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Charcot-Marie-Tooth type 1A disease: PXT3003, a low-dose combination of Baclofen, Naltrexone and Sorbitol, appears safe

Using combinations of well-known approved drugs has for the first time been shown to be potentially safe in treating a rare disease.
The study has also shown some promising preliminary results for the efficacy of the drug combination.

Charcot-Marie-Tooth type 1A disease ( CMT1A ) is a rare genetic condition that affects around one in 5,000. The disease leads to loss of nerve fibers, muscle wasting and weakness, and causes slowly progressive sensory defects and loss of fine motor skills.

Researchers at Marseilles University Hospital, Hôpital de la Timone, Marseilles ( France ), tested the potential of PXT3003, a low-dose combination of three well-known compounds already approved for other conditions.
Baclofen is used to treat spasticity, Naltrexone for opiate and alcohol addiction, while Sorbitol is prescribed for intestinal disorders.
Combination treatments are based on the idea that diseases can be more efficiently treated using multiple disease-relevant targets.

The phase 2 randomized clinical trial involved 80 adult patients with mild-to-moderate CMT1A at six hospital sites in France. The participants received twice-daily placebos or one of the three increasing doses of PXT3003 over one year.

The safety and tolerability of PXT3003 was found to be good. Results showed no indication of the drug negatively influencing vital signs ( blood pressure, heart rate and weight ), electrocardiogram measurements or blood tests.

In addition, there were some promising preliminary results for the drug's efficacy, including an improvement in measurements that took account of everyday activities, sensory and motor symptoms, and arm and leg strength. Among the three increasing doses tested, the highest one showed consistent improvement after 12 months.

These preliminary results in adults, where symptoms have evolved since childhood, strongly suggest there could be benefits in testing PXT-3003 in children as a preventative treatment.

Because of the difficulty of arranging large scale clinical studies of rare diseases like CMT1A, the effects of PXT3003 described are preliminary indications of drug activity, rather than definitive conclusions on drug efficacy. However, the results act as a helpful exploratory analysis of the efficacy of PXT3003 for designing the next phase of clinical trials.

The combination treatment is thought to act by controlling the overexpression of the PMP22 gene, involved in the structural protein component of myelin, a protective substance that covers nerves.
In a companion study, the researchers have shown that in rats with CMT1A, the drug successfully lowered PMP22 expression and improved impaired myelination and nerve fiber performances. ( Xagena )

Source: Orphanet Journal of Rare Diseases, 2015