Objective:

Report the safety, tolerability, and PK findings of oral troriluzole in healthy subjects (HS) from
three Phase I studies: BHV4157-101 (first in human, single and multiple dose); BHV4157-103
(multiple-dose) and BHV4157-108 (single escalating doses).

Background:

Riluzole, a glutamate modulator, is approved for amyotrophic lateral sclerosis; but has limitations of high pharmacokinetic (PK) variability (>50-70%), dose-dependent elevations in liver enzymes, relatively low oral bioavailability, and twice-daily dosing. Troriluzole is a novel, optimized, prodrug of riluzole, rationally designed to improve the PK and pharmacodynamic profile of riluzole.

Design/Methods:

In BHV4157-101, 58 HS received single or multiple doses from 17.5 to 200 mg; in BHV4157-
103, 8 HS received 280 mg once daily for 5 days. In BHV4157-108, 30 HS received 280 to 840
mg. Troriluzole was administered fasted.

Results:

Troriluzole was readily absorbed and rapidly converted to its active metabolite riluzole. Riluzole AUC_0-inf and C_max were dose proportional across dose ranges. Within the troriluzole dosage range of 200 to 280 mg/day, T_max of riluzole was ~2-3 hours, with a half-life of 9-12 hours. Riluzole steady state was achieved by Day 5 of troriluzole daily dosing. Repeat dosing of troriluzole was associated with riluzole C_max CVs from 31.6% to 41.2% and AUC CVs from 31.5% to 49.4%. No clinically meaningful riluzole accumulation was observed with once-daily dosing. Troriluzole was well tolerated up to the highest studied dose (840 mg), and the incidence of adverse events (AEs) did not increase with dose escalation. AEs were mostly mild and transient, with headache and somnolence as the most frequent events across studies.

Conclusions:

Troriluzole was well tolerated at single doses up to 840 mg and multiple daily doses up to
280 mg, with no significant clinical safety concerns. Troriluzole offers distinct PK advantages,
with less variability than oral riluzole, and supports once daily dosing.