Inclusion Criteria
1. Participants must be postmenopausal females 45 to 65 years of age. Postmenopausal status must be confirmed based on the protocol-defined criteria.
2. Body mass index must be 25.0 to 35.0 kg/m².
3. Body weight must be stable, with less than 5 kg self-reported change in the 3 months before screening.
4. Participants must not have changed their diet or started a nutritional lifestyle modification program within 3 months before screening.
5. Other inclusion criteria may apply.
Exclusion Criteria
1. History or evidence of any clinically significant medical condition, abnormal physical exam, ECG, vital sign, or laboratory finding that could increase risk or interfere with study participation.
2. History of diabetes, active diabetes, or hemoglobin A1c 6.5% or higher.
3. Endocrine disorders that can cause obesity, such as Cushing's syndrome.
4. History of acute or chronic pancreatitis within 1 year before check-in, pancreatic enzyme elevations greater than 2 times the upper limit of normal, or fasting triglycerides greater than 300 mg/dL.
5. Bleeding or clotting disorders, abnormal coagulation tests, or a history of venous or arterial blood clots or conditions that increase clot risk.
6. LDL cholesterol greater than 159 mg/dL.
7. Migraine with aura, normal pressure hydrocephalus, or ischemic optic neuropathy.
8. Malignancy within the past 5 years, except nonmelanoma skin cancer.
9. Unexplained postmenopausal vaginal bleeding, untreated endometrial disease, or other gynecologic conditions that could worsen with estrogen/progestin therapy.
10. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, or uncontrolled thyroid disease.
11. Gastroparesis, inability to swallow oral medication, clinically important gastrointestinal disease, malabsorption, uncontrolled inflammatory bowel disease, certain gastrointestinal surgeries, or recent bariatric surgery.
12. Clinically significant cardiovascular disease, clinically significant arrhythmia, long QT syndrome, QTcF greater than 470 msec, second- or third-degree atrioventricular block, or clinically important abnormal blood pressure or pulse rate.
13. Allergy, hypersensitivity, intolerance, or contraindication to maridebart cafraglutide, ethinyl estradiol, or orgestimate.
14. Reduced kidney function with estimated glomerular filtration rate 60 mL/min/1.73 m² or lower, ALT or AST greater than 2 times the upper limit of normal, or a history of acute or chronic liver disease, hepatic adenoma, or hepatic carcinoma.
15. Hemoglobin or hematocrit below the lower limit of normal.
16. Positive HIV test, or positive hepatitis B surface antigen or hepatitis C antibody at screening.
17. Lifetime history of suicide attempt, non-suicidal self-injury within 5 years, or unstable major depressive disorder or other severe psychiatric disorder within 2 years.
18. Positive pregnancy test at screening or check-in.
19. Recent use of medications that could affect study participation, including most prescription or over-the-counter medications, systemic hormone replacement therapy, certain contraceptive hormones, CYP enzyme inducers or inhibitors, GLP-1 receptor or GIP receptor agents, and nonpermitted herbal products, vitamins, or supplements.
20. Recent participation in another investigational study, prior participation in this study, or prior exposure to maridebart cafraglutide.
21. Tobacco or nicotine use within 3 months before check-in, positive cotinine test, history of alcoholism or drug abuse, positive alcohol or illicit drug testing, recent illicit drug use, or unwillingness to avoid illicit drugs or cannabinoids during the study.
22. Recent blood, plasma, or platelet donation.
23. Other exclusion criteria may apply.
