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Pharnext’s PXT864 Shows Promising Neuroprotective Effects in ALS, Early Study Shows

Pharnext’s investigational oral combination therapy PXT864 prevents degeneration of motor neurons and their point of contact with muscle cells, as well as the buildup of toxic TDP-43 protein aggregates — all hallmarks of amyotrophic lateral sclerosis (ALS) — in cellular models of the disease.

The data also showed that the neuroprotective effects were even more pronounced when PXT864 was combined with riluzole, the first approved treatment for ALS, marketed as Rilutek by Sanofi and Tiglutik by ITF Pharma.

These findings suggest PXT864 as a potential new therapy for ALS, added to standard treatment, and call for further studies in animal models of the disease or directly in patients, the researchers noted.

ALS is characterized by the progressive degeneration of neuromuscular junctions — the point of contact where a motor neuron reaches a muscle cell — followed by loss of upper and lower motor neurons, leading to muscle weakness and paralysis.

Neurodegeneration in ALS is thought to be associated with several disease-associated processes, including excitotoxicity, in which excessive levels of glutamate — the main excitatory chemical brain messenger — lead to prolonged, damaging, nerve cell activation. Nerve cell hyperactivity also can promote the accumulation of toxic clumps of proteins, such as TDP-43, a hallmark of ALS.

PXT864 combines low doses of two repurposed therapies: baclofen, currently used to treat spasticity (stiff, heavy, and difficult-to-move muscles) in ALS patients; and Campral (acamprosate calcium), a treatment for alcohol dependence.

It works by restoring the balance between excitatory and inhibitory signals in the brain, as baclofen promotes signalling of gamma-aminobutyric acid (GABA) —the main inhibitory chemical brain messenger — and Campral lessens glutamate-induced excitotoxicity.

Of note, excitatory and inhibitory signals are responsible for maintaining adequate stimulation, and therefore communication, of brain nerve cells. Excitatory signalling from one nerve cell to the next makes the latter cell more likely to fire an electrical signal. Inhibitory signalling makes the latter cell less likely to fire. Treatment with PXT864 had been shown previously to result in therapeutic benefits in cellular and animal models of Alzheimer’s disease and Parkinson’s disease, two neurodegenerative diseases that share several disease-associated mechanisms with ALS, including an imbalance of excitatory and inhibitory signals.

Therefore, researchers at Pharnext set out to evaluate whether PXT864 would promote similar benefits in cellular models of ALS.

They analyzed the effects of PXT864 in human-rat neuromuscular junctions, motor neurons from a rat model of ALS, and rat neurons from the cortex — a brain region affected in ALS — all grown in the lab with excessive levels of glutamate to induce excitotoxicity.

The team also assessed whether combining PXT864 with riluzole, which is thought to block glutamate signalling, resulted in even greater therapeutic benefits.

Results showed that PXT864 effectively protected neuromuscular junctions, motor neurons, and cortical neurons against glutamate‐induced injury, preventing their degeneration and death.

The combination therapy also prevented the formation of stress-induced TDP‐43 clumps, which may be indirectly associated with a restored glutamate/GABA balance, the team hypothesized.

Notably, combining PXT864 with riluzole showed greater neuroprotective effects than either therapy alone, “confirming the potential future use of PXT864 with the standard of care as a promising investigational treatment in ALS patients,” the researchers wrote.

They noted that more studies are needed to understand the mechanism of action underlying the positive interaction between PXT864 and riluzole.

“The converging evidence from different cellular models relevant for the disease strengthens the therapeutic potential of such a safe combination to be tested in animal models of ALS or directly in patients due to the lack of robust animal models of this devastating disease and the urgent need of new therapeutic options,” the team concluded.

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