The main aim of the study is to assess the effect of RO7204239 in combination with tirzepatide, compared to placebo in combination with tirzepatide, on body weight loss after 48 weeks of treatment in adults with obesity or overweight with at least one weight-related comorbidity, but without diabetes mellitus (DM). The study comprises of a 4-week screening period; a 48-week core treatment period, where all participants will receive tirzepatide as background treatment and will be randomized to one of the 4 treatment arms; a 24-week treatment extension period, where participants will stop treatment with tirzepatide and a 24-week post-treatment follow-up (FU) period.

Inclusion Criteria:

• BMI ≥ 30.0 kilograms per square meter (kg/m²) (additional weight-related comorbidities are not required for inclusion)
• BMI ≥ 27.0 kg/m² and < 30.0 kg/m² with at least one weight-related comorbidity such as: hypertension, dyslipidemia, obstructive sleep apnea and any cardiovascular disease
• History of at least one self-reported unsuccessful dietary or exercise effort to lose body weight
• Weight stability: self-reported change in body weight less than 5 kilograms (kg) (11 pounds [lbs]) within 3 months prior to screening

Exclusion Criteria:

• Prior history or diagnosis of DM
• Presence of non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy or diabetic macular edema
• Have obesity induced by other endocrinologic disorders
• Participation in unbalanced/extreme diets
• Prior or planned surgical treatment for obesity
• Endoscopic and/or device-based therapy for obesity or device removal within 6 months prior to screening
• Have a known clinically significant gastric emptying abnormality
• Have any of the following cardiovascular conditions within 6 months prior to screening: acute myocardial infarction, cerebrovascular accident (stroke), unstable angina, or hospitalization due to congestive heart failure (CHF)
• Have evidence of significant active, uncontrolled cardiovascular, autoimmune, endocrine, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease, a neurological or psychiatric condition, or a history of any neuromuscular disorder or autoimmune/inflammatory disorders that may cause muscle wasting or medical condition capable of constituting a risk when taking the study medication or interfering with the interpretation of data, as judged by the investigator at screening
• Have evidence of a significant, uncontrolled endocrine abnormality
• Have a history of an active or untreated malignancy or are in remission from a clinically significant malignancy
• Have evidence of a significant, active autoimmune abnormality
• Have anemia
• Have signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease
• Have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females)

For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data\_sharing