Pivotal CMT1A Trial to Begin Patient Enrollment Soon

An international Phase 3 clinical trial investigating Pharnext‘s investigational therapy PXT3003 for treating Charcot-Marie-Tooth disease type 1A (CMT1A) is on track and expected to enroll its first participants in March, the company announced.

Dubbed PREMIER, the trial will include about 350 patients with mild-to-moderate CMT1A across 50 clinical sites. Findings are expected to support the filing of an application with the U.S. Food and Drug Administration  (FDA) requesting the approval of PXT3003 for this disease subtype.

Meanwhile, the company is interacting with the regulatory agency to gain a special protocol assessment for PREMIER to ensure the trial’s design, clinical endpoints (goals), and planned analyses are acceptable to the FDA.

“Our clinical development and regulatory teams have made significant progress towards gaining final agreement on the pivotal trial requirements for submission with the FDA and [European Medicines Agency], as well as beginning our PREMIER trial by the end of [2021’s first quarter],” David Horn Solomon, CEO of Pharnext, said in a press release.

CMT1A, the most common form of CMT, is caused by an extra copy of the PMP22 gene, leading to an overproduction of the PMP22 protein. This causes problems in the myelin coating — a fat-rich substance that helps nerve cells send electrical signals more efficiently — of nerve fibers

PXT3003 is a fixed-dose combination of three approved treatments — baclofen, naltrexone and sorbitol — that act on different receptors in the nervous system. The combination of the three components and their modulation of different pathways ultimately causes a decrease in PMP22 and, consequently, boost myelination (the process of surrounding neurons with myelin).

While PXT3003 has been deemed safe and effective in CMT1A patients in a prior pivotal trial — the PLEO-CMT Phase 3 clinical trial (NCT02579759) — the trial had missing data due to a manufacturing problem and a temporary treatment interruption, leading the FDA to request an additional trial.

The PREMIER trial will assign patients randomly to receive either a high dose of oral PXT3003 or a placebo for 15 months. As agreed with regulatory agencies, the primary goal is to assess changes in functional disability throughout the trial, as measured with the Overall Neuropathy Limitation Scale (ONLS).

Secondary goals include measures of walking speed, muscle strength in hands and feet, as well as the degree of disease severity assessed by the CMT neuropathy score version 2 (CMTNSv2). The CMTNS is a composite 36‐point scale based on a patient’s symptoms, signs at neurological examination, and neurophysiological assessment.

Patients’ beliefs about the effectiveness of treatment, namely concerning changes in clinical status and disease severity, as well as safety and tolerability, also will be assessed.

Besides PREMIER, the FDA has requested a preclinical study testing the individual components of PXT3003 in an established CMT1A animal model. This will allow researchers to estimate the effects of each component to the overall effectiveness of this treatment.

Meanwhile, Pharnext is continuing its open-label extension PLEO-CMT-FU trial (NCT03023540) in 187 patients with mild-to-moderate disease, who participated initially in PLEO-CMT.

Currently, 130 CMT1A patients are still being treated with a high-dose of PXT3003, and have been followed for more than two years. Top-line interim data is expected to be released by June.

“We are excited to continue advancing PXT3003 towards approval for CMT1A patients,” said Solomon.

“Further, the readout of our phase III extension study before the end of [June] will permit further understanding and validation of the role PXT3003 may play in assisting these patients and their families with this severe, debilitating, chronic inherited neuropathy,” he said.