The primary objective of this study is to demonstrate that maridebart cafraglutide is superior to placebo for percent change in body weight and proportion of participants with ≥ 5% reduction in body weight.

Inclusion Criteria:

• Age ≥ 18 years.

• History of at least 1 self-reported unsuccessful attempt at weight loss by diet and exercise.

• Body mass index (BMI) ≥ 35 kg/m^2 at screening with a current diagnosis of at least 1 of the weigh-related comorbidities specified in the Japan Society for the Study of Obesity (JASSO) guideline OR BMI ≥ 27 kg/m^2 to < 35 kg/m^2 at screening, with a current diagnosis of at least 2 of the weight-related comorbidities specified in the JASSO guideline.

• For both BMI categories, at least 1 of the weight-related comorbidities must be hypertension, dyslipidemia, or T2DM according to the definitions below:

  1. hypertension: treated, or with SBP ≥ 140 mmHg, or DBP ≥ 90 mmHg at screening.
  2. dyslipidemia: treated, or with LDL > 140 mg/dL (3.6 mmol/L), or triglycerides ≥ 150 mg/dL (1.7 mmol/L), or non-HDL cholesterol > 170 mg/dL (4.4 mmol/L) or HDL < 40 mg/dL (1.0 mmol/L) at screening.
  3. T2DM: diagnosed ≥ 180 days before screening, and treated with diet and exercise alone and/or a stable treatment for at least 90 days before screening with up to 3 oral glucose-lowering medications (as per local labeling) (except for glucagon-like peptide-1 receptor agonists [GLP-1RA] and dipeptidyl peptidase-4 [DPP-4] inhibitors), and have a HbA1c ≥ 7% and ≤ 10% (53-86 mmol/mol) at screening.

• In the opinion of the investigator, well-motivated and willing to:

  1. Follow study procedures for the duration of the study, including, but not limited to, follow lifestyle advice, maintain a study log(s)/diary(ies), and complete required study visits and questionnaires.
  2. Perform self-monitoring blood glucose (SMBG) per protocol (only for participants with T2DM).

Exclusion Criteria:

• Obesity induced by other endocrinological disorders or monogenetic or syndromic forms of obesity.
• Self-reported change in body weight > 5 kg within 90 days before screening.
• Previous or planned (during the study) surgical, endoscopic, or device-based treatment for obesity.
• For participants without diabetes at screening, type 1 or 2 diabetes mellitus or any other types of diabetes mellitus (except history of gestational diabetes).
• For participants with T2DM at screening, any other type(s) of diabetes mellitus except T2DM.
• History of chronic pancreatitis or history of acute pancreatitis within 180 days before screening.
• Family (first-degree relative[s]) or personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN-2).
• History of unstable major depressive disorder (MDD) or other severe psychiatric disorder within 2 years before screening.
• Lifetime history of suicide attempt.

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.

Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.