Our portfolio of precision cardiovascular therapeutics includes multiple cardiac muscle activator programs aimed at increasing contraction of the heart muscle to improve blood flow. We are initially targeting precision indications in systolic heart failure and specifically, dilated cardiomyopathies (DCM).
Danicamtiv (formerly MYK-491) is an oral small molecule, selective cardiac myosin activator. In the heart, myosin is the motor protein that binds to actin to generate the force and movement of contraction. In patients with dilated cardiomyopathy and systolic heart failure, contraction is inadequate as the left ventricle of the heart is too distended and weak to adequately pump blood to meet the body’s needs. The goal of danicamtiv is to increase the ensemble force of contraction and improve cardiac output during systole without detracting from the ability of the heart to relax and fill with blood during diastole. Danicamtiv has been shown to increase the probability for myosin-actin engagement while preserving the detachment of myosin from actin at the end of contraction, thereby improving cardiac contractility while preserving diastolic function and allowing for normal filling.
MyoKardia intends to advance danicamtiv into two Phase 2 clinical trials in distinct patient subgroups: dilated cardiomyopathy patients with certain genetic mutations, and patients with reduced systolic function and atrial fibrillation.
In early clinical testing, danicamtiv has demonstrated an ability to improve in stroke volume without impairing the heart’s ability to relax and fill. In our Phase 2a placebo-controlled multiple-ascending dose study in patients with stable heart failure with reduced ejection fraction, danicamtiv treatment was associated with clinically meaningful improvements in left ventricular (LV) contractility, including statistically significant increases in LV stroke volume, without impairing the heart’s ability to relax and fill. Danicamtiv treatment also improved left atrial (LA) volume and function, a new and potentially important finding given left atrial size is a well-established prognostic factor for atrial fibrillation. Nonclinical studies indicated danicamtiv directly activates the left ventricle and left atrium, providing compelling mechanistic rationale for the robust changes observed clinically.
Danicamtiv has been generally well tolerated in early-stage clinical studies intended to assess safety and tolerability and no maximum tolerated dose or dose-limiting toxicities have been identified. Adverse events observed in our phase 1 and Phase 2 studies were benign and transient.