Objective:

Evaluate FE on riluzole after oral administration of troriluzole
(BHV4157-101, BHV4157-105) and BA of riluzole from troriluzole vs oral riluzole
(BHV4157-107) in Phase 1 clinical studies.

Background:

Troriluzole, a novel, optimized, oral prodrug of the glutamate modulating agent riluzole
(approved for amyotrophic lateral sclerosis), was rationally designed to overcome
significant first-pass metabolism, dose-dependent transaminase elevations, low oral
bioavailability (BA), high PK variability and negative food effect (FE) with dosing.

Design/Methods:

All three studies assessed single dose troriluzole in healthy subjects. BHV4157-101
(N=6) and BHV4157-105 (N=20) assessed FE on riluzole administered as troriluzole
(200 and 280 mg, respectively). BHV4157-107 (N=24) assessed relative BA of riluzole
from troriluzole (equimolar dose of 100 and therapeutic dose of 280 mg) vs oral riluzole
50 mg. Riluzole PK parameters were calculated by noncompartmental analysis.

Results:

In BHV4157-101 and 105, riluzole median T_max was delayed by 1.25-1.4 hours and C_max
was reduced 22-38%; however, riluzole AUC was unaffected by food. Riluzole AUC_0-inf
values were 40% and 50% higher after troriluzole 100 mg and 280 mg, respectively vs
oral riluzole 50 mg (BHV4157-107). After troriluzole, riluzole C_max was similar and T_max
delayed by 1 hour vs riluzole (median T_max 1.99 vs 0.824 hours). Riluzole variability was
consistently lower after troriluzole (AUC CV ~40% vs 54%).

Conclusions:

Absorption of riluzole from troriluzole was not impacted by food. Troriluzole displayed
higher riluzole BA (80-90%) vs oral riluzole (60%), suggesting that troriluzole bypasses
first pass metabolism and lowers the initial liver burden of riluzole. Delayed plasma
appearance and lower variability of riluzole represents an optimized profile allowing
once daily administration. The lack of FE, higher oral BA, and once daily dosing with
troriluzole confer important PK enhancements versus riluzole.