Study to Assess the Safety, Tolerability and PK Response and Explore the PD Response Following 4 Weekly SC Injections of PB1046 in Subjects With Stable Heart Failure With Reduced Ejection Fraction (HFrEF)

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.

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.