REGN5381 in Adult Participants With Heart Failure With Reduced Ejection Fraction

Open to people ages 18 years and up

1. Body mass index (BMI) between 18 and 45 kg/m², inclusive, at initial screening visit
2. Diagnosis of chronic heart failure
3. Left ventricular ejection fraction 20-49% by echocardiogram performed within 3 months of screening
4. Plasma NT-proBNP ≥800 pg/mL (or ≥1000 pg/mL if in atrial fibrillation) at screening (visit 1) and NT-proBNP ≥600 pg/mL (or ≥800 pg/mL if in atrial fibrillation) approximately 30 days prior to randomization (visit 5)
5. Receiving optimized standard of care therapy for heart failure as described in the protocol
6. Sacubitril-valsartan treatment:
   1. Treatment with sacubitril-valsartan at screening and at baseline permitted in Part A2 sacubitril-valsartan cohort and in Part B if supported by safety data from the Part A2 sacubitril-valsartan cohort as described in the protocol
7. Estimated Glomerular Filtration Rate (eGFR) levels:
   1. eGFR of ≥30 mL/min/1.73 m2 according to locally used formula (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] preferred), at screening (visit 1) or approximately 30 days prior to randomization (visit 5) as described in the protocol

1. Hospital discharge within 180 days of anticipated randomization
2. Resting SBP that remains out of range after two repeated measurements prior to randomization as described in the protocol
3. Current or recent diagnosis of acute coronary syndrome or myocardial infarction as described in the protocol
4. History of symptomatic autonomic dysfunction as evidenced by orthostatic hypotension and/or syncope
5. Unexplained syncope <12 months prior to initial screening or during the Run-in period
6. History of clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, psychiatric, or neurological disease, as assessed by the investigator that may confer unreasonable risk to the participant's participation in the study
7. Uncorrected congenital heart disease
8. Cardiac surgery within 6 months prior to screening or any planned surgery during the study
9. Implantation of a cardiac resynchronization therapy device in the prior 90 days, or planned during the study, or planned device optimization 30 days prior to randomization or during the study
10. Current chronic lung disease requiring long-term oxygen therapy

Note: Other protocol-defined inclusion/ exclusion criteria apply