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PXT3003 Meets Phase 3 Primary End Point in Charcot-Marie-Tooth Disease Type 1A

Despite being discontinued early, patients in the high-dose group of the PLEO-CMT trial experienced statistically significant improvement in Overall Neuropathy Limitations Scale total score.

Data from the phase 3 PLEO-CMT trial (NCT02579759) in patients with mild-to-moderate Charcot-Marie-Tooth disease Type 1A (CMT1A) show a high dose of PXT3003 (Pharnext)—a novel fixed-dose synergistic combination of baclofen, naltrexone, and sorbitol—met its primary end point in demonstrating a statistically significant improvement in the Overall Neuropathy Limitations Scale (ONLS) total score, compared with placebo. The treatment also had a good safety profile, according to findings published in the Orphanet Journal of Rare Disease (OJRD) in October.1,2

The double-blind, placebo-controlled study included a total of 323 patients from 29 treatment centers in Europe, the US, and Canada. Participants were between the ages of 16 to 65 years and were randomly assigned 1:1:1 to receive 5 mL of high- or low-dose PXT3003 or placebo, with treatment taken orally twice daily for a period of up to 15 months.

ONLS scores decreased in both high-dose and low-dose PXT3003 groups, but scores increased in the placebo group, suggesting worsening disability. Those in the high-dose group had a significant improvement in the ONLS total score from baseline to 15 months, compared with placebo (mean difference, –0.37 points [97.5% CI, –0.68 to –0.06]; P = .008). Treatment effects were consistent in the sensitivity analysis, and both high and low doses were found to be safe and well-tolerated. When evaluating secondary end points, investigators saw statistically significant improvement in the 10 Meter Walk Test for patients in the high-dose PXT3003 group (P = .016).2

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"CMT1A is an indication with currently no existing approved therapies, and I am delighted to be part of the clinical development program of this promising new therapy,” lead author of the study and lead investigator of the PREMIER trial in Europe, Shahram Attarian, MD, PhD, head, neuromuscular disease and ALS department, University Hospital La Timone, Marseille, France; and coordinator, FILNEMUS Rare Diseases Network and Neuromuscular Diseases Reference Centers, France, said in a statement.1 “The publication into the OJRD is very encouraging for the ongoing trial and I am grateful to all participants, their families and investigators for their support."

The high-dose PXT3003 group was discontinued prematurely due to the unexpected formation of crystals, leading to the US FDA requesting an additional phase 3 study of the treatment. The PREMIER trial, the second international phase 3 study of PXT3003, was initiated in the US in March 2021. Approximately 350 patients with mild-to-moderate CMT1A are anticipated to be enrolled in centers in the US, Canada, Europe, and Israel, with 40 of 50 centers already actively screening and enrolling patients as of October 18, 2021. 

“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, Pharnext, said in a statement.1 “This is further validation of our therapeutic candidate in CMT1A and we hope the efficacy and safety of PXT3003 observed in this first phase 3 clinical study will be replicated in our ongoing pivotal Phase 3 PREMIER trial. We look forward to potentially making the first approved therapy for CMT1A available to patients in due course.”

No treatment-related serious adverse events were reported, but a smaller proportion of subject did report treatment-emergent adverse events (TEAEs), which were mostly mild to moderate in severity and related to the gastrointestinal and nervous systems. No notable difference in TEAEs were observed between treatment groups. 

Patients enrolled in PLEO-CMT were also eligible to enroll in the open-label follow-up extension study, the PLEO-CMT-FU trial (NCT03023540). The study is ongoing and treating 130 patients with high-dose PXT3003. 

1. Data from first phase 3 clinical study of PXT3003 in Charcot-Marie-Tooth Disease type 1A, the PLEO-CMT trial, published in the Orphanet Journal of Rare Diseases. News release. Pharnext. October 18, 2021. Accessed November 12, 2021. https://www.biospace.com/article/releases/data-from-first-phase-iii-clinical-study-of-pxt3003-in-charcot-marie-tooth-disease-type-1a-the-pleo-cmt-trial-published-in-the-orphanet-journal-of-rare-diseases/
2. Attarian S, Young P, Brannagan TH, et al. A double-blind, placebo-controlled, randozimed trial of PXT3003 for the treatment of Charcot-Marie-Tooth type 1A. Orphanet J Rare Dis. 2021;433(16). doi.org/10.1186/s13023-021-02040-8