PXT3003 Improves Clinical Outcomes and Stabilizes Disease Progression in CMT1A Patients, Extension Study Shows

Pharnext’s oral experimental treatment PXT3003 was found to be safe and effective for patients with Charcot-Marie-Tooth type 1A (CMT1A), improving clinical outcomes and stabilizing disease progression over the course of two years of treatment, according to data from a Phase 3 trial and its open-label extension study.

“Although these data were generated from an open-­label study, the data seem to support the efficacy signal observed in the primary Phase 3 trial and suggest potential sustained efficacy over the course of two years,” Maggie C. Walter, MD, associate neurology professor at the Friedrich-­Baur-­Institute at the Ludwig-Maximilians-­University of Munich, in Germany, said in a press release.

In December 2015, Pharnext launched a 15-month, randomized, double-blind Phase 3 trial called PLEO-CMT (NCT02579759) to investigate the safety and efficacy of PXT3003 in 323 CMT1A patients, ages 16 to 65. Participants were randomly assigned to receive either a low or high dose of PXT3003 or a placebo twice a day, taken orally in the morning and evening with food.

The main goal of the study was to assess changes in the degree of physical disability — measured by the Overall Neuropathy Limitation Scale (ONLS) — from baseline until the end of a 12- and 15-month treatment period.

The company announced in October 2018 that PLEO-CMT met its primary goal of demonstrating significant differences in ONLS between patients treated with the highest dose of PXT3003 and those treated with a placebo.

Those who completed the trial were given the option to continue treatment with PXT3003 by enrolling in an open-label extension study, called PLEO-CMT-FU (NCT03023540).

In this study, patients continued to receive the same dose (D1 for low dose or D2 for high dose) that they had been given originally. Those who had been treated with a placebo were randomly assigned, in a 1:1 ratio, to start PXT3003 treatment at the lowest dose (P-D1 group) or highest dose (P-D2 group).

An unexpected issue with the D2 formulation of PXT3003 in September 2017 led to the discontinuation of the D2 group and to a temporary treatment interruption in some patients during both studies.

Following this event, those who were supposed to receive the D2 formulation in extension study received twice the volume of the D1 formulation, while those who were switching from a placebo to PXT3003 were assigned to the D1 formulation.

From the 323 who participated in PLEO-CMT, 187 decided to enroll in the extension study and 185 of them were eligible for analyses, including 62 from the D1-D1 group, 69 from the D2-D2 group, 46 from the P-D1 group, and eight from the P-D2 group.

Nine-month data from the extension study showed an overall improvement in ONLS scores in all treatment groups (D1-D1 and D2-D2), compared to placebo groups (P-D1 and P-D2). Moreover, those who had been originally treated with a placebo significantly improved their ONLS scores after switching over to PXT3003.

Pooled data from the studies revealed that those treated with both dose formulations experienced an improvement or stabilization of their ONLS scores over a treatment period of nearly 25 months, despite the unexpected treatment interruption that lasted five months on average.

Although ONLS scores decreased during the treatment interruption in the D1-D1 and D2-D2 groups, they improved shortly after participants resumed treatment. The cumulative change over 25 months showed a -0.26 point ONLS improvement, Pharnext stated.

“These data further reinforce our confidence in the safety and efficacy signals from the previous clinical studies,” Daniel Cohen, MD, PhD, Pharnext’s co-­founder and CEO, said.

Pharnext is planning to continue dosing in the extension study until PXT3003 is commercially available. The company also expects to announce detailed findings from this study later this year.

The company is currently in discussions with the U.S. Food and Drug Administration (FDA) to plan a second Phase 3 trial of PXT3003. The FDA requested that the company conduct this additional study due to missing data caused by the unexpected issue with one of PXT3003’s dose formulations in PLEO-CMT. The protocol for this new Phase 3 trial should be completed during the first half of 2020.

Pharnext is also planning to use data from this new Phase 3 trial to support the submission of a marketing authorization application for PXT3003 in Europe.

“We look forward to continuing our discussions with the U.S. Food and Drug Administration and expect to align on the design of an additional pivotal Phase 3 trial in the first half of 2020, with the goal of initiating the study as soon as possible,” Cohen said.

PXT3003 is an investigational combination therapy of baclofen, naltrexone, and sorbitol — three approved treatments that act on the nervous system — and is formulated as an oral solution that is given twice a day. The therapy had previously received the designations of orphan drug and fast track from the FDA.