Maridebart Cafraglutide in Heart Failure With Preserved or Mildly Reduced Ejection Fraction and Obesity (MARITIME-HF)

Prior treatment

• 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
• In the opinion of the investigator, use within 90 days prior to or during the screening period of medications that may cause significant weight gain
• Any of the following psychiatric history: -History of unstable major depressive disorder or other severe psychiatric disorder within 2 years prior to screening or during the screening period -Lifetime history of suicide attempt -History of non-suicidal self-injury within 5 years prior to screening or during the screening period.
• Currently receiving treatment in another investigational device or drug study, or less than 90 days (or 5 half-lives, whichever is longer) prior to randomization since ending treatment in another investigational device or drug study(ies)
• Previous or planned participation in a study that includes maridebart cafraglutide or AMG 598
• Hospitalization with a primary diagnosis of decompensated HF which required IV loop diuretic treatment, within 30 days prior to randomization
• 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
• Planned bariatric surgery at the time of screening, or performed within 180 days of Screening
• History of acute pancreatitis in the 180 days before screening or during the screening period
• Severe, concomitant disease that is expected to reduce life expectancy to < 1 year
• Use of any GLP-1 RA, 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 study
• Treatment with continuous SC insulin therapy during screening or participants on intensive insulin therapy guided by carbohydrate counting
• Use within 90 days prior to or during the screening period of medications prescribed for weight loss

Other illness

• Type 1 diabetes mellitus, or any type of diabetes with the exception of T2DM or history of gestational diabetes
• Heart failure due to: hypertrophic cardiomyopathy (obstructive and non obstructive), infiltrative cardiomyopathy (including cardiac sarcoid, lymphoma, cardiac amyloid, endomyocardial fibrosis), active or chronic myocarditis, constrictive pericarditis, cardiac tamponade, arrhythmogenic right ventricular or left ventricular cardiomyopathy/dysplasia, uncorrected primary valvular heart disease, clinically significant congenital heart disease
• Any personal lifetime history of, or family history (first-degree relative[s]) of medullary thyroid carcinoma or MEN-2
• History of malignancy within the last 5 years prior to screening or during the screening period
• History of chronic pancreatitis
• Family (first-degree relative[s]) or personal history of medullary thyroid carcinoma or MEN-2
• Obesity induced by specific endocrinologic disorders or monogenetic or syndromic forms of obesity
• Recipient of heart transplant or listed for any other major organ transplant, listed for heart transplant, or anticipated to receive chronic mechanical circulatory support or heart transplantation within 12 months from randomization
• History of any other condition that, in the opinion of the investigator, may preclude the participant from following the protocol and completing the study.

Lab values

• For participants with a prior diagnosis of T2DM (including those diagnosed during screening): -HbA1c > 10.0% (86 mmol/mol) at screening -Uncontrolled diabetes requiring immediate therapy at randomization in the judgement of the investigator -History of diabetic ketoacidosis or hyperosmolar state/coma within 12 months before randomization -One or more episodes of severe hypoglycemia within 6 months before randomization and/or history of hypoglycemia unawareness -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
• Acute or chronic hepatitis; signs and symptoms of any liver disease other than MSALD; or ALT > 3.0 x ULN, during screening or TBL > 1.8 x ULN during screening
• eGFR < 20 mL/min/1.73 m2 according to the 2021 CKD-EPI creatinine (Cr)-cystatin C equation or receiving dialysis at screening

Other

• Calcitonin ≥ 50 ng/L (pg/mL) at screening
• Clinically significant gastric-emptying abnormality
• Hospitalized with acute decompensated HF at the time of or during the screening period

• Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years) at the time of informed consent
• BMI ≥ 30 kg/m2 at randomization
• HF diagnosed for at least 30 days with NYHA Class II-IV at the time of informed consent
• Managed with HF standard of care therapies consistent with regional clinical practice guidelines, stable for at least 14 days before randomization, according to investigator judgment
• Documented LVEF of > 40% measured by any modality within 12 months, before randomization
• For participants with a prior diagnosis of T2DM at screening or new diagnosis of T2DM during screening: Treatment of T2DM with diet, exercise, and/or glucose-lowering medications according to local label with stable dosing for at least 14 days prior to randomization