A Phase 3 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Impactof Maridebart Cafraglutide on Cardiovascular Outcomes in Participants with Atherosclerotic Cardiovascular Disease and Overweight or Obesity (MARITIME-CV)

The primary objective is to demonstrate that maridebart cafraglutide is superior to placebo when administered as an adjunct to standard of care with respect to reducing cardiovascular morbidity and mortality, assessed through dual primary endpoints. This objective addresses a critical clinical need in patients with atherosclerotic cardiovascular disease and overweight or obesity, populations at elevated risk for adverse cardiovascular outcomes.

The secondary objectives are:

• To demonstrate that maridebart cafraglutide is superior to placebo when given as an adjunct to standard of care with respect to reducing the incidence of 3-point major adverse cardiovascular events (3-P MACE) or heart failure events.

• To demonstrate that maridebart cafraglutide is superior to placebo when given as an adjunct to standard of care with respect to reducing the incidence of 3-P MACE or coronary revascularization.

The clinical trial enrolled a total of **7,236 participants** diagnosed with **atherosclerotic cardiovascular disease** and comorbid **obesity** or **overweight**. The study population consisted of both male and female adults aged **45 years or older** at the time of screening. Participants were required to have a **body mass index** of **27 kg/m² or greater**. The trial population was selected based on documented history of atherosclerotic cardiovascular disease, evidenced by at least one of the following conditions: prior **myocardial infarction**, prior **ischemic stroke** (including ischemic stroke with hemorrhagic transformation), or symptomatic **peripheral arterial disease** demonstrated by intermittent claudication with **ankle-brachial index** less than 0.9 at rest, peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease. All participants provided informed consent prior to initiation of any study-specific activities or procedures. The trial did not involve vulnerable populations.

This is a phase 3, randomized, double-blind, placebo-controlled clinical trial evaluating the impact of maridebart cafraglutide on cardiovascular outcomes in participants with atherosclerotic cardiovascular disease and overweight or obesity. The investigational medicinal product, AMG 133, is a solution for injection containing maridebart cafraglutide as the active substance, which is a human IgG1 monoclonal antibody against gastric inhibitory polypeptide receptor fused to a glucagon-like peptide 1 analog. The product is administered via subcutaneous route. The trial also includes a placebo comparator arm to maintain blinding throughout the study.

The primary objective of the trial is to demonstrate that maridebart cafraglutide is superior to placebo when given as an adjunct to standard of care with respect to reducing cardiovascular morbidity and mortality. The trial employs dual primary endpoints consisting of time to first occurrence of a composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke (3-point major adverse cardiac events), and time to first occurrence of a composite endpoint of all-cause death, myocardial infarction, ischemic stroke, coronary revascularization, or heart failure event (5-point major adverse cardiac events). Secondary endpoints include time to first occurrence of cardiovascular death, myocardial infarction, ischemic stroke, or heart failure event, as well as time to first occurrence of cardiovascular death, myocardial infarction, ischemic stroke, or coronary revascularization.

Eligible participants must be at least 45 years of age at screening with a body mass index of at least 27 kg/m² at screening. Participants must have a documented history of atherosclerotic cardiovascular disease as evidenced by at least one of the following: prior myocardial infarction, prior ischemic stroke (which may include ischemic stroke with hemorrhagic transformation), or symptomatic peripheral arterial disease as evidenced by intermittent claudication with ankle-brachial index less than 0.9 at rest, peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease. Informed consent must be provided before initiation of any study-specific activities or procedures.

The estimated recruitment start date for the trial is October 13, 2025, with an estimated end date of September 30, 2030. The overall trial duration spans approximately five years from recruitment initiation to study completion. Participant involvement extends throughout the treatment period and follow-up phase until the occurrence of a primary endpoint event or completion of the scheduled study visits. Early termination from the study may occur under specific conditions as defined in the protocol, including withdrawal of consent, safety concerns, protocol violations, or investigator discretion based on the participant's best interest.

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 active substance is classified as a protein of other origin. AMG 133 is formulated as a solution for injection and is administered via subcutaneous use. The dosage is expressed in milligrams, with a maximum daily dose amount of 9999 mg and a maximum total dose amount of 9999 mg. The maximum treatment period is specified as 9999 days. The product is supplied with a delivery device for administration purposes. Multiple formulations of AMG 133 are utilized in this clinical trial, all sharing the same active substance, pharmaceutical form, and route of administration.

A placebo for maridebart cafraglutide is included in the study as a comparator treatment. The placebo does not contain any active pharmaceutical ingredient and is designed to match the experimental medication to maintain blinding in this double-blind trial design. The placebo serves as a control to evaluate the efficacy and safety of maridebart cafraglutide when both treatments are given as an adjunct to standard of care.

Efficacy will be assessed through two dual primary endpoints. The first primary endpoint is the time to first occurrence of a composite endpoint consisting of cardiovascular death, myocardial infarction, or ischemic stroke (3-point major adverse cardiac events). The second primary endpoint is the time to first occurrence of a composite endpoint consisting of all-cause death, myocardial infarction, ischemic stroke, coronary revascularization, or heart failure event (5-point major adverse cardiac events). Secondary endpoints include the time to first occurrence of a composite endpoint consisting of cardiovascular death, myocardial infarction, ischemic stroke, or heart failure event, as well as the time to first occurrence of a composite endpoint consisting of cardiovascular death, myocardial infarction, ischemic stroke, or coronary revascularization. The study aims to demonstrate that maridebart cafraglutide is superior to placebo when given as an adjunct to standard of care with respect to reducing cardiovascular morbidity and mortality.