Adrian Hepner, MD, PhD, Chief Medical Officer at Pharnext, discusses the history of PXT3003, an investigational combination therapy for the treatment of Charcot-Marie-Tooth disease Type 1A (CMT1A).

CMT1A is a rare inherited neurological disorder that causes damage to the peripheral nerves. It is caused by a duplication of the PMP22 gene. This duplication  leads to excess PMP22 protein, which disrupts proper formation of myelin in the peripheral nervous system and loss of nerve fibers and muscle shrinkage. The disease may progress slowly. For example, people with CMT1A are slow runners in childhood, can develop high arches and hammertoes and often require the use of braces for ankle support. Problems with balance because of ankle weakness and loss of proprioception are common. Most patients remain ambulatory throughout their lives and life expectancy is normal. Treatment for this condition may include physical therapy; occupational therapy; braces and other orthopedic devices; orthopedic surgery; and pain medications.

As Dr. Hepner explains, PX3003 is a combination therapy containing three existing treatments: baclofen, naltrexone, sorbitol. The combination is intended to reduce the levels of PMP22 protein, promote nerve fiber integrity, and improve 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.

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 who were randomly assigned to a low, medium, or high dose of PXT3003 or a placebo for 12 months. Patients in the high-dose group showed significantly slower or no deterioration after 1 year compared to the placebo group Charcot-Marie-Tooth neuropathy score and the Overall Neuropathy Limitations Scale (ONLS).

Following the phase 2 study, a phase 3 trial (NCT02579759) followed, evaluating the safety and effectiveness of PXT3003 in 323 CMT1A patients over 15 months. 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.

The open-label extension study (NCT03023540) enrolled 187 people who participated in the previous trial. All are currently being treated with 5 ml of PXT3003. An interim analysis of the extension study 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 the phase 3 PREMIER trial, 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.

To learn more about CMT1A and other rare neurological disorders, visit