EPI-743 reverses the progression of the pediatric mitochondrial disease—Genetically defined Leigh Syndrome

• Published in: Molecular genetics and metabolism Vol. 107; no. 3; pp. 383 - 388
• Main Authors: Martinelli, Diego, Catteruccia, Michela, Piemonte, Fiorella, Pastore, Anna, Tozzi, Giulia, Dionisi-Vici, Carlo, Pontrelli, Giuseppe, Corsetti, Tiziana, Livadiotti, Susanna, Kheifets, Viktoria, Hinman, Andrew, Shrader, William D., Thoolen, Martin, Klein, Matthew B., Bertini, Enrico, Miller, Guy
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2012
• Subjects: Adolescent; Child; Child, Preschool; Compassionate Use Trials; Disease Progression; Drug Administration Schedule; EPI-743; Female; Humans; Infant; Leigh Disease - drug therapy; Leigh Disease - genetics; Leigh Disease - metabolism; Leigh Disease - pathology; Leigh syndrome; Male; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial disease; Psychomotor Performance - drug effects; Quality of Life; Severity of Illness Index; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacokinetics; Ubiquinone - pharmacology; Ubiquinone - therapeutic use; EPI-743; Mitochondrial disease; Leigh syndrome
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2012.09.007

Genetically defined Leigh syndrome is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. No treatment is available. EPI-743 is a novel small molecule developed for the treatment of Leigh syndrome and other inherited mitochondrial diseases. In compassionate use cases and in an FDA Expanded Access protocol, children with Leigh syndrome treated with EPI-743 demonstrated objective signs of neurologic and neuromuscular improvement. To confirm these initial findings, a phase 2A open label trial of EPI-743 for children with genetically-confirmed Leigh syndrome was conducted and herein we report the results. A single arm clinical trial was performed in children with genetically defined Leigh syndrome. Subjects were treated for 6months with EPI-743 three times daily and all were eligible for a treatment extension phase. The primary objective of the trial was to arrest disease progression as assessed by neuromuscular and quality of life metrics. Results were compared to the reported natural history of the disease. Ten consecutive children, ages 1–13years, were enrolled; they possessed seven different genetic defects. All children exhibited reversal of disease progression regardless of genetic determinant or disease severity. The primary endpoints—Newcastle Pediatric Mitochondrial Disease Scale, the Gross Motor Function Measure, and PedsQL Neuromuscular Module—demonstrated statistically significant improvement (p<0.05). In addition, all children had an improvement of one class on the Movement Disorder-Childhood Rating Scale. No significant drug-related adverse events were recorded. In comparison to the natural history of Leigh syndrome, EPI-743 improves clinical outcomes in children with genetically confirmed Leigh syndrome. ► We performed a prospective open label trial of the novel therapeutic EPI-743 for children with Leigh syndrome ► There was a statistically significant improvement in all trial outcome measurements signifying arrest and reversal of disease progression ► There were no drug related adverse events or clinical laboratory abnormalities