Researchers at Children’s Hospital of Philadelphia (CHOP) have reported new preclinical findings on the drug zagociguat, which is currently in clinical trials for Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome. The study, published in Frontiers in Pharmacology, found that zagociguat was safe and effective in several zebrafish models of primary mitochondrial disease.
Primary mitochondrial diseases are a group of genetic disorders caused by mutations affecting how cells produce and use energy. MELAS is one example, with symptoms often impacting the nervous system and muscles. There are no FDA-approved treatments for these conditions, highlighting the need for ongoing drug development.
Zagociguat (CY6463) is designed to treat neurodegenerative diseases by stimulating soluble guanylate cyclase (sGC), which affects learning and memory through the nitric oxide pathway. It is being studied in a phase 2B clinical trial for MELAS at multiple sites including CHOP.
“There are hundreds of mitochondrial diseases with distinct symptoms and medical needs, which makes developing therapeutic interventions incredibly challenging,” said senior study author Marni Falk, MD, an attending physician, professor and Executive Director of the Mitochondrial Medicine Frontier Program at CHOP. “In this instance, the encouraging early data surrounding zagociguat led us to explore the possibility of using it for other primary mitochondrial diseases -both those manifesting with dysfunction in the brain and nervous system as well as more generalized symptoms.”
The research team used various zebrafish animal models to test zagociguat. They found that oral dosing resulted in similar concentrations in both brain and muscle tissue without toxic effects. The drug protected neuromuscular function and improved survival under stress conditions in both genetic and toxin-induced models of mitochondrial disease. Swimming ability—a marker of proper energy use—was preserved across several disease models. Mechanistically, zagociguat showed positive effects on mitochondrial biogenesis and physiology.
“These preclinical results in diverse vertebrate animals that model distinct types of mitochondrial disease provide objective evidence to suggest there may potentially be wider clinical applications for zagociguat, including metabolic stroke prevention in pediatric Leigh Syndrome Spectrum and improvement of exercise performance and neuromuscular function in diverse genetic and acquired myopathic forms of primary mitochondrial disease,” Falk said. “We remain deeply committed to use cutting-edge science to accelerate discovery and advancement toward precision clinical trials of data-driven therapeutic options that may benefit mitochondrial disease patients more strategically than was previously possible.”
The study received support from a sponsored research agreement grant provided by Cyclerion Therapeutics.
Burg et al., “Zagociguat prevented stressor-induced neuromuscular dysfunction, improved mitochondrial physiology, and increased exercise capacity in diverse mitochondrial respiratory chain disease zebrafish models.” Front Pharmacol. Online July 24, 2025. DOI: 10.3389/fphar.2025.1588426.
