Efficacy and Safety of Zenagamtide (NNC0487-0111) 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 change in body weight and change in knee osteoarthritis related pain in participants with overweight or obesity. 5, 3.

Secondary objectives include the evaluation of the following clinical outcomes:

• Changes in physical function as measured by the WOMAC index and the SF-36v2 Acute health survey.
• Impact on Body mass index (BMI), waist circumference, and lipids.
• Effects on glucose metabolism and inflammatory markers such as high-sensitivity C-reactive protein (hsCRP).
• Assessment of stiffness, blood pressure, and pain intensity via the Numerical Rating Scale (NRS).
• Evaluation of analgesic use and the safety and tolerability of the investigational product. 4, 5.

This clinical trial involves 180 participants consisting of both males and females. The study population includes adults aged 18 years or older with a clinical diagnosis of knee osteoarthritis and overweight or obesity. Eligible individuals must demonstrate radiographic changes classified as Kellgren-Lawrence grades 2 to 4. Participants are required to have symptomatic pain in the target knee for more than 90 days prior to screening. The study 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 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. The study focuses on participants presenting with overweight or obesity and knee osteoarthritis. The research methodology aims to confirm the superiority of various doses of the test substance regarding the relative change in body weight and the change in the WOMAC Osteoarthritis Index pain score. The investigation includes a screening visit to assess eligibility based on body mass index and radiographic changes classified by the Kellgren-Lawrence grades. Throughout the study, assessments will be conducted to monitor secondary endpoints, including waist circumference, blood pressure, and lipid profiles. Participants must adhere to a washout period for analgesics prior to specific visits to ensure accurate pain measurement. The total trial period is estimated to span from April 2026 to July 2028. Clinical monitoring will track treatment-emergent adverse events to ensure participant safety.

The experimental treatment consists of zenagamtide, administered as a solution for injection in pre-filled pen. This substance is delivered via subcutaneous injection on a once-weekly schedule.

A placebo is utilized as a comparator in this clinical trial.

The assessment of efficacy in this study focuses on participants with overweight or obesity and knee osteoarthritis. The primary endpoints include the relative change in body weight and the change in the WOMAC Osteoarthritis Index NRS 3.1 (24-hour) pain score.

Secondary efficacy parameters involve several clinical measures:

• Changes in body mass index, waist circumference, and body weight.
• Changes in WOMAC physical function score, stiffness score, and total score.
• Changes in SF-36v2 Health Survey Acute physical functioning score.
• Alterations in systolic blood pressure and diastolic blood pressure.
• Changes in lipids, including total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, non-HDL cholesterol, and triglycerides.
• Changes in high-sensitivity C-reactive protein, glycated haemoglobin, and fasting plasma glucose.
• Assessment of knee pain intensity via the Numeric Rating Scale.
• Evaluation of pain medication use, including the frequency, amount, and change in consumption, as well as the use of allowed rescue analgesics during the washout period.
• The Clinical Connectedness Index is also evaluated.