A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants

Abstract

This phase 1, randomized, double-blind, placebo-controlled study of aficamten (formerly CK-3773274) in healthy adults identified a pharmacologically active range of doses and exposures. At doses that were pharmacologically active (single doses of ≤50 mg or daily dosing of ≤10 mg for 14 or 17 days), aficamten appeared to be safe and well tolerated. Adverse events were generally mild and no more frequent than with placebo. Pharmacokinetic assessments showed dose proportionality over the range of single doses administered, and pharmacokinetics were not affected by administration with food or in otherwise healthy individuals with a cytochrome P450 2D6 poor metabolizer phenotype. (A Single and Multiple Ascending Dose Study of CK-3773274 in Health Adult Subjects; NCT03767855).

Keywords: AE, adverse event; AUC24, area under the plasma concentration–time curve from time 0 to 24 hours; CV%,, percent coefficient of variation; CYP, cytochrome P450; CYP2D6-PM, cytochrome P450 2D6 poor metabolizer phenotype; Cmax, maximum plasma drug concentration; DLRC, Dose Level Review Committee; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; LV contractility; LV, left ventricle; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; MAD, multiple ascending dose; PD, pharmacodynamic; PK, pharmacokinetic; QTcF, QT interval corrected for heart rate using Fridericia’s formula; SAD, single ascending dose; TEAE, treatment-emergent adverse event; aficamten; cardiac myosin inhibitor; hypertrophic cardiomyopathy; phase 1.

Conflict of interest statement

The study was funded by Cytokinetics, Inc. At the time of the study, Dr Malik, Dr Robertson, Mr Robbie, Dr Osmukhina, and Ms Xu, were employed by and owned stock in Cytokinetics, Inc. Dr Armas was employed by Celerion, Inc. Dr Li was employed at Certara, Inc. Drs Li and Solomon are consultants to Cytokinetics, Inc. Dr Solomon has received research support from Cytokinetics, Inc; has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

© 2022 The Authors.

Figures

Graphical abstract

Figure 1

Schematic Overview of the Study Design The study included SAD cohorts, MAD cohorts, a CYP2D6-PM cohort, and a food-effect cohort. The MAD and CYP2D6-PM cohorts began when a tolerated, pharmacologically active dose (reduction in LVEF of approximately 5%) was identified in the SAD cohorts. The food-effect cohort began following completion of the last SAD cohort. Criteria to stop dose escalation were met in the SAD 75-mg dose cohort, and remaining patients in this cohort received 50 mg. Subsequently, the final SAD cohort was completed using 40 mg of aficamten. CYP2D6-PM = cytochrome P450 2D6 poor metabolizer phenotype; d = day; LVEF = left ventricular ejection fraction; MAD = multiple ascending dose; qd = once daily; SAD = single ascending dose.

Figure 2

Maximum Plasma Concentrations and Exposure With Single Doses of Aficamten (A) Mean (SE) Cmax and (B) exposure (AUC24) of aficamten increased in a dose-proportional manner following single oral doses between 1 mg and 50 mg. AUC24 = area under the plasma drug concentration–time curve from 0 to 24 hours; Cmax = maximum plasma concentration.

Figure 3

Plasma Concentration Over Time With Multiple Doses of Aficamten Mean (SE) aficamten plasma concentrations are displayed. Data points are offset for clarity. Aficamten plasma concentrations increased between the 5-mg dose and the 2 higher doses; however, by day 2, there was no difference between mean concentrations of the 7.5-mg and 10-mg doses. Clearance was similar for the 5-mg and 10-mg doses, and the accumulation ratio was similar for all 3 doses. For days 7, 8, 10, 11, 12, and 13, only trough measurements are shown. For the 5-mg and 10-mg cohorts, the dosing period was 14 days with a 3-day follow-up. For the 7.5-mg cohort, dosing was extended to 17 days with a 3-day follow-up, and it was confirmed that the steady state was achieved after 10 to 12 days. qd = once daily.

Figure 4

Change From Baseline in LVEF (A) SAD cohorts. (B) MAD cohorts. Mean (SE) change from baseline in LVEF is displayed. Data points are offset for clarity. In both the SAD and MAD cohorts, reductions in LVEF within the target range (5%-15% reduction) were observed. In the SAD cohorts, there were generally small decreases in LVEF, with mean maximum reduction of 5.8% in the 50-mg group (at 1.5 hours postdose). In the MAD cohort, the greatest mean reduction in LVEF from baseline occurred in the 10-mg group (mean change of 5.0% 1.5 hours after dosing on day 14). Abbreviations as in Figure 1.

Figure 5

Change From Baseline in LVEF vs Time-Matched Plasma Concentration of Aficamten (A) Analysis of the SAD cohorts showed that as the plasma concentration of aficamten increased, there was a trend toward a decrease in LVEF. (B) Analysis of the MAD cohorts showed minimal suppression of LVEF in most participants at plasma aficamten concentrations of ≤180 ng/mL. Abbreviations as in Figure 1.