PXT3003 Continues to Safely Treat CMT1A Patients Over Long Term

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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PXT3003 | Charcot-Marie-Tooth News | CMT1A trial update | news illustration

Pharnext’s PXT3003, a potential treatment for Charcot–Marie–Tooth type 1A (CMT1A), continues to show sustained safety and efficacy in a Phase 3 open-label extension study.

Data collected in April show that PXT3003 continues to ease disabilities, based on scores in the overall neuropathy limitations scale (ONLS), a way of assessing limitations in the everyday use of the arms and legs, the company reported.

Efficacy was greatest in patients treated for the longest time with PXT3003 — five years in total.

“As an investigator involved since the beginning in the clinical development of PXT3003 in CMT1A, I find these long term safety and efficacy data very encouraging,” Shahram Attarian, MD, PhD, lead researcher of PXT3003 clinical trials’ in Europe, said in a press release.

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“Being able to stabilize, or even improve, patients with CMT1A is an extremely worthwhile goal particularly as these individuals will inevitably decline following the long-term natural course of the disease with the currently available standard of care,” Attarian said. “The entire CMT community is hopeful that PXT3003 could be the first approved therapy for this debilitating disease.”

The PLEO-CMT-FU extension study (NCT03023540) enrolled 187 individuals, ages 16 to 67, with mild to moderate CMT1A who had previously participated in the main PLEO-CMT study (NCT02579759).

The original study, which enrolled 323 patients across Europe, the U.S., and Canada, assessed the safety and efficacy of PXT3003, given either a high dose or a low dose, twice daily for 15 months against a placebo.

The trial’s high dose group, however, was stopped in September 2017 after an unexpected formation of crystals, a stability concern, in that dose.

Data at the time supported greatest improvement, as shown in ONLS scores, in patients treated at high dose. The therapy was also found to be safe and well-tolerated.

After the formulation issue, the PLEO-CMT-FU extension study was re-designed and divided into two periods.

In period one, over nine months of treatment, patients given PXT3003 in the original trial continued to receive the same dose (low or high). However, the high dose was given at twice the volume of the low dose formulation. Those previously on a placebo moved to a low dose of PXT3003.

In period two, which is underway, all 153 participants were switched to the high dose of PXT3003 used in part one.

Reported results support the long-term efficacy of PXT3003 in easing functional disability. While placebo-group patients had shown worsening disability during the main study, this eased over the extension phase with PXT3003 treatment. Those showing the best efficacy results were the group on the therapy’s high dose over the five years since the main study’s start.

According to the press release, PXT3003’s safety and tolerability are evaluated every three months and changes in ONLS every six months. Results of the PLEO-CMT-FU trial, due to end in December 2024, will be released once a year.

“The data announced today, while generated from an open-label extension study, show a sustained treatment benefit with PXT3003 High Dose for patients with CMT1A,” said Burkhard Blank, chief medical officer at Pharnext.

Pharnext also launched the Phase 3 PREMIER study (NCT04762758), which is assessing PXT3003 at high dose versus a placebo over 15 months in up to 350 people with mild to moderate CMT1A. Data collection is expected to finish in October 2023.

This trial was requested by regulatory agencies in the U.S. and Europe, following the formulation issues of the PLEO-CMT study.

“As we approach completion of enrollment in our pivotal Phase III study, the PREMIER trial, in the same mild to moderate CMT1A patients’ population, with the same High Dose of PXT3003 and using the same primary efficacy ONLS endpoint [goal], this reinforces our confidence in potentially confirming the safety and efficacy of PXT3003,” Blank said.

PXT3003 is an oral combination of baclofen, naltrexone, and D-sorbitol. Each compound reduces the levels of PMP22 protein — excessive in people with CMT1A — in different ways.

Preclinical studies have indicated that PXT3003 suppresses PMP22 production and improves neuromuscular function.