title: An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A.
abstract: BACKGROUND
  Charcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3).
  
  
  METHODS
  80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes.
  
  
  RESULTS
  This trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group.
  
  
  CONCLUSIONS
  These results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults.
  
  
  BACKGROUND
  EudraCT Number: 2010-023097-40. ClinicalTrials.gov Identifier: NCT01401257. The Committee for Orphan Medicinal Products issued in February 2014 a positive opinion on the application for orphan designation for PXT3003 (EMA/OD/193/13).
authors.forename: Shahram
authors.initials: S
authors.lastname: Attarian
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vallat
authors.forename: Laurent
authors.initials: L
authors.lastname: Magy
authors.forename: Benoît
authors.initials: B
authors.lastname: Funalot
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Gonnaud
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lacour
authors.forename: Yann
authors.initials: Y
authors.lastname: Péréon
authors.forename: Odile
authors.initials: O
authors.lastname: Dubourg
authors.forename: Jean
authors.initials: J
authors.lastname: Pouget
authors.forename: Joëlle
authors.initials: J
authors.lastname: Micallef
authors.forename: Jérôme
authors.initials: J
authors.lastname: Franques
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Lefebvre
authors.forename: Karima
authors.initials: K
authors.lastname: Ghorab
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Al-Moussawi
authors.forename: Vincent
authors.initials: V
authors.lastname: Tiffreau
authors.forename: Marguerite
authors.initials: M
authors.lastname: Preudhomme
authors.forename: Armelle
authors.initials: A
authors.lastname: Magot
authors.forename: Laurène
authors.initials: L
authors.lastname: Leclair-Visonneau
authors.forename: Tanya
authors.initials: T
authors.lastname: Stojkovic
authors.forename: Laura
authors.initials: L
authors.lastname: Bossi
authors.forename: Philippe
authors.initials: P
authors.lastname: Lehert
authors.forename: Walter
authors.initials: W
authors.lastname: Gilbert
authors.forename: Viviane
authors.initials: V
authors.lastname: Bertrand
authors.forename: Jonas
authors.initials: J
authors.lastname: Mandel
authors.forename: Aude
authors.initials: A
authors.lastname: Milet
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Hajj
authors.forename: Lamia
authors.initials: L
authors.lastname: Boudiaf
authors.forename: Catherine
authors.initials: C
authors.lastname: Scart-Grès
authors.forename: Serguei
authors.initials: S
authors.lastname: Nabirotchkin
authors.forename: Mickael
authors.initials: M
authors.lastname: Guedj
authors.forename: Ilya
authors.initials: I
authors.lastname: Chumakov
authors.forename: Daniel
authors.initials: D
authors.lastname: Cohen
mesh_terms: D000328:Adult; D001418:Baclofen / Q000008:administration & dosage*; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000008:administration & dosage*; D013012:Sorbitol / Q000008:administration & dosage*
chemical_list: D013012:Sorbitol; D009271:Naltrexone; D001418:Baclofen