REGN5381 in Heart Failure Adult Participants With Elevated Pulmonary Capillary Wedge Pressure

Key Inclusion Criteria:

1. Body mass index (BMI) between 18 and 35 kg/m^2, inclusive, rounded to the nearestwhole number

2. Ambulatory participants with New York Heart Association (NYHA) class II/III heartfailure and at least 1 sign and/or symptom of congestion (eg, dyspnea on exertion,worsening edema, orthopnea, etc.)

3. Left ventricular ejection fraction (LVEF) ≥20 % and <50% on echocardiogram (ie,HFrEF participants) within 90 days prior to randomization (only for HFrEFparticipants in Group A and Group B).

4. Participants who, in the opinion of the investigator, require a right heartcatheterization (not applicable for HFrEF patients not taking sacubitril/valsartan [Group A]).

5. Left ventricular ejection fraction (LVEF) ≥50% on echocardiogram (ie, HFpEFparticipants) within 90 days prior to randomization (only for HFpEF participants inGroup C)

6. NT-proBNP >1000 pg/mL or Brain Natriuretic Peptide (active form) (BNP) >300 pg/mL asdescribed in the protocol within 30 days prior to randomization measured by thelocal laboratory (only for HFrEF participants [Group A and Group B]).

7. Pulmonary capillary wedge pressure (PCWP) ≥15 mmHg and right artrial pressure (RAP) >5 mmHg on right heart catheterization (RHC) the morning of anticipated study drugdose administration (not applicable for HFrEF participants not takingsacubitril/valsartan [Group A] as described in the protocol).

8. Systolic blood pressure (SBP) ≥110 mmHg at the screening visit and on day -1

9. Hematocrit >30% at the screening visit and day -1

Key Exclusion Criteria:

1. Currently taking IV vasodilators and/or inotropes

2. Taking sacubitril/valsartan (only for HFrEF and HFpEF participants not takingsacubitril/valsartan [Group A and Group C, respectively])

3. Taking a phosphodiesterase (PDE) inhibitor (eg, sildenafil), or a soluble guanylatecyclase stimulator (SGCS; ie, vericiguat) within 2 weeks of the screening visit orplanning on taking valsartan/sacubitril, a PDE inhibitor, or a SGCS at any pointduring the study

4. More than moderate valvular regurgitation/stenosis (ie, moderate-to-severe orsevere) on echocardiogram within 90 days prior to randomization

5. Known infiltrative or hypertrophic cardiomyopathy

6. Acute coronary syndrome within prior 6 months of randomization

7. History of cardiac arrest

8. Cardiac surgery within 3 months of randomization

9. Pacemaker or defibrillator placement within prior 30 days of randomization

10. Severe chronic obstructive pulmonary disease (COPD) (defined as Forced ExpiratoryVolume in 1st second [FEV1] <50% of predicted or Global Initiative for ChronicObstructive Lung Disease [GOLD] 3 or 4)

11. Pulmonary arterial hypertension (World Health Organization [WHO] Group 1) and anymedical history at any time of more than moderate pulmonary hypertension (ie,moderate-to-severe, or severe pulmonary hypertension, as described in the protocol

12. Congenital heart disease (repaired or unrepaired)

13. Inability to lie flat for cardiac catheterization

Note: Other protocol-defined Inclusion/ Exclusion Criteria apply