A Potential Breakthrough for Mitochondrial Disease

Mitochondrial diseases, a group of debilitating disorders with no known cure, affect the body’s ability to produce energy.These diseases are often caused by mutations in mitochondrial DNA, disrupting the organelle’s function. The severity and presentation of mitochondrial disease can vary greatly due to differences in heteroplasmy – the ratio of mutant to healthy mitochondria – across cells and individuals.

For U.S. families impacted by these conditions, the lack of effective treatments is a major concern. Many rely on supportive care to manage symptoms. However, results from a Phase 2b trial offer a glimmer of hope.

Sonlicromanol Shows Promise in clinical Trials

Khondrion, a biopharmaceutical company, recently announced positive results from a Phase 2b trial of their drug, sonlicromanol. The trial focused on patients with the m.3243A>G mutation,a common genetic cause of mitochondrial disease. The study, published in the journal Brain, demonstrated that sonlicromanol was safe, well-tolerated, and led to notable health improvements.

Understanding the m.3243A>G Mutation

The m.3243A>G mutation disrupts the function of a specific mitochondrial tRNA, impairing the synthesis of proteins essential for energy production. This mutation can lead to a range of progressively worsening symptoms, including deafness and stroke-like episodes. Currently,ther are no effective treatments available to address these symptoms.

Sonlicromanol is designed to target key pathways involved in mitochondrial energy production and oxidative stress. The oral medication boosts ATP production, reduces oxidative damage and inflammation, and prevents cell death.

The trial involved an initial randomized controlled trial (RCT) to determine the optimal drug dosage, followed by a 52-week open-label extension study to evaluate long-term safety, efficacy, and tolerability.

Significant Improvements Observed

The study revealed that sonlicromanol improved patients’ quality of life, mood, fatigue, and muscle function, as measured by standardized tests. Notably, patients’ scores on the Newcastle Mitochondrial Disease Adult Scale (NMDAS), wich assesses the severity of mitochondrial disease, trended downward after treatment, indicating improved disease status.

That, I’ve never seen before.
Jan Smeitink, Khondrion

Jan Smeitink noted that he had never observed a decline in NMDAS scores in his extensive experience with mitochondrial disease patients. It was far beyond expectations, he said.

While the drug did not significantly improve cognitive function as measured by an identification task in the main analysis, further analysis adjusting for baseline scores indicated enhancement in cognitive function.

Challenges and Future Directions

Mike murphy, a biochemist at the University of Cambridge, acknowledged the challenges inherent in testing a drug in patients with varying symptom severities. it’s very challenging to do any trial like this. We’ve got a very variable cohort of patients and a small number [of them]. And if you look at the variation even in the mutation load, that was also quite challenging.

Despite the challenges, Murphy commended Khondrion’s dedication to improving the lives of patients with mitochondrial disease. Khondrion is preparing for a Phase 3 clinical trial to further assess sonlicromanol. The FDA has cleared their Investigational new Drug (IND) application, enabling them to proceed with this pivotal trial phase.The trial aims to enroll 150 adult patients with the m.3243A>G variant.

We expect to have the first patients in early in the second half of this year, Smeitink said. The sooner, the better.

Implications for U.S. Patients

The development of sonlicromanol has significant implications for U.S. patients with mitochondrial disease. If proven effective in Phase 3 trials, this drug could become the first approved treatment targeting the underlying cause of the disease. This would provide a much-needed option for managing the debilitating symptoms and improving the quality of life for affected individuals and their families.

The FDA’s clearance of the IND application signifies a critical step toward making sonlicromanol available to U.S. patients. As the Phase 3 trial progresses,the mitochondrial disease community in the U.S. will be closely watching for updates and hoping for a positive outcome.