RARE Daily

A Company in the Fold of Rare Disease

September 21, 2023

Protein misfolding is an underlying issue for many diseases, including lysosomal storage disorders and some neurodegenerative conditions. When a protein misfolds, its three-dimensional structure is disrupted, and it can no longer function properly. Gain Therapeutics is using its AI-driven discovery platform to identify novel targets to fuel a pipeline of therapies that focus on enzymes involved in rare genetic diseases, but that also share genetic profiles with more prevalent ones. We spoke to Matthias Alder, CEO of Gain Therapeutics, about the role protein misfolding plays in a range of diseases, Gain’s platform technology, and its lead experimental therapy in development to treat Gaucher disease.

Daniel Levine: Matthias, thanks for joining us.

Matthias Alder: Hi Danny. Thanks for having me.

Daniel Levine: We’re going to talk about Gain, misfolding proteins, and the potential to use small molecule therapies for serious conditions where protein misfolding is at the root. Let’s start with protein misfolding. What’s the relationship between the shape of a protein and its function?

Matthias Alder: What we know about proteins is that they’re expressed by a gene and they go through a transformation. These are not static objects in a cell, but they’re their able to move and modulate themselves in terms of their shape. And proteins, in order to actually exert the function that they have, whatever that may be in a particular cell or biological process, they need to have the proper form and shape in order to exert that function. So that’s a normal protein properly folded and is able to exert the activity that it needs to.

Daniel Levine: Well, what happens biologically to cause a protein to become misshapen?

Matthias Alder: That’s obviously a good question. There’s not a single reason for that to happen. We know that in the cell there is a protein quality control system. The job of that quality control system is to remove misfolded and dysfunctional proteins, and that exists in every cell. And so even in normal cells it occurs that a protein that is expressed by a gene turns out to be not working properly and is misfolded and then it gets degraded and removed by that protein quality control system in the cell. Now in diseased cells, whether it’s not working properly because there is something not going right in that cell, the origin of that dysfunction can be a range of different causes. It could be just general aging and some kind of inflammatory process that happens in a cell that causes ultimately a protein to not work properly and be misfolded. But very often it is actually a genetic mutation. So, the gene that expresses a protein ends up somehow having a mutation and as a result expresses a misfolded and dysfunctional protein.

Daniel Levine: I can think of both genetic and infectious diseases where protein misfolding is implicated. What happens in these cases and is there any sense what percentage of these conditions have a genetic root, or are there other causes that might be at play?

Matthias Alder: I couldn’t really quote you a specific percentage. We know that most rare diseases are caused by genetic mutations that occur rarely, but have an effect of causing pathology in a patient. In terms of the numbers, it varies. Obviously rare diseases are rare and so it doesn’t affect that many people. Nevertheless, these are very devastating diseases that are worthy of being pursued and looking for treatment. That’s one of the missions that we have here at Gain.

Daniel Levine: Gain’s developing a pipeline of therapies that focus on enzymes involved in rare genetic diseases but that share genetic profiles with more prevalent diseases. You’re looking at a broad set of indications, but a number of different lysosomal storage disorders including Gaucher, GM1 gangliosidosis, and Krabbe. Let’s focus on your work around Gaucher. For listeners not familiar with it, what is it?

Matthias Alder: So Gaucher disease is a rare disease caused by a mutation of a gene called the GBA1 gene. It occurs in a small number of children, a childhood disease, and it takes different forms. So there is different types of Gaucher disease depending on what the manifestations of the disease are. There is a Gaucher disease type 1, which primarily shows up in different organs of the patient and results in organ dysfunction, be that the spleen or other organs. There are also Gaucher type 2 and type 3, which are where the organ that’s implicated is actually the brain. So, this is also called neuronal pathic Gaucher disease. And so there the manifestations are just development deficits, cognition deficits in these patients as a result of that genetic mutation that causes the expression of a dysfunctional enzyme that plays a critical role in the cell system.

Daniel Levine: So, there are enzyme replacement therapies for some of these lysosomal storage disorders, including Gaucher. How effective have they been?

Matthias Alder: These enzyme replacement therapies are actually quite effective and you see patients who are treated with these enzyme replacement therapies actually living full lives way into their adulthood. The issue, the problem with these enzyme replacement therapies is that they are not able to cross the blood brain barrier. So, while they work for Gaucher type 1 where the impact of the disease is shown in various organs other than the brain, they don’t work for Gaucher type 2 and type 3 where the primary effect of the disease shows up in the brains of patients. And so these are the patients who currently do not have any available therapies and that’s also the area that we’re focusing on with our program.

Daniel Levine: And in terms of the treatment regimen, how much of a burden is that on patients?

Matthias Alder: I guess it is a burden because it’s repeated injections—they have to be repeated on a regular basis. It obviously beats the alternative. If you are on the enzyme replacement therapy and it works, I think you are able to actually manage the manifestations of the disease in Gaucher type 1. And so that’s why there is actually a high level of patient adoption and persistence. In terms of sticking with the treatment for Gaucher type 2 and type 3, as I mentioned, there are no current therapies out there, but what we’re doing at Gain is we’re developing a small molecule therapy that crosses the blood brain barrier and can be administered orally, so like with a pill. So that’s a very low burden on the patient for taking that therapy once we get it into patients in the next phase of clinical development.

Daniel Levine: You’re targeting the GBA1 gene in your experimental therapy for Gaucher. You’re targeting the same gene in your treatment for Parkinson’s disease. What’s the relationship between these two conditions and are you using the same drug for both of these indications?

Matthias Alder: So yes, GBA1 is the gene that is the main focus right now in terms of our therapy. We’re not actually a gene therapy, so we’re not actually acting on the gene itself. What we’re doing is we are acting on the enzyme that is expressed by that gene and if that gene is mutated, the enzyme that’s called G-case expressed by the GBA1 one gene is misfolded and [becomes] dysfunctional. And what we are doing with our small molecule therapies is we’re binding to that misfolded enzyme, stabilizing it such that it survives that quality control system in the cell that I had mentioned before. And as a result, that enzyme is able to get into at the place in the liver it needs to do its perform its function, which is to remove toxic materials from the lysosome, which is the waste bin of the cell. And binding to that enzyme with our small molecule ensures that it can get to the right place and perform its job, which is to remove toxic materials from the cell. And as a result, we’re restoring a healthy cell that survives and as a result we’re able to interrupt the disease process and it gives us the potential to slow or even stop the progression of the disease with our therapy.

Daniel Levine: So, in Parkinson’s disease, are you saying that same toxic accumulation in the lysosomes?

Matthias Alder: Yes, and in fact in Parkinson’s disease, Parkinson’s disease also is heterogeneous. So there are different factors that ultimately can cause the development of Parkinson’s disease symptoms. What we’re focusing on initially is on the portion of Parkinson’s patients who have a mutation of that GBA1 gene and it’s the same gene that we’re seeing in Gaucher disease and the same enzyme that we’re targeting. And in fact it’s the same molecule that applies to both Gaucher disease and Parkinson’s disease.

Daniel Levine: Before we talk about the drug itself that’s in development, I thought it might be useful to explain a concept in lay terms for listeners. What is an allosteric enzyme?

Matthias Alder: So, if you’re thinking about a protein in a cell, it has a job to play. That’s why it’s there. And it gets either activated or inhibited by a natural binder that exists in the body that goes to that protein and binds to what is the active orthosteric binding site. That’s the normal binding site and the current therapy of a protein and current therapeutics, small molecule therapeutics, try to act on that active binding site—that orthosteric binding site–that either displaces or enhances the activity of the protein by binding to that active binding site. Gain has actually a very unique discovery platform, drug discovery platform, computational based, that allows us to scan the surface of proteins and find binding sites for small molecules that are not the active binding site, but any place else on the protein surface and any binding site that is not the active or orthosteric binding site that is called an allosteric binding site. And so, what we’re doing with our small molecule here is actually quite unique, and enabled by binding to that allosteric binding site, is stabilizing that protein by binding to that allosteric binding site and as a result restoring and causing a gain of function of that protein, of that enzyme. And that’s gain of function, Gain Therapeutics. That’s actually the origin of the company name.

Daniel Levine: Walk me through your platform technology. What is the starting point? Do you begin with a target protein?

Matthias Alder: Yeah, so it computational, it’s a drop discovery platform based on computational models. It allows us to predict binding sites on proteins, or allosteric binding sites, as well as finding through virtual screening small molecules that bind to those novel binding sites. And as a starting point, the only thing we need is a 3-D structure of a protein and these 3-D structures of a protein that we use as a starting point for working on the protein with our modeling system can be either one that is derived experimentally. There are experimental methods like Cryo-EM crystallography and things like that that allow you to see the 3-D structure of a protein. There are at this point also AI-based models that predict a 3-D structure of a protein based on the 1-D amino acid sequence. And these are actually very powerful AI tools that have a very high predictive value of what the protein ultimately looks like. So, for example, Google set up a company called DeepMind and they developed this open source database or tool where you can enter a DNA sequence and it creates, ultimately it gives you the shape of that protein. And so, we can use either an experimentally derived structure or an AI-derived structure as a starting point and then we’re investigating the surface of that protein with our models, which are actually physics based. So we’re not using AI directly to look at the protein surface and find these novel binding sites. We’re using a physics-based approach, very tangible, very practical, looking at the binding energy of our molecular probes on the protein surface and as a result, in getting a very good idea about where are the most interactions of our molecular probes with a protein surface and which are potential hotspots and binding sites that we can exploit for pharmaceutical intervention. And then we take that binding site that we have identified—that predicted one—on a protein model, but running then a virtual screening process that allows us to find small molecule structures that bind to that binding site. And then we take these, once we find these binders, we take about, of the thousand or so that we typically find in a screening campaign, we take about the 100 that we believe are most suitable for pharmaceutical development and test them in real life experiments because what you’re getting from a computational drug discovery system is really a prediction of binding and effect. And you need to obviously then confirm that in real life experiments.

Daniel Levine: I don’t have a problem imagining a misfolded protein or what its correct shape should be, but what is a small molecule drug doing to take a misfolded protein and get it to conform to its proper shape?

Matthias Alder: Typically, what we have with our model, it’s actually a molecular dynamic model. So the protein that we’re investigating in our platform is moving around as it does in real life in a real cell. And so if you have a misfolded protein, you need to find the conformation of that protein that when you’re binding at a specific spot on that protein surface, it creates a tether, like a break or something. It prevents the protein from going into its misfolded shape and that’s essentially what we can do with allosteric binding sites and small molecules that bind there. You bind anywhere in the protein surface, you look at where it binds and you find a small molecule that binds there and stabilizes that protein in the proper conformation that then allows that protein to go on and do its job as we’re doing with our enzyme target protein G-case.

Daniel Levine: In the case of Gaucher, what is your experimental therapy?

Matthias Alder: Well, in the case of Gaucher, so it’s the same as in GBA Parkinson’s disease. So, we’re looking at both. It’s the same small molecule that binds to that G-case enzyme that is misfolded as a result of a genetic mutation of the GBA1 gene. In Gaucher patients that is a homozygous mutation. So both alleles are impaired and have a mutation and as a result it’s actually a more severe form. Gaucher disease is a more severe form of Parkinson’s disease and occurs early in the lives of these patients in childhood, whereas in Parkinson’s patients that have that genetic mutation, it’s a heterozygous mutation. So only one allele is mutated, which means it’s a milder form of that same disease mechanism, that same disease process. And as a result it shows up much later in the lives of these patients and Parkinson’s you typically get in your sixties and seventies much later in your life.

Daniel Levine: Well, what’s known about it from the studies you’ve done to date?

Matthias Alder: What we’ve been able to do with our small molecule is essentially prove out preclinically both in cell-based models and in animal models, the full mechanism of action that we have that we’re predicting here. So, what we have shown in our assays and models is that with our small molecule we’re binding to G-case. That’s the enzyme expressed by that misfolded GBA1 gene. So we have evidence that we’re binding there, we have evidence that we are increasing the levels of that enzyme in the cell, which means the degradation process is prevented. So we’re protecting that enzyme from degradation in the cell. We also have shown that we bring more of those enzymes into the lysosome, which is the waste bin of the cell where that toxic material aggregates and the job of G-case is to remove that toxic material. And so, because we have more G-case enzyme going into the lysosome, we then have also shown that in the lysosome we are actually eliminating the toxic materials that are building up and as a result we’re seeing increased cell survival, reduction of inflammatory markers, a reduction of inflammation, which means we have healthier cells and in the Parkinson’s animal models that we have run, we have also then showed behavioral improvements of the animals who have received our therapy. So, we’re seeing from the beginning, from binding to the G-case enzyme to ultimately the effect of having a restored function of that G-case enzyme. At every step of the way, we have proof that the drug works as predicted and as expected.

Daniel Levine: What’s the development path forward?

Matthias Alder: So, we are just about to kick off our first clinical study with this molecule, so it’s an exciting time for us. We are transitioning the company from a research and preclinical biotech complex to a clinical stage biotech company. We just had our quarterly report that we filed and we announced that we have filed the application, the dossier, with the ethics committee that it needs to approve the start of the phase 1 clinical study and we expect to be able to kick off that phase 1 clinical trial in the coming couple of months.

Daniel Levine: Gain went public in 2021, it raised $46 million as a preclinical company. Why did you decide to go public at such an early stage rather than going the venture capital route?

Matthias Alder: Yeah, it’s a question we get a lot and people always have the present situation mind. If you’re looking at capital markets, at the time Gain went public, this was a very robust market for biotech investing and you had numerous preclinical stage biotech companies accessing capital on the public markets. Essentially the IPO is just accessing capital, bringing in money into the company to advance the activities and the programs that we have. And because it was possible to do that in the public markets at that point in time, that’s the path the company chose to pursue and we were lucky, at the back end of the big hype that happened in biotech during the pandemic, we were able to tap into that, raise that $46 million and still today we’re actually working with the money we raised during the IPO and still have a cash runway into the third quarter of 2024—still very robust, which allows us to actually complete that phase 1 clinical study.

Daniel Levine: Gain went public at $11. The stock is trading around $3.50, $4 today. What’s the conversation with investors?

Matthias Alder: Yeah, I think everybody appreciates and understands the share price dynamics and market dynamics that have occurred since 2021. We essentially went into a deep freeze, a flight of generalist investors from biotech after the Covid exuberance dissipated. And we’re not actually different than most other biotech companies who went public then or even before that have seen a significant share price decline. We essentially moved with the overall market. If anything, we’ve held up a bit better than others. The conversation with investors is like, “look at the time of the IPO $11 was the share price partly driven by exuberance. If anything, today we’re trading at essentially venture capital valuations—so pre-IPO valuations of the company—having though made incredible progress with our lead program and created incredible value, intrinsic value in the company by taking this program that was in early preclinical stage at the time of the IPO to be a clinical stage program today, having established a full mechanism of action, having passed the gate, the hurdles of preclinical toxicology studies, having made the submission to the ethics committee to start the clinical study. So we’re inherently intrinsically more valuable to today. So, if anything, we’ve actually achieved buy.”

Daniel Levine: Well, how far will existing cash take you and what’s the plan for raising additional capital?

Matthias Alder: So, we have a cash runway into the third quarter of 24 based on the full plan that we have for the company that’s not just running a phase 1 clinical study with our lead program. It’s advancing a backup program that we have just in case, it’s advancing our rare disease programs, it’s advancing our oncology programs. So all of that is baked into that cash runway and we have the ability to obviously modulate our plans depending on the availability of capital. The main focus clearly now needs to be on the lead program and which drives a lot of discussions that we have as most biotech companies do with pharma companies and peer companies about partnering and licensing some of our programs and advancing them as part of a collaboration as opposed to pushing all of these programs forward on our own with the money that we have raised. And so we have a lot of flexibility in terms of the cash runway itself. We have interesting partnering opportunities for our pipeline programs and so we have been successful actually in attracting grant funding, including a recent grant of $2.8 million for our lead program that we’re taking into the clinic. And so we’re looking to continue to tap into these, into grant funding, non-dilutive funding through partnering, and if need be at the right point in time, accessing public markets.

Daniel Levine: Matthias Alder, CEO of Gain Therapeutics. Matthias, thanks so much for your time today.

Matthias Alder: Thanks for having me, Danny.

This transcript has been edited for clarity and readability.



Stay Connected

Sign up for updates straight to your inbox.