Researchers in the Mitochondrial Medicine Frontier Program at Children’s Hospital of Philadelphia (CHOP) found that a new drug therapy currently in clinical trials for a form of primary mitochondrial disease – Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome – was safe and effective in multiple preclinical zebrafish models. These encouraging findings suggest the drug may have broader use in other forms of primary and secondary mitochondrial disease. The findings were published recently by the journal Frontiers in Pharmacology.
Primary mitochondrial diseases are a growing class of genetic-based mitochondrial disorders, caused by inherited mutations in any of more than four hundred different genes that impact the body’s ability to create and use energy generated by the cell’s batteries, mitochondria. MELAS is a highly variable example of one primary mitochondrial disease clinical syndrome, causing a range of symptoms that most commonly affect the nervous system and muscles. There are no currently approved FDA treatments for the broad class of primary mitochondrial disease, which is why advancing drug development related to mitochondrial disorders remains so critical.
Zagociguat (CY6463) is a proprietary drug being developed as a treatment for neurodegenerative diseases by acting as a stimulator of soluble guanylate cyclase (sGC), which plays a role in learning and memory by activation of the nitric oxide signaling pathway. Zagociguat is currently being evaluated for MELAS in a phase 2B clinical trial ongoing at multiple sites, including at CHOP. With promising early phase 2A trial results, the researchers sought to evaluate if the drug had broader applications beyond MELAS in other primary mitochondrial diseases.
“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.”
Using a series of preclinical zebrafish animal models, the researchers found that zagociguat was well-tolerated without toxic effects, and oral dosing achieved similar concentrations in brain and muscle tissue. Researchers observed protection of neuromuscular function and improved survival under stress conditions in both primary (NDUFS2 CRISPR/Cas9 gene deletion based) complex I disease and secondary (acute toxin based) mitochondrial complex I or IV deficient larval animals. Larval swimming ability, which helps show researchers proper energy use and exercise, was also preserved in FBXL4 disease larvae, as well as in a SURF1 disease adult zebrafish model. At a mechanistic level, zagociguat had beneficial effects on mitochondrial biogenesis and key aspects of mitochondrial physiology.
With promising early results demonstrating zagociguat’s safety, tolerability, penetrance of the central nervous system, protection of neuromuscular function and improved mitochondrial physiology, the researchers suggest that the drug may hold value for study in a broader array of acute and chronic mitochondrial disease beyond MELAS. Its potential could extend to Leigh syndrome spectrum disorder, which most commonly affects children, as well as primary mitochondrial myopathies.
“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.”
This study was supported an investigator-initiated sponsored research agreement grant from 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.
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Researchers in the Mitochondrial Medicine Frontier Program at Children’s Hospital of Philadelphia (CHOP) found that a new drug therapy currently in clinical trials for a form of primary mitochondrial disease – Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome – was safe and effective in multiple preclinical zebrafish models. These encouraging findings suggest the drug may have broader use in other forms of primary and secondary mitochondrial disease. The findings were published recently by the journal Frontiers in Pharmacology.
Primary mitochondrial diseases are a growing class of genetic-based mitochondrial disorders, caused by inherited mutations in any of more than four hundred different genes that impact the body’s ability to create and use energy generated by the cell’s batteries, mitochondria. MELAS is a highly variable example of one primary mitochondrial disease clinical syndrome, causing a range of symptoms that most commonly affect the nervous system and muscles. There are no currently approved FDA treatments for the broad class of primary mitochondrial disease, which is why advancing drug development related to mitochondrial disorders remains so critical.
Zagociguat (CY6463) is a proprietary drug being developed as a treatment for neurodegenerative diseases by acting as a stimulator of soluble guanylate cyclase (sGC), which plays a role in learning and memory by activation of the nitric oxide signaling pathway. Zagociguat is currently being evaluated for MELAS in a phase 2B clinical trial ongoing at multiple sites, including at CHOP. With promising early phase 2A trial results, the researchers sought to evaluate if the drug had broader applications beyond MELAS in other primary mitochondrial diseases.
“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.”
Using a series of preclinical zebrafish animal models, the researchers found that zagociguat was well-tolerated without toxic effects, and oral dosing achieved similar concentrations in brain and muscle tissue. Researchers observed protection of neuromuscular function and improved survival under stress conditions in both primary (NDUFS2 CRISPR/Cas9 gene deletion based) complex I disease and secondary (acute toxin based) mitochondrial complex I or IV deficient larval animals. Larval swimming ability, which helps show researchers proper energy use and exercise, was also preserved in FBXL4 disease larvae, as well as in a SURF1 disease adult zebrafish model. At a mechanistic level, zagociguat had beneficial effects on mitochondrial biogenesis and key aspects of mitochondrial physiology.
With promising early results demonstrating zagociguat’s safety, tolerability, penetrance of the central nervous system, protection of neuromuscular function and improved mitochondrial physiology, the researchers suggest that the drug may hold value for study in a broader array of acute and chronic mitochondrial disease beyond MELAS. Its potential could extend to Leigh syndrome spectrum disorder, which most commonly affects children, as well as primary mitochondrial myopathies.
“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.”
This study was supported an investigator-initiated sponsored research agreement grant from 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.
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