A Phase 3 Randomized, Double-blind,Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Maridebart Cafraglutide in Adult Participants with Obstructive Sleep Apnea not on Positive Airway Pressure Therapy and Living with Overweight or Obesity (MARITIME-OSA-2)

The primary objective of this study is to demonstrate the superiority of maridebart cafraglutide compared to placebo in improving the Apnea-Hypopnea Index (AHI) in adults with moderate to severe obstructive sleep apnea who are not receiving positive airway pressure therapy and are living with overweight or obesity. The AHI represents a fundamental polysomnographic measure quantifying the frequency of apneic and hypopneic events per hour of sleep, serving as the primary diagnostic and severity stratification parameter for obstructive sleep apnea. Improvement in this metric reflects reduction in respiratory event burden and is clinically relevant for assessing therapeutic efficacy in obstructive sleep apnea management.

The secondary objectives aim to demonstrate the superiority of maridebart cafraglutide over placebo across multiple clinically relevant domains. These include evaluation of percent change in AHI, achievement of clinically meaningful AHI reduction, and attainment of obstructive sleep apnea remission or mild asymptomatic disease state. Additional secondary objectives assess reduction in body weight, reduction in hypoxic burden, reduction in systemic inflammation, and improvement in systolic blood pressure. Further objectives evaluate improvement in patient-reported sleep-related impairment, reduction in central adiposity and neck circumference, improvement in lipid parameters and metabolic parameters, and improvement in diastolic blood pressure. The study also aims to characterize the safety and tolerability profile of maridebart cafraglutide and to characterize its pharmacokinetics.

This clinical trial enrolled a total of **135 participants** diagnosed with **moderate to severe obstructive sleep apnea** who were living with **overweight** or **obesity**. The study population included both male and female adults aged 18 years or older, or the legal age of adulthood in their respective country if older than 18 years. Participants were required to have a **body mass index** of at least 27 kg/m² at screening and a documented history of previously diagnosed moderate-to-severe obstructive sleep apnea with an **Apnea-Hypopnea Index** of 15 or greater. All participants had a history of at least one unsuccessful attempt at weight loss through diet and exercise. A key requirement for enrollment was that participants must not have used **positive airway pressure therapy** for at least four weeks prior to screening, were unwilling or unable to use such therapy, and did not plan to use it during the study period. The trial population was selected based on confirmed polysomnographic evidence of an Apnea-Hypopnea Index of 15 or greater at baseline before randomization.

This is a phase 3, randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy, safety, and tolerability of maridebart cafraglutide (AMG 133) in adult participants with moderate to severe obstructive sleep apnea who are not receiving positive airway pressure therapy and are living with overweight or obesity. The investigational medicinal product, maridebart cafraglutide, is a human IgG1 monoclonal antibody against gastric inhibitory polypeptide receptor fused to a glucagon-like peptide 1 analog, administered as a solution for injection via subcutaneous route. The study includes a comparator arm receiving placebo for maridebart cafraglutide. The maximum treatment period is 52 weeks.

The primary objective is to demonstrate that maridebart cafraglutide is superior to placebo for improvement in Apnea-Hypopnea Index (AHI). The primary endpoint is the change in AHI from baseline at week 52. Secondary endpoints include percent change in AHI from baseline at week 52, achieving at least 50% AHI reduction from baseline at week 52, achieving AHI less than 5 or AHI 5 to 14 with Epworth Sleepiness Scale score of 10 or less at week 52, change in sleep apnea-specific hypoxic burden from baseline at week 52, percent change in body weight from baseline at week 52, change in high sensitivity C-reactive protein from baseline at week 52, change in systolic blood pressure from baseline, and change in Patient-Reported Outcomes Measurement Information System Short Form sleep-related impairment score from baseline at week 52.

Principal inclusion criteria require that participants provide informed consent before any study-specific activities. Eligible participants must be 18 years of age or older, or the legal age within the country if older than 18 years. Participants must have documented history of previously diagnosed moderate-to-severe obstructive sleep apnea with an AHI of 15 or greater, as diagnosed with polysomnography, home sleep apnea testing with respiratory event index of 15 or greater, or other method meeting local guidelines before screening. An AHI of 15 or greater on polysomnography at day 1 before randomization is required. Participants must have a body mass index of 27 kg/m² or greater at screening and a history of at least one unsuccessful attempt at weight loss by diet and exercise. Participants must not have used positive airway pressure therapy for at least 4 weeks before screening, are unwilling or unable to use positive airway pressure therapy, and do not plan to use positive airway pressure therapy during the study.

The estimated recruitment start date is February 23, 2026, and the estimated end date is August 30, 2028. Participant involvement extends through the 52-week treatment period with assessment visits scheduled throughout the study duration. The study design includes a screening visit with polysomnography at day 1 before randomization, followed by regular follow-up visits during the treatment period, and an end-of-study visit at week 52. Early termination from the study may occur under conditions specified in the protocol, although specific termination criteria are not detailed in the provided information.

The experimental medication under investigation is **AMG 133**, containing the active substance **maridebart cafraglutide**. Maridebart cafraglutide is a human IgG1 monoclonal antibody against gastric inhibitory polypeptide receptor fused to a glucagon like peptide 1 analog. The investigational product is supplied as a **solution for injection** in **pharmaceutical form** for **subcutaneous** administration. The maximum treatment period with AMG 133 is 52 weeks. The product is manufactured by AMGEN INC and is classified as a protein-based substance.

A **placebo** for maridebart cafraglutide (AMG 133) is utilized as the **comparator treatment** in this randomized, double-blind, placebo-controlled study. The placebo serves as the control arm to evaluate the superiority of the experimental medication against a non-active treatment. The maximum treatment period for placebo administration is also 52 weeks, matching the duration of the active treatment arm.

All study medications are administered via the subcutaneous route using a device for injection. The study design incorporates a double-blind methodology to ensure unbiased assessment of efficacy, safety, and tolerability outcomes in adult participants with obstructive sleep apnea not on positive airway pressure therapy and living with overweight or obesity.

Efficacy will be assessed using the Apnea-Hypopnea Index (AHI) as the primary endpoint, measured as the change from baseline at week 52. Secondary efficacy endpoints include percent change in AHI from baseline at week 52, the proportion of participants achieving at least 50% AHI reduction from baseline at week 52, and the proportion achieving AHI less than 5 or AHI 5 to 14 with Epworth Sleepiness Scale (ESS) score of 10 or less at week 52. Additional secondary endpoints include change in Sleep Apnea-specific Hypoxic burden (expressed as %/min/hour) from baseline at week 52, percent change in body weight from baseline at week 52, change in high sensitivity C-reactive protein (hs-CRP) from baseline at week 52, change in systolic blood pressure (SBP) measured in mmHg from baseline, and change in Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form v1.0 Sleep-Related Impairment 8a score from baseline at week 52. Baseline AHI will be determined by polysomnography (PSG) at day 1 before randomization, with eligibility requiring an AHI of 15 or greater.