Synonyms: BHV-4157, trigriluzole, FC-4157
Chemical Name: Glycylglycyl-N2-methyl-N-[6-(trifluoromethoxy)-2-benzothiazolyl]-glycinamide
Therapy Type: Other
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3)
Company: Biohaven Pharmaceuticals
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.
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 is 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).
Troriluzole is in Phase 3 trials for obsessive-compulsive disorder and spinocerebellar ataxias. In 2020, the company terminated development for generalized anxiety disorder after a Phase 3 failure. Under the name of trigriluzole, the same drug is in Phase 1 as part of a combination therapy for various cancers.
For details on all troriluzole trials, see clinicaltrials.gov.
Last Updated: 22 Jan 2021
- Okamoto M, Gray JD, Larson CS, Kazim SF, Soya H, McEwen BS, Pereira AC. Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer's disease. Transl Psychiatry. 2018 Aug 14;8(1):153. PubMed.
- Hunsberger HC, Weitzner DS, Rudy CC, Hickman JE, Libell EM, Speer RR, Gerhardt GA, Reed MN. Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression. J Neurochem. 2015 Oct;135(2):381-94. Epub 2015 Aug 13 PubMed.
- Pereira AC, Gray JD, Kogan JF, Davidson RL, Rubin TG, Okamoto M, Morrison JH, McEwen BS. Age and Alzheimer's disease gene expression profiles reversed by the glutamate modulator riluzole. Mol Psychiatry. 2016 Mar 29; PubMed.
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- Grassi G, Cecchelli C, Vignozzi L, Pacini S. Investigational and Experimental Drugs to Treat Obsessive-Compulsive Disorder. J Exp Pharmacol. 2020;12:695-706. Epub 2021 Jan 5 PubMed.