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Mitochondrial Challenges: Innovations in Research and Patient-Centered Care

 

Every 30 minutes, a child is born who will develop a mitochondrial disease by age 10. Already an estimated one in 5,000 people suffers from some form of the disease, many of whom struggle to walk, talk, see, or digest food.

 

Mitochondrial disease affects men and women, children and adults, and individuals of all ethnic and racial groups, with complications that range from seizures to strokes to death.

 

Currently, there are no cures for mitochondrial diseases. 

 

“But we’re getting close!” says Philip Yeske, Ph.D., Science and Alliance Officer at the United Mitochondrial Disease Foundation (UMDF). Yeske is dedicated to promoting mitochondrial disease research both as a scientist and as a parent who lost his daughter, Natalie, to mitochondrial disease 19 years ago when she was just a baby.

The Mighty Mitochondria

Mitochondria are little power factories inside almost every cell in the human body where the food we eat and the oxygen we breathe are converted into energy in the form of adenosine triphosphate (ATP). ATP powers nearly all cellular activities, including those that generate muscle movement and fuel brain functions.

 

“Mitochondrial energy is used for everything: walking, breathing, thinking… existing as an entity on the planet,” says Niall O’Donnell, Ph.D., managing director of the life sciences venture capital firm RiverVest Venture Partners. “There’s not a single process in your body that doesn’t require energy from the mitochondria.” 

 

Mitochondria are unique because they contain their own genetic material known as mitochondrial DNA (mtDNA) in addition to the more familiar nuclear DNA (nDNA). 

Mitochondria contain their own genetic material known as mitochondrial DNA (mtDNA) in addition to nuclear DNA.

Broadly speaking, mitochondrial disease is caused by mutations in mtDNA and nDNA that disrupt the ATP creation pathway, stunting the ability of mitochondria to create energy.

 

There are hundreds of variants of mitochondrial disease, and they can involve any organ or tissue. The diseases are often relentlessly progressive with high rates of morbidity and mortality. Childhood-onset mitochondrial diseases tend to be more life-threatening than those that present in adulthood. 

Voice of the Patient

“The key to unlocking mitochondrial disease therapies – or any orphan disease therapy – is establishing symbiotic relationships between drug researchers and patient advocacy groups,” says Wendy Newman, MPH, head of global patient advocacy at Reneo Pharmaceuticals, Inc. “Researchers need empirical data gathered by patient advocacy groups, and patients need access to cutting-edge clinical trials."

 

Patient advocacy groups such as UMDF facilitate the collection of empirical data through natural history studies. The data, which include both quantitative and qualitative responses from patients and caregivers, should ideally inform every part of the therapy development process.

 

“Patient-derived data often include quality-of-life priorities that researchers don’t anticipate,” says Yeske. For example, “burden of care” is a leading concern for patients and caregivers but is rarely seen as a primary endpoint in clinical trials. “Drug developers need to understand patient priorities if they want to develop therapeutics that are not only helpful, but also impactful,” says Yeske.

 

Patient advocacy is a global imperative. Alison Maguire, head of research and finance at the Lily Foundation, the United Kingdom's leading mitochondrial disease charity and the largest charitable funder of mitochondrial research in Europe, stresses the importance of involving the patient early in the research and development process.

 

"When designing a clinical study, for example, talk to the patients," says Maguire. "Ask them to share their views on whether a study design is practical, if the research is meaningful to them, and if it addresses a real unmet need.” 

 

Like Yeske, Maguire knows firsthand the devastating loss of a child to mitochondrial disease. After her four-year-old daughter Niamh passed away in 2009, Maguire chose to channel her grief and her medical experience into promoting mitochondrial disease research and awareness through the Lily Foundation. 

 

“Remember, it's the patients and their families who are the real experts on mitochondrial disease,” says Maguire. “They live with it every day.” 

“The key to unlocking mitochondrial disease therapies – or any orphan disease therapy – is establishing symbiotic relationships between drug researchers and patient advocacy groups.”

WENDY NEWMAN, MPH

Head of Global Patient Advocacy

Reneo Pharmaceuticals, Inc.

The Road to a Cure

One company on the frontlines of therapeutic development for patients with mitochondrial disease is Reneo Pharmaceuticals (NASDAQ: RPHM), co-founded by O’Donnell and RiverVest in 2014. Rather than focus on individual genetic mutations (there are far too many variants for a single drug developer to tackle), the team decided to prioritize a common morbidity that affects the majority of patients with mitochondrial disease: alleviating the weakness, fatigue, cramping, and wasting of muscle (myopathy) experienced when mitochondria fail to produce adequate levels of ATP. 

 

O’Donnell hypothesized that a chemical could be used to induce expression of a hormone receptor known as peroxisome proliferator-activated receptor delta (PPAR-delta), which would increase the amount of ATP energy within cells, thereby treating the myopathy experienced by mitochondrial disease patients.

 

“Evolution has designed PPAR-deltas as a sort of regulatory switch for boosting mitochondrial function,” explains Dr. O’Donnell. “They respond to nutrition, exercise, and activity, so if you’re exercising a lot or eating a certain diet, they will boost the number and workload of existing mitochondria to produce more energy.” 

 

The Reneo team set out to discover if they could tap into a person’s PPAR-delta pathways with a novel drug that would convince their body to produce ATP, even when mitochondrial disease prevents them from doing so. If so, could that induction of PPAR-delta boost ATP energy within the cells sufficient to alleviate myopathy and prevent downstream morbidity and mortality?*

“Patients and their families are the real experts on mitochondrial disease. They live with it every day.”

ALISON MAGUIRE

Head of Research & Finance

The Lily Foundation

In the Clinic

Reneo’s lead drug candidate mavodelpar (REN 001) is a potent and selective agonist of PPAR-delta that has been clinically shown to increase fatty acid oxidation and may promote formation of new mitochondria. It is being tested in two groups of rare genetic diseases that typically present with myopathy and for which there is no approved treatment: 

Primary mitochondrial myopathies (PMM) are a group of complex, rare, often life-threatening diseases caused by mutations in genes of the mitochondria resulting in energy deprivation in different tissues, particularly nerves and muscles.

 

Long-chain fatty acid oxidation disorders (LC-FAOD) are rare autosomal recessive disorders that affect the body’s ability to use fats from food as an energy source. If undiagnosed and untreated, these disorders can lead to serious complications resulting in hospitalizations, and in some cases, death.

 

© Copyright 2023 – Reneo Pharmaceuticals, Inc.

A pivotal Phase 2b clinical trial (the “STRIDE” study) of mavodelpar in patients with PMM with mitochondrial DNA (mtDNA) mutations and myopathy is in progress*, with 213 adult patients participating. The primary endpoint of the study is the change in distance walked during a 12-minute walk test from baseline to Week 24. 

 

A primary endpoint in any clinical trial should be clinically relevant, unbiased, interpretable, sensitive to the effects of intervention, and practical to measure. Yeske describes such an endpoint as “the marriage of clinical relevance and statistical reasoning.”

 

In the case of Reneo’s STRIDE study, the team used both patient symptom questionnaires and the Phase 1b trial 12-minute walk test data results to design the study and define its endpoints. 

 

“It’s important to remember that every data point – especially in the rare disease space – is extremely valuable, whether a clinical trial is successful or not,” says Yeske. “Each trial builds on the next, testing the drug candidate’s safety and efficacy in larger groups or other diseases. We need that data to educate the FDA and to design new trials. That’s when the floodgates of activity start to open.” 

 

Reneo continues to strive to develop therapies for patients with mitochondrial diseases so they can live healthier, happier lives. Ultimately, through innovative science, they hope to find a cure. O’Donnell acknowledges that will take a while. “What we can do in the shorter term is build upon and apply our knowledge of the mitochondria to reduce myopathy and improve the quality of life for patients and their families in ways that are most meaningful to them.”

 

“It’s not enough,” he says. “But it’s a great start.”

 

* 12/14/2023: Reneo’s STRIDE study in adult patients with primary mitochondrial myopathies did not meet its primary efficacy or secondary efficacy endpoint. The company is exploring strategic options. 

“It’s important to remember that every data point – especially in the rare disease space – is extremely valuable… We need that data to educate the FDA and to design new trials. That’s when the floodgates of activity start to open.”

PHILIP YESKE, Ph.D.

Science & Alliance Officer 

United Mitochondrial Disease Foundation (UMDF)

Learn more about Mitochondrial Disease

United Mitochondrial Disease Foundation

UMDF’s mission is to promote research and education for the diagnosis, treatment and cure of mitochondrial disorders and to provide support to affected individuals and families.

The Lily Foundation

The Lily Foundation is the UK’s leading mitochondrial disease charity and the largest charitable funder of mitochondrial research in Europe. Our mission is to improve the lives of people affected by mitochondrial diseases, while working towards a future where mitochondrial diseases can be effectively treated or cured.

Reneo Pharmaceuticals, Inc. (NASDAQ: RPHM)

Reneo is a clinical-stage pharmaceutical company focused on the development of therapies for patients with rare genetic diseases including mitochondrial diseases with significant unmet medical needs.

World Mitochondrial Disease Week

World Mitochondrial Disease Week raises awareness of mitochondrial disease (mito) on a global scale through educational, fundraising and advocacy activities.

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About RiverVest

RiverVest Venture Partners is a leading venture capital firm building life science companies to address significant unmet needs of patients and deliver consistently strong results to investors.