Inclusion Criteria:

All Participants

• Willing and able to comply with clinic visits, preparation for visits, and study-related procedures.
• Provide informed consent signed by study participant or legally acceptable representative.

Part A (in addition to criteria listed in All Participants)

• Male or female participants age ≥18 to ≤55 years of age at the time of screening
• BMI ≥ 18 and ≤ 32 kg/m2 , at the screening visit.
• Is judged by the investigator to be in good health based on medical history, physical examination, vital sign measurements, and ECGs performed at screening and/or approximately within 24 hours (up to 7 days) prior to administration of study drug.

Part B (in addition to criteria listed in All Participants)

• Male or female participants ≥ 18 to ≤ 80 years of age at the time of screening
• BMI ≥ 30 kg/m2
• History of 1 or more self-reported unsuccessful dietary attempts to lose weight
• Able to understand and complete study-related questionnaires

Exclusion Criteria:

All Participants

• History of diabetes (Type 2 or Type 1). History of gestational diabetes is permitted.
• Previous bariatric surgery or planned bariatric surgery.
• History of hypertrophic cardiomyopathy.
• Abnormal ECG findings at screening that meet Cornell voltage criteria for left ventricular hypertrophy.
• Any malignancy in the past 5 years prior to screening (except for nonmelanoma skin cancer that has been resected with no evidence of metastatic disease for 3 years prior to screening).
• History of poorly controlled hypertension, as defined by:
  • Systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg at the screening visit
  • Systolic blood pressure of 160 mm Hg to 179 mmHg or diastolic blood pressure of 100 mmHg to 109 mmHg at the screening visit, AND a history of end-organ damage (including history of left-ventricular hypertrophy, heart failure, angina, myocardial infarction, stroke, transient ischemic attack, peripheral arterial disease, end-stage renal disease, and moderate-to-advanced retinopathy [hemorrhages or exudates, papilledema])
• Have a history of any other condition (such as known drug abuse, alcohol abuse, diagnosed eating disorder, or a severe mental illness) that, in the opinion of the investigator, may preclude the participant from following and completing the protocol.
• Have history of use of marijuana/THC within 3 months of enrollment and are unwilling to abstain from marijuana/THC use during the trial.
•  Women who are pregnant or breast feeding
•  WOCBP* who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 24 weeks after the last dose. Highly effective contraceptive measures include:
  • stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;
  • intrauterine device; intrauterine hormone-releasing system;
  • bilateral tubal occlusion/ligation;
  • vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure) Pregnancy testing and contraception are required for WOCBP. Pregnancy testing and contraception are not required for women who are postmenopausal or permanently sterile. *WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to the Clinical Trial Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
• Male who is unwilling to practice highly effective contraception with WOCBP prior to the initial dose/start of the first treatment, during the study, and for at least 24 weeks after the last dose. Sperm donation is prohibited from the initial dose/start of treatment, during the study, and for at least 24 weeks after the last dose.
• Is committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• Presents any concern to the study investigator that might confound the results of the study or poses an additional risk to the participant by their participation in the study.
• Is positive for HIV, HBsAg, or HBcAb at the screening visit.
• Is positive for hepatitis C antibody and positive for qualitative (ie, detected or not detected) HCV RNA test at the screening visit.
• Participated in any clinical research study evaluating another investigational drug including biologics or therapy, including specific immunotherapy, within 90 days or at least 5 half-lives (whichever is longer) of an investigational biologic drug, or at least 4 weeks for other investigational drug, prior to the screening visit.

Part A (in addition to All Participant exclusion criteria)

• History of clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, psychiatric, neurological, or dermatologic disease, as assessed by the investigator, that may confound the results of the study or poses an additional risk to the subject by study participation.
• Presents any concern to the study investigator that might confound the results of the study or poses an additional risk to the participant by their participation in the study.
• Has undergone a regimen change in any chronic medication within 2 weeks prior to the screening visit, or is expected to have a change in medication throughout the study.
• Was hospitalized (ie, > 24 hours) for any cause within the last 3 months before screening visit.
• Whole blood donation within the previous 56 days or plasma donation within the previous 7 days prior to screening.
• Is a member or immediate family member of the clinical site study team, unless prior approval granted by the sponsor.
• Has a history of hypersensitivity reactions to any study drug products or excipients.
• Insufficient venous access to enable venous blood sampling for the duration of the study, in the opinion of study site clinical staff.
• Impaired renal function defined as estimated glomerular filtration rate 2 x ULN at screening (1 repeat measurement is allowed)

Part B (in addition to All Participant exclusion criteria)

• HbA1c at screening ≥ 6.5%.
• A change of body weight > 5 kg within 90 days of screening.
• Has received any anti-obesity medication within 90 days of enrollment.
• Has undergone a regimen change in lipid-lowering medication within 2 weeks prior to the screening visit, or is expected to have a change in lipid medication through week 26.
• Has undergone a regimen change in thyroid medication within 3 months prior to the screening visit, or is expected to have a change in thyroid medication through week 26.
• History of pancreatitis.
• Obesity induced by other endocrine disorders (for example, Cushing syndrome) or syndromic forms of obesity.
• Does not fit within measurement boundary of the site-associated DXA table, in supine position with arms at sides, or exceeds the weight limit of the site-associated DXA machine.
• Family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2.
• Hospitalization for heart failure in the last year or New York Heart Association Class 3 or 4.
• Taking antiplatelet therapy (eg, clopidogrel) or anticoagulants (eg, warfarin, heparin, factor Xa inhibitor, or thrombin inhibitors) in the last 30 days (or within 5 half-lives of the therapy, whichever is longer) or likely to require this antiplatelet/anticoagulant therapy during the course of the study. Low-dose acetylsalicylic acid (aspirin ≤ 100 mg/day or ≤ 150 mg/day, based on local practice) is acceptable.
• Any history of severe, non-traumatic bleeding requiring transfusion or hospitalization for hemodynamic compromise (eg, severe nose bleeds requiring hospitalization, nasal packing or cauterization, menstrual bleeding that is prolonged/heavy).
• Any history of hypersensitivity reactions to semaglutide or to any study drug products or excipients.
• Known pre-existing medical history of a bleeding diathesis (eg, hemophilia A, von Willebrand’s Factor deficiency, platelet count ≤ 20 × 109 /L).
• Known history of cerebral vascular malformation.
• Insufficient venous access to enable intravenous dosing for the duration of the study, in the opinion of study site clinical staff.
• Any history of suicide attempt, or any suicidal ideation corresponding to type 4 or 5 on the C-SSRS within the past 30 days at screening.
• Have received treatment (within 3 months prior to randomization) with medications that may cause significant weight gain, including but not limited to: high dose oral corticosteroids, tricyclic antidepressants, atypical antipsychotic, and mood stabilizers.
• Have any contraindication to semaglutide as per Wegovy product labeling.
• Have previously had intolerance to GLP-1 agonist therapy resulting in treatment discontinuation.
• Was hospitalized (ie, > 24 hours) for any reason within 30 days of the screening visit.
• Impaired renal function defined as estimated glomerular filtration rate < 30 mL/min/1.73m2 calculated by the Modification of Diet in Renal Disease equation (1 retest is allowed).
• Has changed or plans to change smoking status including e-cigarettes (stopped smoking 3 months prior to the screening visit or plans to stop smoking during the study).
• Has any of the following laboratory parameter assessments at screening (1 repeat measurement is allowed): ALT and/or AST > 3 x ULN

Exclusion from MRI substudy only – having any of the following criteria will not exclude a potential participant from the main study

• Standard contraindication to MRI, such as persons with cardiac pacemaker, non-MRI compatible metal implants such as cochlear implant, nerve stimulators, magnetic vascular clips, and metallic heart valve, presence of shrapnel in strategic locations, metal in the eye, presence of electronic devices or ferromagnetic metallic foreign or implanted objects that could constitute a hazard during MRI or any other contraindications for MRI.
• Have claustrophobia precluding completion of an MRI examination. Note: Investigators may offer, at their discretion, a light sedative. If the participant is not willing to attempt MRI with light sedation, the participant should be excluded from the MRI evaluation. Open MRI is not permitted.
• Have a weight or waist circumference that exceeds the scanner capabilities.
• Have any condition or circumstance that, in the opinion of the investigator, would interfere with the completion of MRI examinations.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 2/28/2024. Questions regarding updates should be directed to the study team contact.