Second Phase 3 Clinical Trial for CMT1A “Pleodrug”

After the setback of having to do a second Phase 3 clinical trial, Pharnext‘s ongoing drug trials for PXT3003 show positive results in people with CMT1A.

The combination of existing drugs in PXT3003 appears to reduce or stabilize symptoms as measured by the Overall Neuropathy Limitation Scale (ONLS) — a relatively new diagnostic instrument in the form of a simple questionnaire that you can get right here to assess your level of disability, no matter what kind of CMT you may have:

PXT3003 is classified as a “pleodrug” developed through “pleotherapy.” The pleo- prefix is Greek in origin, and it means “more,” in reference to the combination of multiple drugs. Dr. Daniel Cohen, CEO and co-founder of the Paris-based Pharnex explains the concept:

Pleotherapy assumes that any molecule can be used for different functions. The Pleotherapy approach combines low doses of existing drugs to develop treatments for new indications using big data analysis of genomics and pharma, to match the properties of drug combinations with specific diseases. Pharnext’s use of drugs that have been approved by the FDA, combined with its proprietary data analysis, allows the company to shave as much as seven years off the typical 15- to 20-year drug approval process.

—Daniel Cohen, Pharnext CEO

What drugs are combined in this “pleodrug?”

PXT3003 “is an oral fixed-low dose [5ml] combination of baclofen, naltrexone hydrochloride, and D-sorbitol given twice daily,” according to Pharnext’s Chief Pharmacology Officer, Dr. Rodolphe Hajj:

[PXT3003] has multiple main mechanisms of action: an inhibition of PMP22 gene overexpression associated with a synergistic myelination improvement, direct nerve protection, and additional positive effects on: muscle cells, neuromuscular junctions, and immune cells. Positive data from the PXT3003 Phase 2 program served as proof-of-concept for this novel, pleotherapy approach to drug development.

CMT News further explains,

The combination of the three treatments is intended to reduce the levels of PMP22 by targeting the pathways that promote PMP22 gene expression. Furthermore, sorbitol is thought to act as a “chaperone,” which increases the chances of the PMP22 protein being correctly processed and becoming functional. This should result in lower overall levels of nonfunctional PMP22, resulting in less disruption of the surrounding cells and more functioning PMP22 that can be incorporated into the myelin sheath.

In a rat model of CMT1A, PXT3003 successfully reduced PMP22 gene expression and increased myelination more effectively than a single treatment. Increased myelination should improve the transmission of nerve signals and protect nerve cells from damage.

PXT3003 may also have beneficial effects on other cells such as muscle cells, cells at the junction between muscle and nerve cells, and immune cells.

Acceleron’s ACE-083 is the only other drug currently in clinical trials for CMT after failing to produce results for muscular dystrophy patients. Maybe it will prove to have some benefit for people with CMT.

Acceleron’s ACE-083 is the only other drug that was recently tested with CMTers. It failed to produce results with both MD and CMT patients alike.

What are your hopes and questions about drug research for CMT? Let me know in the comments.

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