Phase 2 Randomized, Double-Blind, Placebo-Controlled Study on Maridebart Cafraglutide Efficacy and Safety in Type 2 Diabetes Mellitus

The primary objective of this study is to assess the **dose-response relationship** of maridebart cafraglutide on glucose control in adult subjects with **Type 2 Diabetes Mellitus** compared with placebo. This is clinically relevant as optimizing glucose control is crucial in managing Type 2 Diabetes Mellitus, potentially reducing the risk of complications associated with poor glycemic control.

Secondary objectives include evaluating the effects of maridebart cafraglutide on various metabolic and physiological parameters, which are important for comprehensive diabetes management:

• Assess the effect on body weight and achieving specific categories of body weight reduction.
• Evaluate the impact on reaching specific HbA1c targets, fasting glucose, and lipids.
• Assess the effect on blood pressure and systemic inflammation.
• Characterize the pharmacokinetics of maridebart cafraglutide.
• Evaluate the safety, tolerability, and immunogenicity of the treatment.

The clinical trial involves a total of **187 participants** diagnosed with **Type 2 Diabetes Mellitus**. The study population includes both male and female subjects, aged 18 years and older, with a **Body Mass Index (BMI)** ranging from 23 to 50 kg/m². Participants were selected based on their ability to provide informed consent and their diagnosis of Type 2 Diabetes Mellitus at least 180 days prior to screening, as per the World Health Organization classification. The trial excludes vulnerable populations and requires participants to have an HbA1c level between 7.0% and 10.5% at screening. Additionally, participants must have been on a stable dose of metformin, with or without an SGLT2-inhibitor, for at least 90 days before screening. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial aims to assess the dose-response relationship of maridebart cafraglutide on glucose control compared with placebo.

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled, dose-ranging study designed to evaluate the efficacy, safety, and tolerability of **maridebart cafraglutide** in adult subjects with **Type 2 Diabetes Mellitus**. The primary objective is to assess the dose-response relationship of maridebart cafraglutide on glucose control compared with placebo. The trial is expected to commence recruitment on November 21, 2024, and conclude by July 25, 2026, with a total duration of approximately 48 weeks for each participant.

Participants will be randomly assigned to receive either maridebart cafraglutide or a placebo, both administered as a **solution for injection** via subcutaneous use. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, **BMI**, and **HbA1c** levels, followed by regular follow-up visits to monitor treatment effects and safety. The primary endpoint is the change in hemoglobin A1c from baseline to week 24, with secondary endpoints including changes in body weight, fasting glucose, and lipid profiles, among others.

The expected length of participant involvement is approximately 24 weeks, with regular assessments to ensure compliance with the study protocol. Conditions that may lead to early termination from the study include non-compliance with study procedures, withdrawal of consent, or the occurrence of significant adverse events. The study aims to provide valuable insights into the potential benefits of maridebart cafraglutide for individuals with Type 2 Diabetes Mellitus, contributing to the broader understanding of its therapeutic profile.

The clinical trial involves the administration of **AMG 133**, an experimental medication formulated as a **solution for injection**. The active substance in AMG 133 is **maridebart cafraglutide**, a protein-based compound classified as a human IgG1 monoclonal antibody against the gastric inhibitory polypeptide receptor, fused to a glucagon-like peptide 1 analog. This investigational drug is provided by Amgen Inc. and is intended for **subcutaneous use**. The trial is designed to evaluate the efficacy, safety, and tolerability of maridebart cafraglutide in adult subjects with Type 2 Diabetes Mellitus. The dosing schedule and frequency of administration are determined by the study protocol, with a maximum treatment period of 48 weeks. The trial aims to assess the dose-response relationship of maridebart cafraglutide on glucose control compared with placebo.

The study also includes a **placebo** group, which receives a placebo formulation designed to match the experimental medication in appearance but contains no active substance. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This allows for an unbiased comparison of the effects of AMG 133 against a control group. The placebo is administered following the same route and schedule as the experimental drug to ensure consistency in the study design.

The efficacy of **maridebart cafraglutide** in the treatment of Type 2 Diabetes Mellitus will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline to week 24 in hemoglobin A1c (HbA1c) levels. Secondary endpoints include the percent change from baseline to week 24 in body weight, achieving HbA1c levels of less than 7.0% and 6.5% at week 24, and achieving a reduction in body weight of at least 5% and 10% from baseline at week 24. Additional secondary endpoints involve changes from baseline to week 24 in fasting glucose, lipid profiles including total cholesterol and various lipoprotein levels, systolic and diastolic blood pressure, and high-sensitivity C-reactive protein (hs-CRP).

Plasma concentrations of maridebart cafraglutide, including observed predose plasma concentration (Cpredose) at week 20 and maximum observed plasma concentration (Cmax) as defined by week 20 day 5 to 14 postdose sample, will also be measured. The incidence of treatment-emergent adverse events, serious adverse events, and anti-maridebart cafraglutide antibody formation, including neutralizing antibodies against native glucagon-like peptide 1 (GLP-1), will be monitored. These efficacy parameters will be collected and analyzed at specified timepoints, primarily focusing on the 24-week mark, to determine the dose-response relationship of maridebart cafraglutide on glucose control compared with placebo.