Single and Multiple Ascending Dose Study of AMG 133 in Participants with Obesity

- Participant has provided informed consent before initiation of any study-specific activities/procedures. - Age ≥ 18 years to ≤ 65 years, at the time of signing the informed consent. - Except for obesity, otherwise healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, and ECGs on day -2 (cohorts 1-6, cohort 11-13) or day -1 (cohorts 7-10) and screening. - Body mass index between ≥ 30.0 kg/m^2 and ≤ 40.0 kg/m^2. - Have a stable body weight (< 5 kg self-reported change during the previous 8 weeks) before screening. - Willing to maintain current general diet and physical activity regimen, except for the physical activity in the 72 hours before each blood sample collection for the clinical laboratory analysis, which should not be strenuous. - Females must be of nonreproductive potential • Postmenopausal as defined as: - Age of ≥ 55 years with no menses for at least 12 months; OR - Age < 55 years with no menses for at least 12 months AND with a follicle-stimulating hormone level > 40 IU/L or according to the definition of “postmenopausal range” for the laboratory involved; OR • History of hysterectomy; OR • History of bilateral oophorectomy. - For patients in cohorts 7-10 only, participants must have a smartphone device with the capability of downloading apps or other digital tools required for this cohort.

- History or clinical evidence of diabetes mellitus, including hemoglobin A1c (HbA1c) > 6.5% and/or a fasting glucose ≥ 125 mg/dl (6.9 mmol/L) at screening. - Triglycerides ≥ 5.65 mmol/L (ie, 500 mg/dL) at screening. - Screening calcitonin ≥ 50 ng/L. - Hepatic liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, or total bilirubin levels > 1.5 times the upper limit of normal (ULN) at screening. If ALT is > 1.5 x the ULN at screening AND the AST, alkaline phosphatase, and total bilirubin levels are within normal limits, then participant may be eligible for enrollment after a discussion with the medical monitor. - History or clinical evidence of bleeding diathesis or any coagulation disorder, including prothrombin time (PT), activated partial thromboplastin time (PTT), international normalized ratio (INR), or platelet count outside of the laboratory’s normal reference range at screening. If a single value (PT, PTT, INR, or platelet count) is outside the normal reference range at screening and the participant does not have evidence of any other bleeding or coagulation disorder, then the participant may be eligible for enrollment after a discussion with the medical monitor. - History of gastrointestinal abnormality that could affect gastrointestinal motility (including small bowel or colonic resection, inflammatory bowel disease, irritable bowel disease, and colon or gastrointestinal tract cancer). - Participants with a family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 or a personal history of nonfamilial medullary thyroid carcinoma. - Participants with a history of confirmed chronic pancreatitis or idiopathic acute pancreatitis. - Participants with a history of gall bladder disease (ie, cholelithiasis or cholecystitis) not treated with cholecystectomy. - Untreated or uncontrolled hypothyroidism/hyperthyroidism defined as thyroid stimulating hormone > 6 mIU/L or <0.4 mIU/L. - A corrected QT interval (QTc) at screening of > 450 msec in males or > 470 msec in females or history of long QT syndrome. - Participants with a history of renal impairment or renal disease and/or estimated glomerular filtration rate ≤ 60 mL/min/1.73 m^2. - Obesity induced by other endocrinologic disorders (eg, Cushing’s Syndrome). - Previous surgical treatment for obesity (excluding liposuction if performed >1 year before study entry) and/or participants with recent (within 6 months) or planned endoscopic treatment for obesity. - History of major depressive disorder. - History of other severe psychiatric disorders, eg schizophrenia, bipolar disorder. - Any lifetime history of a suicidal attempt or of any suicidal behavior. - Surgery scheduled for the study duration period, except for minor surgical procedures, at the discretion of the investigator. - Positive results for human immunodeficiency virus antibodies, hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C virus RNA. For hepatitis C, hepatitis C antibody testing is done at screening, followed by hepatitis C virus RNA by polymerase chain reaction if hepatitis C antibody is positive. - Systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure ≥ 90 mm Hg at screening, or on day -2. For each visit, if the initial blood pressure is elevated, the reading may be repeated once at least 15 minutes later and the lower of the 2 readings may be used. - History of malignancy of any type, other than in situ cervical cancer or surgically excised nonmelanomatous skin cancers occurring more than 5 years before randomization. - Use of the following agents are excluded unless there is a prior consultation between the investigator and Amgen medical monitor: • Prescription and nonprescription drugs within 14 days or 5 half-lives, whichever is longer, before the first dose of investigational product, with exception of hormone replacement therapy (eg, estrogen, thyroid). • All herbal medicines, vitamins, and supplements within 30 days before receiving the first dose of investigational product. • Exceptions must be reviewed and approved by the investigator and Amgen medical monitor. Written documentation of this review and Amgen acknowledgment is required for participant participation. - Current or history of treatment with medications that may cause significant weight gain or loss, within 3 months before screening, including systemic corticosteroids (except for a short course of treatment, ie, 7 to 10 days), tricyclic antidepressants, atypical antipsychotic and mood stabilizers (eg, imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, and lithium). - Current participation (or within the last 3 months) in an organized weight reduction program or currently using or used within 3 months before screening: pramlintide, sibutramine, orlistat, zonisamide, topiramate, phentermine, naltrexone, bupropion, lorcaserin, metformin, or any GLP-1R agonists (either by prescription or as part of a clinical study). - Prior exposure to maridebart cafraglutide or AMG 598 or currently receiving treatment in another investigational device or drug study, or less than 5 half-lives since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded. - Female participants with a positive pregnancy test assessed at screening and/or day -2 by a serum pregnancy test and/or urine pregnancy test) or female participants who are breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 5 months after the last dose of maridebart cafraglutide. - Male participants with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use an acceptable method of contraception during treatment and for an additional 5 months after the last dose of maridebart cafraglutide. - Male participants unwilling to abstain from donating sperm during treatment and for an additional 5 months after the last dose of maridebart cafraglutide. - Participant has known sensitivity to maridebart cafraglutide or components thereof or a history of drug or other allergy that is in the opinion of the investigator or medical monitor (if appropriate), contraindicates their participation. - Participant has a known sensitivity to GLP-1R agonists. - Participant has known sensitivity to mammalian derived products. - Participant has an allergy or known sensitivity to acetaminophen. - Participant is unwilling or unable to limit alcohol consumption throughout the course of the study. Alcohol is prohibited 48 hours before day -2 and is limited to no more than to 2 drinks per day for males and 1 drink per day for females for the duration of the study (1 drink being equivalent to 12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces of wine, or 1.5 ounces of 80 proof distilled spirits). - Participant uses nicotine or tobacco containing products (including but not limited to: snuff, chewing tobacco, cigars, cigarettes, e-cigarettes, pipes, or nicotine patches) within 6 months before screening. Participant is unwilling or unable to abstain from nicotine or tobacco, cigars, cigarettes, pipes, or nicotine patches throughout the course of the study. - Participant is tested positive for alcohol and/or drugs of abuse at screening. - History of substance abuse (ie, alcohol, licit or illicit drugs) within 12 months before screening. - Participant is unwilling to refrain from strenuous exercise (eg, heavy lifting, weight training, and aerobics) for 72 hours before each blood collection for clinical laboratory tests. - Participant has donated or lost ≥ 500 mL of blood or plasma within 60 days of day -2. - Participant likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the participant and investigator’s knowledge. - History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to participant safety or interfere with the study evaluation, procedures or completion. - For participants in cohorts 7-10 and cohorts 12-13 only, the Patient Health Questionnaire-9 (PHQ-9) score of ≥ 10 up to day 1. - For participants in cohorts 7-10 and 12-13 only, any suicidal ideation as identified by endorsement of (answered yes to) any of the items numbered 1-5 on the Columbia Suicide Severity Rating Scale (C-SSRS) up to day 1. - For participants in cohorts 7-10 and 12-13 only, participant has systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure ≥ 95 mm Hg on day 1. For each visit, if the initial blood pressure is elevated, the reading may be repeated once at least 15 minutes later and the lower of the 2 readings may be used. - For participants in cohorts 7-10 and 12-13 only, a QTc of > 450 msec in males or > 470 msec in females up to day 1.