Objective:

Characterize the hepatic safety profile of troriluzole from an extensive clinical program
across a diverse range of disorders.

Background:

Troriluzole, a novel, optimized prodrug of the glutamate modulating agent riluzole, was
designed to overcome the liabilities of riluzole (i.e., significant first-pass metabolism, dose-
dependent transaminase elevations, low oral bioavailability, high PK variability and negative
food effect). Approximately 50% of riluzole-treated patients experience increased ALT: 8% >
3xULN and 2% > 5xULN. Elevated ALT leading to discontinuation and fatal hepatic injury have
been reported with riluzole. Troriluzole bypasses first-pass metabolism reducing riluzole burden
on the liver and is expected to have a superior hepatic safety profile.

Design/Methods:

Hepatic safety data were analyzed from troriluzole treated participants across 6 completed and ongoing phase 2/3 clinical trials in spinocerebellar ataxia (SCA; n=337), obsessive-compulsive disorder (OCD; n=397), generalized anxiety disorder (GAD; n=335) and Alzheimer’s disease (AD; n=276). Doses studied ranged from 140-280 mg QD for SCA/AD/OCD and 100mg BID for GAD.

Results:

A total of 1,386 participants received troriluzole 140,200 or 280mg QD or 100mg BID and 1,345 had on-treatment liver function test data. Mean (SD) average daily dose across indications was 205 (45) mg, and mean (SD) treatment duration was 323 (343) days. A total of 35 (2.6%) participants had ALT > 3xULN and 8 (0.6%) had ALT > 5xULN. Liver enzyme increases generally occurred within the first 12 weeks of treatment and resolved fully with continued treatment or with discontinuation. No signal of severe drug-induced liver injury was reported.

Conclusions:

Troriluzole exhibited a favorable hepatic safety profile in a large clinical trial safety database. The cumulative frequencies of ALT > 3xULN (2.6%) and > 5xULN (0.6%) were substantially lower than those reported for riluzole (8% and 2%, respectively), confirming troriluzole’s hepatic safety advantages.