Novel Drug Eases Charcot-Marie-Tooth Disability in Phase 3 Trial

Deborah Brauser

May 07, 2019

PHILADELPHIA — A novel drug known as PXT3003 (Pharnext) has provided "first evidence of a meaningful improvement" in patients with Charcot-Marie-Tooth Type 1A disease (CMT1A), investigators from a new phase 3 trial report. The product is an oral, fixed-dose combination of baclofen, naltrexone, and sorbitol.

In the PLEO-CMT trial, which included more than 300 patients with mild-to-moderate CMT1A, participants who received a high dose of PXT3003 (12 mg baclofen, 1.4 mg naltrexone, 420 mg sorbitol) showed greater reduction on the Overall Neuropathy Limitations Scale (ONLS) after 15 months of treatment than those who received matching placebo, meeting the primary endpoint.

The high-dose group also showed significant improvement on the 10-meter walk test.

In addition, "PXT3003 was safe and well tolerated and showed a similar safety profile as in phase 2," lead author Florian P. Thomas, MD, PhD, director of the Hereditary Neuropathy Center and chair of the Department of Neurology at Hackensack University Medical Center, New Jersey, told attendees here at the American Academy of Neurology (AAN) 2019 Annual Meeting. The findings were presented today at an Emerging Science session.

On the basis of these results, there are now plans to file for market approval in both the United States (US) and the European Union (EU), the manufacturer has reported.

Gene Overexposure

"The genetic mutation responsible for CMT1A is a duplication of the PMP22 gene coding for a peripheral myelin protein. Overexposure of this gene causes degradation of the neuronal sheath (myelin) and nerve dysfunction," Pharnext noted in a press release announcing topline results from the trial late last year.

CMT disease refers to a group of progressive, chronic peripheral neuropathies. The most common type of this disease is CMT1A, which affects about 125,000 individuals in the US and EU. Patients with CMT1A have progressive muscle atrophy, leading to difficulties with walking, balance, and hand coordination, as well as the possible loss of sensation. First symptoms of this disorder commonly occur during childhood and about 5% of patients need wheelchairs.

There are currently no curative or symptomatic medications approved for CMT1A.

PXT3003, which currently has an orphan drug designation, inhibits the overexpression of the PMP22 gene. Based on positive preclinical and phase 2 studies, the PLEO-CMT study was initiated in December 2015 to assess two doses of the combination drug vs placebo.

The researchers enrolled 323 patients ages 16 to 65 years at 30 US, European, and Canadian sites. All were randomly assigned to receive the study drug at a higher dose (n = 113), the study drug at a lower dose (6 mg baclofen, 0.7 mg naltrexone, 210 mg sorbitol; n = 109), or matching placebo (n = 101). All treatments were administered twice daily for up to 15 months.

The primary endpoint was the ONLS, with a 0.3-point reduction determined to convey meaningful outcome. Results showed that the higher-dose group had a mean 0.37-point reduction on the ONLS (95% confidence interval, 0.1 – 0.6; P = .008 vs placebo).

The higher-dose group also had a mean reduction of 0.5 seconds on the 10-meter walk test (P = .016 vs placebo), and showed a "trend for improvement" in ONLS score vs baseline (P = .098).

Treatment-emergent adverse event (TEAE) rates were similar between the groups at 77% and 81.7% for the high- and low-dose groups, respectively, and 82.2% for the placebo group.

Rates of TEAEs leading to drug withdrawal were 5.3%, 5.5%, and 5.6%, respectively. There were also 3, 10, and 5 serious TEAEs. The one report of a serious TEAE leading to drug withdrawal (benign thyroid adenoma) occurred in the low-dose group.

Based on the overall results, the manufacturer has noted that a phase 3 trial evaluating the drug in pediatric patients with CMT1A is expected to begin soon.

Using a "Cocktail of Factors"

Session co-moderator Massimo Pandolfo, MD, a neurologist with an interest in genetics and a professor of neurology in Brussels, Belgium, commended the investigators for conducting an international, collaborative, multicenter, randomized trial, "which is what we need in these rare diseases."

"In terms of the rationale for this study, this disease is due to a duplication of a gene that causes an overexpression of a protein. And this study used a cocktail of three factors that have been found to downregulate the expression of this protein. The idea is that by combining these factors, there may be a synergistic effect," Pandolfo told Medscape Medical News.

"And I think the results are encouraging. It's probably not going to be curative for the disease, but they had some positive results not only in safety, which is of course important, but also in terms of efficacy," he added.

The other session co-moderator, Jessica Robinson-Papp, MD, a neurologist with a focus on neuropathic pain, New York City, told Medscape Medical News that she was impressed that it was a large study, especially in a rare disease; and she noted several "interesting" points with the methodology.

"I think putting together three different drugs to try and make the best likelihood that you're going to have a good outcome is a really interesting approach to take," Robinson-Papp said. "As it was mentioned, there are no treatments for this disease at all. And it's a really hard disease to study because it's extraordinarily slowly progressive. So to try and show difference over an amount of time that is practical for a clinical trial is really difficult."

The study was funded by Pharnext. Thomas has reported receiving personal compensation for serving on scientific advisory boards and speaking from Pharnext, Acceleron, Genentech, Novartis, and Sanofi. Pandolfo and Robinson-Papp have reported no relevant financial relationships.

American Academy of Neurology (AAN) 2019 Annual Meeting: Abstract ES.001. Presented May 7, 2019.

Follow Deborah Brauser on Twitter: @MedscapeDeb

For more Medscape Neurology news, join us on Facebook and Twitter


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.