Authors :
Presenting Author: Rosa Chan, PhD – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S)
Jonathan Williams, PhD – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S)
Rajareddy Kallem, PhD – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S)
Shelah Mendoza, PhD – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S)
Chad Orevillo, MPH – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S)
Nuggehally Srinivas, PhD, FCP – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S)
Randall Kaye, MD – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S), La Jolla, CA, USA
Rationale:
Bexicaserin is an oral, highly selective 5-hydroxytryptamine 2C (5-HT2C) superagonist in development for the treatment of seizures in patients with developmental and epileptic encephalopathies (DEEs). Since ethnic differences could potentially affect the disposition of bexicaserin, this study evaluated the safety, tolerability, and pharmacokinetic (PK) profile of bexicaserin in healthy Japanese, Chinese, and Caucasian participants.
Methods:
This was a Phase 1, open-label, single and multiple dose study evaluating bexicaserin in 3 ethnic cohorts (n=15 per cohort) of healthy Japanese, Chinese, and Caucasian participants aged 18-50 years. Part 1 included a single 6-mg dose; in Part 2, multiple doses were administered, starting with an up-titration from 6 mg and 9 mg TID, followed by a 12-mg TID maintenance dose. The primary objectives were to characterize the PK of bexicaserin and to assess the ethnic differences in the PK of bexicaserin. The primary PK endpoints were Cmax and AUC0-tau. The secondary objective was to evaluate safety and tolerability across all cohorts. The inferential statistical analysis was performed using an analysis of variance (ANOVA) to assess the differences between ethnic groups for the PK parameters. The two-sided 90% confidence interval (CI) of the ratio of geometric least-squares means (GeoMean) was used to assess the magnitude of the difference.
Results:
A total of 45 participants were enrolled in the study. GeoMean Cmax was slightly higher for Japanese (46.8 ng/mL) and Chinese (51.3 ng/mL) vs Caucasian (36.3 ng/mL) participants (Japanese/Caucasian ratio estimate [90% CI]: 1.416 [1.079, 1.858]; Chinese/Caucasian ratio estimate [90% CI]: 1.292 [0.965, 1.729]). GeoMean AUC0-tau was similar for Japanese (252 h*ng/mL) and Chinese (232 h*ng/mL) vs Caucasian (192 h*ng/mL) participants (Japanese/Caucasian ratio estimate [90% CI]: 1.312 [0.982, 1.752]; Chinese/Caucasian ratio estimate [90% CI]: 1.2089 [0.8947, 1.6334]). Following multiple oral doses of bexicaserin 12 mg TID, median Tmax occurred at 2 hours for all cohorts. The elimination half-life of bexicaserin ranged from 4.36-5.04 hours. The exposure variations observed for bexicaserin ranged from 1.04- to 1.43-fold across the ethnic cohorts. The intersubject coefficient of variation for the PK parameters was approximately 40%-50%. There were no deaths, no serious or severe treatment-emergent adverse events (TEAEs), nor discontinuations due to TEAEs.
Conclusions:
The GeoMean PK exposure 90% CI values for key exposure parameters either included unity or were slightly above unity, suggesting minor differences, if any, between the Chinese/Japanese cohorts vs the Caucasians cohort. Furthermore, given the high intersubject coefficient of variation, the observed minor ethnic differences in PK exposure were not considered clinically relevant. Overall, the data demonstrated no apparent race-specific differences, thereby suggesting no requirement for dose adjustment for bexicaserin across these ethnicities.
Funding:
This study was sponsored by Longboard Pharmaceuticals (now a part of H. Lundbeck A/S; La Jolla, CA, USA).