Cytokinetics, Incorporated (Nasdaq: CYTK) has announced the initiation of the AMBER-HFpEF (Assessment of CK-586 in a Multi-Center, Blinded Evaluation of Safety and Tolerability Results in HFpEF) Phase 2 clinical trial. This trial will evaluate CK-4021586 (CK-586) in patients with symptomatic heart failure with preserved ejection fraction (HFpEF) who have a left ventricular ejection fraction (LVEF) of 60% or greater. The study is now open for enrollment.
CK-586 is an investigational cardiac myosin inhibitor being developed for a subset of HFpEF patients characterized by hypercontractility and ventricular hypertrophy. The AMBER-HFpEF trial is designed as a randomized, placebo-controlled, double-blind, multi-center, dose-finding study.
Trial Objectives and Design
The primary objective of the AMBER-HFpEF trial is to evaluate the safety and tolerability profile of CK-586 compared to placebo. Secondary objectives include assessing the effect of CK-586 on LVEF and NT-proBNP levels, as well as determining its pharmacokinetics and pharmacodynamic relationship. The trial will also explore the effect of CK-586 on patient function, symptoms, and measures of cardiac function.
The trial plans to enroll approximately 60 patients, randomized in a 3:1 ratio to receive CK-586 or placebo across three dose escalation cohorts. Patients will receive escalating doses of CK-586 over 12 weeks. Cohort 1 will receive once-daily doses of 150 mg and 300 mg, Cohort 2 will receive 300 mg and 450 mg, and Cohort 3 will receive 450 mg and 600 mg. An echocardiogram at Week 6 will determine if patients are up-titrated to the higher dose. Inclusion criteria require patients to have an LVEF of 60% or greater, NT-proBNP levels of 300 pg/mL or greater for those in sinus rhythm, or 900 pg/mL or greater for those with atrial fibrillation or flutter (AFF), and be classified as New York Heart Association (NYHA) Functional Class II or III.
CK-586: A Novel Cardiac Myosin Inhibitor
CK-586 is designed as a selective, oral, small molecule cardiac myosin inhibitor aimed at reducing hypercontractility in HFpEF. Preclinical models have shown that CK-586 reduces cardiac hypercontractility by decreasing the number of active myosin cross-bridges during cardiac contraction, thereby reducing contractile force without affecting calcium transients. In vitro studies in engineered human HCM heart tissues demonstrated improved lusitropy.
HFpEF and Unmet Needs
Heart failure affects over 64 million people worldwide, with approximately half of these patients having HFpEF. The prevalence of HFpEF is increasing, and it carries a poor prognosis, with approximately 75% of patients dying within five years of initial hospitalization and 84% being rehospitalized. According to Stuart Kupfer, M.D., Senior Vice President, Chief Medical Officer, despite recent advances, patients with heart failure and supranormal ejection fraction continue to have a poor prognosis following hospitalization. A subset of HFpEF patients with hypercontractility, ventricular hypertrophy, elevated biomarkers, and symptoms of heart failure may benefit from treatment with a cardiac sarcomere inhibitor.
Strategic Context
The development of CK-586 in HFpEF builds on the mechanistic similarities between HFpEF and non-obstructive hypertrophic cardiomyopathy (nHCM). Data from a Phase 2 clinical trial of aficamten, another cardiac myosin inhibitor developed by Cytokinetics for nHCM, showed that aficamten was well-tolerated and improved patient-reported outcomes and biomarkers relevant to HFpEF.
