DUBLIN – Shares in Pharnext SA plunged by more than 40% Friday on news that the FDA requires the company to undertake a second phase III trial of its Charcot-Marie-Tooth disease type 1A (CMT1A) therapy PXT-3003.

It's a significant setback for Paris-based Pharnext, which would otherwise have been expecting to commence an NDA filing shortly. Now it must roll up its sleeves and prepare for another expensive pivotal trial.

Although the company reported positive top-line data for its first phase III trial of PXT-3003 last October, the study was compromised by formulation stability issues, which affected its high-dose arm. The trial recruited 323 patients, but the efficacy analysis only considered data from 235 of them. Even so, it had remained confident that the statistical analysis it performed did uncover an efficacy signal. But getting approval based on a single, flawed pivotal trial always looked like a hard sell. (See BioWorld, Oct. 17, 2018.)

The additional trial will likely add a two- to three-year delay to the program – the original phase III trial began in December 2015 and was completed in September 2018. The most optimistic scenario would see the second phase III study start in the first half of next year. The company will first need to agree on a study protocol with the FDA.

"We are disappointed in the delay, especially for patients," Pete Collum, Pharnext's chief financial officer and chief business officer, told BioWorld. "We do understand the FDA's perspective. We remain highly confident in PXT-3003's potential impact on CMT1A. We remain committed to pursuing approval in the U.S. in coordination with the FDA."

A key issue to address will be how to manage the stability issue. When it first emerged, Pharnext adopted the simple stratagem of administering the low dose of PXT-3003 twice. It is not yet clear whether the FDA will agree to this approach or whether it will require additional formulation work.

PXT-3003 is the lead drug candidate to emerge from Pharnext's computational approach to drug discovery, which involves the identification of combinations of known molecules that have synergistic effects on disease pathways. It comprises the muscle relaxant baclofen, the opioid receptor antagonist naltrexone and the sugar alcohol sorbitol.

The company has long enjoyed a lead in CMT1A, an autosomal dominant condition usually caused by a duplication of the gene encoding peripheral myelin protein 22 (PMP-22). As with other forms of CMT, the condition leads to progressive damage of the peripheral nerves and can cause muscle wasting in the feet, legs and hands.

Cambridge, Mass.-based Acceleron Pharma Inc. expects to report phase II data in CMT later this for ACE-083, a locally acting molecule based on follistatin, a naturally occurring protein involved in promoting muscle growth. Sarepta Therapeutics, Inc., also of Cambridge, licensed rights to a gene therapy program originally developed at the Nationwide Children's Hospital, in Columbus, Ohio, which involves the delivery of an adeno-associated virus 1 (AAV1) vector encoding the neurotrophic factor neurotrophin-3.

Meanwhile, Pharnext is gearing up to raise more cash or to find a partner. In addition to PXT-3003, it also has an Alzheimer's program, PXT-864, which comprises baclofen and acamprosate, a drug used in the treatment of alcohol dependence.

Shares in Pharnext (PARIS:ALPHA) dropped as low as €7.02 Friday before closing at €7.16, down 41% on the previous close of €12.15.

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