Maridebart Cafraglutide in Heart Failure With Preserved or Mildly Reduced Ejection Fraction and Obesity

Inclusion Criteria:

• Age ≥ 18 years at the time of informed consent.

• BMI ≥ 30.0 kg/m^2 at the time of randomization.

• HF diagnosed for at least 30 days with New York Heart Association (NYHA) Class II-IVat the time of informed consent.

• Managed with HF standard of care therapies.

• Left ventricular ejection fraction (LVEF) of > 40% within 12 months from thebeginning of screening.

• Elevated NT-proBNP.

• Participants must have at least one of the following:

1. Structural heart disease within 12 months prior to screening OR

2. Documented hospitalization with a primary diagnosis of decompensated HF whichrequired IV loop diuretic treatment > 30 days and < 12 months prior torandomization OR

3. Evidence of elevated filling pressures within 12 months before randomization.

Exclusion Criteria:

• History of any of the following within 60 days prior to or during screening: Type I (spontaneous) MI, valvular replacement or repair, coronary revascularization,coronary artery bypass graft surgery or other major cardiovascular surgery, stroke.

• HF due to: hypertrophic cardiomyopathy, infiltrative cardiomyopathy, activemyocarditis, constrictive pericarditis, cardiac tamponade, arrhythmogenic rightventricular or left ventricular cardiomyopathy/dysplasia, uncorrected primaryvalvular heart disease, clinically significant congenital heart disease.

• Any lifetime history of LVEF ≤ 40%.

• Hospitalized with acute decompensated HF at the time of or during the screeningperiod.

• Type 1 diabetes mellitus, or any type of diabetes with the exception of T2DM orhistory of gestational diabetes.

• For participants with a prior diagnosis of T2DM (including those diagnosed duringscreening):

1. HbA1c > 10.0% (86 mmol/mol) at screening

2. Uncontrolled diabetes requiring immediate therapy

3. History of diabetic ketoacidosis or hyperosmolar state/coma within 12 monthsbefore randomization

4. One or more episodes of severe hypoglycemia within 6 months beforerandomization and/or history of hypoglycemia unawareness

5. History or presence of either proliferative diabetic retinopathy, or diabeticmaculopathy, or severe non-proliferative diabetic retinopathy; or currentlyreceiving or planning to receive treatment for diabetic retinopathy and/ormacular edema.

• SBP ≥ 180 mmHg during the screening period, or on three or more bloodpressure-lowering drugs with a SBP > 160 mmHg during the screening period.

• History of chronic pancreatitis or acute pancreatitis in the 180 days beforescreening or during the screening period.

• Any personal lifetime history of, or family history(first-degree relative[s]) ofmedullary thyroid carcinoma or MEN-2.

• eGFR < 20 mL/min/1.73 m^2 (CKD-EPI creatinine (Cr)-cystatin C equation) or receivingdialysis at screening.

• Calcitonin ≥ 50 ng/L (pg/mL) at screening.

• Acute or chronic hepatitis.

• Any of the following psychiatric history:

1. History of unstable major depressive disorder or other severe psychiatricdisorder within 2 years prior to screening or during the screening period

2. Lifetime history of suicide attempt

3. History of non-suicidal self-injury within 5 years prior to screening or duringthe screening period.

• History of any other condition that, in the opinion of the investigator, maypreclude the participant from following the protocol and completing the trial.

• Use of any glucagon-like peptide 1 receptor agonist (GLP-1 RA), glucose-dependentinsulinotropic polypeptide (GIP) agonists or antagonists, or amylin analogs within 90 days prior to or during the screening period or planned use during the conduct ofthe trial.