Restoring Cellular Power Outages: A New Drug to Treat Mitochondrial Diseases


A small biotech company is aiming to recharge tired cells, giving mitochondrial disease patients new hope of a disease-specific treatment.

“We focus on patients, going after diseases with high unmet needs, like primary mitochondrial myopathies,” Niall O’Donnell, Ph.D., President, CEO and Director of Reneo Pharmaceuticals, told BioSpace.

Despite COVID-19 crashing the party and stopping their Phase Ib trial early, the company still showed that their drug candidate REN001 was safe in PMM patients, paving the way to a large trial slated to begin in early 2021. The FDA also gave REN001 Orphan Drug Designation for PMM in June.

Alejandro Dorenbaum, MD, Chief Medical Officer at Reneo, recently gave a clinical trial update at the virtual UMDF Power Surge 2020 conference (see the “Clinical Trial Updates” video around 25:35).

How exactly does REN001 recharge cells in mitochondrial disease patients? To answer that question, we’ll have to take a journey inside our cells to the mitochondria.

Tired cells

Mitochondria are little power factories inside almost every cell in the body; they provide each cell with the energy it needs to function. You can thank your mom for your mitochondria (sorry dads, you can’t pass along your mitochondria).

Mitochondria are unique because they contain their own genome, completely separate from the entire nuclear genome you usually think about. The mito genome is small but mighty – 16,500 bp (only about 0.0005 percent of the entire genome) containing 37 genes. Thirteen of these genes encode enzymes needed to convert food you eat into the cellular energy molecule adenosine triphosphate (ATP).

Mutations in mitochondrial genes can disrupt the ATP creation pathway, stunting mitochondria’s ability to create energy. Dysfunctional mitochondria leave cells fatigued.

Primary mitochondrial myopathies (PMMs) are a group of rare, often life-threatening, mitochondrial diseases where genetic mutations in the mitochondria cause muscle dysfunction and weakness, among other problems.

“There are at least 50 different syndromes under the category of PMMs, it’s an alphabet soup,” commented O’Donnell. “We have a wealth of information on genetic lesions and the syndromes they cause. A lot of syndromes overlap, and, thanks to mitochondrial sequencing, we now know they are caused by the same genetic lesion.”

Mitochondrial diseases as a whole affect an estimated 1 in 5,000 people in the US (about 66,000 people), a majority of which are thought to be PMMs – O’Donnell estimated there are about 40,000 PMM patients in the U.S.

PMM can be mild (appearing later in life) or more severe (appearing earlier); however, most PMM ultimately cause life-threatening muscle problems, such as weakened chest muscles causing breathing problems, heart problems, or difficulty swallowing leading to nutritional deficiencies.

“People with a PMM experience severe impacts on their daily functions – they have severe fatigue, can’t walk or exercise, and have an impaired quality of life,” O’Donnell said.

Unfortunately, there is currently no cure for PMM, only supportive treatments, like dietary supplements, physical therapy, and exercise, to help patients better manage symptoms. (Yes, despite the fatigue and exercise intolerance many PMM patients experience, they are often encouraged to exercise to strengthen their muscles.) Some patients take unique combinations of vitamins, antioxidants, and other supplements that may support mitochondrial function. However, some patients don’t benefit from these “mito-cocktails” and clinical evidence from controlled trials has not shown clear benefits.

Restoring the power outage

Reneo’s drug directly addresses the molecular dysfunctions causing mitochondrial problems. REN001 is a small molecule peroxisome proliferator-activated receptor delta (PPAR-delta) agonist, which stimulates the receptor. PPAR-delta is a key receptor in mitochondria, regulating energy production. Although it is expressed in all cells, it’s highly expressed in skeletal muscles.

“This receptor regulates the interaction between metabolites and energy needs, telling cells to increase energy production during exercise, for example,” explained O’Donnell.

PPAR-delta is a master conductor of the mitochondrial orchestra. Activating PPAR-delta increases expression of enzymes that metabolize fats to generate energy and stimulates the genes involved in forming new mitochondria, causing more mitochondria to be created, Dorenbaum explained in his presentation.

“If we can improve how the mitochondria function and we can expand the number of mitochondria in the cell, we can provide better energy for the muscle to work well,” said Dorenbaum.

REN001 is not an entirely new compound – it was licensed to Reneo in 2017 from vTv Therapeutics (then called HPP593) as a potential treatment for fatty acid oxidation disorders, another group of rare diseases.

“When we evaluated REN001, it already had extensive safety, pharmacology, and chronic toxicology studies that had been completed in animals, so we had a lot of understanding about how this drug may be tolerated and how it may work in patients with PMM,” Dorenbaum highlighted in his Power Surge presentation.

Now, it’s being put to the test as a treatment for PMMs.

The Phase 1 results are in

Although Reneo’s open-label Phase Ib trial was terminated early due to COVID-19, the company had enough data to assess REN001’s safety.

REN001 was given orally once per day for 12 weeks in 23 adult PMM patients; most patients chose to continue treatment in a 36-week extension. In addition to monitoring safety and tolerability, patients underwent functional tests and muscle biopsies to study the mitochondria before and after treatment.

“REN001 was safe and well-tolerated in patients, offered a low burden dosing schedule for patients, and had good pharmacokinetics for oral delivery,” O’Donnell explained. “The muscle biopsy data are currently being worked on now.”

“The advantage of this drug is that it can be given once a day by mouth, very easy to take,” Dorenbaum said in his presentation.

Dorenbaum also explained the six preliminary functional endpoints evaluated in the trial: three patient-reported symptom questionnaires (36-item Short Form Survey, SF-36; Modified Fatigue Impact Scale, MFIS; and Brief Pain Inventory, BPI); and three exercise tests (a 12-minute walk test, a peak exercise test, and a sub-maximal exercise test). He reported “promising improvements in the walk test and in symptom questionnaires.”

“We wanted to see how each of these tests behave in the patients, whether patients can complete them, and what kind of information these tests give us,” explained Dorenbaum. “We decided to choose the walk test as the test we plan to use in future clinical trials.”

These data enable the company to design their larger trial, a double-blinded, placebo-controlled trial that will recruit 200 adult PMM patients from approximately 20 global trial sites. Patients will take REN001 or placebo for 24 weeks, then their ability to complete the walk test will be assessed and they will report their symptoms through questionnaires.

The company is currently working with regulatory agencies in various countries to get the trial sites set up for the trial to begin in the first few months of 2021.

REN001 is one of only a few PPAR-delta-targeting drugs being pursued to treat PMMs, including Mitobridge’s drug candidate MA-0211 (ASP0367). MA-0211 is currently listed on the company’s website as being in Phase I trials, but there were no trials of the drug in mitochondrial myopathies listed on as of the end of July.

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