PXT3003 at High Dose Shows Potential to Safely Treat CMT1A in Phase 3 Trial

PXT3003, a potential treatment for Charcot–Marie–Tooth type 1A (CMT1A) being developed by Pharnext, showed “promising” results and good safety at high dose in a recently completed first Phase 3 clinical trial, researchers reported.

The therapy was found to ease disabilities in those affected by the disease, based on scores in the overall neuropathy limitations scale (ONLS), a way of assessing limitations in upper and lower limbs in everyday activities.

But the high-dose group in the PLEO-CMT study was stopped early due to “stability issues” that led to crystals forming in that dose, and a second Phase 3 trial into the therapy’s safety and efficacy at high dose is underway.

The study reporting the findings, “A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A,” was published in the Orphanet Journal of Rare Diseases (OJRD).

“We are pleased that the OJRD has published data from the PLEO-CMT trial and that the authors have concluded the high-dose PXT3003 group demonstrated a good safety profile and statistically significant improvement in the functioning of CMT1A patients, as evaluated by the ONLS, compared to placebo,” Adrian Hepner, MD, PhD, chief medical officer of Pharnext, said in a press release.

CMT1A, the most common form of Charcot-Marie-Tooth disease, is caused by a duplication of the PMP22 gene that is responsible for the production of the peripheral myelin sheath protein. Its duplication leads to abnormal levels of PMP22 protein, which, in turn, leads to a failure in the production of normal myelin — the protective coat of nerve fibers that helps to sustain the appropriate speed for neuronal messaging. The lack of myelin results in reduced motor nerve conduction velocities and axon loss (axons are the projections of neurons that carry nerve impulses).

PXT3003 is an oral therapy based on a combination of baclofen, naltrexone, and D-sorbitol. Each compound reduces PMP22 levels in different ways, making PXT3003 a potential treatment for CMT1A. Preclinical studies have shown that PXT3003 appeared to suppress PMP22 production and improve neuromuscular function.

PLEO-CMT (NCT02579759) was an international, placebo-controlled, double-blind trial in which 323 people with mild to moderate CMT1A were given either a high dose or a low dose of PXT3003, or a placebo, twice daily for 15 months. The goal was to test the therapy’s safety and efficacy at different doses.

Results showed that, from the baseline (study start) measures until the end of treatment, the ONLS score decreased in both groups receiving PXT3003, indicating an easing in disability. In contrast, the ONLS score increased in the placebo group, indicating worsened disability.

The change in ONLS score was greatest in the group receiving PXT3003 high-dose — the mean effect was a reduction of 0.37 points in ONLS score compared with placebo. Mean effect was not statistically significant when comparing low-dose patients with placebo groups.

“High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo,” the researchers wrote, adding that “both PXT3003 doses were safe and well-tolerated.”

No treatment-related serious adverse events were reported. The most common side effects of the treatment included nausea, diarrhea, headache, and dizziness, with no major differences between groups. Most were mild or moderate in severity.

“Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot–Marie–Tooth disease type 1A,” the team wrote.

Stability concerns for the PXT3003 high-dose formulation, however, were found during the PLEO-CMT trial, as crystals formed inside some bottles. Based on this finding, and as required by the German regulatory authorities, all patients in the country discontinued the study. Pharnext also decided to take all patients being treated at high dose off the medication.

Final analysis of trial data was adjusted for this high discontinuation rate.

“The mean treatment duration was slightly reduced in the high-dose arm [398.9 days] compared to the low-dose [420.2 days] and placebo arms [418.9],” the researchers wrote, adding that “a modified full analysis set was used in the main analyses.”

Patients who completed the PLEO-CMT trial were eligible to enroll in an open-label extension study, called PLEO-CMT-FU trial (NCT03023540), and be given PXT3003. According to the release, this extension study is ongoing, and 130 patients are being treated with PXT3003 at an equivalent high dose.

Due to the trial’s problems in that one arm, an additional Phase 3 trial was requested by regulatory agencies in the U.S. and Europe.

This second international Phase 3 trial, called PREMIER (NCT04762758), opened in March and is testing PXT3003 at a high-dose equivalent to the PLEO-CMT trial, but given in a different manner, to further assess its safety and efficacy.

The trial is expected to enroll 350 CMT1A patients across 50 centers in the U.S., Canada, Europe, and Israel. Over 40 sites are currently screening and enrolling participants; contact and site information is available here. Early results are expected to be announced in the fall of 2023.

“This is further validation of our therapeutic candidate in CMT1A and we hope the efficacy and safety of PXT3003 observed in this first Phase III clinical study will be replicated in our ongoing pivotal Phase III PREMIER trial,” Hepner said. “We look forward to potentially making the first approved therapy for CMT1A available to patients in due course.”