Editorial note: This post refers to Pharnext and its experimental CMT1A therapy PXT3003. Pharnext is no longer operating, and PXT3003 is not an approved or available treatment. We have kept this post as part of our historical record.

Pharnext SA announced on April 28, 2021, that new interim analysis results from the ongoing open-label Phase III extension study (PLEO-CMT-FU) show sustained treatment benefits for patients with Charcot-Marie-Tooth disease type 1A (CMT1A) treated with PXT3003 at high dose (HD). At the time of this announcement there was no approved drug treatment for CMT1A.

The data readout covered 54 months of total trial time, combining the original double-blind Phase III study (PLEO-CMT) and the open-label extension (PLEO-CMT-FU). Key highlights from the available data include:

  • PXT3003 was safe and well tolerated, consistent with the safety profile observed in prior clinical trials.
  • On the Overall Neuropathy Limitations Scale (ONLS), a measure of patients’ functional motor disability, patients treated with placebo in the double-blind phase declined on average, while patients treated with PXT3003 improved on average. The strongest efficacy signal was seen in the high-dose cohort.
  • In the open-label extension, patients across all cohorts improved on average on ONLS. Patients who had been on placebo during the double-blind phase began to improve after switching to PXT3003.
  • Results after 54 months of total trial time continued to suggest a better efficacy signal with PXT3003 HD in this patient population.

Adrian Hepner, MD, PhD, Chief Medical Officer of Pharnext, commented: “Although these new data were generated from an open-label study, the findings are consistent with the safety and efficacy results of PXT3003 observed in prior clinical studies in CMT1A. In addition, the fact we have just initiated the PREMIER trial in a similar patient population, using the same High Dose of PXT3003 and measuring the same efficacy endpoint ONLS, reinforces our confidence in the potential positive outcome of our ongoing pivotal Phase III study.”

Florian P. Thomas, MD, PhD, Founding Chair and Professor, Department of Neurology, Hackensack University Medical Center and Hackensack Meridian School of Medicine, and U.S. lead investigator of the PLEO-CMT trial, added: “These new results from the interim analysis of the ongoing open-label Phase III extension study show very promising safety and efficacy data of PXT3003 in CMT1A after more than four years of treatment. It reinforces our hope that PXT3003 could be the first treatment approved for patients suffering from this debilitating disease.”

About the PLEO-CMT Trial

The PLEO-CMT trial was an international, randomized, double-blind, placebo-controlled Phase III study evaluating the efficacy and safety of PXT3003 in patients with CMT1A over 15 months. Two dose levels (low dose and high dose) were tested in patients diagnosed with mild-to-moderate CMT1A. A total of 323 patients were enrolled at 29 centers across Europe, the United States, and Canada by December 2016; last-patient-last-visit occurred in March 2018. An unexpected issue with the high-dose formulation led to early discontinuation of the HD arm in September 2017. Analysis of the primary endpoint (ONLS) from the HD arm suggested preliminary efficacy. The study also demonstrated the safety and tolerability of PXT3003. Further information is available on ClinicalTrials.gov (NCT03023540).

About the PLEO-CMT-FU Trial

All randomized CMT1A patients who completed PLEO-CMT were eligible for the open-label extension (PLEO-CMT-FU), which enrolled 187 patients and was designed primarily to assess the long-term safety and tolerability of PXT3003. The trial was divided into two periods: Period 1 (March 2017 to April 2019) and Period 2 (from July 2018, ongoing at the time of this announcement), in which the 153 enrolled patients were all switched to PXT3003 HD. Efficacy using ONLS was evaluated every six months and results were reported annually. Further information is available on ClinicalTrials.gov (NCT03023540).

About the PREMIER Trial

The PREMIER trial is an international, randomized, double-blind, placebo-controlled pivotal Phase III study evaluating the efficacy and safety of PXT3003 versus placebo in mild-to-moderate CMT1A patients over 15 months. The dose tested corresponds to the high dose used in PLEO-CMT. The primary efficacy endpoint is ONLS; secondary endpoints include the 10-Meter Walk Test, quantified muscular testing, patient global impression measures, the CMT Neuropathy Score version 2 (CMTNS-v2), and hand grip strength. Further information is available on ClinicalTrials.gov (NCT04762758).

About CMT1A

Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies (conditions affecting the nerves outside the brain and spinal cord). CMT1A is the most common subtype. It is caused by a duplication of the PMP22 gene, which leads to overproduction of a myelin protein and impairs the ability of Schwann cells to produce normal myelin, the protective sheath around nerve fibers. The resulting disruption to nerve conduction and progressive axon loss causes muscle weakness and wasting in the legs and arms, walking and balance difficulties, and sometimes mild to moderate sensory changes. Symptoms typically begin in adolescence and progress throughout life. Rates of severity vary by individual; in the most severe cases, patients require mobility devices. To date, no curative or symptomatic medications have been approved; treatment consists of supportive care such as orthotics, braces and other supports, and physical and occupational therapy. CMT1A affects an estimated 150,000 people in Europe and the United States and approximately 1,500,000 people worldwide.

About PXT3003

PXT3003 is a fixed-dose oral combination of three components (baclofen, naltrexone, and sorbitol) given twice daily. The components were selected to reduce overexpression of the PMP22 protein, thereby improving nerve signaling in the damaged peripheral nerves central to CMT1A. PXT3003 showed consistent results across preclinical studies and clinical trials in Phase II and Phase III.