Inclusion Criteria:

• Participants, 18 to 85 years of age, inclusive.
• Participants with NYHA functional Class II-III for at least 8 weeks prior to screening AND:
  • Cohort 1 (LVEF ≤ 40%): A screening LVEF ≤ 40% in the absence of hemodynamically significant and/or severe valvular disease (other than mitral valve regurgitation and/or tricuspid regurgitation) on 2D-TTE, with at least one other documented LVEF measurement ≤ 40% within the last 52 weeks prior to screening determined by echocardiography, radionuclide ventriculogram, cardiac computed tomography (CT), or cardiac magnetic resonance imaging (CMR).
    • In participants with a screening LVEF ≥ 30% and ≤ 40%, elevated level of NT-proBNP (≥ 300 pg/mL);
    • Participants who have undergone coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or implantation of a CRT device must have a measurement of LVEF ≤ 40% at least 12 weeks after the intervention to be eligible for screening.
  • Cohort 2 (LVEF > 40% and ≤ 65%): A screening LVEF between 40% and 65% in the absence of hemodynamically significant and/or severe valvular disease on 2D-TTE, with at least one other documented LVEF measurement between 40% and 65% and within 52 weeks prior to screening as confirmed by echocardiography, radionuclide ventriculogram, cardiac CT, or CMR, AND;
  • Elevated level of NT-proBNP (≥ 600 pg/mL). ii. Documented evidence of paroxysmal (on ≥ 2 occasions ≥ 1 week apart), persistent or permanent atrial fibrillation/flutter by ECG, Holter, implantable device, or telemetry-based event monitoring of at least 2 hours duration at one of these timepoint within the last 5 years.
• Stable HF defined as no hospitalizations for cardiac-related issues within 4 weeks prior to the initial screening visit or between screening and randomization, other than for routine percutaneous procedures such as device battery/generator changes or new pacemaker lead insertion.
• Participants should be established on background optimal medical therapy for HF and be treated according to locally recognized guidelines with both drugs and devices, as appropriate.
  • Guideline-recommended HF medications should be used at recommended doses unless contraindicated or not tolerated, or at the discretion of the Investigator;
  • HF medications should be at stable doses for at least 8 weeks prior to screening, other than diuretics, which should be stable for at least 2 weeks prior to screening (if not, can be discussed with the Medical Monitor to determine eligibility), and throughout the duration of the study.
• Screening hemoglobin ≥ 9.0 g/dL.
• Sexually active male participants whose partner(s) are of childbearing potential must agree to use a medically accepted method of effective contraception (see Appendix 2) from the start of the study until 90 days after the last dose of study drug.
• Women of childbearing potential (WoCBP; i.e., those who are not chemically or surgically sterilized or who are not postmenopausal; see Appendix 2):
  • Must present with a negative serum pregnancy test, must not be breastfeeding;
  • If sexually active with a biologically male partner(s), must be willing and able to adhere to the contraceptive methods outlined in Appendix 2) from the start of the study until 90 days after the last dose of study drug.
• Capable of providing signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Willing and able to comply with the requirements of the protocol.
• For participants with a history of cancer:
  • For participants with in situ or resected cancers (other than adequately treated cutaneous basal or squamous cell carcinoma with no evidence of recurrence), no cancer within the last 5 years;
  • For participants with metastatic cancer, no cancer within the last 10 years;
  • Participants with diagnosed pre-malignancies are eligible (e.g., colonic polyps, skin lesions). *Note: All participants are encouraged to undergo cancer screening prior to enrollment in accordance with local guidelines.

Exclusion Criteria:

Cardiac-Related Criteria

• Uncontrolled hypertension (defined as systolic BP ≥ 180 mmHg, or based on the opinion of the Investigator) during the screening visit.
• Sustained systolic BP < 90 mmHg and/or diastolic BP < 50 mmHg (confirmed by a duplicate seated reading) on at least 3 consecutive readings during the screening visit.
• Participants with poor echo windows that preclude accurate repeat assessments of LVEF.
• HF due to hypertrophic cardiomyopathy, restrictive and/or infiltrative cardiomyopathy, arrhythmogenic right ventricular dysplasia, Fabry disease, or Noonan syndrome with LV hypertrophy or a positive serum immunofixation result.
• Diagnosis of stress-induced (Takotsubo) cardiomyopathy, myocarditis, or peripartum cardiomyopathy.
• Diagnosis of chemotherapy- or radiation-induced cardiomyopathy.
• Diagnosed with stroke or TIA within 12 weeks of screening.
• History of syncope within the last 12 weeks prior to screening or sustained ventricular tachycardia without an implantable cardioverter-defibrillator.
• Moderate or severe aortic and/or mitral valve stenosis.
• Medically documented unstable angina, acute coronary syndrome (e.g., myocardial infarction, troponin-positive with symptoms of angina or unstable angina) within the last 8 weeks prior to start of screening.
• Medically documented ST-elevated myocardial infarction within 12 weeks of screening.
• Any narrow complex tachycardia (inclusive of atrial fibrillation or atrial flutter) with a resting ventricular rate > 110 beats per minute at screening.
• For participants with a history of AF or atrial flutter, not on adequate anticoagulant therapy via non-vitamin K oral anticoagulants or warfarin if the CHA2DS2-VASc score is ≥ 2 in men or ≥ 3 in women or per local guidelines;
  • Percutaneous occlusion of the left atrial appendage alone is not adequate.
• AF ablation within the last 12 weeks prior to screening or planned during the study duration.
• Symptomatic bradycardia or second (Mobitz Type II)- or third-degree heart block without a pacemaker.
• Cardiac surgery, coronary artery revascularization or indication for coronary artery revascularization, percutaneous coronary intervention, valve repair/replacement or valvuloplasty within 12 weeks prior to screening.
• Implantation of a CRT within 12 weeks prior to screening, or intent to implant a CRT device during the course of the study.
• Previous cardiac transplantation, or any use of mechanical circulatory support or similar device, or implantation expected after randomization.
• Receiving mechanical hemodynamic support (e.g., intra-aortic balloon pump counter pulsation) or invasive mechanical ventilation within the last 8 weeks prior to screening.
• Receiving IV inotropes (e.g., dobutamine, milrinone, levosimendan) or IV vasopressors (e.g., epinephrine, norepinephrine, dopamine, or vasopressin) within the last 8 weeks prior to screening.
• Receiving IV vasodilators within the last 4 weeks prior to screening. 

Non-Cardiac Criteria

• Participating in any other study and have received any other investigational drug, biologic, or device within 30 days prior to screening or 5-half-lives, whichever is longer, or any other investigational implanted device within 30 days prior to screening, or are taking part in a nonmedication study which, in the opinion of the Investigator, would interfere with study compliance or outcome assessments.
• Any past participation in a study that has investigated the NRG-1 pathway (e.g., Neucardin, cimaglermin, JK07).
• Pregnant or breastfeeding women.
• Participants with orthopedic impairment that would prohibit credible or adequate assessment of 6-minute walk test (6MWT).
• Has severe chronic obstructive pulmonary disease, or other severe pulmonary disease, requiring home oxygen, chronic nebulizer therapy, chronic oral steroid therapy or hospitalized for pulmonary decompensation within 12 months of informed consent.
• Any major surgical procedure, that at the discretion of the Investigator would compromise participant safety and/or study integrity, within 4 weeks prior to screening or any planned major surgical procedure during the study period.
• Clinically significant renal dysfunction as measured by the estimated glomerular filtration (eGFR) rate of < 30 mL/min/1.73 m2 (Cockcroft-Gault equation for estimation of creatinine clearance; Cockcroft and Gault, 1976) at screening, or a clinically significant change in renal function between screening and baseline.
• Receiving noninvasive mechanical ventilation (e.g., bilevel positive airway pressure or continuous positive airway pressure) within the last 8 weeks prior to screening;
  • The use of noninvasive ventilation for sleep disordered breathing is permitted.
• Clinically significant liver dysfunction at screening as measured by alanine aminotransferase (ALT) > 3.0 × upper limit of normal (ULN), aspartate aminotransferase (AST) > 3.0 × ULN, or total bilirubin > 2 × ULN, other than diagnosed Gilbert’s syndrome, at time of screening.
• Active alcohol abuse or abuse of illicit drugs, per Investigator discretion, within 6 months prior to randomization (excluding medical or recreational use of marijuana or cannabidiolbased products).
• Other medical or psychiatric condition that, in the opinion of the Investigator, would preclude obtaining voluntary consent/assent or would confound the secondary objectives of study.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 2/08/2024. Questions regarding updates should be directed to the study team contact.