Conference Coverage

CMT1A neuropathy improves with investigational drug PXT3003



A three-drug combination agent called PXT3003 led to an improvement in symptoms for patients with Charcot-Marie-Tooth (CMT) disease type 1A, according to new research.

“The study has established for the first time that patients after up to 15 months of treatment had a statistically significant and clinically relevant disability improvement as illustrated by the change from baseline of their ONLS [Overall Neurology Limitations Scale] scale,” concluded Florian Thomas, MD, PhD, of Hackensack (N.J.) University Medical Center, and his associates at Pharnext. “PXT3003 with dose 4 has at least stabilized, even improved, the disease.”

The researchers presented their findings in a poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The PLEO-CMT study was an international, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial that evaluated the efficacy and safety of PXT3003, an oral 3-drug combination, for CMT1A. CMT1A neuropathy, occurring in an estimated 1 in 5,000 people, is characterized by distal muscle atrophy that affects walking and causes stocking-glove sensory loss and lower quality of life.

The trial enrolled 323 patients, aged 16-65, who had mild to moderate CMT1A that had been genetically confirmed. The modified full set analysis (n = 235), which represented the main study analysis for the primary endpoint, included a placebo group of 87 participants while two other groups received one of two doses of the fixed-dose drug combination twice daily: Ninety-three participants received 3 mg baclofen, 0.35 mg naltrexone, and 105 mg sorbitol (dose 1), and 55 participants received twice that dose (dose 2).

The primary endpoint was mean change from baseline to 12 and 15 months on the ONLS. At baseline, 90% of patients had an ONLS score of 2-4, and the researchers determined an average 0.3 points reduction to be a clinically meaningful effect.

Secondary endpoints included the 10-meter walk test, the 9-hole peg test, and a subscore of Charcot-Marie-Tooth neuropathy score version 2 (CMTNSv2).

Only those taking the higher dose (dose 2) showed a clinically significant drop in ONLS, –0.37 points, compared with those taking placebo (P = .0008). The in-group change from baseline to 15 months in ONLS score for patients taking dose 2 showed a trend of improvement that did not reach significance (–0.20; P = .098).

Participants receiving dose 2 of PXT3003 also walked 0.47 seconds faster on the 10-meter walk test, compared with those receiving placebo (P = .016). No significant differences occurred in the other secondary endpoints, although nonsignificant trends of improvement occurred.

Treatment-emergent adverse events were similar across all three groups and led to trial withdrawal at similar rates for dose 1 (5.5%), dose 2 (5.3%), and placebo (5.9%). One serious adverse event, benign thyroid adenoma, led to trial withdrawal, but no serious adverse events occurred related to the treatment.

Pharnext funded the research. Dr. Thomas is a researcher with Pharnext and Acceleron and has received speaking or advisory board fees from Novartis, Acceleron, Sanofi, and Genentech. The other seven authors are employees of Pharnext.

SOURCE: Thomas F et al. AANEM 2019, Abstract 92.

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