Using Model Systems to Find Drugs to Repurpose for Rare Diseases

July 23, 2021

The use of model system, such as fruit flies and worms, to screen existing drugs for their potential to treat rare genetic diseases offers a relatively fast and economic method to find candidates for repurposing. The success at screening 4,000 compounds in a worm model of the neurodegenerative disease ALS to identify a candidate that is now in human clinical testing gave rise to Modelis, a Canadian company that is now repeating the exercise in other rare diseases. We spoke to James Doyle, CEO of Modelis, about model system, how the company creates genetic avatars of patients; and how it works with rare disease drug developers, patient organizations, and patients to identify candidates for repurposing.

Daniel Levine: James. Thanks for joining us.

James Doyle: Thank you for having me, Danny. How’s your day going so far?

Daniel Levine: It’s going well, thank you. We’re going to talk about Modelis, it’s use of model systems, and how it accelerates personalized drug discovery through repurposing existing therapies to treat rare genetic diseases. Perhaps we can begin with model systems, which are widely used throughout the drug discovery and development process. What are model systems and how have they generally been used?

James Doyle: Model systems are really any biological tool that can be used to study or gather information about a rare disease. For example, something that tells us about the genetics of a rare disease, some of the underlying pathology of a rare disease, what the cellular effect of a genetic mutation [is] on a disease, what therapeutic targets are, or what the pathways involved are in a rare disease. Those are all things that model systems can help us answer. So, model systems are actually quite varied and quite broad, but I think the best two buckets to set them into would be, in vitro and in vivo. In vitro, which is Latin for ‘in the glass,’ are typically cell-based systems that are cultured in the lab. Think of your fibroblasts or IPCs, things like that, those are in vitro systems. Then you also have the in vivo systems, and in vivo systems are in the living. Those are all your animal models. Things like fish, worms, mice, flies, dogs, and non-human primates, those are all in vivo model systems. In vitro, and in vivo would be the best ways to kind of group those two together.

Daniel Levine: How predictive are things like worms and flies when it comes to the workings of human genetics? What can we do with these simple model systems?

James Doyle: I’ve been working with worms since the beginning of my Ph.D. So, I’ve been asked that question quite a bit. To be honest, the answer to that question was not obvious to me in the beginning either. What we have to remember is that, yes, a worm, a fly, and a human look very different, but if you zoom down and you look at the DNA, our DNA is basically the same. We have all the same genes. It’s the same DNA molecules but the letters are just arranged a little bit differently. If you zoom out a little bit, if you compare a worm cell and a human cell next to each other, they’re very similar to each other. They look the same way because they essentially function the same way. They have all the same sub cellular structures, they have the same nuclei, they have the same mitochondria, and they have the same lysosomes. All of those sub-cellar structures are there and they all interact with each other in basically the same way. The underlying biology of a worm cell is basically the same as that of a human cell. It’s just how they’re arranged to make the organism, a worm versus a human, where it differs quite significantly, but at the cellular level they function the same way. That means that if you model a genetic mutation that causes a disease in humans, and you mimic that same mutation in that same gene in worms, flies, fish, or some of these other smaller model organisms, you’re likely to disrupt the same pathways in the same way that the human pathways are disrupted. Thereby, these small animal models allow you to gain really valuable information about the underlying causes of human disorders. I’m a little bit biased towards the in vivo systems and some of the advantages that they offer over the in vitro system, the cell-based systems, especially when it comes to understanding the underlying causes of some of these genetic disorders. What these in vivo model systems allow you to do is to understand the impact of a genetic mutation at the organismal level. So, we’re not just talking about the impact of this mutation in this cell in a dish, but the impact of this mutation to a live biological organism.

Daniel Levine: How do we know a finding in a simple model system is valid?

James Doyle: We don’t always. Just like we’re not always sure how things like therapies will translate from, let’s say, in vitro systems to humans. This is where it’s advantageous to always have a plan in mind. I don’t think that one single model organism is going to help answer all questions related to a rare disease or related to a therapeutic drug discovery program. Yet, having multiple models systems in your pocket, having the largest number of assays, and the largest number of tools available can help you to answer the broadest range of questions. Things can be validated from worms to fish or from worms to mice. That’s how we can validate and ensure that you’re moving the findings along that have the highest translational potential, the highest chance of ultimately working in humans.

Daniel Levine: You’ve taken these model systems and created a process for screening drugs. I thought we could, as an example, go through the work you’ve done finding a drug that could be repurposed to treat the neurodegenerative condition ALS. For listeners not familiar with ALS what is it?

James Doyle: ALS is a devastating neuromuscular disorder. People will also know it as motor neuron disease or Lou Gehrig’s disease. It’s an absolutely devastating and fatal neuromuscular disorder. There are multiple different genetic causes underlying the condition, but typically what happens is that the motor neurons denervate the muscles. So, the motor neurons die, retract from the muscles, the muscles are no longer stimulated so the muscles atrophy, and patients ultimately die from the disorder. It’s incredibly fast acting. Symptom onset to patients dying from the disease can occur anywhere from six months to five years. It’s an incredibly devastating disorder. Unfortunately, although there’s definitely a lot of interest in developing therapies for it, it’s still uncured and there is a large unmet need.

Daniel Levine: Walk us through the project. What did you do? Take us through each step and what it is and how long it takes.

James Doyle: The work that we do at Modelis and how it was applied to ALS came out of a research project led by one of our co-founders, Dr. Alex Parker, who is a professor of neuroscience at the University of Montreal. He had an idea to generate worm models of ALS: taking mutations that cause ALS in humans, mimicking them in worms, and then asking and answering the question, “If we find drugs that can make the ALS worms better, could they also make ALS patients better?” It seemed like a pretty crazy idea at the time, because it definitely is a big leap to go from worms to humans, but he tried it. He screened thousands and thousands of drugs on these sick ALS worms and identified some that made them better, but obviously the jump from worms to humans is quite large. This is where we touch back on the point of having multiple models available to validate the translational aspect of our discoveries—so, validating drug hits from worms to ALS fish and from fish to ALS mice. That led to the identification of a compound, a repurposed drug called pimozide, that’s been around for about 50 years now. It turns out that it actually has a really good therapeutic potential for ALS. Based off these clinical findings from worms to fish to mice, it went into a small, 25 patient clinical trial at one site up here in Canada, which was successful, and now is being tested in a hundred patients across the country. It was the first example of going from worms all the way through to humans in purely translational drug discovery. I think it really set the stage for changing how we think about small animals, like worms and fish, in translational drug discovery. Since that success, we founded the company, Modelis, so we could apply this approach to drug screening and to genetic disorders more broadly.

Daniel Levine: What is pimozide and what did you see in the animal models to suggest that this could have potential in ALS in humans?

James Doyle: Pimozide is an anti-psychotic that’s been around for about 50 years, but it’s typically thought of as a last resort anti-psychotic. It’s what we call a dirty drug. It has a lot of off target effects and it’s difficult to tolerate, and that’s why it’s not commonly used. It’s really one of those last resort anti-psychotic drugs. As it turns out, among its many side effects, one of them is that it acts on calcium channels at the neuromuscular junction, which is not something that was known before but something which was identified out of this study. What we think is happening is that pimozide is actually targeting T type calcium channels at the neuromuscular junction helping stabilize the interaction between neurons and muscles, helping stimulate that, and essentially keeping the neurons healthy and active to prevent, or at least delay, the retraction and neuronal death that typically leads to symptom onset in ALS.

Daniel Levine: In terms of moving this forward, has Modelis’ work ended or has someone stepped in and doing the clinical studies now?

James Doyle:

This is in phase 2b clinical trial in about a hundred patients across Canada. This work is led at the University of Calgary, by a clinician named Dr. Lawrence Korngut, who’s actually our chief medical officer at Modelis. We’re anxiously awaiting the results of the clinical trial. Since this was an academic project, Modelis itself is not actively involved in this project anymore. We are looking towards the future and applying this approach to genetic disorders more broadly.

Daniel Levine: In the future, would you expect to be doing the clinical development of these drugs?

James Doyle: It really depends on what the nature of the drug is. For certain diseases or certain rare disorders in some of the projects we’re working on or we’ll work on in the future, it would make sense to go into clinical trials or at least try to take the first in human studies of those drugs. In other cases, it might make sense to sell it and out-license the IP to groups that have more experience or a track record in those specific indications. It really depends. We are a small biotech. We’d like to think of ourselves as a drug discovery platform or a preclinical platform. Yes, we do like to think of ourselves as bench to bedside, but primarily we are a drug discovery platform. It’s our job to identify hits and we’ll go into clinical trials where it makes sense, but otherwise we’re looking to identify hits for others to take them into clinical trials.

Daniel Levine: What is the business model? Who’s the customer and how do you fund your work?

James Doyle: The ultimate clients for Modelis are pharmaceutical companies or clinical stage biotechs who’ll eventually in-license or buy the molecules that we’re identifying. They can then continue clinical development and take it through to commercialization, and ultimately get those drugs to patients. We also work directly with patient advocacy groups or patient organizations, who represent rare diseases or have loved ones with rare disorders. Part of our mission, as scientists-founders of our company, is to help groups like this. We’re very flexible on how these kinds of partnerships work. We like to think of our partners as helping advance the goal of these organizations through drug repurposing screens. So, trying to identify drugs that can easily be repurposed or even new chemical entities that could have therapeutic potential against rare disorders. We work with groups really from bench to bedside. So, working from the very beginning in developing new animal models for these disorders to try and better understand the underlying causes of the diseases that we can then use for this high throughput drug screening, either new drug screening or drug repurposing, to try and identify potent therapeutic compounds against these ultra-rare disorders.

Daniel Levine: How expensive is this to do? What would it take for an individual patient or patient organization to have you model their disease and identify potential drugs to repurpose?

James Doyle: It really depends. All of our projects are custom designed to meet our partners’ exact needs and we’re very flexible in our offerings. It also depends on whether we are doing this as a fee for service, or as a partner with shared interests in the results of the project. We’re very flexible on that. As I said, it’s really our goal to help advance the goals of our partner organizations and we’re very flexible in how we approach that.

Daniel Levine: I know Modelis has talked about venture philanthropy models, where families have a stake in financial outcomes. Have you actually structured any that way?

James Doyle: We operate through this venture philanthropy for the partnership or for the shared results. The venture philanthropy would typically kick in once there is a partner to then continue developing that program. As hits are identified, as those get sold or out-licensed, it will kick in then. The way that is structured and the way the venture philanthropy is set up, really depends on the partner organization. We’re flexible on this, either it’s to share revenues, or trying to negotiate a special access program with the partner organization or with the partner biotech group to get patients on the drugs faster. It really depends because we do see this as a partnership. Working with patient advocacy organizations they do help fund the upfront cost of the R&D related to the projects. We want this to be a win-win-win, where if we identify a therapy, it’s not just a win for patient community, but also for Modelis, and then also for the patient organization itself, to be able to use either proceeds or results to continue advocating and doing the great work that they do for the community.

Daniel Levine: How many conditions has Modelis looked at to date?

James Doyle: Right now, we have about six ongoing programs.

Daniel Levine: It sounds like you’re really focused on the discovery side. What’s the furthest you might take a program on your own?

James Doyle: On our own it would likely be a phase 2 clinical trial. Beyond that, it will likely become too large for who we are and who we’re trying to be as a platform drug discovery biotech. But I guess only the future will tell. We’ll cross that bridge once we get there because obviously if there’s good opportunity to take some things further ourselves, then we don’t want to shy away from that.

Daniel Levine: James Doyle, CEO of Modelis. James, thanks so much for your time today.

James Doyle: Thanks so much Danny.


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