The purpose of this study is to identify the weekly oral dose of VRB-101 (oral ecnoglutide) that can effectively maintain body weight in participants with a history of obesity or overweight with weight-related comorbidities.

This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral ecnoglutide (VRB-101) in participants with a history of obesity or overweight who have achieved weight reduction after 6 months of treatment with injectable semaglutide or tirzepatide. The study comprises three active arms and one placebo arm.

The study will include a Screening Period of approximately 4 weeks, followed by a 16-week Treatment Period and a 4-week Safety Follow-up Period prior to the end of the study.

Inclusion Criteria:

• Have a history of BMI of ≥30 kg/m2 OR ≥27 kg/m2 and <30 kg/m2 with at least 1 weight-related comorbidity at the time of initiation of subcutaneous (SC) semaglutide and/or tirzepatide treatment.
• Documented history of having obesity or overweight with weight-related comorbidities per medical records at the time of initiation of SC semaglutide and/or tirzepatide treatment.
• History of treatment with weekly SC semaglutide and/or tirzepatide for a minimum of 6 months prior to Screening.
• Documented weight reduction of ≥10% in 6 months and no clinically relevant weight regain.
• Participants of childbearing potential (POCBP) must be non-pregnant and non-lactating and must agree to use study-specified contraceptive methods.

Exclusion Criteria:

• Current or past diagnosis of diabetes mellitus [type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM), or other forms of diabetes mellitus]. A participant with a history of gestational diabetes may be included in the study if the participant has HbA1c <6.5% at Screening and is not on medication to lower glucose.
• At least 1 laboratory value suggestive of diabetes during screening, including 1 or more of HbA1c ≥6.5% (48 mmol/mol) or random glucose ≥200 mg/dL (11.1 mmol/L).
• Diagnosed with obesity due to endocrinologic disorders (for example, Cushing's syndrome) or diagnosed monogenetic or syndromic forms of obesity (for example, melanocortin 4 receptor deficiency or Prader-Willi syndrome)
• History of clinically significant gastric emptying abnormality (for example, severe gastroparesis or gastric outlet obstruction).
• Evidence of uncontrolled hypothyroidism or hyperthyroidism based on an abnormal thyroid-stimulating hormone (TSH).
• Personal or family history (first-degree relative) of multiple endocrine neoplasia type 2A or type 2B, thyroid C-cell hyperplasia, or medullary thyroid carcinoma.
• Evidence of a significant, uncontrolled endocrine abnormality (for example, thyrotoxicosis or adrenal crises)
• Renal impairment measured as eGFR <30 mL/min/1.73 m2
• History of acute or chronic pancreatitis or clinically significant gallbladder disease.
• Triglycerides >500 mg/dL (5.7 mmol/L) at Screening.
• Poorly controlled hypertension or an elevated resting pulse rate (>100 bpm).
• Current treatment with or history of treatment with (within 3 months prior to Screening) medications that may cause significant weight gain.
• Prior or planned surgical treatment for obesity, plan to have endoscopic and/or device-based therapy for obesity or have had device removal within the last 6 months prior to Screening.
• Known hypersensitivity to any of the study drug ingredients.
• Are pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study and for at least 60 days after completion of the study.