Efficacy and Safety of Zenagamtide in Participants with Overweight or Obesity and Obstructive Sleep Apnea Treated with Positive Airway Pressure Therapy

The primary objectives of this study are to confirm the superiority of NNC0487-0111 compared to placebo regarding the change in body weight and the change in the apnoea-hypopnoea index (AHI) in participants with overweight or obesity and obstructive sleep apnoea (OSA) undergoing positive airway pressure (PAP) therapy. The secondary objectives include evaluating:

• Relative and clinically meaningful changes in AHI.
• Achievement of OSA remission or mild asymptomatic OSA.
• Ancillary polysomnography-derived sleep parameters.
• Daytime sleepiness, sleep-related impairment, and sleep disturbance.
• Changes in body mass index (BMI), waist circumference, neck circumference, and blood pressure.
• Impact on lipids, high-sensitivity C-reactive protein (hsCRP), and glucose metabolism.
• Potential for withdrawal of PAP therapy.
• Safety and tolerability.

This study involves 185 participants consisting of both males and females. The study population includes individuals aged 18 years or older who are diagnosed with overweight or obesity and obstructive sleep apnoea. Participants must be receiving positive airway pressure therapy and have a previously diagnosed moderate-to-severe condition characterized by an apnoea-hypopnoea index of 15 or greater, as determined by polysomnography, home sleep apnoea test, or other clinically accepted diagnostic methods. The primary objectives are:

• To confirm the superiority of specific doses of NNC0487-0111 versus placebo regarding changes in body weight.
• To confirm the superiority of specific doses of NNC0487-0111 versus placebo regarding changes in the apnoea-hypopnoea index.

This Phase III clinical trial is designed to evaluate the efficacy and safety of zenagamtide administered via subcutaneous injection once weekly compared to a placebo. The study focuses on participants presenting with overweight or obesity and obstructive sleep apnoea who are receiving positive airway pressure therapy. The primary research objectives are to confirm the superiority of the test substance over placebo regarding the relative change in body weight and the change in the apnoea-hypopnoea index. The estimated duration of the trial spans from April 2026 to July 2028. The methodology includes a screening visit to assess eligibility based on criteria such as age and previous diagnosis of moderate-to-severe sleep apnoea via polysomnography or home sleep apnoea test. Study procedures involve regular monitoring of secondary endpoints, including body mass index, waist circumference, systolic blood pressure, and glycated haemoglobin. Participants may undergo early termination from the study based on clinical requirements or the occurrence of treatment emergent adverse events.

The experimental treatment consists of zenagamtide, which is administered as a solution for injection in pre-filled pen. The subcutaneous administration of this substance is performed on a once-weekly basis.

A placebo is utilized as a comparator treatment in the study.

The efficacy assessment focuses on participants with overweight or obesity and obstructive sleep apnoea receiving positive airway pressure therapy. The primary endpoints for evaluating the superiority of zenagamtide compared to placebo include the relative change in body weight and the change in apnoea-hypopnoea index.

Secondary efficacy parameters include:

• Relative change in AHI and the achievement of a 50% reduction in this index.
• Achievement of specific criteria involving AHI and the Epworth Sleepiness Scale score.
• Change in sleep apnoea specific hypoxic burden.
• Changes in Patient-Reported Outcomes Measurement Information System scores for sleep-related impairment and sleep disturbance.
• Changes in body mass index, waist circumference, and neck circumference.
• Reduction in obstructive sleep apnoea severity category.
• Withdrawal of therapy.
• Changes in systolic blood pressure, diastolic blood pressure, high-sensitivity C-reactive protein, and lipids, including total cholesterol, high-density lipoprotein, low-density lipoprotein, very low-density lipoprotein, non-HDL cholesterol, and triglycerides.
• Changes in fasting plasma glucose and glycated haemoglobin.