World's first mitochondrial disease treatment drug: Tohoku University and others launch phase II clinical trial of "MA-5"

A research group led by Professor Takaaki Abe of the Graduate School of Pharmaceutical Sciences at Tohoku University, Professor Kei Murayama of the Graduate School of Medicine at Juntendo University, and Lecturer Yohei Honkura of the Department of Otolaryngology and Head and Neck Surgery at Tohoku University Hospital announced on November 19 that they will begin investigator-initiated Phase II clinical trials of "MA-5 (Mitochonic Acid 5)" at four medical institutions in Japan. The candidate treatment drug for mitochondrial disease has been developed with support from Japan Agency for Medical Research and Development (AMED). The drug can be administered orally, and Phase I clinical trials in healthy subjects have demonstrated it has almost no side effects. The drug is expected not only to treat mitochondrial disease, for which there is currently no remedy, but also to be developed as a therapy for improving frailty and other conditions.

MA-5 has been shown to bind to mitofilin, a protein that maintains the folded internal structure (cristae) where ATP synthesis occurs in mitochondria. By altering the shape of the cristae in a way that constricts the entrance to the folds, MA-5 promotes the polymerization of ATP synthase enzymes and increases ATP production efficiency.

In this Phase II clinical trial, different doses (low dose, high dose) of MA-5 or placebo will be orally administered to mitochondrial disease patients with hearing loss in a double-blind manner. Safety and pharmacokinetics will be evaluated, and hearing will be assessed using auditory brainstem response (ABR). Additionally, effects on muscle strength, kidney, heart, and other organs will be examined for a comprehensive evaluation.

The investigational drug administration period is 12 weeks, followed by a 12-week late observation period. Phase II is scheduled to run from December of 2025 to December of this year. Since this is a rare disease, it has not yet been decided whether Phase III will be conducted.

Phase II will be conducted at four facilities: Juntendo University Hospital, Tohoku University Hospital, Tokyo Medical Center, and Jichi Medical University Hospital. Previously, the research group confirmed that MA-5 improves survival rates in cultured skin cells from approximately 100 patients with mitochondrial diseases. Represented illnesses include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); Leigh syndrome; Leber's hereditary optic neuropathy; and Kearns-Sayre syndrome. The group also confirmed that administration to mice with mitochondrial dysfunction improved cardiac and renal dysfunction and enhanced survival rates. Furthermore, administration to various mouse models of hearing loss (age-related, noise-induced, and drug-induced hearing loss) showed improvements in hearing. Studies using iPS cell-derived inner ear cells revealed that MA-5 increases ATP in inner ear cells and activates cellular function.

Mitochondrial disease is a collective term for rare diseases caused by dysfunction of mitochondria, which produce 95% of the cellular energy ATP. Various symptoms appear due to congenital ATP depletion. While it is a serious disease that can develop at any age from childhood to old age, diagnosis is difficult because the pathways of onset are complex and symptoms vary widely. Currently, there is no drug for fundamental treatment. Taurine has been shown to be therapeutically effective only for MELAS, one type of mitochondrial disease, but it is not effective for other mitochondrial diseases. Since mitochondrial dysfunction is observed not only in mitochondrial diseases but also in a wide range of conditions - including hearing loss, Alzheimer's disease, and frailty - the treatment drug is expected to be broadly effective.