Old Title: International, multi-center, open label 9-month FOLLOW-UP extension study assessing the long term safety and tolerability of PXT3003 in patients with Charcot-Marie-Tooth Disease type 1A.;New title : International, multi-center, open label FOLLOW-UP extension study assessing the long term safety and tolerability of PXT3003 in patients with Charcot-Marie-Tooth Disease type 1A.

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). It isexpressed 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 primary objectives:
Period 1:
The primary objective is to assess the long-term (up to 2 years) safety and
tolerability of two doses of PXT3003.
Period 2:
For patients continuing after V9, the main objective will be to offer patients
the opportunity to access to twice Dose 1 equivalent to Dose 2 of PXT3003, with
a regular safety follow-up


The secondary objectives are:
Period 1:
- To gather long-term data (up to 2 years) to assess and estimate the long-term
effect of PXT3003 on clinical, functional and electrophysiological endpoints;
- To compare the effect of PXT3003 in patients receiving PXT3003 active dose
from the start of the primary study versus patients assigned to a delayed start
(i.e., who received placebo during the primary study) in order to show if
PXT3003 slows the progression of the disease, as measured via clinical scores;
- To assess the evolution of potential blood biomarkers and molecular changes
in skin biopsy on longer term.
Period 2:
For patients continuing after V9, sefty follow-up and ONLS score follow-up on a
6-month frequency.

Period 1 : International, multi-center open-label, study testing two doses of
PXT3003 during 9 months, following the up to 15-month primary study (
CLN-PXT3003-02).

Period 2 : International, multi-center, open-label study offering access to
twice Dose 1 equivalent to Dose 2 of PXT3003 until the first marketing
authorization is obtained (estimated in 2024).

Period 1:
PXT3003 is a fixed dose combination of RS-baclofen, naltrexone hydrochloride
and Dsorbitol.
Two active doses will be tested:
Dose 1 = 3 mg baclofen, 0.35 mg naltrexone and 105 mg sorbitol given per oral
route twice daily; 5 ml per intake
Dose 2 = 6 mg baclofen, 0.70 mg naltrexone and 210 mg sorbitol given per oral
route twice daily; 10 ml per intake.
Investigational treatments will be supplied as 100 mL clear oral solution in
amber glass bottle (for 10 days of treatment); they will be provided in carton
boxes of 4 bottles. Since this is a double blind study, both doses will be
provided with the same presentation and taste.
Bottle will be delivered with a plastic adapter and an adaptable plastic
pipette for medication dispensation. The pipette will have 2.5-mL and 5-mL
graduations, corresponding to half-dose and full dose of the medication to be
administered twice daily (morning and evening with food).

To improve treatment tolerability, all the patients will take the half-dose
during the first two weeks before the full dose during the rest of the 9
months.
Patients in dose 1 will take 2.5 mL, twice daily in first 2 weeks and
thereafter 5 mL, twice daily. Patients in dose 2 will take 5 mL, twice daily in
first 2 weeks and thereafter 10 mL (2x5), twice daily.

Period 2:
After V9, only twice dose 1 equivalent to dose 2 of PXT3003 will be used:
D2 = equivalent to twice D1 (6 mg baclofen, 0.70 mg naltrexone and 210 mg
sorbitol) given per oral route (10 mL total volume, i.e. twice 5 mL) twice
daily.

The study includes administration of the study drug twice daily during 9 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.