Phase 2 Study Showing Promise for Patients with Charcot-Tooth-Marie

James Radke

Combining previously approved drugs (eg, baclofen, naltrexone and sorbitol) to treat a rare condition without an approved treatment (eg, Charcot-Marie-Tooth Neuropathy) is the goal of the France based company Pharnext.  Creating a new treatment by combining older drugs in a logical and safe manner is what the company calls a pleodrug.  And the concept seems to be paying off. Data from their double-blind, placebo-controlled Phase 2 clinical trial published in Orphanet Journal of Rare Disorders indicates the pleodrug PXT-3003 (baclofen + naltrexone + sorbitol) may be effective in treating patients with Charcot-Marie-Tooth Neuropathy.
The study by Attarian and colleagues involved 80 patients with mild to moderate Charcot-Tooth-Marie type 1A who received either placebo or one of three escalating doses of PXT-3003 orally for one year [Low dose ( 0.6 mg baclofen, 0.07 mg naltrexone and 21 mg sorbitol), Intermediate dose (1.2 mg baclofen, 0.14 mg naltrexone and 42 mg sorbitol) or High dose (6 mg baclofen, 0.7 mg naltrexone and 210 mg sorbitol) of PXT-3003]. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes.
This trial confirmed PXT-3003 is safe and well tolerated. The percentage of patients with treatment-emergent adverse events after one year was similar across treatment groups (47% in Placebo, 23% in Low dose PXT-3003, 33% in Intermediate dose,  and 31% in High dose PXT-3003, P= 0.48). Most of the related adverse events were mild and benign (eg, gastrointestinal, nausea).
In an examination of the drugs efficacy, the study observed the highest dose of PXT-3003 showed improvements in the CMTNS and OLNS scores.
The authors of the study concluded that “these results confirm that PXT-3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults.”
To that end, the makers of PXT3003, Pharnext are planning a phase 3 study.  Daniel Cohen, M.D., Ph.D., chairman and chief executive officer of Pharnext, said:

"Positive preclinical and Phase 2 data for PXT-3003 validate our pleotherapy approach based on network pharmacology. We look forward to continuing the development of PXT-3003 with an international Phase 3 clinical trial set to begin in 2015."

About Charcot-Marie-Tooth

Charcot-Marie-Tooth neuropathy is an inherited disorder affecting the peripheral motor and sensory neurons. The most common type of Charcot-Marie-Tooth is Charcot-Marie-Tooth type 1a which affects about 100,000 in Europe and United States. Although it is an inherited condition, the main signs and symptoms such as decreased muscle size and weakness may not present until adolescence or early adulthood. As a result of peripheral nerve degradation, patients suffer from progressive muscle atrophy of legs and arms causing walking, running, balance problems and abnormal hand functioning.

To date, no curative or symptomatic medications have been approved and treatment consists of supportive care such as orthotics, leg braces, physical and occupational therapy or surgery.

Catherine Scart-Gres, M.D., chief medical officer of Pharnext, said:

"Charcot-Marie-Tooth is a rare and progressive hereditary neurological disease with no currently approved or effective treatment available. PXT-3003 was well tolerated and produced a consistent dose effect on most efficacy endpoints. In a disease such as Charcot-Marie-Tooth Type 1A that begins in childhood and is progressive, a therapy that can not only stabilize but also improve symptoms can have a profound impact on the course of the disease and patient lives."

About Pharnext and Pleodrugs

Pharnext is an advanced clinical stage biopharmaceutical company developing new therapeutics that simultaneously target multiple key disease pathways for severe orphan and common neurological diseases. The proprietary research and development platform of Pharnext is based on network pharmacology. It allows the development of synergic combinations of repositioned drugs: pleodrugs. The company's two lead pleodrugs are PXT-3003 for the treatment of Charcot Marie Tooth type 1A (Phase 2 clinical trial completed) and PXT-864 for Alzheimer's disease (Phase 2 clinical trial ongoing) and other neurological indications (Parkinson's disease, ALS).


Attarian S, Vallat J-M, Magy L, et al. An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2014;9:199. doi:10.1186/s13023-014-0199-0

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