title: EPI-743 reverses the progression of the pediatric mitochondrial disease--genetically defined Leigh Syndrome.
abstract: BACKGROUND
  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.
  
  
  METHODS
  A single arm clinical trial was performed in children with genetically defined Leigh syndrome. Subjects were treated for 6 months 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.
  
  
  RESULTS
  Ten consecutive children, ages 1-13 years, 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.
  
  
  CONCLUSIONS
  In comparison to the natural history of Leigh syndrome, EPI-743 improves clinical outcomes in children with genetically confirmed Leigh syndrome.
authors.affiliation: Bambino Gesù Children's Hospital, IRCCS, Division of Metabolism, Piazza S Onofrio 4, 00165 Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Martinelli
authors.forename: Michela
authors.initials: M
authors.lastname: Catteruccia
authors.forename: Fiorella
authors.initials: F
authors.lastname: Piemonte
authors.forename: Anna
authors.initials: A
authors.lastname: Pastore
authors.forename: Giulia
authors.initials: G
authors.lastname: Tozzi
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pontrelli
authors.forename: Tiziana
authors.initials: T
authors.lastname: Corsetti
authors.forename: Susanna
authors.initials: S
authors.lastname: Livadiotti
authors.forename: Viktoria
authors.initials: V
authors.lastname: Kheifets
authors.forename: Andrew
authors.initials: A
authors.lastname: Hinman
authors.forename: William D
authors.initials: WD
authors.lastname: Shrader
authors.forename: Martin
authors.initials: M
authors.lastname: Thoolen
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Klein
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Guy
authors.initials: G
authors.lastname: Miller
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D057176:Compassionate Use Trials; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D011788:Quality of Life; D012720:Severity of Illness Index; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D014451:Ubiquinone; C571746:alpha-tocotrienol quinone