Pharnext Plans Final Trial to Support PXT3003 Approval for CMT1A

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by Vanessa Pataia |

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PXT3003 Phase 3 trial

With guidance from the U.S. Food and Drug Administration (FDA), Pharnext is planning a pivotal, final Phase 3 clinical trial of its investigational therapy PXT3003 for the treatment of Charcot-Marie-Tooth disease type 1A (CMT1A).

The trial, set to begin early next year, is expected to support a new drug application (NDA) asking for PXT3003’s approval for treating this CMT subtype, pending positive results. 

“We are grateful that the FDA has provided strong and specific guidance to complete pivotal studies towards NDA submission and approval for PXT3003 in CMT1A,” David Horn Solomon, PhD, CEO of Pharnext, said in a press release.

PXT3003 is a combination of three existing and approved treatmentsbaclofen, naltrexone, and sorbitol — that act on three different receptors in the nervous system. 

It is intended to reduce the production of PMP22, a protein found in high levels in people with CMT1A. These high levels are due to a duplication in the PMP22 gene, which leads to the loss of the myelin sheath that surrounds and protects the nerve cells of the peripheral nervous system (PNS). The PNS encompasses nerves outside the brain and spinal cord. 

The investigational therapy has been deemed safe and effective in CMT1A patients included in the pivotal PLEO-CMT Phase 3 clinical trial (NCT02579759) and its open-label extension PLEO-CMT-FU study (NCT03023540).

PLEO-CMT involved 323 CMT1A patients, ages 16 to 65, who were randomly assigned to receive either a low or high dose of PXT3003, or a placebo, given as an oral solution twice daily for 15 months. After completing the trial, 187 participants decided to enter the extension study, in which all received PXT3003 for nine months.

The trial’s main goal was to assess changes in the extent of physical disability among participants, as measured by the Overall Neuropathy Limitation Scale (ONLS). Changes were measured from baseline, or the start of the study, to months 12 and 15. This goal was met, with patients receiving the highest dose of PXT3003 showing a mean ONLS reduction of 0.4 points compared with a placebo, which was deemed meaningful.

The higher dose also improved walking speed, while being well-tolerated by and safe for patients.

However, an unexpected issue in September 2017 with PXT3003’s highest dose formulation led to the discontinuation of treatment among participants in the group receiving that dosage. It also caused a temporary treatment interruption for some patients during both PLEO-CMT and its extension study that lasted five months on average.

Due to missing data in this trial, the FDA requested that an additional pivotal Phase 3 trial be conducted to support PXT3003’s approval for CMT1A.

After meeting with the FDA, Pharnext has announced that this upcoming trial will be very similar in design to PLEO-CMT, with the same primary goal of improving ONLS scores. However, this study will have only two treatment arms: high dose PXT3003 and placebo.

The company says it has resolved the manufacturing issue with the high dose PXT3003. The medication now will be delivered in a greater volume of liquid, packaged into sachets, to simplify and improve accuracy of dosing.

“We have addressed earlier manufacturing issues and look forward to initiating the Phase III clinical trial before the end Q1 2021,” Solomon said.

“Our goal at Pharnext is to provide CMT1A patients and their caregivers a new therapeutic to treat this disease where no therapy currently exists,” he added.

The FDA will allow Pharnext to evaluate the effects of the individual components of PXT3003 on the same CMT1A rat model used in preclinical studies. Typically, a company is required to instead conduct a human Phase 3 clinical trial. The animal study is a requirement for Pharnext’s NDA filing for PXT3003.

“Both the Phase III clinical trial as well as the preclinical animal study will be informed in their design by the earlier Phase III clinical trial that provided encouraging top-line results, and the earlier animal study that was successful, respectively,” Solomon said.

PXT3003 has been granted orphan drug and fast track designations by the FDA to support and speed up its development.