weight, particularly when it was combined with Part 2.
There's a growing regulatory concern about the clinical meaningfulness of an examination without an understanding of the clinical impact of that impairment on a person's function. So both at the U.S. FDA and at the EMA and the E.U., there's a greater reliance on the self-report of function that is Part 2. So usually, currently, Part 2 is thought of as having more regulatory traction than Part 3. That said, Part 3 is the quickest way. This is the motor examination is the quickest way to see the impacts on the motor features of the disease, which are the core features of the disease. How do we use these scores? How can they be used in the context of clinical trials? The most traditional way is to look at mean changes. How bad is the impairment or the motor features at one point in time?
How bad are they at a second point in time? And look at the mean change. Some of these events are pretty slow-moving. Some of the changes, particularly in Part 2, take really six to nine months to evolve in early and even mid-stage Parkinson's disease. So seeing these changes can take quite a long time. So alternate approaches are being thought about, including what's here in the middle, is using a survival or time-to-end point kind of approach. We see this in cardiovascular trials, time-to-MI or time-to-cardiac death or time-to-stroke. Using that kind of time-to-end point analysis has also been used.
So for example, in the Roche studies of prasinezumab, looking at time-to-change of a certain magnitude in Part 3, five-point change, which is thought to be, on its face, clinically meaningful, or the Biohaven study of their TYK2/ JAK inhibitor, looking at time-to-two-point change in Part 2, which again is thought to be, on its face, clinically meaningful. So this may improve the efficiency of trials, looking at the time-to-event of a modicum of change in a scale which is thought to represent a significant clinical deterioration. So there are pros and cons of using the mean change versus time-to-event kind of approach. But both of these are trying to identify a clinically meaningful change in the status of patients. Part 2 is probably the scale which, on its face, is most accepted by regulators, but others can be argued.
There's other scales that you'll hear about that Jonas will talk about, scales of cognition, things, and scales of function. They carry a bit less regulatory weight at this point, but help describe the overall response to the intervention in this kind of patient population. So with that, I'll hand it over to Jonas.
Thank you, Karl. Thank you, Ken. It's a very, very nice overview of both of your sections. So I'm going to talk about some interim results that we have from the study that Gene was describing earlier. So this is a 90-day phase I-B safety and tolerability study in people with Parkinson's that's ongoing in Australia. And this study had the aim of enrolling 15-20 participants with Parkinson's. And we completed enrollment in early September. And we have 21 participants. We screened a total of 27.
The 90-day part of the study, which we now call Part 1, because we have the extension that Gene also mentioned. This first 90-day period will be completed by the end of this year. All these 21 patients will have completed their 90 days of dosing. That's when we'll have the full data set from this Part 1. The extension will continue. Some patients already rolled over into the extension, and we will have more in the coming months. That will, because it's a nine-month duration, go into the first half of next year. We'll have data from that part to Part 2 in the second half of next year. What do we have so far in terms of demographics? We have, as I said, 21 participants, three of whom are women, eight are men.
And only two of these are treatment naive. The majority are on treatment. So most of these patients are on levodopa, and some of them also take other dopaminergic or other Parkinson's drugs. And then two of them are on deep brain stimulation. So it's a sort of mixed population that's reflective of the stage of disease. So the mean age of these participants is about 64, three years of disease duration, the mean. We have a cutoff at seven. And then the mean Hoehn and Yahr stage, which is a sort of a staging scale used in Parkinson's, is 1.6. So these participants are fairly representative of an early to mid-stage Parkinson's population. With regards to genetics, we have some genotyping data still pending.
But what we know so far is that of the people who have been genotyped, we have three GBA carriers, two of whom have the severe variants and one of whom has a mild variant. So the GBA variants that also Gene was speaking about earlier, depending on how they affect Gaucher disease, which when you're homozygous, they're classified into severe and mild. And that appears to have an impact in Parkinson's too, so that the severe variants are associated with a faster rate of progression in Parkinson's. With regard to safety and tolerability, so as Gene also mentioned, we did a phase I study in healthy volunteers last year. And this drug was overall safe and well tolerated in that study. We dosed only for 14 days in that study. And here we're dosing up to 90 days. So we have more safety data with longer duration of dosing.
What we've seen so far is that out of the 21 participants, 18 have had adverse events, so 93 total adverse events. The majority of these, about 85%, were mild. And then the remainder were moderate and some were severe. The most common adverse events is what's listed here, so headaches, lab abnormalities, diarrhea, fatigue, and nausea. And these are, for the most part, transient, short-lived, and, as I said, mild. So these adverse events have not led to discontinuation except for one participant. And this was a person who was on a study drug for about a month, but then they had panic attacks. They also had nausea and headaches and decided to withdraw from the study. Now, whether this is related to the drug or not, this is hard to say. We've had a couple of or three patients who have had to reduce their dose.
So if you remember the slide that Gene was showing earlier, there's the proviso that you can reduce from 13.5 mg / kg to 11 mg / kg in case there's an issue with tolerability. And we had three people do that. So one was due to headaches, and two did this because of lab abnormalities, which I'll get to in a second. And we also had some dosing interruptions. And this was discussed with the site investigators on a sort of case-by-case basis. One interrupted drug for about a week due to constipation. Again, whether this is related to the drug is hard to know because it's a very common non-motor symptom in Parkinson's patients. And we have two patients who interrupt the drug due to lab abnormalities. So one of them had transient changes in liver enzymes, so primarily alkaline phosphatase and GGT.
And the other one had transient changes in lipase. And these were so the doses were reduced in these two patients. And then when the drug was, and there was also an interruption. When the drug was reintroduced, these lab abnormalities had normalized and continued to be normal for the remainder of the 90 days. Regarding plasma levels and plasma exposures, we see basically exactly the same that we saw in the phase I study in healthy volunteers. So in healthy volunteers, they're predominantly younger than the typical Parkinson's population. So it's not always the case that PK is similar in younger individuals and older individuals because our metabolism changes, our liver metabolism.
But in this case, the exposures that we see, so both the Cmax, the peak plasma concentration, and the overall exposure, so the area under the curve, is very similar to what we saw in healthy volunteers at the same dose level. And the important thing is that this exposure is within the window where we think the therapeutic exposure is. And that's, again, based on all the rodent data we have. We know that in our mouse models, there are certain plasma levels that are associated with a variety of improvements in brain pathology and biomarkers, etc. And we're achieving those same exposures in these patients. And lastly, Karl was speaking about the MDS-UPDRS, which is very helpful because here are some data on that. So again, important to keep in mind, this is an open-label study, so we don't have a placebo control.
So these data have to be taken in with that caveat in mind. However, what is interesting is if you look at the mean change over time, if you look at the graphs there on the right, there seems to be no mean improvement by day 30. So there's no sort of acute dopaminergic type effect that you would see with, say, levodopa or dopaminergic. But by the time they get to day 90, there is a mean improvement. So again, whether that is a real improvement in the absence of placebo is very difficult to say. But that is one of the reasons we decided to extend the study because we want to characterize this slope further. So we're going to take this out from 90 days all the way out to a year to see if there's further improvement or sustained improvement in these UPDRS scores.
And as you can see here, also the Part 3 is the one that changes the most. And as Karl was mentioning before, that's the one that changes more easily because it's a clinician-rated scale, whereas Part 2 tends to change more slowly if it changes. So that's also another reason to see if this small improvement in Part 2 will continue over the course of the next nine months. So what are the next steps in the development of this drug? So as I said, the 90 days of Part 1 of the study, the 90-day part will be completed by the end of this year. So we'll have a full data set. So we'll have all the safety and tolerability data. We'll have all the PK data. We'll have all the UPDRS data. And then most importantly is the biomarker data.
So going back to what Ken was talking about before, we are measuring a variety of biomarkers that are associated with this mechanism, so sort of target engagement biomarkers, and biomarkers that are associated with the disease like alpha-synuclein. And those will tell us both whether the drug has its intended biological effects from what we've observed in both in vitro and in vivo. And most importantly, whether the drug has an apparent effect on the biology of Parkinson's disease. So these biomarkers will be coming out again towards the end of the year. And we are planning for a phase II study. So once we have this full data set, a phase II study that would start sometime towards the end of the second half of first half of the next year, so in Q2 of next year.
This will be a placebo-controlled study to really determine whether this improvement in UPDRS scores that we see is real when you have a concurrent placebo control. The IND for that phase II study is planned to be submitted by the end of this year. With that, I'm going to hand over to Tara, I think.
Yeah. Thanks, Jonas. I'm just going to summarize. Thanks, Ken. I just want to summarize a couple of things from the call, a couple of things. First of all, we want to thank the patients and clinicians involved in the study. This is not a trivial matter for them. It's some invasive sampling with lumbar punctures. So we're grateful and in their debt and are gratified that they have, in a large majority, chosen to stay on GT-02287 through the extension phase of the study, where we'll be able to gather even more important evidence because I think, as I hope all of you have gotten a chance to appreciate, it's a very difficult thing to impact the biology of these patients in a meaningful way to lead to a clinical outcome that is observable within a 90-day time frame.
We think the extension phase of the study will bear this out for us a bit more and really show us exactly how far we can go in delaying the signs and symptoms of Parkinson's disease. So, we're very, very excited to have the extension phase running. We're very, very excited to get the biological evidence that we're hoping to find in these patients that have been improving at least somewhat in the early days of the study. So stick with us and stay tuned. We're going to open up the call to Q&A. I believe we have some already queued up, and I'm going to hand it over to somebody much more capable of doing that. And what we'll do is, as the questions come, maybe we'll just sort of try to guide them towards the right speaker if it's not obvious.
Great. Thanks, Gene. So yeah, please hold for a brief moment while we poll for our questions. So our first question comes from Jay Olson at Oppenheimer. Please go ahead, Jay.
Oh, hey, guys. Congrats on all the progress. And thank you for hosting this educational event. We had a couple of questions. Are there any differences in the rate of Parkinson's disease progression between GBA1 mutation carriers versus idiopathic patients? And I guess, is the GBA1 mutation considered a prognostic factor for Parkinson's patients? And then we had a couple of follow-ups, if we could, please.
Karl, that's probably right up your alley.
Yeah. And Ken may have thoughts. Traditionally, the GBA-PD phenotype is thought to be slightly more severe than idiopathic and have more cognitive features and perhaps have a more rapid rate of deterioration. More looking at that data doesn't call into question how different they are. But if anything, they're slightly more cognitive impairment, maybe slightly more rapid progression. But it's not notably different. I don't know, Ken, if you feel differently than that.
No, I would agree with that and also just point out that there are a number of GBA mutations, some of which seem to be more severe than others. So there's a range of mutations and a range of how that influences the severity of illness. But I agree with Karl that typically, it's a little bit more severe than a typical PD individual.
Great. Thank you for that. And then based on the mechanism of GT-02287, how long would you expect it to take to see changes in UPDRS Part 2 or Part 3 scores, especially since other therapies like alpha-synuclein antibodies have taken a while to show separation fairly late in the course of treatment? And then depending on the changes that you do see with 2287, how would you distinguish between symptomatic treatment benefits versus disease-modifying benefits?
Yeah. I can take that one. So, I think those are two key questions, right? So I think we expect our drug to be more like Roche's alpha-synuclein antibody because presumably our mechanism is disease-modifying, and we don't see the typical acute effects that you see with the dopaminergics, for instance, or levodopa.
Now, the fact that we've seen some improvement at 90 days was somewhat surprising, so we don't really understand the mechanism behind that, but as I said before, it's not the typical fast effect that you'll see because levodopa, you see, in a matter of hours, right, and days. It's not that effect. It's something that takes longer that may happen inside the cell so that you have dopamine neurons that are not functioning well because of these pathway abnormalities, and then GT-02287 corrects some of that, and that over a matter of weeks enables those neurons to work better, right?
So that's a hypothetical explanation at this point. But I think to see a really robust effect, we have to look at much longer studies. So that's why the next study is a year and also the reason for the extension. I think that the question of symptomatic versus disease-modifying is also tricky because what you're trying to demonstrate here, I think, as I'm taking Karl's words here, is that you're making patients not get worse as fast, right? So you're not expecting an improvement, necessarily expecting them to, over a long period of time, not get worse as much as if they didn't take the drug. And that just by that inherent characteristic of the disease requires much longer trials.
Great. Super helpful. Thanks so much for taking the questions.
Great. Thanks for the questions, Jay. Our next question comes from Tom Shrader at BTIG. Please go ahead, Tom.
Can you hear me okay?
Yes, we can.
Well, I have such KOLs on the line. I kind of had a remedial question on alpha-synuclein. I think more about Alzheimer's disease. Is it closer to Aβ where there are all levels of pathology before you really have clinical symptoms, or is it closer to tau where if you're seeing alpha-synuclein, you're really in the steep part of the curve and it's time to treat? Is it known at that level yet?
Yeah, that's a great question, and I think I can answer it on a couple of levels. I think in some ways, of course, alpha-synuclein is like Aβ in that it occurs very early and that it is possible to have synuclein present for many, many years without any symptoms at all, and then ultimately, it will, in some individuals, lead to symptoms. On the other hand, it also has some similarities to tau in that unlike Aβ , which by the time symptoms arise is everywhere in the brain, synuclein is in specific locations in the brain and tends to spread like tau over time, and at that point, causing symptoms which seem to be related to the spread of the synuclein.
So I think we need to learn more about that, and the biomarkers that we have now and are acquiring will help us, but I think it also raised the point that really, as we think about neurodegenerative diseases, these proteinopathies occur often together. They have their functions and their malfunction is similar in different ways, and I think one of the real questions is why synuclein, why Aβ occurs in individuals as they age, so that's an important issue. And again, it's often the case that these occur as co-pathologies. And so maybe we should be thinking about neurodegeneration as a wider view, not so much as either AD or PD.
Okay. A couple of more clinical follow-ups. To follow on Jay's first question, just from what you know about these rating scales, is there anything you would expect to change first? Any leading indicators? And then you flashed a little bit of data very quickly. And I just noticed one of the patients, I think 003, 001, was up 10 in the first three months and then down 15. Is that kind of the inherent noisiness of the data? Do you really need a lot of patients to see an active drug? If a drug is clearly active in a meaningful way, how many patients do you think you need to see it, I guess, is the way, I guess I'd love an estimate for. Thank you.
I'll jump in on the clinical scales. Are they that noisy? Yes, especially in people who are already on dopaminergic treatment and how they respond to coming on and off. These are somewhat artificial states that we're measuring people in terms of practically defined off state. So yes, there is a lot of noisiness in the point estimate or the point measurements at any point in time, and we do power around that. So for drugs that are clearly effective in terms of symptomatic improvement, like dopamine agonists, which is not as powerful as levodopa, maybe 50 a group is the size you need to show changes.
Levodopa, you can show with half that because it's a monster effect. And that's short-term improvement. It's a little bit more complicated of how many do you need to show long-term less worsening, as Jonas was saying. And then again, the variability comes into play. But probably the effects there are going to be smaller. I mean, look at lecanemab and donanemab. These are 20% reduction in deterioration rates. You would hope for something more potent than that. But there are large numbers to be able to detect those kind of differences.
And then any thoughts on what is there any one scale or something that if you saw a change, you'd say, "Yeah, that's pretty meaningful"?
No, I think parsing the subparts of these scales, either two or three, to say that's the leading indicator from within the scale is not a fool's errand, but I think can be more misleading than informational. I don't know. Ken, you might feel differently about that.
I think it's unclear which of these, which of the parts is most effective. I mean, typically, you see greater change in Part 3 than Part 2. So you can so I think that's always encouraging and gets more widely used in that regard. But I don't know that there's a leading indicator that's reliable.
All right. Great. Thank you for all the details.
Thanks for the questions, Tom. Our next question comes from Boobalan Pachaiyappan at Roth. Please go ahead, Boobalan.
Hi. Can you hear me okay?
Yes, we can.
Awesome. Congratulations on the progress, and thanks for taking our questions. Two from us, firstly, talking about the treatment adherence rate, can you maybe discuss at a high level how does the treatment adherence rate in IPD patients compare to the GBA1-PD cases? And then I see that there's more than 50% opted to enroll in the open-label stage of the study. So assuming there is also treatment discontinuation in the subpopulation during the course of the therapy, what is the minimal sample size that must complete the nine months of treatment in order to get some preliminary thoughts on functional improvements?
Right. So yeah, I can take that one. So we have only had one participant discontinue so far, and that was a person with idiopathic Parkinson's. So we can't really tell if there's a difference between GBA and idiopathic. My guess is that the adverse events or the tolerability challenges that some of these people may experience are unrelated to the genetic background. That would be the most likely explanation or scenario. So, in that case, the discontinuation would be sort of a random event that a certain person has problems tolerating, has more side effects, right? We don't know how many of the people who continue into the extension for nine months. My guess is that if they all have tolerated the drug and some of them have improved over the course of three months, then they will be likely to stay on.
But part of that is our hope, right? We don't know yet. So, we'll see. And that's important information that we'll get from the study as well as adherence rates and attrition.
All right. Great. I have one question for KOLs. So how normal or abnormal is it for patients who are treated with investigational agents such as GT-02287 to show stabilization or improvements in UPDRS Part 2 and Part 3 in like 90 days? And how does the safety efficacy profile of 2287 compare to some of the other clinical agents that also target similar pathway like GCase? Thank you.
Maybe Karl can, just in your experience with other agents, how does GT-02287 sort of fit in terms of side effect? I think it's one of the things that people are trying to get at. Ken, you want to?
I mean, I can start. Yeah. So I think it is not common to see clinical effects at 90 days. And I think, as Jonas already mentioned, I think it's hard to interpret that. That's really why you need to really extend that period to really understand better if these changes are meaningful. I think the safety profile is a favorable profile so far. And of course, additional information will be acquired as the studies are expanded. But certainly, it's a favorable profile with regard to other tested drugs, yeah.
I Agree.
All right. Thank you.
Thanks for the questions, Boobalan. Our next question comes from Chad Yahn at Maxim. Please go ahead, Chad.
Hi, guys. Thanks. I'll be brief. So granted, it's still quite early, but do you think the motor improvements we're seeing point to lysosomal restoration in dopaminergic pathways, or could they just be downstream?
That's a question we want to know the answer to, right? So based on what we have seen in animals, the restoration of some of these pathways is fairly fast. We see a decrease in alpha-synuclein aggregation in the brains of these animals. And so, these are mice. We see an improvement in lysosomal function, improvement in mitochondrial function. But which one of those or which combination of those is the one that then leads to the behavioral improvements in animals, we don't really know because it's very difficult to correlate. And the same is true in humans, right? That's something we may never have the answer to, we may o nce we have biomarker data, we may see that certain biomarkers change more than others. Then we can at least hypothesize that those things are driving any clinical effects. But it's kind of an inscrutable question.
I will just say that interfering potently with the biologic process like might be happening here does, to your point, have the possibility to relieve synaptic dysfunction. It's a broad kind of category that Jonas was talking about, and relief of synaptic dysfunction could lead to either stabilization or actually short-term improvement, neither of which is a bad thing in the long run, as well as the slower deterioration, sort of stabilizing your background, so it may not be necessary, but it may be part of the treatment effect. I wouldn't confuse that with being "symptomatic." It probably has a longer time frame than dopaminergic drugs to see the relief of synaptic dysfunction. It may evolve over weeks, but that could happen if that's what you're getting at, Chad.
Got it. Thanks, guys.
Thanks for the question, Chad. Our final question comes from Ram Selvaraju at H.C. Wainwright. Please go ahead, Ram.
Thanks very much for taking my questions. Firstly, I wanted to ask if it would be possible, perhaps, for the KOLs to correlate impact on GCase the way, for example, a drug like GT-02287 is purported to act with the likelihood of impact on a particular stage of Parkinson's disease. So for example, would we consider a drug acting on GCase to be particularly beneficial in earlier stage or later stage patients, just based on the mechanism of action? Secondly, I was wondering if you could perhaps comment on where a mechanism like this, an intervention with a mechanism like this, might fit within the overall Parkinson's armamentarium, in particular when we think about other drugs that are used to typically manage Parkinson's disease, where this drug might fit best with what additional existing approved medications it might synergize best?
And then lastly, maybe it would be possible to comment briefly on the mode of improvement that we are seeing so far and correlate that perhaps to some of the animal evidence, some of which, if my memory serves me correctly, did indeed not only point to the potential for this compound to slow disease, but also potentially even reverse certain symptoms of disease. And I was just wondering whether the KOLs might venture an opinion on what the likelihood is of potentially seeing some kind of symptom reversal or functional recovery as we go further into clinical investigation with the compound. Thank you.
Go ahead, Ken.
So those are three great questions. Now I've already forgotten the first and the second one. But I think at what stage might this be useful? I think it's, of course, hard to predict that, but I think typically, it is kind of likely that at an earlier stage of disease before degeneration has occurred, this strategy, in fact, like other strategies, might be more useful. That's not to say it could not be useful later, but I think that would be what I would suspect would be the case. I think that now I have really forgotten the second question, but the last question is really related to could this result in a reversal of symptoms? Certainly, that's possible, as Karl just mentioned. If this really does affect synaptic dysfunction, theoretically, that would be so.
My guess, it would take some time for that to happen. But I think that would be a wonderful thing. But I would just point out that even the slowing of progression or the stabilization of illness would be a remarkable effect that would be really of great value for patients. So I think why we'd like to see a reversal, even without that, it would be very valuable.
Yeah. I think hoping for improvement might be too much. And there's kind of this yin and yang of the impact of treating very early is going to be greater. You're going to be able to spare more neurons. Going early is the optimal strategy. But from the pragmatic point, it's hard to measure things very early because very little is moving. So you'd rather get a little later so that you have more signal to measure that things are deteriorating or stabilizing, even though there's more neurons lost. So there's this tension between going early and late. And you try to find the right spot in there where people are not too far gone. So you really don't want to.
This is probably not a drug for people who have already had major complications. They're demented. They're far on into their disease. It's probably not the right. But everything before that, it makes sense because it could help stabilize them, potentially improve them, and try to drive towards the earliest stages to do the most preservation that's possible.
Yeah. I would agree with exactly what Karl just made one other point, which is that as we are moving toward a nearer where we may well have biomarkers that move prior to the onset of symptoms, it may open up the opportunity to really see more of a change due to therapies, even at these earlier stages. So that's just another option as we move forward. I think, again, I would agree that this mechanism could easily work later as well. But I think that it's always a good idea to try to stop the process as soon as you can after you know someone has the biology that's going to lead to Parkinson's disease.
And, Ram, I can follow up on that a little bit by just saying that coming out of the MDS conference where we just were presented some of Jonas's clinical data there, that there was, in some cases, there is an emphasis in trying to relieve the dependency on dopamine derivatives. And if we can affect some of that by creating a situation where patients need less dopamine over time and over duration, then I think this would be a very, very successful compound, unless you guys would disagree with that. But I took that away from the MDS conference, that there's a lot of emphasis on trying to relieve patients from the need for dopamine.
Okay. I believe we are out of questions, and we're a little over time. I want to thank everybody, particularly Dr. Marek and Dr. Kieburtz, for joining us today and doing their best to lend some insight on our clinical program. And Jonas, of course, for his help as well. And all of your participation, time, and interest is all greatly appreciated. And we look forward to getting in front of you very, very soon with some more exciting data.