A Small Molecule Therapy to Regenerate Muscle in People with DMD

Duchenne muscular dystrophy is an inherited disease caused by genetic mutations that no longer allow the dystrophin protein to function properly. It turns out that dystrophin not only plays a role in muscle fiber, but in muscle stem cells as well and is critical for regeneration of muscle tissue. Without dystrophin, people with Duchene suffer progressive muscle tissue damage, functional decline, and ultimately loss of life. Satellos is developing an experimental small molecule therapy that restores innate muscle repair and regeneration. We spoke to Frank Gleeson, co-founder and CEO of Satellos, about its regenerative therapy for Duchenne, how it works, and why it may provide benefits to patients with other conditions that result in muscle degeneration.

Daniel Levine: Frank, thanks for joining us.

Frank Gleeson: Thank you for the invitation and I’m very pleased to be here and speak with you and your audience.

Daniel Levine: We’re going to talk about Duchenne muscular dystrophy, Satellos Bioscience, and its efforts to develop small molecule therapies to restore muscle growth and conduct repair. Let’s start with Duchenne. For listeners not familiar with the condition, what is it?

Frank Gleeson: Duchenne is a genetic condition, so Duchenne or Duchenne muscular dystrophy starts with the mutation of a gene called dystrophin. This particular gene is important in muscle stability. It encodes a protein called dystrophin, and when this protein isn’t there or when the gene is damaged and the protein is severely damaged, it causes a situation where the children with this particular genetic mutation lose their muscles, their skeletal muscle breaks down in a progressive continuous basis during the course of their lives, and they basically lose all function that requires any strength of any type. It starts with losing the ability to walk, then gradually, sometimes more quickly, the ability to raise their upper arms, then difficulty with respiration, and so forth. It’s a fatal condition and people who live with this condition do so very, very bravely against very, very difficult conditions.

Daniel Levine: What’s the prognosis today for someone with the condition?

Frank Gleeson: So, the prognosis essentially is the same today as it was 40 or 50 years ago when Jerry Lewis was running telethons for Duchenne muscular dystrophy. And that is that the child with this particular condition will progressively deteriorate and will ultimately succumb to most likely heart failure or respiratory failure in their twenties.

Daniel Levine: We’ve seen a lot of efforts to bring new therapies to treat Duchenne to market, including a range of genetic medicines. How effective are the available treatments today?

Frank Gleeson: So, the treatments that are in development, some of which have been approved, really provide hope that the pace of decline can be slowed so that the disease can be stabilized for a period of time, and what is today a pretty rapid destruction of muscle can be slowed down, and so they provide, which is non-trivial. So this would be a significant step forward for individuals and their families that are seeing every day less and less functionality.

Daniel Levine: One of the issues with DMD is that even if you are successful at halting progression of the disease, it does nothing to reverse the damage that’s been done. What’s the need and the opportunity for a regenerative therapy to address this?

Frank Gleeson: Yeah, so we think this is absolutely the critical aspect of this disease, that even if the existing technologies in development or some of the recently approved products, are able to slow progression, they’re not designed to bring back muscle. They’re not designed to bring back function. So normally when an individual damages their muscles, which we all do on a regular basis, whether by accident or deliberately, if we’re high performance athletes, for example, muscle repairs itself, muscle regenerates. Muscle is the most regenerative organ in the human body. We don’t consciously think of it because it’s very seamless to us, but you tear a muscle, your muscle comes back, and if you take care of it, it will come back stronger. Well, for individuals with Duchenne muscular dystrophy, this natural repair and regeneration process is broken, and this is the area, in our view, of greatest need—approaches that will restore the regeneration process to not only slow down progression, to not only stabilize, but to bring back function.

Daniel Levine: I think many people when they think of regenerative therapies will think of stem cells. Satellos actually has platform technology to generate small molecule drug candidates to address the loss of muscle tissue. Perhaps it would be useful to explain what muscle progenitor cells are and the role they play in muscle cell growth and regeneration.

Frank Gleeson: Yes, absolutely. The field of stem cells is an area that my co-founder, Dr. Michael Rudnicki and I have a long history in. We are both alumni of the Canadian Stem Cell Network, which is the body in Canada that funds the field of stem cell research in this country. I’m a past chairman of the board. Michael is a scientific director and a past president of that organization. And we deliberately, many, many years ago, back in the early 2000s, began to fund projects that were focused not only on cell therapy, which is how people think about stem cells, take a cell, take it out of the body somehow, treat it, grow it, expand it, put it back in the body—cell therapy. We thought, what if we could find a way to fix or stimulate stem cell activity inside the body? This would remove the need for taking cells out and growing them in various types of expansion vessels and so on, and maybe lead to a much easier way from an administration point of view to treat patients. And we identified that in muscular dystrophy through Michael’s academic work. And subsequently through our work as a company of Satellos, we identified that the stem cells of children with Duchenne muscular dystrophy, the muscle stem cells are not functioning properly. They’re not able to divide properly to create new muscle cells, and the starting point for a new muscle cell is called a muscle progenitor cell. It kind of makes sense. It’s the progenitor that ultimately leads to the muscle cell. So we need these muscle progenitor cells in order to create new muscle cells and repair and regenerate our muscle fibers. It’s sort of a progressive development that happens biologically. And the muscle stem cell is the genesis of all of that. If that muscle stem cell cannot divide properly to create two cells that are different from each other, one of which is a muscle progenitor cell, the body simply cannot repair and replace and regenerate damaged or missing tissue, and that’s what we are focused on trying to fix—that specific problem.

Daniel Levine: Is it understood whether that dysfunction of the progenitor cells in people with Duchenne is a result of a lack of dystrophin?

Frank Gleeson: Yes. This is our work. This is our discovery. Michael’s discovery, in particular, published in Nature Medicine a number of years ago, that the dystrophin protein, which is absent or severely damaged in Duchenne patients is critical for this division process I just described. When it’s not there or it’s severely mutated, the stem cells are unable to divide properly. If you think of it as sort of the earth on its axis, the stem cell needs to be on a north/south axis and without dystrophin, dystrophin is the agent that sets the axis of the stem cell to a north/south placement. Without that, the stem cell can’t divide properly. It’s kind of lost in space.

Daniel Levine:

Satellos has developed what it calls the MyoReGenX platform. What is that and how does it work?

Frank Gleeson: MyoReGenX is our discovery platform: myo for muscle—myo cells, muscle cells, and ReGenX for regeneration. So what we are able to do is look at the muscle itself and the muscle, kind of the microenvironment of the muscle in which the stem cells reside because the stem cells are kind of buried deep within muscle fibers. They’re sort of protected in a niche area, and they’re typically quiet or dormant until called upon by injury or stimulus related to injury. And we’ve recapitulated this environment in a system we call MyoReGenX, which allows us to study very carefully and quantitate very accurately stem cell divisions and determine if our drug candidates are having an effect or not on the processes we’re trying to modulate. So it really allows us to telescope time, and it really is a way for us to get quick feedback to improve our technology and our drug candidates.

Daniel Levine: Satellos is doing preclinical development of an experimental therapy SAT-3247. What is it and how does it work?

Frank Gleeson: SAT-3247 is a member of a new class of small molecule drug candidates that we will be making available in a pill or a tablet form for patients as a treatment for Duchenne muscular dystrophy. The drug works by specifically reorienting this stem cell division process that I’ve described in muscle stem cells. So, it’s been designed to interact very specifically with a particular protein that we’ve identified can replace the missing role of dystrophin in stem cells. So, this protein, which is called adapter associated kinase one, AAK1 for short in the lexicon of the industry, is a well-known protein. We designed a drug to inhibit that protein in a particular way for a particular amount of time, and it enables the stem cell to reset kind of the axis I talked about, to get back into its north/south orientation and to divide properly to create progenitor cells, and then we can track those progenitor cells as they go forward to create muscle and to provide muscle strength. So that’s what 3247 is designed to do, and we couldn’t be more excited about this new drug candidate and what we believe is the hope that it will offer patients.

Daniel Levine: Given that you’re not relying on dystrophin, would this be pursued as a monotherapy or would you expect it to be used in combination with other treatments?

Frank Gleeson: Well, this is a great and very insightful question, and it’s so important in this disease area. Many, many patients that live with Duchenne are not eligible for even the new treatments that are being developed because they have the wrong genetic mutation for those treatments or because they might be outside of an age boundary for those treatments. Our treatment is designed to be totally agnostic to the genetic mutations a person may have, to whether the person is ambulatory or not ambulatory, but at the same time, this approach may very well make some of those other treatments more effective. So this could be an add-on therapy, but we see it as therefore having this duality. It’s like two mints in one. It can be standalone, but it could also be combination.

Daniel Levine: How novel approach is this?

Frank Gleeson: This is novel. This is very, very original work. It’s novel to the point that we’ve taken a lot of abuse almost over this idea that dystrophin could have had another role, dystrophin could be expressed in stem cells, that regeneration might be the key to the whole puzzle. And so over a period of now several years, because we’re very persistent and we believe that this is not just right, but absolutely important, we stayed with it. We’ve continued to generate data, and now we’re seeing that some of the important advocacy bodies in the field are beginning to come around to the idea that regeneration is the next horizon; that we need to address the body’s ability to repair and create new muscle and to create strong muscle in order to make truly meaningful changes in the life course of individuals living with Duchenne.

Daniel Levine: You touched a bit on the work that was done that led to this, but can you expand on how Sataellos came to develop this? What the science behind it was?

Frank Gleeson: The science behind this is really a science of passion and love for discovery, but also a desire to link discoveries to actual patient lives. So, my colleague, Dr. Rudnicki, is a world authority on muscle stem cells, how they function, how they’re regulated, and he became very interested in linking that in a tangible way to disease conditions. And he reasoned that in Duchenne muscular dystrophy, which has had a very long history of treatments that haven’t worked, of treatments that have been marginally beneficial, and now of treatments that may possibly stabilize but not necessarily change the course of the disease. He thought there must be something else happening in this disease condition that we’re missing. There must be something else to explain the progressive loss of muscle because unlike many other disorders of muscle weakness or muscle loss, in this case, skeletal muscle actually disappears, literally disappears, and is replaced with fat and fibrosis. And so in doing that, he uncovered this finding that the way stem cells divide is damaged or broken in Duchenne muscular dystrophy. And he published a landmark paper in Nature Medicine in 2015 describing this discovery, and that was really the starting point for Satellos, and since then, together, we have been moving this forward and this has become, I guess you could say it’s now reached, it’s become our life work. We want to get this treatment opportunity into patients as quickly as we can and see if we can be helpful.

Daniel Levine: What’s the development path forward and how soon might you be in the clinic?

Frank Gleeson: We’re now very close to the clinic. We are literally months away, just a few months away from initiating safety trials in healthy volunteers as a small molecule drug. That’s the paradigm to start with healthy volunteers to ensure the drug has the potential to be safe, and that we understand the pharmacokinetic properties of the drug in human beings. And then from there into patients. In approximately a year from now, we’ll be moving to initiate clinical trials in Duchenne patients once we show the drug is safe.

Daniel Levine: There are many other conditions where there is progressive deterioration to the muscle where a therapy like this could have a very meaningful impact. Is this specific to Duchenne, and if so, does it point to a way forward for other conditions?

Frank Gleeson: Yes, it does point a way forward for other conditions. It is not specific to Duchenne, although we believe it will have a significant impact in Duchenne, and that’s where the original discovery was made. But wherever there is a regeneration deficit, so there are many dystrophies, FSHD for example, the dystrophy that affects the upper body has a regeneration deficit. We’ve shown that we might have the potential to be helpful in that disease condition by restoring some of that regeneration that’s lost. There are other degenerative conditions. There are diseases one doesn’t necessarily think of as degenerative of muscle, but in cancer, for example, cancer cachexia is actually the destruction of muscle by the cancer itself. And the biology of it is remarkably similar to what we see happening in the genetic condition of Duchenne muscular dystrophy. And aging, of course, is an area of generalizable muscle weakness and loss. So there are many, many areas that we can look at for the future, including in healthy individuals. Otherwise healthy individuals who suffer severe muscle injury, muscle loss, surgical intervention stays in the ICU. These are all areas where we believe we can have an effect.

Daniel Levine: How is Satellos funded to date?

Frank Gleeson: Satellos has been funded initially through high net worth individuals, and then ultimately we took the company public three years ago and now we have very substantial institutional investment behind us. We have some of the leading biotechnology specialist funds in the U.S. invested in our company, and we are on a good path moving forward with funding that will now allow us to execute on the clinical trials that I’ve described over the next couple of years.

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

Frank Gleeson: Yeah, so in biotechnology, one is always thinking about capital raise. That’s the nature of the business because growing the company requires that fuel. At the moment, we’re well funded to execute on the plans that I’ve described over the next couple of years, and we will look to the market on a regular basis to see when that right timing of expanding our plans versus opportunity to raise capital in a productive manner fits for us.

Daniel Levine: Frank Gleeason, co-founder and CEO of Satellos. Frank, thanks so much for your time today,

Frank Gleeson: Danny. Thank you. And thanks to your audience for being interested in Satellos.

This transcript has been edited for clarity and readability.

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