PI-063 - DISPOSITION OF BEXICASERIN TO ITS MAJOR METABOLITE, N-CARBAMOYL GLUCURONIDE (M20), IS NOT INFLUENCED BY GENETIC POLYMORPHIC METABOLISM

R. Chan¹, N. Srinivas², G. O'Connell², C. Orevillo², R. Kaye³; ¹Longboard Pharmaceuticals, La Jolla, CA, USA, ²Longboard Pharmaceuticals, LA JOLLA, United States, ³Longboard Pharmaceuticals, LA JOLLA, CA, USA.

Background: Bexicaserin (LP352) is a potent and selective 5-hydroxytryptamine 2C (5-HT2C) superagonist in clinical development for the treatment of seizures associated with developmental and epileptic encephalopathies (DEEs). Bexicaserin is primarily metabolized to N-carbamoyl glucuronide (M20), via several UDP-glucuronosyltransferase with 2B sub-family enzymes (UGT2B7, UGT2B15 and UGT2B17). The objective of this analysis was to evaluate the relationship between bexicaserin and M20 exposures to determine if there is an effect of genetic polymorphism influencing the pharmacokinetics (PK) of bexicaserin.

Methods: In this comprehensive retrospective meta-analysis, first dose pharmacokinetic data (Cmax and AUC) was gathered from participants (n=153) across all Phase 1 studies. Molar metabolite (M20) to parent (bexicaserin) ratio (MPR) as well parent to metabolite ratio (PMR) exposure parameters were visualized in either ascending or descending fashion to ascertain any signals for pharmacogenetic variants. The ratios were statistically analyzed by Laplace Demon test and Hartigan Dip test to assess the modality of distribution.

Results: The MPR and PMR Cmax and AUC ratios in this large pool of Phase 1 study participants (n=153) suggested absence of pharmacogenetic variants. Furthermore, arrangement of MPR or PMR Cmax or AUC ratios in ascending or descending order displayed no distinct visual signals for any trends in polymorphic metabolism. The distribution of MPR/PMR ratios failed to show a bimodal distribution. The p-values were not statistically significant indicating the distribution of MPR/PMR ratios as unimodal. Taken together, the data suggests a lack of genetic polymorphisms associated with UGT2Bs influencing the PK of bexicaserin. In general, bexicaserin metabolizes similarly across the studied populations, albeit showing ~35 to 40% PK variability.

Conclusion: The pooled exposure data gathered in 153 participants across various racial subgroups enabled a rigorous retrospective evaluation for the involvement of genetic polymorphism. The lack of distinct separation in MPR/PMR ratios with unimodal distribution supports that the N-glucuronidation pathway of bexicaserin did not exhibit genetic polymorphisms among these individuals based on their enzymatic activity or genetic variability.