Aficamten Shows Potential for Hypertrophic Cardiomyopathy in REDWOOD-HCM


Presented at HFSA 2021, results of REDWOOD-HCM provide insight into the effects of the oral selective cardiac myosin inhibitor aficamten in patients with obstructive hypertrophic cardiomyopathy.

Martin Maron, MD, Tufts University

Martin Maron, MD

Data from a phase 2 clinical trial presented at the Heart Failure Society of America 2021 Annual Scientific Meeting suggests use of aficamten could improve functional capacity in patients with obstructive hypertrophic cardiomyopathy.

A novel, second-generation selective cardiac myosin inhibitor being evaluated as an oral drug therapy, results of the REDWOOD-HCM trial suggest aficatem was well-tolerated and use resulted in the elimination resting left ventricular (LV) outflow tract gradients among 93% of the trial’s high-dose cohort. Investigators also pointed out use of aficamten associated with reductions in NT-proBNP.

“Results from REDWOOD-HCM underscore the potential clinical utility of aficamten based on the elimination of resting LV outflow tract gradients in nearly all patients, substantial improvement in heart failure symptoms, rapid onset and reversibility of effect, and the ability to use precise echo-guided titration without treatment interruptions,” said principal investigator Martin Maron, MD, director of the Hypertrophic Cardiomyopathy Center at Tufts University School of Medicine, in a statement from Cytokinetics Inc. “We look forward to investigating aficamten further in a large phase 3 clinical trial that we expect to start by year end.”

After showing promise in preclinical trials, the Randomized Evaluation of Dosing With CK-274 in Obstructive Outflow Disease in HCM (REDWOOD-HCM) trial was designed to further assess the potential effects of aficamten as a potential treatment for hypertrophic cardiomyopathy (HCM). A multicenter, randomized, placebo-controlled, double-blind, dose finding clinical trial, the trial randomized patients to receive 1 of 2 aficamten dosing regimens, which included echocardiography assessments to guide dose levels, or placebo therapy for 10 weeks.

For inclusion in the study, patients were required to be 18-85 years of age, have LV wall thickness of 15 mm or greater, symptomatic NYHA FC II-III obstructive hypertrophic cardiomyopathy, a baseline LVEF of 60% or greater, and on stable doses of background medical therapy. Outcomes of interest in the trail included resting and Valsalva LVOT, change in LVEF, NYHA class, NT-proBNP, and safety and tolerability.

Patients included in either of the aficamten cohorts were given 3 doses of the study drug, with cohort 1 receiving doses of 5, 10, and 15 mg and cohort 2 receiving doses of 10, 20, and 30 mg. At conclusion of the trial, 13 patients were included in the placebo group, 14 were included in aficamten cohort 1, and 14 were included in aficamten cohort 2. Investigators noted the 10-week treatment period of the study was followed immediately by a 2-week washout period.

Upon analysis, results from the trial suggested use of aficamten was associated with statistically significant reductions from baseline versus placebo in mean resting LVOT-G (P=.0003, P=.0004, Cohort 1 and Cohort 2, respectively) and in mean post-Valsalva LVOT-G (P=0.001, P <.0001, Cohort 1 and Cohort 2, respectively). Additionally, investigators pointed out 78.6% of patients in cohort 1 and 92.9% of patients in cohort 2 achieved the target goal of treatment, which was defined as a resting gradient less than 30 mmHg and a post-Valsalva gradient less than 50 mmHg at week 10. This was only achieved among 7.7% of patients in the placebo arm of the trial.

Additional observations highlighted included reductions in LVOT-G occurring within 2 weeks of initiating treatment, maximizing within 2-6 weeks of dose titration, and being sustained until the end of treatment at 10 weeks. Investigators noted reversibility of the pharmacodynamic effect of aficamten was observed after the 2-week washout period, when resting LVOT-G, post-Valsalva LVOT-G, NT-proBNP, and LVEF returned to baseline values. Further analysis indicated the observed reductions were dose-dependent.

Investigators also pointed out use of aficamaten was associated with significant reductions in NT-proBNP (P=.003) in both cohorts 1 and 2 compared to placebo. Additionally, an improvement of at least 1 NYHA class was observed among 31% of the placebo group compared to 43% (P >.01) of patients in aficamten cohort 1 and 64% (P =.08) of patients in aficamten cohort 2.

This study, “Redwood-HCM: A Randomized, Double-blind, Placebo-controlled, Dose-finding Trial Of The Cardiac Myosin Inhibitor, Aficamten, In Obstructive Hypertrophic Cardiomyopathy,” was presented at HFSA 2021.

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