Background

PXT864 is an example of a repurposed drug combination. It uses baclofen and acamprosate, taken twice a day. Baclophen is a derivative of y-aminobutyric acid, aka GABA, and acts as a GABA-B receptor agonist. It is used as a muscle relaxant to treat spasticity, for example in cerebral palsy and multiple sclerosis. Acamprosate is a drug of unclear mechanism of action, which is used to treat alcohol dependence. Pharnext claims that the low-dose combination of these two compounds, PXT864, is neuroprotective by way of restoring the brain’s balance between excitatory glutamatergic and inhibitory glycine and GABA activity, which in Alzheimer’s disease is disrupted by Aβ oligomers (Chumakov et al., 2015). The company also published positive preclinical data in Parkinson’s disease animal models (Hajj et al., 2015), and cell models of amyotrophic lateral sclerosis due to SOD1 mutations (Boussicault et al., 2020).

Findings

From February 2013 to June 2015, Pharnext ran PLEODIAL I, a Phase 2 study in Bordeaux and several other sites in France. It compared an eight-week course (four weeks treatment, four weeks washout, four more weeks of treatment) of PXT864 to placebo in 47 participants with mild Alzheimer's disease. The trial used three doses—0.4 mg acamprosate and 6 mg baclofen, 1 mg acamprosate and 15 mg baclofen, 20 mg acamprosate and 12 mg baclofen—with acamprosate and baclofen being taken as separate capsules twice daily. Primary endpoints included change from baseline in the ADAS-cog11 and adverse events; secondary outcomes included several cognitive, clinical, and global measures.

In addition, the trial used EEG measures of cognitive event-related potential (ERPs) as an ancillary outcome measure. At the 2016 AAIC conference in Toronto, Pharnext collaborators reported that the cognitive ERP results indicated neurophysiological activity of PXT864 in three patients (see abstract).

From June 2013 to December 2015, Pharnext ran a six-month open-label extension trial of PXT864 for 45 people who had completed the PLEODIAL 1 trial. Here, too, ADAS-cog 11 and safety were the main outcomes. According to data presented at meetings, there was no significant change from baseline in ADAS-Cog after 36 weeks in any group. People in each dose group declined more slowly on the ADAS-Cog over the entire 36-week trial than expected based on historical controls. However, the results may have been affected by some participants taking donepezil during the last 12 weeks of the trial (Dec 2016 conference news; Touchon et al., 2017).

According to Pharnext's website, PXT864 is in Phase 1 for amyotrophic lateral sclerosis as well, but no trial has been registered.

On Feb 14, 2023, the company announced it would stop PTX864 development for Alzheimer’s disease, citing financial reasons (press release).

For all trials of PXT864, see clinicaltrials.gov.