Pharnext Reports Positive Results from Late-Stage CMT Trial Published in Journal

Pharnext reported that the company’s phase 3 placebo-controlled clinical study of PXT3003 in Charcot-Marie-Tooth disease type 1A, a rare genetic condition that causes peripheral nerve degradation, demonstrated a statistically significant improvement in the primary endpoint compared to placebo, and showed a good safety profile.

The results, published in the Orphanet Journal of Rare Disease, support the use of the high dose tested in the study, the authors said.

Charcot-Marie-Tooth (CMT) disease encompasses a heterogeneous group of inherited, severe, debilitating, progressive and chronic peripheral neuropathies. CMT1A is the most common type of CMT. The genetic mutation responsible for CMT1A is a duplication of the PMP22 gene coding for a peripheral myelin protein. The duplication of this gene results in a failure to produce normal myelin, the protective coating on nerves. The lack of a normal myelin structure and function leads to abnormal peripheral nerve conduction and axonal loss. As a result of peripheral nerve degradation, patients suffer from progressive muscle atrophy in both the legs and arms causing problems with walking, running, and balance as well as abnormal hand functioning. They might also suffer from mild to moderate sensory disorders. There are no curative or symptomatic medications approved and treatment is limited to supportive care.

PXT3003 is a novel, fixed-dose, synergistic combination of baclofen, naltrexone, and sorbitol formulated as an oral solution given twice a day. The three individual components of PXT3003 were selected to downregulate the overexpression of PMP22 protein, leading to improvement of neuronal signaling in dysfunctional peripheral nerves that are an essential part of the pathophysiology of this disease. PXT3003 could also have a positive effect on other cellular types of the motor unit such as the axon, neuromuscular junctions, or muscle cells.

The PLEO-CMT trial was an international, randomized, double-blind, placebo-controlled, phase 3 study evaluating the efficacy and safety of PXT3003 in patients with CMT1A, over a 15-month period. Two dose levels, named low dose and high dose, of PXT3003 in comparison to placebo were tested in patients diagnosed with mild-to-moderate CMT1A.

A total of 323 patients were enrolled in 29 centers across Europe, the United States, and Canada by December 2016 and last-patient-last-visit occurred in March 2018. Due to an unexpected issue in the high-dose formulation, the high-dose arm was prematurely stopped in September 2017. A revised statistical analysis plan was developed to take into account the premature high-dose arm discontinuation.

Analysis of the primary endpoint, Overall Neuropathy Limitations Scale (ONLS) from all investigated populations in the high dose arm suggested preliminary efficacy in humans. The study further demonstrated the safety and tolerability of PXT3003. Despite promising efficacy and safety data obtained in the PLEO-CMT trial, the U.S. Food and Drug Administration and the European Medicines Agency have requested a second phase 3 clinical study as a result of the premature discontinuation of the high-dose PXT3003 group due to an unexpected crystal formation in the high-dose formulation.

The second international, randomized, double-blind, two-arm placebo-controlled phase 3 study of PXT3003, the PREMIER trial, was initiated in March 2021 in the United States. The dose of PXT3003 tested in the PREMIER trial versus placebo is equal to the high-dose tested in the PLEO-CMT and PLEO-CMT-FU trials. The main objectives of the PREMIER trial are to evaluate the safety and efficacy of PXT3003 for the treatment of CMT1A. The trial will enroll approximately 350 subjects with mild-to-moderate CMT1A in 50 centers across the United States, Canada, Europe, and Israel. The trial is on track to complete enrollment in second quarter of 2022. Topline results of this trial are expected to be announced in the third quarter of 2023.

Author: Rare Daily Staff