AIM: To obtain confirmation of efficacy and safety of PXT3003 as a specific treatment for CMT1A 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 efficacy of PXT3003 compared to placebo clinical scores (ONLS and CMTNS-v2) functional tests ( 10mWT, 9-HPegT, QMT hand grip & dorsiflexion) electrophysiological parameters ( CMAP, SNAP, NCV) measures of quality of life (EQ-5D and VAS) Safety and tolerability of PXT3003 compared to placebo PXT3003 plasma sample (Cmax and through) for population pharmacokinetics Change over time of potential blood biomarkers Molecular changes in skin biopsy (ancillary study) Potential imaging changes through leg MRI (ancillary study).

1. INTERNATIONAL, MULTICENTER, 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 FOR 15 MONTHS
Attarian S1, De Visser M2, Roberts M3, Thomas F4, Sevilla T5, Van Damme P6, Young P7, Bertrand V8, Guedj M8, Scart-Grès C8, Lewis R9, Vallat JM10, Lehert
P11, Cornblath DR12 & Cohen D8
BACKGROUND AND RATIONALE: To date, no treatment is available for Charcot-Marie-Tooth type 1A (CMT1A) disease. CMT1A is a rare peripheral neuropathy
associated with PMP22 gene duplication. In pre-clinical experiments PXT3003, a fixed combination pleodrug comprising low doses of baclofen, naltrexone hydrochloride
and sorbitol, down-regulated the overexpression of PMP22 gene both in vitro and in vivo in the PMP22 transgenic rat model of CMT1A. Its pleiotropic effect improved
important disease hallmarks in CMT rats and acute peripheral nerve generation in mice (Chumakov et al., 2014). PXT3003, administered orally twice per day for 12
consecutive months, was safe and well tolerated in a multicenter, randomized, placebo controlled phase II study in adult outpatients (n=80) with mild to moderate CMT1A
(Attarian et al., 2014). Moreover, this study provided preliminary evidence of clinical efficacy (e.g. Overall Neuropathy Limitations Scale (ONLS), CMT Neuropathy Score
(CMTNS)) of PXT3003 compared to placebo, which manifested as a modest improvement beyond stabilization of the disability. These findings could herald identification
of a therapeutic approach capable of early, meaningful change in disease course, based on comparison to placebo and meta-analysed data from multiple clinical CMT1A
studies (Mandel et al., 2015) and justify further investigation of PXT3003. Consequently, in consensus with regulatory agencies (FDA and EMA) and principal
investigators, a pivotal phase III was initiated in December 2015 to assess the efficacy and safety of PXT3003 in patients with CMT1A.
*
METHODOLOGY:
Multicenter: 31 investigational sites (Belgium (1), Canada (1), France (6),
Germany (4), Netherlands (1), Spain (4), UK (3) and USA (11))
Randomized to study treament: a 1:1:1 fashion using IWRS
PXT3003 (low dose): 3 mg baclofen, 0.35 mg naltrexone and 105 mg
sorbitol (twice daily, per os)
PXT3003 (high dose): 6 mg baclofen, 0.70 mg naltrexone and 210 mg
sorbitol (twice daily, per os)
Placebo (twice daily, per os)
Double-blind, placebo-controlled phase III study (CLN-PXT3003-02)
300 eligible patients with CMT1a
An independent data and safety monitoring board (DSMB) will be
involved to Issue formal recommendations for continuation/modi-
fication/discontinuation of the study to the Pharnext
Patients who completed the study will be allowed enter into the 9-month
extension study (CLN-PXT3003-03). Placebo patients will be re-
randomised to receive either low or high dose PXT3003 in a balanced
fashion
INCLUSION CRITERIA:
Male or female, aged from 16 to 65 years
Patient with a proven genetic diagnosis of CMT1A
Mild-to-moderate severity assessed by CMTNS-v2 with a score > 2 and ≤ 18
Muscle weakness in at least foot dorsiflexion
Motor nerve conduction of the ulnar nerve of > 15 m/sec
Providing signed written informed consent to participate in the study and willing and able to
comply with all study procedures and scheduled visits.
MAIN EXCLUSION CRITERIA:
Any other significant neurological disease or concomitant major systemic disease
Any other associated cause of peripheral neuropathy such as diabetes
Limb surgery within 6 months before randomization or planned before trial completion
Unstable medical illness since the last 30 days (unstable angina, cancer…) that may jeopardize the
participation in the study
Clinically significant abnormalities on the pre-study physical evaluation, ECG or lab tests
(ASAT/ALAT > 3 x ULN or creatinine levels > 1.25 x ULN)
alcohol or drug abuse, or history of non-adherence with treatment or other experimental protocols;
Patients using unauthorized concomitant treatments including but not limited to opioids, levo-
thyroxin, high doses of ascorbic acid (≥1g/day), potentially neurotoxic drugs (a list will be
provided), and pharmaceutical form of baclofen, naltrexone, sorbitol
Participation in another trial of investigational drug(s) within the past 30 days
If a patient from the same family, living in the same household, has already been included in this
study, it will not be possible to include another patient from the same family to avoid mixing of
therapeutic units; therefore there would be a risk of inversion of the blind treatments which could
jeopardize the interpretation of study results.
AIM: To obtain confirmation of efficacy and safety of PXT3003 as a specific
treatment for CMT1A
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 efficacy of PXT3003 compared to placebo
clinical scores (ONLS and CMTNS-v2)
functional tests ( 10mWT, 9-HPegT, QMT hand grip & dorsiflexion)
electrophysiological parameters ( CMAP, SNAP, NCV)
measures of quality of life (EQ-5D and VAS)
Safety and tolerability of PXT3003 compared to placebo
PXT3003 plasma sample (Cmax and through) for population
pharmacokinetics
Change over time of potential blood biomarkers
Molecular changes in skin biopsy (ancillary study)
Potential imaging changes through leg MRI (ancillary study).
STATUS (August 18th 2016):
Active sites: 17 (55%), all sites expected to be activated by mid
September 2016
Screened patients: 194
Screen failures: 53 (27%)
Randomized eligible patients: 128, i.e. 43% required number of patients
Drop-outs: 3 (2.3%; 1 AE related to study treatment, 2 other unrelated)
Patient accrual expected to be completed by October 31st 2016
CONCLUSION:
Promising preclinical and clinical “Proof of concept” data of using a novel
pleodrug, PXT3003, formed the rationale for this ongoing, pivotal study to
assess the efficacy and safety in the treatment of patients with Charcot-Marie-
Tooth type 1A.
The first patients are expected to complete the pivotal study and to be eligible to
enter the extension study in February 2017.
References:
Attarian S, Vallat J-M, Magy L, et al. Orphanet J Rare Dis. 2014 Dec 18;9(1):65–15.
Chumakov I, Milet A, Cholet N, et al. Orphanet J Rare Dis. 2014 Dec 10;9(1):78–33.
Mandel J, Bertrand V, Lehert P, et al. Orphanet J Rare Dis. Orphanet Journal of Rare Diseases; 2015 Jun 24;10(1):1–4.
Contact details:
René Goedkoop, MD, CMO rgoedkoop@pharnext.com
Pharnext SA
11 rue des Peupliers
92130 Issy les Moulineaux
France
www.clinicaltrials.gov: NCT 02579759
CMTR 2016: P2-20, September 9th 2016
1CHU La Timone, Marseille, France; 2Academisch Medisch Centrum-Universiteit van Amsterdam, Netherlands; 3Salford Royal NHS Foundation Trust, Manchester, UK; 4Saint-Louis University, Saint-Louis, USA; 5Hospital Universitari i Politécnic La Fe, Valencia, Spain;
6UZ Leuven, Belgium; 7University Hospital Munster, Germany; 8Pharnext, Issy-Les-Moulineaux, France; 9Cedars-Sinai’s Department of Neurology, Los Angeles, USA; 10CHU de Limoges - Hôpital Dupuytren, Limoges, France; 11University of Melbourne, Australia and
Faculty of Economics, UCL Mons, Louvain, Belgium; 12Johns Hopkins Outpatient Center, Baltimore, USA
STUDY DESIGN OF THE 15 MONTHS PHASE
III AND THE 9 MONTHS EXTENSION STUDY