Powering Cells in People with Rare Mitochondrial Myopathies
January 20, 2023
Primary mitochondrial myopathies are a group of rare, often life-threatening disorders caused by genetic mutations that affect the energy needs of skeletal muscles and can impact the ability to walk, lift, or do other everyday activities. High energy tissues like the heart, brain, and muscle are most affected by these disorders. Currently, there are no approved drugs to treat people with these conditions. Reneo Pharmaceuticals is developing an experimental therapy that works by increasing the transcription of genes involved in mitochondrial function, increasing fatty acid oxidation, and promoting the formation of new mitochondria. We spoke to Greg Flesher, president and CEO of Reneo, about mitochondrial myopathies, the company’s efforts to develop an experimental therapy to treat these conditions, and how it works.
Daniel Levine: Greg, thanks for joining us.
Greg Flesher: Thank you for inviting me.
Daniel Levine: We’re going to talk about rare mitochondrial myopathies, Reneo Pharmaceuticals, and its efforts to develop treatments for these conditions. Perhaps we can start with mitochondria itself. These are often called the powerhouse of cells. What exactly are mitochondria and what role do they play in our health and wellbeing?
Greg Flesher: Sure. Mitochondria are very important for humans, actually all animals on this planet. They are small organelles in all the cells of our body that are responsible for metabolizing the foods that we eat and converting it into a common source of energy called adenosine triphosphate or ATP. And tissues in the body that need lots of energy like skeletal muscle, or the heart or the brain, have lots of copies of the mitochondria within each cell of the body so they can produce large amounts of energy.
Daniel Levine: Reneo is focused on primary mitochondrial myopathies. These are considered neuromuscular disorders. What are mitochondrial myopathies?
Greg Flesher: Sure. So mitochondrial myopathies are a heterogeneous group of gene defects in the genes that are important for mitochondrial function. So, as a little background, the mitochondria have their own genome, so they come with their own DNA, and all of the genes produce proteins that are needed for the mitochondria to function within human cells. And our human cells—the nucleus of the cell also has important genes that produce products that the mitochondria need as well. And if you have a gene defect in one or more genes that are important for mitochondrial function, you often have difficulty in metabolizing foods. For folks with primary mitochondrial myopathy or PMM, the primary dysfunction is a lack or inability to fully metabolize fatty acids. And fatty acids are an important component of energy creation when you have longer duration of energy needs. So, very important to be able to metabolize fats, to take them from your storage cells in your body and use them for energy creation. And these patients, unfortunately, are at least somewhat compromised, if not materially compromised in creating ATP out of fatty acids.
Daniel Levine: How do mitochondrial myopathies generally manifest themselves and progress?
Greg Flesher: Yeah, so these are rare genetic diseases. You are born with them. So, you’re born with a gene defect. It is interesting—I had mentioned earlier—there’s gene defects in the nuclear DNA and when this happens, it affects every cell of the body, and it’s usually a more severe type of condition, diagnosed in childhood usually in your first years of life. But the more common gene defect comes from the DNA of the mitochondria itself. And in this scenario, only a portion of your mitochondria are affected. So, the way the mitochondria divide, if the gene mutations or deletions or alterations are derived from the mitochondria itself, you have a condition that’s called hypoplasia, meaning within each cell, some of the mitochondria are healthy and functionally normal and some are abnormal. And in that situation, quite often at birth, you don’t know you have the disease, and in fact, you don’t know you have the condition or the disease until you reach maybe pre-adolescence or adolescence. When you are starting to grow rapidly and your energy demands increase exponentially as your skeletal muscle grows, and your heart and your brain and other organ systems. And in the case for mitochondrial mutations, patients with PMM mitochondrial mutations, quite often you’re diagnosed in adolescence and it manifests as grossly undeveloped skeletal muscle, extreme fatigue and weakness, muscle aching and cramps. And as the child progresses into adulthood, can also progress into a lot of cardiovascular as well as CNS or neurology related symptoms as well.
Daniel Levine: How difficult a diagnosis is this to make and how are patients generally diagnosed?
Greg Flesher: Yeah, the good news is diagnosis has become easier with whole genome sequencing. Twenty years ago, to definitively diagnose the condition you needed to get a sample of muscle, typically skeletal muscle. So, a calf muscle biopsy was probably the most common way to do this. And you would take pieces of calf muscle and do your genetic sequencing to define that you were missing pieces of DNA or had alterations in your DNA. Fortunately, now genetic testing is advanced quite far. We can use blood and we can use buccal swabs to gain the same amount of information in a less invasive way for patients. So, typically diagnosis is a long path. Patients begin to present with a host of neuromuscular symptoms. They often get referred to a neuro specialist, a neuromuscular specialist. And once they rule out some of the more commonly known and recognized diseases, it’s often sort of the last condition of the diagnosis of exclusion. You’ve excluded all other diseases and then referred to a genetic specialist who will find these mutations and diagnosed you as having PMM.
Daniel Levine: What treatment options exist for patients and what’s the prognosis for someone with the condition today?
Greg Flesher: Yeah, so unfortunately, there’s no drugs approved anywhere in the world for the treatment of primary mitochondrial myopathies. Today doctors try herbs and supplements to mitigate some of the symptoms associated with the disease, but unfortunately nothing is approved. Fortunately for us, we think that this could potentially be the first product approved for these patients and would have a profound effect in their day-to-day lives. In terms of prognosis, I know you mentioned the prognosis. Right now, there are a portion of patients born with this that won’t make it out of childhood. Those that do make it out of childhood tend to live not a pleasant life because as you can imagine, as you grow from a child to an adolescent to an adult and your energy demands increase and your cells aren’t able to meet those energy demands, your tissue goes under stress and the tissue dies. So, for these patients, quite often they tend to be wheelchair-bound, have a host of cardiovascular effects, neuromuscular effects, or skeletal muscle effects, as well as centrally driven CNS effects.
Daniel Levine: Reneo’s lead experimental candidate is in development for primary mitochondrial myopathies, as well as long chain fatty acid oxidation disorders. How are long-chain fatty acid oxidation disorders related to PMM?
Greg Flesher: Interesting. So, both FOD and PMM have similar phenotypes. The patients themselves are unable to metabolize certain nutrients to create ATP, or convert to ATP for long chain fatty acid oxidation disorder. These typically come from monogenic mutations, meaning point mutations or single mutations in a specific enzyme. For these patients, they have problems metabolizing long chain fats that you get in your diet. And as you can imagine, as a newborn child who could not yet eat normal food, mother’s milk and formula, which is heavily fat and providing calories tends to be your only source of energy. So, these unfortunate children go through quite a deal to navigate this. PMM patients can metabolize fats but not efficiently, and again, it doesn’t really become a problem until they become older adolescents or adults. And so, both have, again, the same phenotype: significant myopathy, muscle weakness, muscle fatigue, underdeveloped muscle systems, and both have the inability to metabolize fats and fatty acids, but for different reasons.
Daniel Levine: Let’s talk about your lead experimental therapy, REN001. What is it and how does it work?
Greg Flesher: Sure. REN001, it’s scientific name is mavodelpar, is a PPARδ agonist. PPAR biology is a natural biology that all humans have. It is interesting in the metabolism of foods and the creation of energy when we exercise on a regular basis, our body produces PPARδ ligand, it causes the transcription of genes that increase mitochondrial function, and it allows then the mitochondria to produce more energy when our energy demands go up. What we have created and are developing in the clinic is an agonist, a novel agonist of the same pathway. So, we’re trying to turn on or activate to a higher degree a natural pathway that exists in the body today. And that is what REN001 is. It’s oral, it’s a tablet. I’m sorry, it’s a capsule and it’s taken once a day.
Daniel Levine: What’s known about its safety and efficacy from studies that have been done to date?
Greg Flesher: Sure. So, we have completed a number of phase 1 studies with the product. To date, we’ve completed traditional single-ascending dose, multi-ascending dose, a leg immobilization study where we saw the drug was active in skeletal muscle on a functional level as well as a genetic level, as well as have tested it in three open label phase 1b studies. In rare orphan diseases where mitochondrial function has been affected we have quite a bit of knowledge of the safety and tolerability profile of the product. We find it to be very tolerable to date and with a safety profile that would be amenable to a product in the marketplace at some point in the future. And we’ve also seen that the product does a very good job at increasing the oxidation of fatty acid or the consumption of oxygen. We’ve seen this in multiple studies. A consistent finding, and probably the most important, at least for moving into your pivotal studies before speaking to regulators, is the functional benefit of increasing oxygen and consumption. And fatty acid oxidation is the patients have more energy and we can put them through functional walk tests or functional exercise tests and show that they get a pretty sizable improvement in their ability to walk at least greater distances over a period of time. So, for most orphan drugs, what regulators like to see is a meaningful improvement in a functional endpoint as well as symptom resolution, some of the key symptoms that this disease produces.
Daniel Levine: What’s the regulatory path forward?
Greg Flesher: Yeah, so fingers crossed, we have an ongoing pivotal study that’s nearly enrolled. We should finish early in 2023 and have data by the end of the calendar year. So if that study is successful, if we meet our primary efficacy endpoint and have supportive secondary endpoints, we will use that data along with some long-term extension exposure data and go to meet regulators in early 2024 and talk about sending the product in for approval, both in the U.S. and in Europe.
Daniel Levine: Mitochondria are implicated in a broader range of conditions. REN001 is believed to not only increase mitochondrial function but promote the formation of new mitochondria. Is there reason to believe it might have the potential to benefit people with other mitochondrial disorders or other conditions in which mitochondria are implicated?
Greg Flesher: Yeah, it’s a very good question. We do believe that if the product is shown to be safe and effective in our lead program, PMM, that there are a number of other uniquely named orphan diseases in the mitochondrial space where the drug may have a benefit. And we will continue to explore those other indications as we develop this product over time.
Daniel Levine: Reneo completed an IPO in April 2021. You raised $94 million. It’s been a tough time since for public biotechs. Your IPO came at $15 and you’re now just trading above $2. What’s the conversation like with investors these days?
Greg Flesher: <laugh> not fun at times. Noone likes to make an investment and see their investment decline over the course of time. But I think the good thing is our IPOO was entirely purposeful to fund us through our clinical program, our pivotal clinical program. So, unlike the other 95 percent of small companies that went public over the last couple years, the cash that we raised gets us through a very significant milestone event in late 2023. And I think with that in mind, investors have been very patient and they continue to be supportive of the company, and I think will be supportive of the company as we continue to move forward into 2023.
Daniel Levine: So, is the plan to complete the phase 3 before seeking to raise additional capital?
Greg Flesher: I think we explore all options. We have no need to go out and raise capital until we turn the data card later next year. But again, as you know in this industry and you’ve talked to many CEOs and executives, I think when capital is available, one has to consider all the options. I mean, fortunately for us, we think this product can generate enormous revenues in the U.S. alone. And with that option, we may have some non-dilutive capital opportunities facing us in the next year.
Daniel Levine: Greg Flesher, president and CEO of Reneo Pharmaceuticals. Greg, thanks so much for your time today.
Greg Flesher: Thank you very much. Have a nice afternoon.
This transcript has been edited for clarity and readability.
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