Abstract
BackgroundCharcot-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).Methods80 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.ResultsThis 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.ConclusionsThese results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults.Trial registrationEudraCT 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).Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0199-0) contains supplementary material, which is available to authorized users.
Highlights
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 loss and muscle wasting
As it is well known that preclinical and clinical therapeutic efficacy poorly correlate [23] and as individual drugs of PXT3003 combination have rather high safety profile, we decided to rapidly test it in CMT1A patients before studying thoroughly its precise mechanism of action in various models. In this one-year double-blind, randomised, placebo-controlled, dose-ranging Phase 2 study, we explore the potential of PXT3003 for the treatment of CMT1A as a proof of concept to decide on further investigations
In our sample of 80 mild to moderate CMT1A patients (CMTNS ≤ 20), we found that, at baseline, nerve conduction velocities were correlated with disease severity: correlations of MCV with CharcotMarie-Tooth Examination Score (CMTES) and Overall Neuropathy Limitations Scale (ONLS) were respectively of −0.32 (P = 0.0067) and −0.37 (P = 0.0014)
Summary
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 loss and muscle wasting. CMT1A accounts for 50% of patients with CMT, with an estimated prevalence of 1 in 5,000 [1,2,6]. PMP22 1.5-fold overexpression induces abnormal Schwann cell differentiation, homogeneous and diffuse nerve conduction slowing, and dysmyelination, eventually leading to axonal loss and muscle wasting. A typical feature of CMT1A includes weakness of the foot and lower leg muscles which may result in foot drop and a high-stepped gait with frequent tripping or falls [3,4]. The severity of symptoms is quite variable in different patients and even among family members suffering from the disease
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