International, multi-center, randomized, double-blind, placebo-controlled phase III study assessing in parallel groups the efficacy and safety of 2 doses of PXT3003 in patients with Charcot-Marie-Tooth Disease type 1A treated 15 months

CMT1A, the most frequent CMT subtype (40 to 50% of all CMT), belongs to the
group of inherited, progressive, chronic sensory and motor peripheral
neuropathies referred to as Charcot-Marie-Tooth (CMT) disease or also as
*Hereditary Motor and Sensory Neuropathy*
(HMSN) or *Peroneal Muscular Atrophy* (PMA).
CMT1A is caused by a specific duplication in the gene encoding for the
"peripheral myelin protein of 22 Kilodalton" (PMP22) expressed in Schwann cells
and could be defined as a gene-dosage disease causing a 1.5-fold
over-expression of the PMP22 protein in Schwann cells. The moderately elevated
expression of this gene disrupts peripheral nerve myelination by Schwann cells
and consecutively, slows signal transmission alongside the axons and deprives
them of important neurotrophic factors normally provided by mature Schwann
cells. Ultimately, axonal loss is responsible for the clinical phenotype due to
muscle and sensory organ denervation.
PXT3003, is a fixed dose combination of (RS)-baclofen, naltrexone hydrochloride
and Dsorbitol selected via a Systems Biology approach and developed by
Pharnext, with the aim to lower toxic PMP22 gene over-expression in CMT1A.
The expected effect of the combination of the three drugs in the treatment of
CMT1A has been demonstrated first pre-clinically ex vivo and in vivo (Chumakov,
Milet et al., 2014), and then by a phase II proof of concept study testing 3
doses of the combination at the same ratio compared to Placebo in 80 patients
with CMT1A treated for 12 months. This phase II study demonstrated the good
tolerability and safety of 3 tested doses of PXT3003 (primary outcome measure)
and provided preliminary evidence of efficacy with a significant *doseeffect*
and an increasing effect among the 3 tested doses demonstrating positive
results after 12 months on the selected relevant clinical and
electrophysiological outcome measures only for the highest Dose. At this
highest dose baclofen, naltrexone and sorbitol were administrated at much lower
doses (10 to 100 times less) than used for their respective approved
indications as daily doses were 6 mg baclofen, 0.7 mg naltrexone and 210 mg
sorbitol (Attarian, Vallat et al., 2014).
It is postulated that PXT3003 deserves further clinical investigation in a
pivotal confirmatory study in a larger CMT1A population. For this next study, 2
doses will be tested, compared to placebo: the highest dose found effective in
the phase II and a higher dose (double dose with the same ratio between each
active components of PXT3003). The choice for this additional dose was limited
by the baclofen dosage, that could not be increased above 6 mg given twice a
day, in order to avoid known side effects with this drug particularly for
chronic administration in active young people, and to preserve a good safety
profile. As there is no approved treatment in CMT1A, there is no comparator to
introduce, as usually done in
Phase III trials. The 2 tested doses will be compared only to Placebo in a
randomized double-blind design with 3 balanced groups (1:1:1).

Primary objective:
To assess the efficacy of PXT3003 compared to Placebo on the disability
measured by the ONLS score in CMT1A patients treated for 15 months.

Secondary objectives:
- To assess the efficacy of PXT3003 compared to Placebo on clinical and
functional tests, electrophysiological parameters, and measures of quality of
life;
- To assess the safety and tolerability of PXT3003 compared to Placebo;
- To assess plasma concentrations of PXT3003 components (at peak and trough)
when administered with 2 different doses;
- To assess the change over time of potential blood biomarkers;
- To assess molecular changes in skin biopsy, when this procedure will be
possible (ancillary sub-study);
- To explore potential new imaging biomarkers by calf MRI, when this procedure
will be possible (ancillary sub-study).

Phase III, double-blind, international, multi-center randomized,
placebo-controlled study with 3 parallel groups (PXT3003 Dose 1, PXT3003 Dose 2
or matching Placebo (1:1:1)), for 15 months (65 weeks).

A total of 300 patients will be randomized (1:1:1) into 3 parallel groups :
Dose 1 = 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol given twice
daily;
Dose 2 = 6 mg baclofen, 0.70 mg naltrexone and 210 mg sorbitol given twice
daily;
The control group will be matching placebo.

The study drug (PXT3003 or matching placebo) will be administered per oral
route 5 ml twice daily (morning and evening with food) for 15 months.

The study includes administration of the study drug twice daily during 15
month. As with all drugs, the patients may experience adverse events, as
described in section E9, although PXT3003 showed good tolerance.

Patients will undergo other examinations like blood samples,10 min walking
test, ECG, electromyogram. Some discomfort may result of these tests. This is
also described in section E9 of this form.

Patients who are taking the study drug (group dose 1 and 2) may have an
improvement of the disease. All patients will be proposed to participate to an
extension study where they will be given the active product.