PXT3003’s Components Work in Synergy to Improve Outcomes in CMT1A, Study Finds

The three components of the investigational therapy PXT3003 are all essential to significantly improve features of Charcot-Marie-Tooth disease (CMT) type 1A in cell and animal models, a new study suggests.

The findings also indicate that PXT3003 could improve muscle biology in CMT1A by improving the connections between muscles and nerves.

The study, “Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats,” was published in the Journal of Neuroscience Research. It was funded by Pharnext, which is developing PXT3003.

CMT1A, the most common form of CMT, is caused by an extra copy of the gene PMP22. This causes too much of the PMP22 protein to be produced, which ultimately results in problems with myelination — the process of surrounding neurons with myelin, the “sheath” that helps nerve cells send electrical signals more efficiently.

PXT3003 is a combination of three approved treatments that act on different receptors in the nervous system. Baclofen is a muscle relaxant, naltrexone is used to treat addiction, and sorbitol is a treatment for constipation. These three components are believed to act on a variety of pathways throughout the body, ultimately resulting in less PMP22 and increased myelination.

PXT3003 has shown some promising results in clinical trials, but questions remain about exactly how the therapy works, such as the relative contribution of its three components.

In the new study, researchers at the Max Planck Institute of Experimental Medicine, in Germany, compared the efficacy of PXT3003 to its constituent components to better understand the medicine’s mechanism of action.

First, the researchers treated cells in dishes with either the single components — baclofen, naltrexone, or sorbitol — combinations of two, or all three (i.e., PXT3003). While none of the single components or the combinations of two significantly affected myelination, the combination of all three led to a significant increase (24.6%) in myelination.

The researchers then turned to a rat model of CMT1A, which were treated with PXT3003 or with combinations of two of its components for three months. Then, motor and behavioral assessments were performed.

Of note, only male rats were used in the animal studies to minimize sex-related variability that could muddy motor data (i.e., body weight). However, the researchers wrote, previous research has indicated there are no disease-relevant differences between sexes in this rat model of CMT1A, so the results should be applicable across sexes.

Mirroring the cell results, rats treated with PXT3003 had significant improvements in motor parameters (e.g., grip strength) and behavioral tests, compared to rats treated with only two of the components.

“Generally, none of the corresponding two‐drug combinations significantly improved muscle weakness in CMT1A rats … and importantly [the rats] remained significantly weaker compared to [PXT3003]-treated rats,” the researchers wrote.

These findings suggest that the components of PXT3003 act synergistically — that is, there are effects seen with the combination that are not seen with the individual components alone.

Although improvements to motor function were observed in the rats, the researchers found no evidence of widespread improvements in myelination or nerve function. While some improvements were detected, most were small or were not reproduced between different experiments.

“In the present study regimen, PXT3003 treatment resulted in a profound improvement of motor and sensory functions, in the absence of major effects on myelin thickness and intermodal length,” the researchers wrote. While it is possible that myelination effects could be seen under other settings (e.g., longer or earlier treatment), this finding suggested alternative mechanisms of action.

Nerves communicate with muscles using chemical signals. The place where these signals are exchanged is called the neuromuscular junction (NMJ). Compared to healthy rats, the CMT1A rats had significantly smaller NMJs (87.1 vs. 97.7 micrometers), and their NMJs were much more dense (155 vs. 89 per cm²).

Treatment with PXT3003 increased NMJ size (101.3 micrometers) and reduced density (92 per cm²) to within normal ranges. PXT3003 treatment also significantly reduced the proportion of muscle cells undergoing nerve-related atrophy (17.1% vs. 9.4%).

“Thus, the function of NMJ seems to play a decisive role in the development of motor strength in CMT1A which appears uncoupled from the degree of peripheral nerve myelination and which may constitute a new pharmacological target for PXT3003 therapy in adult animals,” the researchers concluded.