Study to Evaluate the Safety and Tolerability of AMG 986 in Healthy Subjects and Heart Failure Patients

Inclusion Criteria • Subject has provided informed consent prior to initiation of any study-specific activities/procedures. • Male and female subjects ≥ 18 to ≤ 55 years old with no history or evidence of clinically relevant medical disorders as determined by the investigator and the Amgen physician (Parts A and B only) • Body mass index (BMI) between 18 and 35 kg/m2, inclusive, at screening. • Physical examination including vital signs, clinical laboratory values, and ECGs are clinically acceptable to the investigator. Abnormal findings for healthy volunteers and unexpected findings for heart failure patient subjects will be discussed with Amgen prior to study enrollment. • Women must be of non-reproductive potential (ie, postmenopausal) • Men must agree to practice an acceptable method of effective birth control while on study through 11 weeks after receiving the last dose of investigational product (AMG 986 or placebo). Acceptable methods of effective birth control include sexual abstinence; vasectomy and testing that shows there are no sperm in the semen; or a condom with spermicide (men) in combination with barrier methods (diaphragm, cervical cap or cervical sponge), hormonal birth control or IUS (women). • Men must be willing to abstain from sperm donation while on study through 11 weeks after receiving the last dose of investigational product (AMG 986 or placebo). • This inclusion criterion only applies to Parts B and C cohorts. Before inclusion in the study, subjects will undergo a screening echocardiogram to ensure that the following parameters can be accurately measured: left ventricular end-systolic and end-diastolic volumes, left atrial end-systolic and end-diastolic volumes, ejection fraction, fraction shortening, and end-systolic septal and posterior wall thickness. For Part C Additional Inclusion Criteria for HFrEF Patients • Subject must be of age 18 to 85 years, have a diagnosis of HF confirmed by medical records for ≥ 3 months, and be in stable condition for at least 4 weeks. • Left ventricular ejection fraction (LVEF) ≤ 40% confirmed by echocardiogram, radionuclide ventriculography, cardiac magnetic resonance imaging, or contrast ventriculography within 12 months prior to randomization. • NYHA class II or III at screening • Sinus rhythm • NT-proBNP level ≥ 250 pg/ml • Patients will be treated with stable, optimal pharmacological therapy for a minimum of 4 weeks prior to randomization. Treatment of HFrEF includes at least beta-blockers (carvedilol, metoprolol succinate or bisoprolol) and a RAAS inhibitor (ACEi, ARB or sacubitril/valsartan). Additional Inclusion Criteria for HFpEF patients • Subject must be of age of 18 to 85 years, have a diagnosis of HF confirmed by medical records for ≥ 3 months, and be in stable condition for at least 4 weeks. • Left ventricular ejection fraction (LVEF) ≥50% confirmed by echocardiogram, radionuclide ventriculography, cardiac magnetic resonance imaging, or contrast ventriculography within 12 months prior to randomization. • Left ventricular ejection fraction (LVEF) never ≤ 40% in the past • NYHA class II or III at screening • Sinus rhythm • NT-proBNP level ≥ 250 pg/ml • Patients will be treated with stable, optimal pharmacological therapy for a minimum of 4 weeks prior to randomization. Treatment of HFpEF includes at least a daily dose of diuretics equivalent to furosemide 40 mg. • For subjects in Parts A, B and C: Women must have negative results for both the screening (serum) and day -1 (serum or urine) pregnancy tests Exclusion Criteria • Currently receiving treatment in another investigational device or drug study, or less than 30 days or 5 half-lives (whichever is longer), since ending treatment on another investigational device or drug study(s) prior to receiving the first dose of investigational product (AMG 986 or placebo). • Female subjects who are lactating/breastfeeding or who plan to breastfeed while on study through 11 weeks after receiving the last dose of investigational product (AMG 986 or placebo). • Male subjects with partners who are pregnant or planning to become pregnant while the subject is on study through 11 weeks after receiving the last dose of investigational product (AMG 986 or placebo). • Female subjects of reproductive potential. • Subjects in Parts A and B of the study: estimated glomerular filtration rate (eGFR) within the screening period of less than 60 mL/min/1.73m2 as calculated using the estimated Modification of Diet in Renal Disease (MDRD) formula. • Current or prior malignancy within 5 years of randomization, with the exception of non-melanoma skin cancers, cervical or breast ductal carcinoma in situ, and adenocarcinoma of the prostate Stage I or IIa (defined as T1, T2a or T2b, N0, M0 with documented serum PSA < 20 ng/mL and Gleason score ≤ 7) per the American Joint Committee on Cancer (AJCC) primary tumor, regional lymph nodes, and distant metastasis system. • Positive results for Human Immunodeficiency Virus (HIV), antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HepCAb). • Subject has known sensitivity to any of the products or components to be administered during dosing. • Subject likely to not be available to complete all protocol required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge. • History or evidence of any other clinically significant disorder, condition or disease with the exception of those outlined above that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion. • Subject previously has entered this study or has been previously exposed to AMG 986. • Concurrent or prior use of strong CYP3A4 inhibitors within 14 days of study Day 1, including (not limited to): macrolide antibiotics (eg, clarithromycin, telithromycin), antifungals (eg, itraconazole, voriconazole), antivirals (eg, ritonavir, saquinavir, indinavir, nelfinavir), nefazodone. • Concurrent or prior ingestion of grapefruit or grapefruit products and other foods that are known to inhibit CYP3A4 within 7 days of study Day 1. • Concurrent or prior use of strong CYP3A4 inducers within 28 days of study Day 1, Including (not limited to): phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital. Subjects should also not take St John's Wort. • Concurrent or prior use of strong P-glycoprotein inhibitors within 28 days of study Day 1, including (not limited to): elacridar and valspodar. • All herbal supplements, vitamins, and nutritional supplements taken within the last 30 days prior to dosing on Day 1 (and continued use, if appropriate), must be reviewed and approved by the PI and Amgen Medical Monitor. • For subjects enrolled under Amendments 1-6, inclusive: QTc > 450 msec or history/evidence of long QT syndrome. • Planned elective surgery within 30 days of study completion or before return of red blood cell parameters to normal values. • Blood donation ≥ 500 mL within 60 days of Day 1. • Systolic blood pressure > 150 mm Hg or < 90 mm Hg, or diastolic blood pressure > 95 mm Hg or < 60 mm Hg, assessed on 2 separate occasions prior to enrollment (Parts A and B only). • Heart rate ≥ 100 beats per minute after 5 minutes of rest or an untreated symptomatic bradyarrhythmia within 1 month prior to enrollment. • For Parts A and B: Troponin I at screening > upper limit of normal (ULN). • In the opinion of the Investigator, a condition that compromises the ability of the subject to give written informed consent or to comply with study procedures. • Unwilling or unable to abstain from nicotine or tobacco containing products (including but not limited to: snuff, chewing tobacco, cigars, cigarettes, pipes, or nicotine patches) throughout the screening period and for the duration of the study. • Subjects who are unwilling or unable to limit alcohol consumption to 1 units/day (1 unit = 1 drink and 1 drink is equivalent to 12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces of wine or 1.5 ounces of 80 proof distilled spirits). • Subjects with a positive urine drug screen or alcohol breath test. • Known history of drug or alcohol abuse. • Concurrent use of Phosphodiesterase 5 (PDE5) inhibitors including (not limited to) avanafil, sildenafil, tadalafil, vardenafil. • Concurrent use of vasodilators by healthy subjects in Parts A and B that could in the opinion of the investigator potentially lead to a drop in blood pressure in combination with investigational product. • Severe uncorrected valvular heart disease, or hypertrophic obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease. • For subjects in Part C of the study: estimated glomerular filtration rate (eGFR) within the screening period of less than 30 mL/min/1.732m2 as calculated using the Modification of Diet in Renal Disease (MDRD) formula. • For subjects in Part C of the study: Systolic blood pressure > 160 mm Hg or < 100 mm Hg, or diastolic blood pressure > 110 mm Hg or < 60 mm Hg, assessed on 2 separate occasions prior to enrollment. • For subjects in Part C of the study: Troponin I > ULN if there is also evidence of an acute cardiovascular event. • For subjects enrolled in Part C under Amendment 7: QTc > 500 msec or history/evidence of long QT syndrome.