Towards a Quantitative Understanding of Aficamten Clinical Pharmacology: Pharmacokinetic‐Cardiodynamic Modeling to Support Safety and Efficacy
Year: 2026
Type: article
Abstract: ABSTRACT In the phase 3 study SEQUOIA‐HCM (NCT05186818), aficamten, a next‐in‐class cardiac myosin inhibitor, was safe and efficacious in participants with obstructive hypertrophic cardiomyopathy (oHCM). Using pharmacokinetics/pharmacodynamics (PKPD) modeling, we quantified the relationship between aficamten exposure and cardiodynamic measures of safety (left ventricular ejection fraction [LVEF]) and efficacy (post‐Valsalva left ventricular outflow tract gradient [LVOT‐G]), and used Clinical Trial Simulations (CTS) to predict cardiodynamics for a flexible dose regimen in a post‐approval setting. PKPD relationships between aficamten average concentration over 24 h (C avg,24 ) and LVEF or LVOT‐G were well quantified. Within‐subject variability for LVEF was low (CV = 7.6%), indicating that prior LVEF readings are highly predictive of future readings during stable therapy. A ~2% decrease in LVEF is expected per 100 ng/mL increase in C avg,24 . LVOT‐G slope was ~10‐fold steeper vs. LVEF, suggesting a relatively large therapeutic window. The commercial regimen allows for individualized flexible echocardiography‐based dose titration (every 2–8 weeks) from 5 to 20 mg once daily and flexible maintenance dose monitoring. CTS demonstrated minimal differences in population progression of LVOT‐G < 30 mmHg and LVEF < 50% between evaluated dose‐titration frequencies (every 2, 4, 6, or 8 weeks) over the first 6 months of treatment, supporting a 2–8 week window for dose titration. With maintenance doses, the probability of maintaining LVOT‐G < 30 mmHg (~60%) was high and the probability of occurrences of LVEF < 50% (~3%) was low. Therefore, this regimen should maintain safe and efficacious cardiodynamics while increasing convenience and access for patients with oHCM.
DOI: 10.1002/psp4.70237
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,140
OpenAlex ID: W7160668208