PXT864 is an investigational oral combination, using lower doses of repurposed medications, being developed by Pharnext to possibly treat  neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).

How PXT864 works

PXT864 is a so-called a pleodrug, meaning that it results from the synergistic combination of medications already approved and used in clinical practice so their individual safety and efficacy is known; medications are identified using the company’s Pleotherapy system and intended to be used in combinations that offer more optimal and lower doses.

PXT864 consists of two such repurposed therapies: Kemstro (baclofen), a muscle relaxant and antispastic, and Campral (acamprosate calcium), a treatment for alcohol dependence.

Alzheimer’s disease is thought to be caused by the production and deposition of a substance called β-amyloid peptide (Aβ). Its accumulation results in the toxic amyloid plaques found in the brains of Alzheimer’s patients.

It is thought that amyloid plaques accumulate because the disease alters the natural balance between excitatory and inhibitory signaling pathways in the brain. Glutamate, glycine, and GABA are neurotransmitters, chemical brain messengers that transmit signals between neurons, which play a role in these signaling pathways.

PXT864 works by restoring the balance between excitatory and inhibitory pathways in the brain. It is hoped that restoring this balance will ensure that neurons and brain structures are protected against damaging Aβ clumps.

PXT864 in clinical trials

PXT864 was investigated in an exploratory Phase 2 clinical trial called the PLEODIAL trials. It took place at seven French sites over a period of 36 weeks and consisted of two stages: the first lasted for 12 weeks (PLEODIAL-I, NCT02361424), and the second was an open-label extension study that ran for 24 weeks (PLEODIAL-II, NCT02361242).

The study tested three oral doses of PXT864 in 45 patients with mild Alzheimer’s disease to evaluate the treatment’s safety and preliminary efficacy; 36 patients finished both trials. In PLEODIAL-I, patients received PXT864 during the first four weeks, followed by four weeks of placebo, and then another four weeks of PXT864. Patients who completed PLEODIAL-I then moved to PLEODIAL-II for 24 more weeks, where they remained on their previous PXT864 dose. During the last 12 weeks of the study, patients were co-treated with 5 mg of Aricept (donepezil).

At the 2016 Alzheimer’s Association International Conference (AAIC), Pharnext collaborators reported the first results from PLEODIAL-I, showing that the cognitive event-related potential (ERP), a biologic measure used to diagnose Alzheimer’s disease, indicated neurophysiological activity of PXT864 in three patients (evidence of possible restored pathway signaling). A global cognitive improvement during the treatment period was also observed.

At the 2016 Clinical Trials on Alzheimer’s Disease (CTAD) conference, further results were presented. According to investigators, treatment with PXT864 was safe and well-tolerated alone or in combination with Aricept, with no serious adverse reactions. Furthermore, PXT864 appeared to slow disease progression, as measured by the decline in the Alzheimer’s disease assessment scale-cognitive subscale test (ADAS-Cog-11).

At the 2017 Alzheimer’s Association International Conference (AAIC), two posters were presented with further data for PXT864. One reported that, after 36 weeks of treatment, PXT864 showed excellent safety and tolerability in patients with mild Alzheimer’s disease, and had a stabilizing effect on cognitive function. The other reported the effectiveness of PXT864 combined with Aricept or Namenda (memantine) in a mouse model, and showed that the triple therapy had a synergistic effect in protecting neurons against the disease, with a higher protective effect than the individual medications alone.

At the 2017 Clinical Trials on Alzheimer’s Disease (CTAD) conference, data presented confirmed that treatment with PXT864 showed stabilization of cognitive disability in mild Alzheimer’s patients after 36 weeks.

Other information for PXT864

According to Pharnext, further Phase 2 studies are planned for PXT864 in Alzheimer’s disease, as well as in Parkinson’s disease and ALS.

In its financial report for the end of 2018, Pharnext stated it is planning to do a Phase 2b trial of PXT864 and is looking for a partnership with another company to help conduct the study. No study has been initiated as of August 2019.


Last updated: Aug. 25, 2019


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