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
BHV-4157 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., 2017).
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 are 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 is change from baseline to 48 weeks on the ADAS-Cog11. According to a company press release, as of July 2019, around 400 patients had been screened and 180 randomized. A preplanned interim futility analysis is expected by the end of 2019; the trial ends in February 2020.
Troriluzole is also being clinically trialed in generalized anxiety disorder, obsessive-compulsive disorder, spinocerebellar ataxias, and, under the name of trigriluzole, as part of a combination therapy for lymphoma.
For details on all BHV-4157 trials, see clinicaltrials.gov.
Last Updated: 11 Oct 2019
- 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.
- Brzecka A, Leszek J, Ashraf GM, Ejma M, Ávila-Rodriguez MF, Yarla NS, Tarasov VV, Chubarev VN, Samsonova AN, Barreto GE, Aliev G. Sleep Disorders Associated With Alzheimer's Disease: A Perspective. Front Neurosci. 2018;12:330. Epub 2018 May 31 PubMed.
- Musiek ES, Xiong DD, Holtzman DM. Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp Mol Med. 2015 Mar 13;47:e148. PubMed.