Study to Assess the Safety, Tolerability and PK/PD After 4 Weekly SC Injections of PB1046 in Subjects With Stable HFrEF

This study will be a sequential multiple-dose escalation study that will enroll (randomize and dose) approximately 28 subjects in four cohorts consisting of 3 active and 1 placebo in Cohort 1 and 6 active and 2 placebo in subsequent cohorts. Randomized subjects will receive a fixed weekly dose of study drug or placebo for a 4 week dosing period.

Qualifying subjects will have a diagnosis of NYHA Class II or III heart failure with a reduced ejection fraction (HFrEF), be in stable condition, and be taking clinician-directed appropriate pharmacological therapy (e.g., angiotensin converting enzyme inhibitors, angiotensin receptor blockers or an evidence based beta blocker) for heart failure at stable doses (with the exception of diuretics) for at least 1 month prior to screening.

During the period between screening and randomization (planned first dose), the study subject will remain on stable pharmacological therapy for heart failure. Also the study subject will be in stable health with no hospitalizations or clinically significant acute illnesses between screening and randomization that would put the subject at increased risk for study participation.

Randomized subjects will receive a fixed weekly dose of study drug or placebo for a 4 week dosing period. Dose escalation in subsequent cohorts will continue if the safety and pharmacokinetic profile are deemed acceptable as assessed by the Study Review Committee.

Eligibility Criteria:
Inclusion Criteria:

* Willing and able to sign a written informed consent and follow all study-related procedures,
* Male subjects and female subjects of reproductive or childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 30 days after their last dose of study drug,
* Body mass index ≥ 18 kg/m2 and ≤ 45 kg/m2,
* Receipt of stable pharmacological therapy(ies) for heart failure for a minimum of 1 month prior to screening and between screening and randomization and are in stable clinical condition,
* NYHA Class II or III heart failure diagnosis (ischemic or non-ischemic confirmed by medical history) at least 6 months prior to screening,
* Stable HF defined as no hospitalizations for cardiac related issues within the previous 3 months prior to the screening visit or between screening and randomization,
* A screening or historical Left Ventricular Ejection Fraction ≤ 40% by centralized reading of 2-D echocardiography,
* Screening hemoglobin ≥ 9.0 g/dL secondary to the volume of blood to be collected during the study period,
* Willing and able to return to the study unit for specified study visits, and be able to self-monitor blood pressure while at home,
* Live and work in an area with reliable cellular services (e.g., Sprint®) for real time transmission of telemetry data to the core laboratory.

Exclusion Criteria:

* Have previously received PB1046 or have a known allergy to the study drug or any of its components,
* Participating in any other study and have received any other investigational medication or device within 30 days prior to screening or are taking part in a non-medication study which, in the opinion of the Investigator, would interfere with study compliance or outcome assessments,
* Diagnosed with acute coronary syndrome (ACS) or an acute myocardial infarction (MI) within 3 months of screening,
* Canadian Cardiovascular Society (CCS) Class III or IV angina necessitating frequent use of as needed short acting nitroglycerin,
* Cardiac surgery or valvuloplasty within 3 months prior to screening,
* Cerebrovascular accident or transient ischemic attack within 3 months prior to screening,
* Sustained systolic blood pressure (SBP) \< 110 mmHg and/or diastolic blood pressure (DBP) \< 50 mmHg (confirmed by a duplicate seated reading) on at least 3 consecutive readings (self-monitored or office) prior to randomization or overt symptomatic hypotension,
* Sustained resting heart rate \>100 beats per minute (BPM) at screening (V1) or prior to randomization,
* History or evidence of clinically significant arrhythmias (uncontrolled by drug therapy or use of an implantable defibrillator), long QT syndrome or evidence of QT prolongation demonstrating QTcF \> 460 ms prior to randomization (Subjects with QTcF \>460 ms due to electronic pacing by an implanted pacemaker/ICD device may be enrolled),
* Clinically significant renal dysfunction as measured by the estimated glomerular filtration rate (eGFR) of \< 40 mL/min/1.73m2 as calculated by the CKD-EPI creatinine-cystatin C equation at screening, or a clinically significant change in renal function between screening and baseline,
* Clinically significant liver dysfunction as measured by: alanine aminotransferase \>3.0 × the upper limit of normal (ULN), aspartate aminotransferase \>3.0 × the ULN, or serum bilirubin ≥ 1.6 mg/dL at screening, or a clinically significant change in liver function between screening and baseline,
* Pregnant or lactating female subjects,
* Known history of or active alcohol abuse or use of illicit drugs within 1 year prior to randomization,
* Positive screening for human immunodeficiency virus antibodies, hepatitis B surface antigen, or hepatitis C virus antibodies,
* Any major surgical procedure within 1 month prior to screening or planned surgical procedure during the study period,
* Other medical or psychiatric condition which, in the opinion of the Investigator, would place the subject at increased risk or would preclude obtaining voluntary consent/assent or would confound the secondary objectives of study.