A Phase 2 Randomized, Placebo-controlled, Double-blind, Dose-ranging Study to Evaluate the Efficacy, Safety, and Tolerability of AMG 133 in Adult Subjects With Overweight or Obesity, With or Without Type 2 Diabetes Mellitus.

The primary objective is to compare and assess the dose response of three selected doses of AMG 133 compared with placebo on inducing and maintaining weight loss from baseline at week 52 in subjects with overweight or obesity without diabetes mellitus (cohort A) and in subjects with overweight or obesity with type 2 diabetes mellitus (cohort B). This objective is clinically relevant for determining the optimal therapeutic dose of AMG 133 in achieving sustained weight reduction across different metabolic phenotypes.

The secondary objectives include:

• To evaluate the effect of AMG 133 on achieving specific categories of body weight loss from baseline at week 52 in cohorts A and B

• To evaluate the effect of AMG 133 on glucose metabolism in cohorts A and B

• To characterize the pharmacokinetic (PK) properties of AMG 133

• To evaluate the effect of AMG 133 on waist circumference

• To assess the treatment effect of dose-escalation regimens

• To evaluate the effect of AMG 133 on systolic blood pressure (SBP)

• To evaluate the effect of AMG 133 on body composition in a subpopulation

• To evaluate the effect of AMG 133 on a marker of inflammation

• To evaluate the effect of AMG 133 on body mass index (BMI)

• To evaluate the effect of AMG 133 on lipid parameters

• To evaluate the effect of AMG 133 on diastolic blood pressure (DBP)

This clinical trial enrolled a total of **457 participants** with **overweight** or **obesity**. The study population included both male and female adults aged **18 years or older**. Participants were divided into two cohorts: **Cohort A** consisted of individuals with overweight or obesity without **diabetes mellitus**, while **Cohort B** included individuals with overweight or obesity and **type 2 diabetes mellitus**. All participants had a **body mass index (BMI)** of at least **27 kg/m²** at screening and had previously attempted weight loss through diet and exercise without success. Participants in Cohort A were required to have at least one weight-related complication such as **hypertension**, **dyslipidemia**, **obstructive sleep apnea**, or **cardiovascular disease**, or alternatively, a BMI of at least **30 kg/m²**. These participants also had an **HbA1c** level below **6.5%** without a diagnosis of diabetes. Participants in Cohort B had an established diagnosis of type 2 diabetes for at least 180 days prior to screening, with HbA1c levels ranging from **7% to 10%**. These individuals were either managed with diet and exercise alone or were on stable treatment with **metformin**, a **sulfonylurea**, or a **sodium-glucose cotransporter 2 (SGLT2) inhibitor** as monotherapy or combination therapy for at least 90 days prior to screening.

This is a **Phase 2**, **randomized**, **placebo-controlled**, **double-blind**, dose-ranging clinical trial evaluating the efficacy, safety, and tolerability of **AMG 133** in adult subjects with **overweight** or **obesity**, with or without **type 2 diabetes mellitus**. The study employs a parallel group design with two distinct cohorts: cohort A comprises subjects with overweight or obesity without diabetes mellitus, while cohort B includes subjects with overweight or obesity with type 2 diabetes mellitus. Participants are randomly assigned to receive one of three selected doses of AMG 133 or **placebo**. The investigational medicinal product AMG 133, containing the active substance **maridebart cafraglutide**, is administered as a **solution for injection** via **subcutaneous use**. The maximum daily dose is 420 mg, with a maximum total dose of 10920 mg over a treatment period of 104 weeks.

The primary objective is to compare and assess the dose response of three selected doses of AMG 133 compared with placebo on inducing and maintaining weight loss from baseline at week 52 in both cohorts. The **primary endpoint** is the percent change from baseline to week 52 in body weight. Secondary endpoints include achieving weight reduction thresholds of ≥5%, ≥10%, ≥15%, and ≥20% from baseline at week 52, changes in **hemoglobin A1c (HbA1c)**, fasting serum insulin, fasting plasma glucose, **Homeostasis Model Assessment for insulin resistance (HOMA2-IR)**, and Homeostasis Model Assessment for steady state beta cell function (HOMA2-%B). Additional secondary endpoints encompass **pharmacokinetic parameters** for AMG 133 including maximum observed plasma concentration (Cmax) and area under the concentration-time curve (AUC), changes in waist circumference, body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), **body mass index (BMI)**, and body composition measured by **dual-energy X-ray absorptiometry (DXA)** in a subset of subjects. Percent changes from baseline to week 52 in **high-sensitivity C-reactive protein (hs-CRP)**, **low-density lipoprotein cholesterol (LDL-C)**, total cholesterol, **high-density lipoprotein cholesterol (HDL-C)**, non-HDL-C, very-low-density lipoprotein cholesterol (VLDL-C), triglycerides, and free fatty acids (FFA) are also evaluated.

Principal inclusion criteria require that subjects provide informed consent prior to initiation of any study-specific activities or procedures. Eligible participants must be aged ≥18 years or the legal age within the country if older than 18 years, with a BMI ≥27 kg/m² at screening. Subjects must have had at least one unsuccessful attempt at weight loss by diet and exercise in the opinion of the investigator. For cohort A, subjects must have at least one weight-related complication such as **hypertension**, **dyslipidemia**, **obstructive sleep apnea**, or **cardiovascular disease**, or a BMI ≥30 kg/m². Additionally, cohort A subjects must have HbA1c <6.5% (<48 mmol/mol) at screening without a diagnosis of type 1 or type 2 diabetes mellitus. For cohort B, subjects must have HbA1c ≥7% and ≤10% (53 to 86 mmol/mol) at screening with an established diagnosis of type 2 diabetes mellitus for ≥180 days prior to screening. Cohort B subjects must be either treated with diet and exercise alone or on stable treatment for at least 90 days prior to screening with **metformin**, a **sulfonylurea**, or a **sodium-glucose cotransporter 2 (SGLT2) inhibitor** as monotherapy or combination therapy, per approved local label.

The estimated recruitment start date for the trial is March 13, 2023, with an estimated end date of January 2, 2026. The screening visit involves assessment of eligibility criteria and baseline measurements. Following enrollment, participants attend scheduled follow-up visits throughout the 52-week primary evaluation period and continue through the 104-week treatment period for extended assessment. The end-of-study visit occurs upon completion of the treatment period or at the time of early discontinuation. Expected participant involvement spans up to 104 weeks of active treatment. Conditions that may lead to early termination from the study include withdrawal of consent, protocol violations, adverse events requiring discontinuation, investigator decision, or other safety concerns as determined by the study protocol.

The experimental medication **AMG 133** contains the active substance **maridebart cafraglutide**, which is a human IgG1 monoclonal antibody against gastric inhibitory polypeptide receptor fused to a glucagon-like peptide 1 analog. The product is manufactured by AMGEN INC and is classified as a protein of other origin. AMG 133 is formulated as a **solution for injection** and is administered via the **subcutaneous route**. The maximum daily dose is **420 mg**, with a maximum total dose of **10920 mg** over the treatment period. The maximum treatment duration is **104 weeks**. The study evaluates three selected doses of AMG 133 in a dose-ranging design to assess efficacy, safety, and tolerability in adult subjects with overweight or obesity, with or without **type 2 diabetes mellitus**.

A matching **placebo** for AMG 133 is used as the comparator treatment in this randomized, placebo-controlled, double-blind study. The placebo is designed to maintain blinding throughout the trial and is administered according to the same schedule as the active treatment. The study compares the dose response of AMG 133 against placebo in inducing and maintaining weight loss from baseline at week 52 in two cohorts: subjects with overweight or obesity without diabetes mellitus and subjects with overweight or obesity with type 2 diabetes mellitus.

Efficacy will be assessed using the primary endpoint of percent change from baseline to week 52 in **body weight**. This parameter will be evaluated in adult subjects with overweight or obesity, both with and without **type 2 diabetes mellitus**. The primary objective is to compare and assess the dose response of three selected doses of AMG 133 compared with placebo on inducing and maintaining weight loss from baseline at week 52.

Secondary efficacy endpoints include the proportion of subjects achieving weight reduction thresholds of ≥ 5%, ≥ 10%, ≥ 15%, and ≥ 20% from baseline at week 52. Additional metabolic parameters will be measured, including change from baseline to week 52 in **hemoglobin A1c** (HbA1c), fasting serum insulin, fasting plasma glucose, Homeostasis Model Assessment for **insulin resistance** (HOMA2-IR), and Homeostasis Model Assessment for steady state beta cell function (HOMA2-%B). Changes in waist circumference, body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), **body mass index** (BMI), and body composition (fat mass, lean mass) using **dual-energy X-ray absorptiometry** (DXA) for a subset of subjects will also be evaluated at week 52. Percent change from baseline to week 52 in cardiovascular and metabolic biomarkers will be assessed, including high-sensitivity C-reactive protein (hs-CRP), **low-density lipoprotein cholesterol** (LDL-C), total cholesterol, **high-density lipoprotein cholesterol** (HDL-C), non-HDL-C, very-low-density lipoprotein cholesterol (VLDL-C), triglycerides, and free fatty acids (FFA). Pharmacokinetic parameters for AMG 133, including maximum observed plasma concentration (Cmax) and area under the concentration-time curve (AUC), will also be determined.