Investigational compound PXT3003 consistently eased disability in patients with mild to moderate Charcot-Marie-Tooth disease type 1A (CMT1A), according to top-line Phase 3 results from Pharnext, which also found that the therapy was safe and well-tolerated.
The PLEO-CMT Phase 3 trial (NCT02579759) was a pivotal, 15-month, double-blind study that assessed the efficacy and safety of two doses of PXT3003, which were compared with a placebo in 323 patients (ages 16 to 65) with mild to moderate CMT1A. PLEO-CMT was conducted at 30 sites across the U.S., EU, and Canada.
“We are thrilled with the outcome of the trial and with the clearly demonstrated efficacy of PXT3003 in addressing the debilitating disease progression of CMT1A. We look forward to working closely with regulatory agencies to bring this therapy to patients,” Daniel Cohen, MD, PhD, Pharnext’s co-founder and CEO, said in a press release.
“These results validate the broad potential of our PLEOTHERAPY drug discovery platform in other neurodegenerative and other disorders and, of course, represent a tremendous milestone for Pharnext,” he added.
PXT3003 is a fixed-dose combination of baclofen, naltrexone, and sorbitol, designed to be taken orally. In the trial, it was given twice a day (morning and evening) with food as a liquid formulation. The higher dose consisted of 12 mg of baclofen, 1.4 mg of naltrexone, and 420 mg of sorbitol. The lower dose had 6 mg of baclofen, 0.7 mg of naltrexone, and 210 mg of sorbitol.
Participants were randomly assigned to one of the two PXT3003 doses (93 patients in the lower group and 55 patients in the higher group) or placebo (87 participants). The company noted that the lower number of patients in the higher dose was due to unexpected formulation/stability issues.
The primary objective was improvements according to the Overall Neuropathy Limitation Scale (ONLS), which measured disability, in agreement with the U.S. Food and Drug Administration and European Medicines Agency.
Results showed that, compared with placebo, the higher PXT3003 dose induced a mean ONLS reduction of 0.4 points. A 0.3 point decrease had been determined to be meaningful. This higher dose also led to improvements on the 10-meter walk test — a measure of walking speed — by 0.5 seconds. PXT3003 showed a linear dose effect.
Treatment with the potential medication was safe and well-tolerated, showing a similar safety profile as in a previous Phase 2 study (NCT01401257). Based on these findings, Pharnext plans to file for market approval in the U.S. and EU.
“PXT3003 demonstrated a significant improvement in patients with mild-to-moderate CMT1A and provided encouraging results that indicate PXT3003 may change the treatment paradigm for the disease. As a clinician, I am excited about the therapeutic potential of PXT3003 and what it means for CMT1A patients and their families,” said David Cornblath, MD, a professor of neurology at Johns Hopkins University in Baltimore.
PXT3003 — developed with Pharnext’s Pleotherapy platform — was granted orphan drug status in the U.S. and Europe and priority review by the China Food and Drug Administration. In preclinical studies, it inhibited the abnormally high expression of the PMP22 gene, the duplication of which causes CMT1A; improved the amount of the protective myelin layer around peripheral nerves; and lessened motor and sensory impairments.
Results of the Phase 2 trial, which enrolled 80 adults with CMT1A, also supported the treatment’s efficacy, safety, and tolerability.
“These results are the first direct translation of a preclinical treatment developed in animal models to CMT1A patients,” said Michael Sereda, MD, a professor of neurology at the Max-Planck Institute of Experimental Medicine in Göttingen Germany, adding that he was “impressed” by the consistent therapeutic benefit in both preclinical and clinical studies. “Data derived from CMT rat models give us important insight regarding the effect of PXT3003.”
PLEO-CMT is followed by the ongoing, nine-month, open-label extension study called PLEO-CMT-FU (NCT03023540), started in March 2016. It is intended to confirm the long-term safety and tolerability of PXT3003 in patients who completed PLEO-CMT. Results are expected in the second half of 2019.
Pharnext is also planning a Phase 3 study of PXT3003 in pediatric CMT1A patients in the first half of 2019. The results of this trial are not required for approval for the adult indication, according to the company. Pharnext recently held two conference calls to discuss these Phase 3 results. A live webcast of each can be found here.