Abstract Details

Title Safety, Tolerability, and Pharmacokinetics of Single and Multiple Rising Doses of a Next Generation Prodrug Troriluzole in Healthy Subjects

Topic General Neurology

Presentation(s) P4 - Poster Session 4 (11:45 AM-12:45 PM)

Poster/Presentation
Number 4-012

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_maxwere 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.

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.
Bharat Awsare (Biohaven)	Bharat Awsare has received personal compensation for serving as an employee of Biohaven. Bharat Awsare has or had stock in Biohaven.
Rachel Rozakis	No disclosure on file
Kimberly Gentile	No disclosure on file
Patricia Mydlow (Biohaven)	Patricia Mydlow has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Biohaven Pharma.
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.
Rachel Ham (Allucent)	No disclosure on file
David Stock	David Stock has nothing to disclose.
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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