Rare Community Profiles

Rare Community Profiles is a new Patient Worthy article series of long-form interviews featuring various stakeholders in the rare disease community, such as patients, their families, advocates, scientists, and more.

Reneo Pharmaceuticals is Developing Therapies for Rare Genetic Diseases like PMM and LC-FAOD: An Interview with CMO Alex Dorenbaum, MD

When Alejandro (Alex) Dorenbaum thinks about the future of medicine, one thing is clear: his belief that one day, all diseases will be orphan. He explains:

“We used to talk about cancer as one block. Now we know that if you have breast cancer and a certain receptor, you respond to one medicine. If your cancer is positive for another receptor, you may respond to something else. As we understand biology better, everything is becoming ‘orphan.’ Reneo Pharmaceuticals wants to be at the forefront of developing the right medicine for the right disease at the right time.”

Equally as important, he believes that the medical field will change through increased rare disease research and awareness. He recalls phenylketonuria (PKU), the first disease for which a monogenic gene was identified. Researchers realized that changing behavior and diet could reduce the impact of PKU; they later used this idea to treat more common issues such as high cholesterol. Says Alex:

“We learn from rare diseases to treat common diseases. That’s how medicine advances.”

Reneo Pharmaceuticals was formed to develop therapies for rare genetic diseases, including mitochondrial diseases, with significant unmet needs. The company began by identifying potential drugs that were initially studied for larger indications but were no longer being developed. This is beneficial as it offers preliminary safety and efficacy data that can be used to make drug development more successful.

In Reneo’s case, the company is currently developing mavodelpar (REN001), a peroxisome proliferator-activated receptor delta (PPARδ) agonist. Initially being explored for metabolic diseases, Reneo saw data that highlighted the drug’s ability to target and improve muscle energy. Reneo saw potential in using mavodelpar for primary mitochondrial myopathy (PMM) and long-chain fatty acid oxidation disorders (LC-FAOD).

Alex recently spoke with Patient Worthy about Reneo, mavodelpar, and the need for increased rare disease research and drug development.

About Dr. Alejandro “Alex” Dorenbaum, MD

Alejandro (Alex) Dorenbaum, M.D., is the Chief Medical Officer of Reneo Pharmaceuticals. Alex received his M.D. from the National Autonomous University in Mexico City. He completed his residency in pediatrics at University of Texas Health Science Center and held a fellowship in allergy and immunology at Baylor College of Medicine. Alex began his career in pediatric immunology and worked for several years at the University of California—San Francisco, conducting clinical research to find drugs to treat and prevent HIV transmission in children. He shares:

“During those years, the HIV epidemic was the 4th leading cause of death for children in the United States. I was focused on HIV treatment, as well as the prevention of transmission from mother to child. This is how I learned how to do clinical trials and research, and to evaluate whether candidate medications work to treat a disease. Everything that I learned, I wanted to bring to fruition. So, I transitioned into industry to develop drugs for difficult-to-treat and rare diseases.”

Prior to joining Reneo Pharmaceuticals, Alex was Chief Medical Officer at Allakos, where he achieved proof-of-concept in clinical trials for novel therapeutic antibodies targeting inflammatory cells. He also served as Chief Medical Officer at Lumena Pharmaceuticals until its acquisition by Shire Pharmaceuticals. Prior to that, Alex worked at Genentech, where he was responsible for the respiratory programs for asthma and cystic fibrosis, and at BioMarin Pharmaceutical, where he conducted the clinical development of Kuvan and Palynziq. He maintains an active academic position as Clinical Professor in Pediatrics at Stanford University School of Medicine, where he specializes in allergy and immunology.

Ultimately, he shares, his goal at Reneo is to find treatments for patients who would otherwise not be addressed by big pharma.

Developing Mavodelpar

Currently, Reneo is investigating mavodelpar in the pivotal STRIDE study for adult patients with PMM, though the drug was recently granted Fast Track Designation from the FDA for a second indication  called long chain fatty acid oxidation disorder (LC-FAOD). According to Alex:

“The mechanism of action can be useful in other indications such as fatty acid oxidation disorder (FAOD), a disease that is tested for in newborn screening. Children with this disease struggle to metabolize long chain fats in their body and also experience a lack of energy. Mavodelpar could potentially help these patients as well as adult patients with PMM.”

Reneo describes mavodelpar as:

A potent and selective agonist of the peroxisome proliferator-activated receptor delta (PPARδ) that has been shown to increase transcription of genes involved in mitochondrial function and increase fatty acid oxidation and promote formation of new mitochondria.

PPARs are a receptors that sit near the cell’s nucleus and stimulates gene activation. The genes that are activated are involved in improving and activating mitochondrial function and helping them multiply in the cell. There are existing drugs for PPAR-alpha (PPARα) and gamma (PPARγ), but not for PPARδ. Alex explains that a selective PPARδ agonist holds advantages over existing therapies, noting that stimulating PPAR alpha and gamma may cause additional side effects and toxicity. Mavodelpar is taken orally once per day. Says Alex:

“What really matters is that we believe we can help patients with PMM. And people with PMM have a very complex disease. Many symptoms occur because their mitochondria are not functioning in multiple system organs, and the heart, brain, and muscles are most affected. In developing mavodelpar, we interviewed patients to learn about their symptoms, quality of life, and treatment priorities. People say exercise intolerance is an issue, but it’s really fatigue. They can’t complete activities of daily living. If a patient does laundry, they may not cook to avoid running out of fuel. We’ve held continued conversations with the United Mitochondrial Disease Foundation and other advocacy groups, attend annual meetings, and speak with patients to make sure we’re doing things the right way. In rare disease, there is such limited information that the patient perspective plays a crucial role in drug development.”

So far, patients have seemed to tolerate the medicine well. Now, Reneo is working to complete the clinical studies that will determine whether mavodelpar will improve both symptoms and patient performance in daily activities.

Studying Mavodelpar for PMM

Reneo recently completed enrollment for the STRIDE study, a pivotal Phase 2 clinical trial evaluating mavodelpar for adult patients with primary mitochondrial myopathy with mitochondrial DNA (mtDNA) defects. A pivotal trial is one used to confirm a treatment’s safety and efficacy, leading to potential regulatory approval. As Alex shares:

“When we presented this study to regulatory agencies, we were told that, if it is a successful trial, the data may be sufficient to support the efficacy of mavodelpar in a New Drug Application (NDA) submission in the United States or similar marketing application in Europe. Now, the big job is for Reneo to complete the study, analyze the results, and then put together a package that we can present to the regulators.

One big aspect of this study is proving that mavodelpar is safe and tolerable. One of the companion studies is the STRIDE AHEAD study, a long-term open-label extension (OLE) safety study that is ongoing. Given that many patients are receiving the medicine for longer periods of time, this data would also be included in the submission.

To Alex, seeing mavodelpar be approved would be a dream. He already loves receiving letters from patients that discuss drugs he has helped get approved; there’s nothing like hearing that your work has changed someone’s life for the better. With mavodelpar’s approval, Alex could see the impact on a broader scale where thousands of patients could benefit.

What is Primary Mitochondrial Myopathy (PMM)?

Primary mitochondrial myopathies (PMM) are groups of disorders (and subtypes of mitochondrial disease) are disorders associated with genetic changes in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Mitochondria—the powerhouse of the cell—play a role in cellular energy production and regulation. In PMM, the mitochondria do not produce enough energy for cells to function how they should. As a result, people with PMM experience issues with muscle use and function, often in the skeletal muscles. PMM may occur at any age. However, it is often more severe when symptoms appear earlier in life. Symptoms of PMM may vastly differ from person to person. Potential symptoms may include:

• Muscle weakness, pain, and wasting
• Slurred speech
• Difficulty swallowing and/or breathing
• Double vision
• Drooping of one or both eyes
• Eye movement paralysis
• Nausea
• Headache
• Diabetes
• Abnormal heartbeat
• Extreme fatigue that worsens with activity
• Developmental delays
• Heart failure
• Seizures
• Reduced life expectancy

This is not an exhaustive list of symptoms or characteristics. There are no approved treatments for PMM, but some physicians prescribe alternative therapies to help with some of the symptoms. These include occupational and physical therapy, vitamin therapies, speech therapy, and surgery.