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PHILADELPHIA -- A cocktail of three repurposed drugs targeting multiple disease pathways appeared effective in treating Charcot-Marie-Tooth type 1A, results of the phase III presented here showed.

The investigational combination of baclofen, naltrexone, and sorbitol known as PXT3003, given as a twice-daily oral solution, offered the first evidence of meaningful improvement for patients with Charcot-Marie-Tooth type 1A, said Florian Thomas, MD, PhD, of Hackensack University Medical Center in New Jersey, at the Emerging Science session of the 2019 American Academy of Neurology annual meeting.

Charcot-Marie-Tooth type 1A is a rare, chronic peripheral neuropathy that affects one in 5,000 people. It is caused by peripheral myelin protein-22 (PMP-22) overexpression, which leads to defects in peripheral myelination. Patients experience distal-dominant muscle atrophy, which affects their gait, activities of daily living, and overall quality of life. No treatment has stabilized or reversed the disease to date.

In preclinical studies, PXT3003 inhibited PMP-22 overexpression and alleviated neuromuscular symptoms, Thomas told 番茄社区app. A conducted with 80 Charcot-Marie-Tooth type 1A patients suggested PXT3003 was safe and tolerable. The polytherapy has , according to drug maker Pharnext: a synergistic inhibition of PMP22 gene overexpression associated with myelination improvement, direct nerve protection, and positive effects on muscle cells, neuromuscular junctions, and immune cells.

PLEO-CMT, a pivotal, international, multicenter, double-blind phase III study was launched in December 2015 to assess the safety and efficacy of two doses of PXT3003 -- dose 3 and dose 4 -- in people with mild-to-moderate, genetically confirmed Charcot-Marie-Tooth type 1A. Dose 3 was 6 mg baclofen, 0.70 mg naltrexone, and 210 mg sorbitol; dose 4 was twice as much as dose 3. Both doses were given twice daily for up to 15 months.

The primary endpoint was the effect of the drug on disability, measured by the mean change from baseline on the 12-point (ONLS). The FDA and the European Medicines Agency (EMA) pre-specified that a 0.3 point mean ONLS difference versus placebo would be clinically meaningful, Thomas said. In this study, 90% of patients had baseline ONLS scores from 2 to 4.

The researchers randomized 323 patients 1:1:1 to each of the two doses and placebo. Patients were age 16 to 65 years and characteristics of the three groups were comparable at baseline.

Over 12 to 15 months, patients in the dose 4 group improved while the "placebo [group] deteriorated, as expected," Thomas said. Dose 4 met the primary endpoint, showing a mean difference of 0.37 point in ONLS score (95% CI 0.1-0.64; P=0.008) versus placebo. In addition, patients in the dose 4 group showed a trend for ONLS improvement compared with a baseline of -0.20 point (P=0.098).

In a secondary outcome of the 10-meter walk test (10-MWT), the mean difference in the dose 4 group showed a 0.47 second improvement over placebo (P=0.016).

PXT3003 showed a similar safety profile as it did in the phase II trial. Treatment-emergent adverse events were similar among the three groups and the majority were mild. The rate of treatment-emergent adverse events leading to drug withdrawal also was similar between groups (5.3% for dose 4; 5.5% for dose 3; 5.6% for placebo). A single serious treatment-emergent adverse event leading to treatment withdrawal (benign thyroid adenoma) occurred in the dose 3 group.

"Charcot-Marie-Tooth is a rare disease, so getting this many patients is impressive," said Jessica Robinson-Papp, MD, MS, of Mount Sinai Health System in New York City, who was not involved with the study. "It's also a disease in which demonstrating a treatment effect is tough because it's very slowly progressive."

"Using a combination of three agents is a bold choice that maximizes the likelihood of efficacy, but has the drawback of not providing data on whether all agents are necessary for effect," she told 番茄社区app. "I think it was a good choice, though, given the lack of any treatment known to work in Charcot-Marie-Tooth and the difficulties involved in studying it."

The long-term safety of PXT3003 currently is being evaluated in , an open-label follow-up extension study of patients who completed PLEO-CMT. In February 2019, the FDA granted PXT3003 . The drug previously had been granted by the FDA and EMA.