Abstract
Hypercontractility of the cardiac sarcomere may be essential for the underlying pathological hypertrophy and fibrosis in genetic hypertrophic cardiomyopathies. Aficamten (CK-274) is a novel cardiac myosin inhibitor that was discovered from the optimization of indoline compound 1. The important advancement of the optimization was discovery of an Indane analogue (12) with a less restrictive structure-activity relationship that allowed for the rapid improvement of drug-like properties. Aficamten was designed to provide a predicted human half-life (t1/2) appropriate for once a day (qd) dosing, to reach steady state within two weeks, to have no substantial cytochrome P450 induction or inhibition, and to have a wide therapeutic window in vivo with a clear pharmacokinetic/pharmacodynamic relationship. In a phase I clinical trial, aficamten demonstrated a human t1/2 similar to predictions and was able to reach steady state concentration within the desired two-week window.
Highlights
Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder normally characterized by abnormal thickening of the left ventricular walls that reduces stroke volume and limits cardiac output.1 HCM is one of the most common classes of genetic disease in young adults
A high-throughput screen (HTS) using bovine cardiac muscle myofibrils measuring the rate of ATP hydrolysis was performed, and several novel chemical structures were identified as new starting points for optimization
The preclinical data supported progression of aficamten into phase 1 studies where steady state was reached within 14 days of dosing and the wide therapeutic window observed preclinically appeared to translate to humans
Summary
Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder normally characterized by abnormal thickening of the left ventricular walls that reduces stroke volume and limits cardiac output. HCM is one of the most common classes of genetic disease in young adults. Current treatment for HCM is limited to symptomatic relief and does not treat the root cause of the disease, excessive sarcomere contractility. In a phase 3 trial in patients with oHCM using a pharmacokinetic and echo-based dose-titration strategy to find the optimal dose for each patient, mavacamten demonstrated improvements in peak oxygen consumption (pVO2) and NYHA (New York Health Association) class as well as a reduction in the LVOT pressure gradient, demonstrating a clinical benefit of this therapeutic approach in oHCM patients.. The first objective was to design a compound with a human t1/2 appropriate to allow once a day (qd) dosing and to reach steady state plasma concentrations within two weeks, minimizing the peak to trough ratio which is an important consideration for a cardiac drug and facilitating the ability of clinicians to safely titrate the dose to reach therapeutic concentrations. The third primary objective was the design of a compound with no substantial cytochrome (CYP) P450 induction or inhibition to minimize the potential for CYP-induced drug−drug interactions
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