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

Inclusion Criteria:

• Age ≥ 18 years.

• BMI ≥ 30 kg/m^2.

• HF diagnosed for at least 30 days before screening with New York Heart Association (NYHA) Class II-IV.

• Managed with HF standard of care therapies.

• Left ventricular ejection fraction (LVEF) of > 40%.

• Elevated NT-proBNP.

• Participants must have at least one of the following:

1. Structural heart disease OR

2. Documented hospitalization with a primary diagnosis of decompensated HF within 12 months before randomization OR

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

Exclusion Criteria:

• History of any of the following within 60 days before 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, or uncorrected primaryvalvular heart disease, or clinically significant congenital heart disease.

• Any lifetime history of LVEF ≤ 40%.

• Currently hospitalized with acute decompensated HF or hospitalization with a primarydiagnosis of decompensated HF within 30 days before screening.

• 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 at screening:

1. HbA1c > 10.0%

2. Uncontrolled diabetes requiring immediate therapy

3. History of diabetic ketoacidosis or hyperosmolar state/coma

4. One or more episodes of severe hypoglycemia within 6 months before screeningand/or history of hypoglycemia unawareness

5. History of proliferative diabetic retinopathy, diabetic maculopathy, or severenon-proliferative diabetic retinopathy.

• SBP ≥ 180 mmHg , or on three or more blood pressure-lowering drugs with a SBP > 160mmHg.

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

• Family (or personal) history of medullary 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 before screening

2. Lifetime history of suicide attempt

3. History of non-suicidal self-injury within 5 years before screening.

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

• 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 before randomization or planned use during the conduct of the study.