Repurposed duo vs. Alzheimer’s

Pharnext’s pleotherapy shows synergistic effects in PXT-864 for Alzheimer’s disease

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PARIS—Buoyed by the prospect of data that is “further validation of Pharnext’s pleotherapy approach,” Pharnext SAS announced in early January the publication of preclinical results in Scientific Reports for its lead pleodrug, PXT-864, in Alzheimer’s disease. The company’s pleotherapy research and development approach is based on a proprietary network pharmacology platform that identifies synergic combinations of drugs already approved for other diseases.
In the published report, titled “Combining two repurposed drugs as a promising approach for Alzheimer’s disease therapy,” by Ilya Chumakov, et al., data show that in two different rodent models, PXT-864, a combination of baclofen and acamprosate, demonstrated not simply additive but synergistic effect.
According to Pharnext, multiple induced markers of Alzheimer’s disease models were improved and/or normalized, and the repurposed combo had synergistic and consistent effects on the following: Significant alleviation of induced cognitive deficits in the acquisition of long- and short-term memory, novel objects recognition or learning and spatial working memory; protection of neurons from oxidative stress and death; preservation of the blood-brain barrier that is also damaged in patients with Alzheimer’s disease; normalization in levels of proinflammatory factors associated with neuroinflammation; and normalization of neuronal endogenous toxic factors levels and preservation of synaptic loss.
Consistently with in-vivo data, researchers also noted for PXT-864 a synergistic neuronal and vascular cellular protection in two in-vitro models.
“The preclinical results obtained with PXT-864 open the possibility for a promising therapeutic approach for Alzheimer’s disease,” according to Dr. Catherine Scart-Gres, chief medical officer of Pharnext. “Patients suffering from Alzheimer’s disease are marked by rapid and progressive deterioration of cognitive function leading to a loss of independence. Current treatment options for these patients are only moderately symptomatic, and there is a great unmet need.”
She adds that preliminary data with PXT-864 “are promising results for our future work” and that a Phase 2a trial is currently underway, with first results expected later this year.
Dr. Ilya Chumakov, co-founder of Pharnext and the scientific advisory board chairman, has noted that treatment of Alzheimer’s disease was “a natural direction” for the company’s pleotherapy approach “because there are so many signaling pathways associated with the disease. We designed PXT-864 using our network pharmacology technology to interfere with some of those key pathways. We look forward to continuing the development of PXT-864 further in upcoming clinical trials.”
In the Scientific Reports paper, the authors noted that Alzheimer’s disease “represents a major medical problem where monotherapeutic interventions demonstrated only a limited efficacy so far. We explored the possibility of developing a combinational therapy that might prevent the degradation of neuronal and endothelial structures in this disease. We argued that the distorted balance between excitatory (glutamate) and inhibitory (GABA/glycine) systems constitutes a therapeutic target for such intervention.”
Pharnext’s chairman, CEO and co-founder, Dr. Daniel Cohen, said that the positive data for PXT-864 published in Scientific Reports validate “our network pharmacology approach and pleotherapy platform of synergic repositioned drug combinations. We recently published positive clinical and preclinical data for our other lead pleodrug, PXT-3003, in Charcot-Marie-Tooth disease type 1A. Altogether, these results comfort us in potential clinical efficacy for PXT-864 in Alzheimer’s disease. We believe there is room for development of pleodrugs in many disease conditions.”
Pharnext is a clinical-stage biopharmaceutical company developing new therapeutics that simultaneously target multiple key disease pathways for severe orphan and common neurological diseases. The proprietary research and development platform of Pharnext is based on network pharmacology, which allows the development of synergic combinations of repositioned drugs, or pleodrugs. The company’s two lead pleodrugs are PXT-3003 for the treatment of Charcot-Marie-Tooth type 1A (for which a Phase 2 clinical trial has been completed) and PXT-864 for Alzheimer’s disease (Phase 2 clinical trial ongoing) and other neurologic indications, such as Parkinson’s disease and amyotrophic lateral sclerosis.

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