PXT3003 is an investigational therapy being developed by Pharnext to treat Charcot-Marie-Tooth type 1A (CMT1A).

How PXT3003 works

Charcot-Marie-Tooth (CMT) disease is a group of inherited disorders that affect the peripheral nervous system, which controls movement and relays sensory information from the arms and legs to the brain. A number of genetic defects can lead to poor nerve function in CMT.

CMT1A, the most common form of CMT, is caused by an extra copy of the PMP22 gene. The protein that this gene codes for, also called PMP22, forms part of the myelin sheath — a layer of protein and fatty substances that surrounds nerves and helps them efficiently fire electrical signals.

Before the PMP22 protein can be incorporated into the myelin sheath, it is processed to become functional. The extra copy of the PMP22 gene causes too much PMP22 protein to be made, which disrupts proper formation of myelin in the peripheral nervous system (outside the brain and spinal cord), and leads to loss of nerve fibers and muscle shrinkage.

PXT3003 contains a combination of three existing and approved treatments. Baclofen is a muscle relaxant used to treat spasticity, naltrexone is used to treat opiate and alcohol addiction, and sorbitol is a laxative used to treat constipation.

The combination of the three treatments is intended to reduce the levels of PMP22, promote nerve fiber integrity, and improve myelin formation (myelination). In addition, sorbitol is thought to act as a “chaperone,” which increases the chances of the PMP22 protein being correctly processed and becoming functional.

In a rat model of CMT1A, PXT3003 successfully reduced PMP22 gene activity and increased myelination. Studies in animals have also shown that all three components of PXT3003 are necessary for improvements in motor function and fewer muscle cells undergoing nerve-related shrinkage.

PXT3003 may also have beneficial effects on other cellular targets, such as muscle cells and the junction between muscle and nerve.

PXT3003 in clinical trials

Results of a Phase 2 clinical trial (NCT01401257), published in the Orphanet Journal of Rare Diseases, showed that PXT3003 was a safe and well-tolerated treatment for adults with CMT1A. The trial enrolled 80 CMT1A patients in France who were randomly assigned to a low, medium, or high dose of PXT3003 or a placebo for 12 months.

Participants treated with PXT3003 showed slower or no deterioration after one year, compared with those receiving placebo, based on the Charcot-Marie-Tooth neuropathy score and the Overall Neuropathy Limitations Scale (ONLS). The most important improvement after one year was observed in the high-dose group, while a slight deterioration could be seen in the placebo group.

A Phase 3 clinical trial called PLEO-CMT (NCT02579759) followed, evaluating the safety and effectiveness of PXT3003 in 323 CMT1A patients over 15 months at sites in North America and Europe. All were randomly assigned to low-dose PXT3003, a higher dose, or to placebo. Production problems mid-study made the initial high dose be given in twice the volume of the low-dose formulation.

Company-reported results indicated that PXT3003, at 5 ml twice daily, is safe and well-tolerated, with a significant easing of disability seen as improvements on the ONLS, the trial’s primary measure. Significant improvement was also seen in the 10-meter walk test, which assesses walking ability.

The open-label extension study, PLEO-CMT-FU (NCT03023540), enrolled 187 people who participated in the earlier Phase 3 trial. All are being treated with 5 ml of PXT3003 as an oral solution taken twice daily with food. An interim analysis of the extension study — conducted when the combined trials had been running for approximately 4.5 years — showed that the therapy continued to be safe and effective with long-term use. Among participants given PXT3003 in the original trial, average scores on the ONLS continued to improve in the extension study. Among participants originally taking placebo, ONLS scores worsened while they were on placebo, but they showed improvement after switching to active treatment.

Due to the missing data as a result of manufacturing problems in PLEO-CMT, the U.S. Food and Drug Administration (FDA) requested an additional Phase 3 trial of the therapy. Pharnext is now running a Phase 3 trial called PREMIER (NCT04762758), which aims to recruit approximately 350 patients, ages 16 to 65, who have mild to moderate CMT1A. The trial is recruiting at 50 clinical sites in the U.S., Canada, Europe, and Israel.

Additional information

The FDA and the European Medicines Agency granted PXT3003 orphan drug designation in 2014. The FDA also granted the therapy its fast track designation in 2019. China’s National Medical Products Administration granted the treatment priority review in June 2018.

Last updated: May 11, 2021


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