Overview

This trial will examine if maridebart cafraglutide as an adjunct to standard of care will lead to a reduction in heart failure (HF) events such as HF hospitalizations and urgent HF visits, cardiovascular (CV) deaths and improvement in HF symptoms in participants with HF with preserved ejection fraction (HFpEF) and HF with mildly reduced ejection fraction (HFmrEF) who are obese. This is a phase 3, global, multicenter, 2-part trial with a double-blind period and an open-label extension (OLE). The trial is event-driven, and Part 1 will conclude when approximately 850 primary endpoint events have occurred.

Eligibility

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-IV at the time of informed consent.
• Managed with HF standard of care therapies.
• Left ventricular ejection fraction (LVEF) of \> 40% within 12 months from the beginning 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 which required IV loop diuretic treatment \> 30 days and \< 12 months prior to randomization 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, active myocarditis, constrictive pericarditis, cardiac tamponade, arrhythmogenic right ventricular or left ventricular cardiomyopathy/dysplasia, uncorrected primary valvular 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 screening period.
• Type 1 diabetes mellitus, or any type of diabetes with the exception of T2DM or history of gestational diabetes.
• For participants with a prior diagnosis of T2DM (including those diagnosed during screening):
  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 months before randomization
  4. One or more episodes of severe hypoglycemia within 6 months before randomization and/or history of hypoglycemia unawareness
  5. History or presence of either proliferative diabetic retinopathy, or diabetic maculopathy, or severe non-proliferative diabetic retinopathy; or currently receiving or planning to receive treatment for diabetic retinopathy and/or macular edema.
• SBP ≥ 180 mmHg during the screening period, or on three or more blood pressure-lowering drugs with a SBP \> 160 mmHg during the screening period.
• History of chronic pancreatitis or acute pancreatitis in the 180 days before screening or during the screening period.
• Any personal lifetime history of, or family history(first-degree relative\[s\]) of medullary thyroid carcinoma or MEN-2.
• eGFR \< 20 mL/min/1.73 m\^2 (CKD-EPI creatinine (Cr)-cystatin C equation) or receiving dialysis 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 psychiatric disorder 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 during the screening period.
• History of any other condition that, in the opinion of the investigator, may preclude the participant from following the protocol and completing the trial.
• Use of any glucagon-like peptide 1 receptor agonist (GLP-1 RA), glucose-dependent insulinotropic polypeptide (GIP) agonists or antagonists, or amylin analogs within 90 days prior to or during the screening period or planned use during the conduct of the trial.