Khondrion, a biopharmaceutical company focused on therapies for primary mitochondrial disease (PMD), has received FDA clearance for its Investigational New Drug (IND) application for sonlicromanol. This clearance paves the way for a pivotal Phase 3 clinical trial in adult patients with PMD caused by the m.3243A>G mutation, the most common genetic defect associated with the disease. The trial is expected to begin in 2025.
Sonlicromanol: A Novel Approach to PMD Treatment
Sonlicromanol is a first-in-class, brain-penetrant redox-modulator with anti-inflammatory properties designed to target key metabolic and inflammatory pathways implicated in PMD. There are currently no approved therapies for PMD associated with the m.3243A>G variant, highlighting a significant unmet medical need.
Promising Phase 2b Results
Data from Khondrion’s multicenter Phase 2b program, published in Brain, demonstrated significant patient benefits with sonlicromanol across multiple outcome measures. A 52-week extension study showed sustained improvements in chronic fatigue and muscle weakness, two of the most debilitating symptoms reported by PMD patients. In the 52-week open-label extension part of the Phase 2b program, clinically meaningful and statistically significant results were observed for chronic fatigue (p-value of 0.004) and muscle weakness (p-value of 0.0161).
Phase 3 Trial Design
The upcoming Phase 3 trial is a 52-week, double-blind, randomized, placebo-controlled, multi-center, parallel-group study. It aims to enroll 150 adult patients with a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G variant. The primary endpoints will be assessed using the Neuro-QoL Fatigue short form questionnaire and the Five Times Sit-to-Stand test, focusing on chronic fatigue and muscle weakness.
Management Perspective
"The FDA’s clearance of our IND application for a pivotal Phase 3 trial marks another important milestone for Khondrion’s development of sonlicromanol, a disease-modifying therapy for primary mitochondrial disease that is so desperately needed by PMD patients," said Prof. Dr. Jan Smeitink, Chief Executive Officer at Khondrion. "We look forward to sharing progress of our clinical program including its expected initiation next year."
Broader Implications for PMD Treatment
PMDs are the most prevalent inherited neurometabolic disorders, affecting an estimated 1 in 4,300 individuals, translating to approximately 65,000 people in the US alone. Khondrion's longer-term objective is to make sonlicromanol widely available for the broader PMD patient community. Sonlicromanol has received orphan drug designation in both the US and Europe, as well as a rare pediatric disease designation in the US.
