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

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.

Promoting peripheral myelin repair

“…In a recent systems biology-based approach a novel combination of three repurposed drugs, namely baclofen, naltrexone and sorbitol (named PXT3003) were tested in CMT1A animal models and in a phase 2 clinical trial (Attarian et al, 2014; Chumakov et al, 2014). Prior to the clinical trial, PXT3003 was studied in three distinct experimental models; including myelinating cocultures from CMT1A rats, transgenic PMP22 overproducing rats and in mouse nerve crush injury (Chumakov et al, 2014).…”

“…In each of these experimental paradigms, the three combined drugs proved efficacies in improving myelination and ameliorating neuropathic phenotype, including lowering PMP22 message levels (Chumakov et al, 2014). Significantly, PXT3003 was shown to be safe, with good tolerability in a one-year long clinical trial with 80 adult CMT1A patients (Attarian et al, 2014). Although based on neuropathy assessment scale, only a relatively modest improvement (8–12%) was observed, this trial is the most promising treatment so far for hereditary demyelination (Attarian et al, 2014; Ekins et al, 2015).…”

“…Significantly, PXT3003 was shown to be safe, with good tolerability in a one-year long clinical trial with 80 adult CMT1A patients (Attarian et al, 2014). Although based on neuropathy assessment scale, only a relatively modest improvement (8–12%) was observed, this trial is the most promising treatment so far for hereditary demyelination (Attarian et al, 2014; Ekins et al, 2015). Electrophysiological data from this study suggests that PTX3003 slows disease course in the patients through improving myelin and protecting axons.…”

“…Electrophysiological data from this study suggests that PTX3003 slows disease course in the patients through improving myelin and protecting axons. Because of the positive results from the Phase II clinical trial (Attarian et al, 2014), Pharnext is launching an international, multi-center, randomized, double blind, placebo-controlled Phase III study with PTX3003. Since PTX3003 was effective in improving myelination in the nerve crush injury model (Chumakov et al, 2014) it is possible that this investigational Pleodrug will be beneficial in both chronic and acute demyelination paradigms.…”

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

“…Further links between CMT and alcohol dependence are provided by recent studies, showing that a triple-therapy with a combination of naltrexone, baclofen, and sorbitol (PXT3003) can improve health of patients suffering from CMT disease. 53,54 While PXT3003 was shown to downregulate PMP22 mRNA expression and improve myelination as well as axonal regeneration, 53 both naltrexone and baclofen are also used (partly off-label) to treat alcohol dependence. 55 Acting as an opioid antagonist (naltrexone) and a GABA-B-receptor agonist (baclofen), respectively, these drugs reduce the rewarding effects of alcohol and inhibit dopaminergic neurotransmission.…”