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

This study is a randomized, placebo-controlled, double-blind, single day ascending dose
(SDAD) study (Part A), a multiple daily ascending dose (MDAD) study (Part B), in healthy
subjects, and a MDAD study (Part C) in heart failure patients. In Parts A and B of the study,
healthy volunteers will receive AMG 986 by continuous IV infusion or by oral administration
in a fasted state. IV Infusions will be divided into an initial loading dose (LD) for the
first hour followed immediately by a maintenance dose (MD).

In Part C of the study, patients with heart failure and either reduced (HFrEF) or preserved
(HFpEF) ejection fraction will receive MDAD of AMG 986 or matching placebo once daily by oral
administration for 21 days.

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.