COSMIC-HF - Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure.

Omecamtiv mecarbil (AMG 423, CK-1827452) is a novel small molecule that increases cardiac
contractility by selectively and directly activating the enzymatic domain of cardiac myosin
heavy chain, the force-generating motor protein of the cardiac sarcomere. This is a
randomized, placebo-controlled, multicenter, phase 2 study, consisting of a dose escalation
phase to select 1 of 3 omecamtiv mecarbil oral formulations in 2 dose escalation cohorts,
followed by an expansion phase to evaluate 20 weeks of administration of the selected
omecamtiv mecarbil formulation at 2 target dose levels, compared with placebo.

Inclusion Criteria:

- History of chronic HF, defined as requiring treatment for HF for a minimum of 4 weeks
prior to screening

- Treated with stable, optimal pharmacological therapy for ≥ 4 weeks

- History of left ventricular ejection fraction (LVEF) ≤ 40%

- Elevated N-terminal fragment BNP (NT-proBNP)

Exclusion criteria:

- Severe uncorrected valvular heart disease

- Hospitalization within 30 days prior to enrollment

- Hypertrophic obstructive cardiomyopathy, active myocarditis, constrictive
pericarditis, or clinically significant congenital heart disease

- Acute Myocardial Infarction, Unstable angina or persistent angina at rest within 30
days prior to randomization

- Systolic BP > 160 mmHg or < 90 mmHg or diastolic BP > 90 mmHg

- TBL ≥ 2x ULN; AST or ALT ≥ 3x ULN

- Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2