DUBLIN – Shares in Pharnext SA gained 25 percent Tuesday after the company announced that its lead drug, PXT-3003, hit the primary endpoint of a phase III trial in type 1A Charcot-Marie-Tooth disease (CMT1A). Pharnext now plans to file for approval in the U.S. and Europe in the second half of 2019.

Statistical significance in the high-dose arm of the trial was achieved but with considerably fewer patients than originally intended. The study recruited 323 adult patients, but the efficacy analysis involved only 235 of them. The high-dose arm had just 55 evaluable patients, whereas the low-dose and placebo arms had 93 patients and 87 patients, respectively.

"We lost half the patients on the high dose, roughly," Daniel Cohen, CEO of Paris-based Pharnext, told BioWorld. "Despite the loss of power, we had very strong significance in the results," he added. The modified efficacy analysis was conducted according to the Full Analysis Set methodology, which, according to ICH clinical trial guidelines, permits the exclusion of patients who have been randomized but not treated.

The problem in the high-dose arm arose from unexpected stability issues in its formulation of PXT-3003, an oral fixed-dose combination of the muscle relaxant baclofen (12 mg), the opioid receptor antagonist naltrexone (1.4 mg) and the sugar alcohol sorbitol (420 mg). The company has since rectified the issue simply by administering the low-dose liquid formulation twice.

The primary endpoint of the study was a change in the Overall Neuropathy Limitations Scale (ONLS), a 12-point scale that measures levels of disability in patients' limbs, 12 and 15 months. Those in the high-dose group attained a mean reduction of 0.4 points (p=0.008). "Ninety percent of the patients we recruited were between 2 and 4 [at baseline]," Cohen said.

The reduction in the mean ONLS score implies that there were more responders than nonresponders in the high-dose cohort. In the high-dose arm, 31 percent of patients experienced an improvement while 14 percent declined, whereas in the placebo arm, 18 percent of patients improved while 23 percent declined.

The minimum reduction in an individual's ONLS score is 1 point. "Any single-point change in the scale is very meaningful clinically," he said. It can make the difference between being able or unable to perform a particular task, he added.

PXT-3003 also hit several secondary endpoints, including a mean 0.5-second improvement – about 10 percent – in the performance of a 10-meter walk test (p=0.016).

CMT1A is the most common form of CMT, a set of inherited disorders characterized by peripheral neuropathy and muscle wasting in the limbs. CMT1A is an autosomal dominant condition, usually caused by a duplication of the gene encoding peripheral myelin protein 22 (PMP-22), a component of myelin, which, in the peripheral nervous system, is produced by Schwann cells. Overproduction of PMP-22 compromises the structure and function of myelin, the insulating sheath that coats nerve axons and ensures efficient transmission of nerve impulses. CMT1A can vary greatly in severity, but symptoms include progressive weakness in the feet and lower leg muscles and loss of fine motor skills involving the feet, hands, wrists and tongue.

Safety extension ongoing

PXT-3003 is the lead product from Pharnext's Pleodrugs platform, which employs a systems biology approach to discovering low-dose cocktails of existing drugs that have synergistic and pleiotropic effects on difficult-to-treat conditions. A research collaboration with the Max Planck Institute of Experimental Medicine, in Göttingen, Germany, has demonstrated that the drug has effects on myelin, axon energetics, the neuromuscular junction and muscle fibers, Cohen said.

A safety extension study is currently ongoing, which will be completed in August next year. The company aims to file an NDA shortly afterward. The safety profile is benign – the drugs are administered at about one-tenth of their usual dose. "We had absolutely no safety issues with this trial," Cohen said.

Patients with CMT1A may use orthopedic devices, such as braces, to support their movement or undergo corrective surgery but there are no approved drugs for the condition.

PXT-3003 was previously the subject of a partnering deal with Ipsen SA, but the latter terminated its interest subsequently. Last year, Pharnext entered a joint venture in China with Tianjin-based Tasly Pharmaceutical Co. Ltd. It now intends to commercialize the product itself in the U.S. and Europe, Cohen said. The strength of the data will enable it to build a high-quality commercial operation, he said. (See BioWorld Today, May 17, 2017.)

A handful of other therapeutic programs are underway. The Nationwide Children's Hospital, in Columbus, Ohio, is running a phase I/II gene therapy trial comprising an adeno-associated virus 1 (AAV1) vector encoding neurotrophin-3, a neurotrophic factor expressed by Schwann cells. Cambridge, Mass.-based Acceleron Pharma Inc., is conducting a phase II trial of ACE-083, a small molecule that selectively binds specific members of the transforming growth factor beta (TGF-beta) protein superfamily that are involved in negatively regulating muscle mass growth.

Shares in Pharnext reached a one-year high of €11.70 (US$13.56) during trading Wednesday, before closing at €11.25, up €2.25 since the previous close.

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