Abstract Details

Title Next Generation Prodrug Troriluzole: Increased Bioavailability of Riluzole with No Food Effect in Healthy Subjects

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S5 - ALS and CMT: New Therapeutic Approaches (4:30 PM-4:42 PM)

Poster/Presentation
Number 006

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.

Authors/Disclosures
Heather Sevinsky (Biohaven) PRESENTER	Ms. Sevinsky has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Ms. Sevinsky has stock in Biohaven Pharmaceuticals.
Rachel Rozakis	No disclosure on file
Tracy Nepomuceno (Biohaven)	No disclosure on file
Jo Ann Malatesta (Certara Inc.)	Jo Ann Malatesta has nothing to disclose.
Bharat Awsare (Biohaven)	Bharat Awsare has received personal compensation for serving as an employee of Biohaven. Bharat Awsare has stock in Biohaven.
Eric Ashbrenner	Eric Ashbrenner has received personal compensation for serving as an employee of Biohaven. Eric Ashbrenner has stock in Biohaven. An immediate family member of Eric Ashbrenner has stock in Biohaven.
Stephen Kaplita (Biohaven Pharmaceuticals)	No disclosure on file
Kimberly Gentile	No disclosure on file
Betty Hussey (Allucent)	No disclosure on file
Irfan Qureshi, MD (Biohaven Pharmaceuticals)	Dr. Qureshi has received personal compensation for serving as an employee of Biohaven. Dr. Qureshi has stock in Biohaven Pharmaceuticals.
Vladimir Coric	Vladimir Coric has received personal compensation for serving as an employee of Biohaven. Vladimir Coric has received personal compensation in the range of $1,000,000+ for serving as an officer or member of the Board of Directors for Bioahven. Vladimir Coric has stock in Biohaven. Vladimir Coric has received intellectual property interests from a discovery or technology relating to health care.
Richard Bertz (Biohaven Pharmaceuticals)	Richard Bertz has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Richard Bertz has stock in Biohaven Pharmaceuticals.

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