Summary:

At the Annual Neuro Perspectives Virtual Conference hosted June 27th, H.C. Wainwright hosted a Fireside Chat with Ram Selvaraju, a Senior Healthcare Equity Research Analyst, and Gene Mack, CFO of Gain Therapeutics (NASDAQ: GAPX). They discussed Gain's innovative drug discovery platform and its lead candidate, GT-02287, targeting Parkinson's disease without or without a GBA1 mutation. Gene Mack shared his background in neurology and clinical research, highlighting the platform's unique ability to design small molecules for precise drug-target interactions. The chat covered Gain's focus on Parkinson's, especially the GBA1 subset, and promising preclinical results. They also touched on Gain's broader pipeline, recent equity offering for clinical trials, and global operations.

 

Watch the full video.

Full transcript:

 

Ram Selvaraju: Hello and welcome to the latest in our series of Fireside Chats here at H.C. Wainwright's neurologically focused conference. My name is Ram Selvaraju, and I'm a Managing Director and Senior Healthcare Equity Research Analyst here at the firm. I'm joined here by Gene Mack, recently appointed Chief Financial Officer at Gain Therapeutics. Gain currently trades on the NASDAQ under the ticker symbol GANX. We cover Gain with a buy rating and a 12-month price target of $9. Gene, it's a pleasure to have you with us.

 

Gene Mack: Thanks, Ram. Thanks for having us.

 

Ram Selvaraju: So maybe we could start with some of the reasons that prompted you to join Gain, in particular with respect to the company's commitment to innovation, its unique drug discovery platform, and its lead candidates, most notably the one focused on Parkinson's disease.

 

Gene Mack: Yeah, sure. So, it's an interesting story how I wound up at Gain. I've been a Chief Financial Officer for 10 years at various different companies, and prior to that, much like yourself, I was a senior publishing analyst covering life sciences, biotech, and pharmaceuticals for about 15 years. I got to know lots of management teams, and they've gone off to be on boards in some cases, and two of those, there's two individuals on Gain's current board that introduced me to the company back from when I had relationships with them from the sell-side, which was interesting. And then, on top of all that, early, early, early on in my career, I guess you could say prior to becoming a biotechnology analyst, I was doing clinical research in neurology at Columbia, New York, at New York Hospital Columbia, in the College of Physicians and Surgeons.

So neurology and neurodegenerative diseases are sort of near and dear to me from an early point in my life, and I feel like I have a good understanding of those, and that, combined with some relationships I had at the board, made this a very easy fit for me.

 

Ram Saraju: So turning to Gain's discovery platform, which is focused specifically on a unique approach to the design of de novo small molecules, what would you say is particularly differentiated about it, particularly in the context of what we have been hearing more and more about regarding the application of artificial intelligence and supercomputing to drug discovery and design?

 

Gene Mack: Yeah, so I have to admit I don't understand all the aspects of our drug discovery platform, but it is very impressive and unique, and I've seen demonstrations of the permutations that it goes through as it tries to link these unique binding sites on drug targets with structures of molecules that can then be built to fit and balance those binding kinetics that you really, really want. So what does all that mean? Well, we have this ability, based on a lot of coding that has been done over the last couple of years, where we fused a couple of platforms together, one being a physical chemistry type of application and another one being an actual drug-targeting sort of platform. The two work together to find unique binding sites on drug targets that can then house structures that are possible to build, and then once you do that, hopefully you have a drug that or a drug candidate that more or less has a higher likelihood of success both through clinically and clinically.

 

Ram Selvaraju: And could you perhaps explain the principle of allosteric modulation for our audience?

 

Gene Mack:  Sure. So, particularly on proteins, proteins in the body when they are circulating around cells, they have active sites. That's the part of the enzyme that's actually doing the work that it's meant to do. Some molecules can bind there and either make that active site more active or less active if it's something that they want to turn off. An allosteric molecule is something that binds on a protein or an enzyme, not at the active site, but at some other non-active site of the protein, and usually it keeps a certain conformational change from occurring in that protein. In the case of GT-02287, we are an allosteric binder to an enzyme called GCase, and as a result of the allosteric binding, we're able to keep GCase in its conformational shape to make sure it stays healthy while it traffics through the cell performing many, many tasks.

 

Ram Selvaraju: And it would not be inaccurate to say that allosteric modulation is an elegant way of effectively achieving not a direct on-off switching approach but rather a sort of, shall we say, dimmer approach, where essentially you don't necessarily turn on entirely or turn off entirely an enzyme's activity profile or an enzyme signaling, but effectively you modulate the enzyme's activity in a gentler, more tunable way. Is that correct?

 

Gene Mack: Yeah, and it's really interesting. You can construct these molecules that do this very fine-tuning, as you're describing, and that's one of the things that the Magellan platform, that we have as our drug discovery platform, seeks to achieve. So with respect to Gain's pipeline at this juncture, you're now a clinical-stage company. The company has multiple therapeutic molecules in different therapeutic areas, but as you pointed out earlier, one of the principal focus of Gain is the neurodegeneration field, and in particular, Parkinson's disease.

 

Ram Selvaraju: Tell us a little bit more about how Gain selected Parkinson's disease as a field within which to work, and in particular, GBA1 Parkinson's disease, and what demarcates GBA1 Parkinson's from the broader Parkinson's indication.

 

Gene Mack: Sure. So first, let's talk about why Parkinson's first. So GT-02287 binds to GCase. GCase is an enzyme that is implicated in the progression of Gaucher's disease as well as neurodegenerative diseases like Alzheimer's, well, more dementia with Lewy bodies related to Alzheimer's and Parkinson's disease, so three different but two different neurological diseases there in terms of Alzheimer's and Parkinson's. We've chosen to focus more on Parkinson's versus Gaucher's or Alzheimer's simply because we felt that, as a small company, we'd be most likely able to drive the clinical development of GT-02287 to a more advanced position before we might have to entertain significant interest from partners because we want to control the data package from GT-02287 as long as we possibly can, so Parkinson's is where we focus first.

As far as where we are in the Parkinson's spectrum, it's interesting because we're learning that Parkinson's is a very heterogeneous disease, and it's not, you know, it doesn't have a single pathogenesis or pathophysiology. In fact, it can be broken out, and I think we'll gain more appreciation for this as more work is done in the area, into several different types of Parkinson's disease. GBA1 Parkinson's disease is one such subset of Parkinson's disease that is driven by a genetic mutation in the GBA1 gene. Patients who are heterozygous or homozygous for this gene mutation have dysfunctional GCase, that enzyme that we're talking about. GT-02287 is meant to correct that mutation, although it doesn't impact the gene site, it impacts the expression of the enzyme.

So the patients that develop GBA1 Parkinson's disease, and it's about, in the literature, if you go across the literature, it's anywhere between 10 and 15% of all Parkinson's patients. There are some ethnicities and geographical areas that we're learning have a higher propensity of this mutation. It's just something we're going to have to think, just something we're going to have to learn more about as we learn more about GBA1 Parkinson's disease. But it impacts up to 10 to 15% of the Parkinson's patients who wind up with Parkinson's disease, and unfortunately, with this type of Parkinson's, it is a more aggressive form of the disease, and the progression is faster and more aggressive with patients. So we really are hoping that GT-02287 can make an impact here first, but it also seems as though we may have some application in idiopathic Parkinson's, which is the broader set of Parkinson's patients as well.

So turning now to the clinical data that's been generated with GT-02287, some of this is particularly exciting because of the potential for this molecule to actually reverse the cognitive decline and motor symptoms associated with advanced Parkinson's disease. And in particular, I would note, for those in our audience who may not necessarily be as familiar with Parkinson's, it does afflict over a million people in the United States alone. It is considered a relentless degenerative disease that currently has no cure, and it has historically been treated primarily with either dopamine agonists or supplementary provision of exogenous dopamine through things like levodopa and carbidopa, as well as those molecules that are aimed specifically at addressing the side effects of long-term dopamine supplementation, such as something called dyskinesia.

 

Ram Selvaraju: So clearly, a molecule like GT-02287 would be advantageous because not only could it potentially reverse the symptoms of Parkinson's, but it would not work the same way as dopamine agonists do. It would not carry the same side effect profile as dopamine agonists. Is that correct?

 

Gene Mack: That is very correct, Ram, and you've described it very, very well. And, you know, I would sort of round up what you've said as sort of like, yes, everything, most of the advances in Parkinson's disease have been focused on these sort of symptomatic aspects of the disease.

They don't get to the underlying mechanism of the disease and what is causing it, and GT-02287 hopes to achieve just that. Again, we are protecting that very, very important GCase enzyme as it traffics throughout the cell, and it performs multiple different types of functions in the cell. And if you give me a minute, I can describe sort of why that's important. As the GCase enzyme is expressed, you know, its role is to get out of the endoplasmic reticulum and into the lysosomes and into the mitochondria, where it performs a whole bunch of housekeeping activities, and it's just like any other house. If one room of the house is messy and not clean, it sort of gives you this overall appearance of uncleanliness, and the cell works much the same way.

All the compartments have to be working well, and this housekeeping has to occur in all these very important organelles of the cell, and our GT-02287 chaperones the GCase enzyme as it goes through its traffic pattern in the cell to do all these tasks. And we see in our preclinical models all of this evidence of ER stress reduction, GCase activity increase, mitochondrial functional increase, lysosomal functional increase. So all these things that are shutting down in the pathogenesis of Parkinson's disease are being reversed by GT-02287, and it's that unique binding aspect that we were able to find with the Magellan platform that gives us the ability, we think, more than even our competitors, to be able to protect the enzyme throughout its route through the cell.

 

Ram Selvaraju: And with regard to the specific animal data that, in your view, appears to be most compelling at this juncture, you know, this was recently presented earlier this year, and I think it would be helpful for our audience to better understand, you know, what you're seeing in an actual animal model of disease that might be predictive of the clinical efficacy profile.

 

Gene Mack: Great, yes, great, great question. So while animal models, and I'll preface my answer with saying, you know, no animal model is perfect, right? So, you know, we do the best we can with what we have, and there are very well-accepted animal models of Parkinson's disease, and we use one rat, one such model of rats, where you can induce Parkinsonian disease progression with the use of a compound, and what we find is that when we deliver GT-02287 to these mice, it restores their normal function. So what do I mean by that? Well, there are motor tests and there are cognitive tests that you can perform on mice. One such motor test is what's called a wire hang test. When we induce Parkinson's disease in mice, and we allow them, and we induce them to hang on a wire, they actually literally hang on a wire.

They're not able to hang on to this wire for more than 20 or 30 seconds. When we give them our compound, they're able to hang on this wire for five minutes, at which point they're taken off, but it shows that they're restoring their motor function. They're not able to hang on when they have the symptoms of Parkinson's disease because they just don't have the motor control, they don't have the strength to do so, and when we give them GT-02287, that function, that motor function, is restored. From a cognitive perspective, there's an interesting test you can do with mice, where you give them the materials to build a nest in their cage, and what you find when you induce Parkinson's disease is that the nest is very, very disorganized. The materials are scattered all over the cage, and it's just completely disorganized and not very functional. When we administer GT-02287 to these same mice, they're able to take the material and build what would be considered a very well-organized nest, which is a sort of good marker of some cognitive and motor function, aspects of daily living that we would consider for human beings, being able to organize their space and live in it.

 

 

Ram Selvaraju: And the molecule itself, in these tests, is being applied therapeutically, in other words, after the animals have developed symptoms, is that correct?

 

Gene Mack: That's correct. They're given the inducing agent, which binds to GCase and therefore shuts its activity down, and then our compound is administered after.

 

Ram Selvaraju: And you have some important information coming at this upcoming Federation of European Neuroscience Societies meeting, the FENS Forum in Austria at the end of this month, where you're going to be presenting additional details regarding the procognitive benefits of GT-02287, is that correct?

 

Gene Mack: That's exactly right. So a couple of weeks ago, our presentation, we submitted our abstract, was accepted as a late-breaker presentation for that particular conference, where we will show the data behind that cognitive improvement that I described with the mice and their nest building, so we're really excited about that.

 

Ram Selvaraju: And in parallel, of course, the compound is currently in clinical development actively, and is currently being studied in a Phase 1 single ascending dose and multiple ascending dose trial, the SAD portion of which has already been completed, is that correct?

 

Gene Mack: That's correct. We have completed the SAD portion of that trial, and we are almost at the close of the MAD portion of the trial, the multiple ascending dose portion of the trial. All side effects have been considered mild, and no stoppages related to GT-02287, and no significant adverse events related to GT-02287, so we're really excited about the safety profile that is emerging.

 

Ram Selvaraju: And this is a once-daily regimen, correct?

 

Gene Mack: That it is, one daily regimen, correct. Well, it's one daily, yes, one daily. Now, we are considering potentially dividing doses later, you know, in future clinical trials, but for now, it's just once.

 

Ram Saraju: And at the conclusion of the multiple ascending dose component of the trial, you would effectively be in a position to identify the optimal dose, or maybe a couple of doses, to assess in a Phase 2 context in actual GBA1 PD patients, is that correct?

 

Gene Mack: We believe that. So, prior to running that Phase 2 trial, we are going to do a very important biomarker study, that will be a Phase 1B proof-of-concept study, where we will be administering the, right now, the single ascending and multiple ascending dose Phase 1 trials are being conducted in healthy individuals, so we don't get to see much about the GCase activity enhancement that we're hoping for, since these people presumably have healthy GCase activity. But in a small pilot Phase 1B that is in planning stages now, we're going to get to understand some of the biological activity of GT-02287 in actual GBA1 Parkinson's patients, which we're excited about, and hopefully going to see some important data that help inform our Phase 2 trial timing.

 

Ram Selvaraju: And I'm assuming that once you begin assessing GT-02287 in actual Parkinson's patients, in all likelihood, the principal outcome measure of interest with respect to measuring the efficacy profile of the compound is going to be the Unified Parkinson's Disease Rating Scale, or would you look at other outcome measures as well?

 

Gene Mack: We will absolutely look at other outcome measures as well, but we will use the generally accepted primary endpoints for this.

 

Ram Selvaraju: And I think it would be important to emphasize for our audience that, of course, given the fact that multiple drugs have been brought forward in Parkinson's disease already, there are very well-established drug development paradigms in place for the study of investigational compounds, and therefore, in the long run, looking at selecting the appropriate efficacy outcome measures should not be a particularly onerous or complicated task. And certainly, if you see statistically significant, robust, and clinically meaningful impact on those outcome measures, this should readily meet with the authorization and approbation of the appropriate regulatory authorities.

 

Gene Mack: Yeah, absolutely. There are generally accepted and regulatory guidelines for Parkinson's Disease patients. We expect to show activity there. The other types of endpoints we'd look at would be to just further our understanding and elucidate GBA1 Parkinson's disease a bit more, further elucidate our understanding of the disease in general.

 

Ram Selvaraju: So while we have the remaining few minutes, maybe you could talk a little bit about the other pipeline programs. In particular, you mentioned earlier dementia with Lewy bodies, which is clearly a very closely related medical condition to Parkinson's disease, in many ways also involves protein misfolding, neurodegeneration, and progressive decline. But you also mentioned Gaucher's disease, which is a very well-known lysosomal storage disease, which is currently treated with very expensive enzyme replacement therapy. And I think you're also looking at potentially other enzyme replacement therapy-related disorders, other lysosomal storage diseases. I think you're also looking at, if I remember correctly, alpha-1 antitrypsin, among other things. So maybe you could talk a little bit about the rest of the pipeline and what ongoing developmental work is being done in those areas, as well as what we might expect going forward in the future from Gain.

 

 

Gene Mack: Sure. So, with GT-02287 itself, yes, you pointed out very, very important areas where we hope to expand the application of GT02287. Right now, as I said earlier, we're focused on Parkinson's disease, but given the current state of Gaucher's, where patients endure some pretty invasive infusion-type treatments, we think that if we can administer this orally, it will give patients a much more convenient, more tolerable treatment for their disease that will translate into the same efficacy. We are, at the moment, in preclinical stages of development there.

Those diseases are related in the sense that they are GCase-related diseases, but they're separate patient populations, so you have to enroll them separately. In the case of dementia with Lewy bodies, again, that's a neurodegenerative disease, but a separate sort of patient enrollment and set of endpoints. So, there's no way to do all these at once, and our aim is to show that the drug is safe and effective in GBA1 Parkinson's first, and then broaden the expansion of GT-02287 through a battery of additional Phase 2 trials in these disease indications. As far as things like Gaucher's disease and alpha-1 antitrypsin, we are developing other compounds for these diseases.

We also have some in oncology as well. These are still in sort of the lead optimization stage, though, in preclinical development. And being a small company with limited capital reserves, we are focusing our primary effort right now on GT-02287 and validating our drug development capabilities before really expanding the rest of the pipeline into clinical development. So, again, just to reinforce, obviously, with something as potentially transformational as GT-02287, even when considering the potential applicability of this drug just as a treatment for GBA1 Parkinson's disease, there is potential blockbuster opportunity for that molecule. And all of these other candidates clearly showcase the breadth of applicability of the Magellan platform. We're really looking forward to around this time next year when we'll have the first available data from that Phase 1B biomarker study that I mentioned earlier. We think that's going to be a very, very important milestone for the company and a value inflection point for GT-02287.

 

Ram Saraju: Lastly, since you're the newly appointed Finance Chief, we could talk a little bit about the company's most recent announcement on Friday of the completion of an equity offering and what that does for the company's balance sheet and operational runway, as well as enumerate the potential value inflection points and value-driving catalysts that you expect the company to be able to deliver within that time frame.

 

Gene Mack: With the $11 million that we added on Friday, we believe we have about a year and a half's worth of cash now, which fully funds that Phase 1B trial I was talking about. This was something we started planning earlier this year and realized that we wanted to probably raise a little bit more financing on our balance sheet to make sure that we were able to deliver on that milestone. So, we will get to the end of 2025 with the financing that was announced on Friday, which we're excited about.

 

Ram Saraju: Within that time period, between now and the end of 2025, you anticipate being able at the very least to complete the multiple ascending dose portion of the Phase 1 study, as well as this Phase 1B biomarker study, which, if positive, would obviously put you in a very favorable position from which to begin Phase 2 development in actual GBA1 Parkinson's patients. Is that correct? Would you want to highlight for our audience any additional salient aspects of the company at this point?

 

Gene Mack: I think we're going to try to have a healthy presence at conferences, both scientific and investor conferences, over the next 6 to 12 months, so that we can explain what we're doing with the Phase 1B trial and how important it will be in Parkinson's in general. Very little has been done in this patient population in terms of therapeutic advancement, and we think that the work we're doing right now is going to be important for the field itself, so we're excited about that and Phase 1B.

 

Ram Saraju: Maybe you could also give our audience a flavor of the international exposure of Gain. This is, for all intents and purposes, a Swiss company, but you also have a significant presence in the Barcelona biotech hub, do you not?

 

Gene Mack: That's correct. We have founders that were based in Switzerland, in Lugano, and part of our CMC and finance and HR operations are based in Lugano. We also have a scientific R&D facility in Barcelona, Spain, which is a very efficient group working really hard on some of those earlier-stage programs that we talked about. Additionally, we have a United States-based headquarters, so we are fairly global relative to a lot of other biotechnology companies our size in the United States.

 

Ram Saraju: Well, thank you very much for a very informative discussion, and thank you also for taking the time to explain the Gain story further for our institutional investor audience. I want to thank you very much once more for your participation in our conference, Gene, and I very much look forward to what Gain is likely to deliver next, both on the clinical as well as the preclinical side. I certainly look forward to your having an excellent and productive conference at the end of this month in Vienna.

 

Gene Mack: Thanks, Ram, and thanks for letting me discuss Gain with you.

 

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