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. There are a number of genetic defects that can lead to poor nervous function in CMT.

CMT1A, the most common form of CMT, is often caused by an extra copy of the PMP22 gene. This gene provides instructions for the making of a protein that forms part of the insulating and protective myelin sheath that surrounds the nerve cells of the peripheral nervous system.

Before the PMP22 protein can be incorporated into the sheath, it is processed to become functional. The extra copy of the PMP22 gene causes too much PMP22 protein to be made, which cannot be processed fast enough. This disrupts the development of the surrounding cells and causes instability and demyelination, or loss of the myelin sheath.

Investigational therapy PXT3003 is a combination of three existing and approved treatments that act on three different receptors in the nervous system. Baclofen is a muscle relaxant used to treat spasticity, naltrexone is a medicine 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 by targeting the pathways that promote PMP22 gene expression. Furthermore, sorbitol is thought to act as a “chaperone,” which increases the chances of the PMP22 protein being correctly processed and becoming functional. This should result in lower overall levels of nonfunctional PMP22, resulting in less disruption of the surrounding cells and more functioning PMP22 that can be incorporated into the myelin sheath.

In a rat model of CMT1A, PXT3003 successfully reduced PMP22 gene expression and increased myelination more effectively than a single treatment. Increased myelination should improve the transmission of nerve signals and protect nerve cells from damage.

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

PXT3003 in clinical trials

Results of a randomized, placebo-controlled Phase 2 clinical trial (NCT01401257), published in the Orphanet Journal of Rare Diseases, confirmed 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.

Patients treated with PXT3003 showed slower or no deterioration after one year, compared with those receiving placebo, based on the Charcot-Marie-Tooth neuropathy score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS). Significantly, more patients on the highest dose of PXT3003 were stable or even improved after one year than with the other doses or placebo.

A Phase 3 clinical trial called PLEO-CMT (NCT02579759) — recently completed — followed, evaluating the safety and effectiveness of PXT3003 in 323 CMT-1A patients over 15 months at sites in North America and Europe. All were randomized to low-dose PXT3003, a higher dose, or to placebo; the higher dose was discontinued in mid-study due to production problems, and patients using it were moved to the trial’s long-term extension study. 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 in ONLS, the trial’s primary measure.  Significant improvement was also seen in the 10-meter walk test.

The open-label extension study, PLEO-CMT-FU (NCT03023540), is enrolling patients in the U.S., Canada, and Europe who participated in the earlier Phase 3 trial. All will be treated for nine months with 5 ml of PXT3003 as an oral solution taken twice daily with food. At its anticipated conclusion in October 2019, patients in the original low-dose group will have taken PXT3003 for up to 24 months, and those in the initial placebo group or discontinued high-dose group will have been treated for at least nine months.

Pharnext has announced plans to request that PXT3003 be approved to treat adults with CMT-1A in the U.S. and Europe next year, and to launch a clinical trial in children with CMT-1A in the first half of 2019.

Additional information

Both the U.S. Food and Drug Administration and the European Medicines Agency granted PXT3003 orphan drug designation in March 2014.

The China FDA granted the treatment priority review in June 2018, which can speed the time it takes to make a decision on approval.


Charcot Marie Tooth News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.