Background

Troriluzole is a prodrug formulation of riluzole, a medication used to treat amyotrophic lateral sclerosis. Following oral administration, aminopeptidases in the blood release riluzole from a tripeptide carrier. Unlike riluzole, which must be taken twice a day on an empty stomach, this prodrug requires only once-daily dosing and is unaffected by food.

Riluzole inhibits voltage-dependent sodium channels and reduces synaptic glutamate by increasing its uptake and inhibiting its release. Glutamate dysfunction is a feature of Alzheimer’s disease. Studies in AD mouse models indicate protection from AD-related pathology and cognitive dysfunction by riluzole (Okamoto et al., 2018; Hunsberger et al., 2015). In rats, riluzole was reported to prevent age-related changes in gene expression similar to those seen in AD (Pereira et al., 2016). No preclinical studies are published on troriluzole.

Findings

In July 2018, Biohaven began a Phase 2/3 trial enrolling 292 patients with mild to moderate AD at 44 sites across the U.S. This trial was in cooperation with the Alzheimer’s Disease Cooperative Study (ADCS). After an initial screening period of up to six weeks, participants were randomized to one 280 mg capsule of drug or placebo daily for 48 weeks, followed by four weeks of post-treatment observation. The primary outcome measure was to be change from baseline to 48 weeks on the ADAS-Cog11. Mid-trial, the CDR-SB was added as a co-primary outcome. According to a company press release, as of July 2019, around 400 patients had been screened and 180 randomized. The trial ended in November 2020 with a final enrollment of 350 and on January 18, 2021, Biohaven disclosed top-line results. The treatment group did not differ from placebo on either primary or on a key secondary endpoint of hippocampal volume measured by MRI (press release).

In 2021, the company removed troriluzole’s Alzheimer’s indication from its pipeline. Previously, Biohaven had terminated development for generalized anxiety disorder after a negative Phase 3 trial in 2020. In May 2022, Biohaven reported no effect on the primary outcome in a Phase 3 trial for spinal cerebellar ataxia (press release). Under the name of trigriluzole, the same drug was tested in Phase 1 as part of a combination therapy for various cancers (Silk et al., 2022); a Phase 2/3 study of troriluzole for glioblastoma is ongoing. Phase 3 development for obsessive-compulsive disorder continues.

For details on all troriluzole trials, see clinicaltrials.gov.