Asma Baliouze1, Haden Bunn1, Michael Tagen1, Hiroaki Okutsu2, Samira Merali3
1PumasAI, Inc, 2BristolMyersSquibb, 3BristolMyersSquibb
Introduction: Mavacamten is a reversible selective inhibitor of cardiac myosin that is approved for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) [1] and is currently being studied for non-obstructive HCM. Population pharmacokinetic (PPK) [2] and exposure-response models [3] for measures of efficacy (Valsalva left ventricular outflow tract gradient [VLVOTg]) and safety (left ventricular ejection fraction [LVEF]) were previously developed. The PPK analysis included data from one study in Japanese healthy volunteers. HORIZON-HCM was a BMS sponsored Phase 3, open label, single-arm, clinical study of mavacamten in Japanese adults with symptomatic obstructive HCM [4], giving the opportunity to evaluate ethnic differences in PK, efficacy, and safety. Objectives: •Evaluate ethnic difference between Japanese and non-Japanese patients by updating a previous PPK model for mavacamten •Assess the exposure-response for measures of efficacy and safety in the obstructive HCM Japanese and non-Japanese participants by updating the mavacamten VLVOT and LVEF models Methods: Data from HORIZON-HCM were pooled with the previous dataset of 13 clinical studies, which included 1 study assessing PK in healthy Japanese volunteers and 6 studies assessing safety and efficacy. The PPK base model was developed by re-estimating the parameters of the previous final PPK model with the updated dataset (N=58 Japanese (38 Patients from HORIZON-HCM)/578 non-Japanese). Covariate exploration of ethnic differences (Japanese/non-Japanese) was then conducted. The effect of Japanese ethnicity on mavacamten exposures in obstructive HCM participants of different CYP2C19 metabolizer status was also explored by simulations using the final model. For exposure-response of VLVOTg and LVEF, model development was initiated with the re-estimation of the parameters of the final models from the previous analyses with the updated dataset (N=38/382 Japanese/ non-Japanese for VLVOTg and N=38/438 for LVEF) using Cavg168 as the exposure metric driver for both ECHO response parameters. In both models, Japanese ethnicity was then explored as a covariate. Results: The prior PK model, consisting of a 2-compartment model with linear elimination and first-order absorption with a lag time [2], was successfully fit to the updated dataset. Japanese ethnicity was not a significant covariate on clearance based on an assessment with the full model approach. Simulated exposures following 5 mg QD dosing showed that median mavavamten exposure at Day 1 and steady-state were slightly higher in Japanese than non-Japanese for all CYP2C19 phenotypes likely due to the low body weight in the Japanese population compared to the non-Japanese, but with significant overlap for the two ethnicities. For exposure-response [3], the previously developed VLVOTg and LVEF models were successfully fit to the updated datasets. The higher baseline VLVOTg and LVEF observed in study baseline characteristics were both identified as covariates. Japanese ethnicity had a significant effect on the baseline value of VLVOTg with higher baseline in Japanese participants. Japanese ethnicity also had a significant effect on the baseline value of LVEF with higher baseline in Japanese participants. Japanese patients were estimated to have a shallower “slope” of the exposure-LVEF relationship relative to global participants. Conclusions: Mavacamten exposures in Japanese participants were predicted to be slightly higher than in non-Japanese participants with the same CYP2C19 phenotype likely due to the lower body weights in the Japanese population, but the difference was not considered to be clinically relevant. Baseline VLVOTg and LVEF were higher in Japanese participants relative to non-Japanese, and the slope of the exposure-safety relationship of LVEF was shallower than in non-Japanese.
[1] U.S. Food & Drug Administration. 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf [2] Chang P, Perera V, Salinger D, Merali S, Thaneer N, et al. Characterization of mavacamten pharmacokinetics in patients with hypertrophic cardiomyopathy to inform dose titration. CPT Pharmacometrics Syst Pharmacol. 2024; 13(9): 1462-1475. [3] Merali S, Salinger DH, Palmisano M, Sehnert AJ, Thanneer N, et al. Recommendation of mavacamten posology by model-based analyses in adults with obstructive hypertrophic cardiomyopathy. CPT Pharmacometrics Syst Pharmacol. 2024; 13(9):1448-1461. [4] Kitoaka HK, Ieda M, Ebato M, Kozuma K, Takayama M, et al. Phase 3 Open-Label Study Evaluating the Efficacy and Safety of Mavacamten in Japanese Adults With Obstructive Hypertrophic Cardiomyopathy – The HORIZON-HCM Study. Circ J. 2024; 89(1):130-138.
Reference: PAGE 33 (2025) Abstr 11334 [www.page-meeting.org/?abstract=11334]
Poster: Drug/Disease Modelling - Other Topics