Journal Article

Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy Participants

German, Polina, Simkins, Tyrell J., Heitner, Stephen B., Maharao, Neha, Liu, Genzhou, Griffith, Adrienne, Bowles, Owen, Xu, Donghong, Kupfer, Stuart, Benattia, Youcef

2025

Overview

Aficamten is a next‐in‐class, small‐molecule, cardiac myosin inhibitor in development for treating hypertrophic cardiomyopathy (HCM). This 2‐part study evaluated aficamten's impact on QTc interval in healthy participants. Part A (n = 10) was an open‐label study to find the appropriate dose for thorough QT (TQT) evaluation in Part B. Part B (n = 34) was a double‐blind, 3‐way crossover TQT study conducted as per ICH E14 guidance using negative (placebo) and positive (moxifloxacin) controls. A single 50 mg aficamten dose achieved exposures (Cmax range: 124–1660 ng/mL) comparable to the highest clinical dose (20 mg QD) in obstructive HCM patients (NCT05186818; [Cmax range: 131–1230 ng/mL]) and was chosen for TQT evaluation. Using concentration‐QT (C‐QT) modeling, the placebo‐ and baseline‐corrected QT interval using Fridericia's correction (ΔΔQTcF) was −1.82 msec (90% CI: −3.43, −0.214) at peak aficamten concentrations (298.3 ng/mL) following the 50 mg dose. The 90% CI upper bound of ΔΔQTcF for aficamten was < 10 msec at all post‐dose time points. Assay sensitivity was established by the 90% CI lower bound for moxifloxacin (ΔΔQTcF) exceeding 5 msec. Aficamten did not cause QTc prolongation (using C‐QT and by time point analyses) within observed plasma concentrations up to 1660 ng/mL (aficamten), 213 ng/mL (metabolite CK‐3834282), and 343 ng/mL (metabolite CK‐3834283). No clinically meaningful effect on electrocardiogram parameters, including absolute QTcF (≤ 450 msec) and change from baseline in QTcF (≤ 30 msec) was noted in aficamten‐treated participants. Aficamten was generally well tolerated. In conclusion, there was no evidence of aficamten‐mediated QTc prolongation across the therapeutic concentration range in a formal TQT study.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adult / Cardiomyopathy / cardiovascular disease / Cross-Over Studies / Dose-Response Relationship, Drug / Double-Blind Method / Drug dosages / EKG / Electrocardiography / Electrocardiography - drug effects / Female / Healthy Volunteers / Heart Rate - drug effects / Humans / Long QT Syndrome - chemically induced / Long QT Syndrome - diagnosis / Male / Metabolites / Middle Aged / Molecules / Moxifloxacin / Myosin / phase 1 / Placebos / Plasma / Pyrazoles - pharmacology / QTc interval / safety / Young Adult