Efficacy and Safety of NNC0487-0111 in Participants with Overweight or Obesity and Obstructive Sleep Apnoea Not Treated with Positive Airway Pressure

The primary objectives are to evaluate the efficacy of NNC0487-0111 in participants with overweight or obesity and obstructive sleep apnoea (OSA) not treated with positive airway pressure. The study aims 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).

Secondary objectives include:

• Evaluation of relative and clinically meaningful changes in AHI.
• Assessment of the achievement of OSA remission or mild asymptomatic OSA.
• Measurement of ancillary sleep parameters derived from polysomnography (PSG).
• Evaluation of daytime sleepiness, sleep-related impairment, and sleep disturbance.
• Comparison of effects on body mass index (BMI), waist circumference, neck circumference, and blood pressure.
• Monitoring of lipids, glucose metabolism, and high-sensitivity C-reactive protein (hsCRP).
• Assessment of safety and tolerability.

This clinical trial involves 175 participants. The study population consists of male and female individuals aged 18 years or older. Participants are characterized by overweight or obesity and obstructive sleep apnoea that is not treated with positive airway pressure. Inclusion requires a prior diagnosis of moderate-to-severe obstructive sleep apnoea, defined by an apnoea-hypopnoea index of 15 or greater as determined by polysomnography, home sleep apnoea test, or other standardized methods. The objectives are:

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

This Phase III clinical trial is designed to evaluate the efficacy and safety of zenagamtide compared to a placebo in individuals with overweight or obesity and obstructive sleep apnoea not treated with positive airway pressure. The study methodology focuses on confirming the superiority of the investigational product regarding the relative change in body weight and the change in the apnoea-hypopnoea index. The research involves subcutaneous administration of the study medication once weekly. The trial sequence includes a screening visit to assess eligibility based on criteria such as age and a prior diagnosis of moderate-to-severe sleep apnoea via polysomnography or home sleep apnoea test. Following inclusion, participants undergo a treatment period and subsequent follow-up assessments, concluding with an end-of-study visit. The total duration of the trial is estimated to span from April 2026 to September 2028.

The experimental treatment consists of zenagamtide, administered as a solution for injection in pre-filled pen. The various study arms of NNC0487-0111, including NNC0487-0111 B 10141, NNC0487-0111 B 10142, NNC0487-0111 B 10143, NNC0487-0111 B 10144, NNC0487-0111 B 10145, and NNC0487-0111 B 10146, are administered via the subcutaneous route on a once-weekly dosing schedule.

A placebo is utilized as a comparator in the study.

The efficacy of zenagamtide will be evaluated using several primary endpoints, including the relative change in body weight and the change in the apnoea-hypopnoea index (AHI) in participants with obstructive sleep apnoea and overweight or obesity.

Secondary efficacy parameters include:

• Relative change in AHI and the achievement of a 50% reduction in AHI.
• Achievement of an AHI < 5 or an AHI between 5-14 with an Epworth Sleepiness Scale (ESS) score ≤ 10.
• Change in sleep apnoea specific hypoxic burden (SASHB).
• Change in ESS score and Patient-Reported Outcomes Measurement Information System (PROMIS) scores, specifically the Sleep-Related Impairment 8a and Sleep Disturbance 8b short forms.
• Change in body mass index (BMI), waist circumference, and neck circumference.
• Improvement in obstructive sleep apnoea severity category.
• Change in systolic blood pressure (SBP), diastolic blood pressure (DBP), high-sensitivity C-reactive protein (hsCRP), and fasting plasma glucose.
• Change in glycated haemoglobin (HbA1c) and lipids, including total cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), very low-density lipoprotein cholesterol (VLDL), non-HDL cholesterol, and triglycerides.
• Changes in CCI.