Short-term PXT3003 Treatment Delays Disease Onset in Rat Model of CMT1A, Study Shows

Two weeks of treatment with Pharnext’s PXT3003 delayed disease onset, corrected motor deficits, and improved dysregulated molecular pathways in a young rat model of Charcot-Marie-Tooth disease type 1A (CMT1A), a preclinical study shows.

This finding coincides with recent clinical data from the Phase 3 PLEO-CMT trial (NCT02579759) where treatment with PXT3003 consistently eased disability in patients with mild to moderate CMT1A.

“These results provide key insights into the disease progression of CMT1A and the potential of PXT3003 to slow the onset of the disease, particularly in children and adolescents with CMT1A. Such findings validate our preclinical data on PXT3003 in CMT1A to-date, as well as our clinical data, based on the positive top-line Phase 3 data from October 2018,” Daniel Cohen, MD, PhD, co-founder and CEO of Pharnext, said in a press release.

The study, “Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A),” was published in the journal Plos One.

CMT1A, the most common type of Charcot-Marie-Tooth disease, is caused by a mutation in the PMP22 gene, specifically causing the gene to exist not as one copy but two in Schwann cells.

As a result, the function of Schwann cells, which produce myelin (the fat-rich substance that wraps around and protects nerve fibers, called axons), is impaired. Specifically, the increased PMP22 levels cause the cells to become less mature (differentiated) and unable to perform their myelin-producing functions causing the progressive muscle atrophy seen in CMT1A patients.

In this study, the researchers explored the ability of early, short-term treatment with PXT3003 to decrease the levels of PMP22 and delay disease onset.

PXT3003 is a combination of three therapies — a low dose of baclofen (sold under the brand name Lioresal, among others), naltrexone (marketed as ReVia and Vivitrol, among others), and sorbitol. Each individual therapy has been shown not only to reduce PMP22 levels, but also to play a role in pathways important for myelination and axonal integrity. In rat models of CMT1A, chronic long-term dosing with PXT3003 slowed disease progression.

Researchers treated wild-type (healthy) rats and a rat model of CMT1A (engineered to have increased levels of PMP22 protein) with PXT3003, administered orally, or with a placebo for 13 days (from the sixth day after birth until day 18). The animals received three increasing dosages of PXT3003 and were then followed and examined in the third, ninth, and 12th weeks after birth.

PXT3003 was given to healthy rats to rule out possible adverse effects. No side effects were seen in either the healthy or CMT1A rats treated with PXT3003 concerning body weight, muscle strength, and motor coordination.

The animals’ motor functions were analyzed by the grip strength test, an easy way to quantify the muscular strength of rodents, and the inclined plane test.

In the grip strength analysis, a significant therapeutic improvement in forelimb strength occurred as early as three days after treatment was stopped for all PXT3003 dosages compared with CMT1A control rats.

Hind limb muscle strength also improved by the ninth week, but not before, where it reached the levels seen in the healthy rats and continued to improve until the end of the study at 12 weeks.

A dose-dependent increase in motor performance was also seen in the inclined plane test, with benefits detected as early as three weeks, further increasing until 12 weeks.

None of these improvements were seen in the CMT1A rats given a placebo.

“We were surprised that only two weeks of early, post-natal treatment with PXT3003 dramatically improved the motor phenotype in CMT1A rats reaching wild-type levels,” said Michael Sereda, MD, the study’s lead author and professor of neurology at the Max Planck Institute of Experimental Medicine and the University Medical Center, Göttingen, in Germany.

“Similar to previous preclinical studies, this underlines the importance of treating the molecular defects caused by PMP22 overexpression in CMT1A during this critical time window in myelin development,” he added.

At the end of the study, the researchers looked at the number of axons with myelin, the thickness of the myelin sheath, and the axon’s caliber. The results showed that while PXT3003 had no impact on the first two parameters, it restored the axons’ caliber of peripheral nerves, making them larger, and to a level seen in the healthy control rats.

PXT3003 decreased the levels of PMP22 in CMT1A rats and restored a signaling pathway called AKT/ERK that is perturbed in CMT1A.

This study suggests the potential of PXT3003 in the early treatment of CMT1A.

“Short-term treatment with PXT3003 during early development partially prevents the long-term phenotypical manifestations in CMT1A rats. If translated to CMT1A patients, treatment initiation should preferentially begin as early as possible (e.g. in childhood), in order to slow down or even prevent the progression of the disease,” the study concluded.

“From the findings in this publication, we believe that PXT3003 has the potential to change the treatment paradigm for children with CMT1A — for whom there are currently no pharmacological treatments available — and we look forward to initiating a Phase 3 trial of PXT3003 in pediatric patients by the end of 2019,” Cohen  said.