Efficacy and Safety of Zenagamtide in Participants with Overweight or Obesity and Knee Osteoarthritis

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 knee osteoarthritis related pain in participants presenting with overweight or obesity. The secondary objectives include the evaluation of:

• Changes in physical function as measured by the WOMAC index and the SF-36v2® Acute health survey.
• Alterations in body mass index (BMI), waist circumference, and lipids.
• Impact on stiffness, glucose metabolism, and high-sensitivity C-reactive protein (hsCRP).
• Changes in systolic blood pressure and diastolic blood pressure.
• Assessment of knee pain intensity via the Numerical Rating Scale (NRS) and the use of rescue analgesics.
• Evaluation of safety and tolerability.

The study involves 180 participants diagnosed with overweight or obesity and knee osteoarthritis. The study population includes both male and female individuals aged 18 years or older. Inclusion requires a body mass index of at least 30 kg/m2 and a clinical diagnosis of osteoarthritis based on American College of Rheumatology criteria. Eligible subjects must demonstrate radiographic changes classified as Kellgren-Lawrence grades 2 to 3 in the most symptomatic knee. Furthermore, participants must have experienced symptomatic pain in the target knee for more than 90 days prior to screening, with pain present for over 15 days within the preceding 30-day period. The study objectives are:

• To confirm superiority of NNC0487-0111 doses versus placebo on change in body weight.
• To confirm superiority of NNC0487-0111 doses versus placebo on change in knee osteoarthritis related pain.

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 in participants with overweight or obesity and knee osteoarthritis. The primary objectives are to assess the relative change in body weight and the change in the WOMAC Osteoarthritis Index pain score. Secondary endpoints include evaluations of body mass index, waist circumference, blood pressure, lipid profiles, and various physical function scores. The research methodology involves a period of screening to confirm eligibility based on clinical diagnosis and radiographic changes. Following screening, participants will undergo study visits to monitor treatment response and safety. The trial is estimated to conclude by July 17, 2028.

Zenagamtide is an experimental medication administered as a solution for injection in a pre-filled pen. The drug is delivered via subcutaneous injection on a once-weekly basis to participants with overweight, obesity, or osteoarthritis.

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

The primary efficacy assessment focuses on the relative change in body weight and the change in the WOMAC Osteoarthritis Index NRS 3.1 (24-hour) pain score. The study aims to confirm the superiority of zenagamtide compared to placebo in participants with overweight or obesity and knee osteoarthritis.

Secondary efficacy endpoints include:

• Change in body mass index (BMI) and waist circumference.
• Change in WOMAC physical function score, stiffness score, and total score.
• Change in SF-36v2® Health Survey Acute physical functioning score.
• Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP).
• Changes in lipids, including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, non-HDL cholesterol, and triglycerides.
• Change in high-sensitivity C-reactive protein (hsCRP).
• Change in glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG).
• Assessment of pain medication use, including the amount used and changes in intensity measured via Numerical Rating Scale (NRS).
• Evaluation of rescue analgesics used during the washout period.
• CCI measurements.