Efficacy and safety of zenagamtide versus semaglutide in participants with overweight or obesity and type 2 diabetes

The primary objective is to confirm superiority of zenagamtide versus semaglutide on change in body weight in participants with overweight or obesity and type 2 diabetes. This endpoint is clinically relevant because it evaluates whether the investigational treatment provides greater weight reduction than the active comparator in a population with metabolic disease. The secondary objectives are to confirm non-inferiority on glucose metabolism, and to compare the effects of the two treatments on waist circumference, systolic blood pressure, body weight, body mass index, urinary albumin-to-creatinine ratio, diastolic blood pressure, lipids, high-sensitivity C-reactive protein, and safety and tolerability. These outcomes assess additional cardiometabolic effects, renal risk markers, inflammatory status, and overall treatment safety.

The trial population comprised 560 participants of both sexes, aged 18 years or older, with overweight or obesity and type 2 diabetes. Participants were selected from patients with a body mass index at screening above the specified threshold and a diagnosis of type 2 diabetes mellitus for at least 180 days before screening. Glycaemic status was required to be within the specified HbA1c range at screening. The population also included individuals managed with lifestyle intervention and/or up to three marketed oral antidiabetic drugs, provided treatment was stable before screening. Relevant lifestyle considerations were limited to prior lifestyle intervention and antidiabetic treatment as described. Key inclusion criteria included male or female sex at birth, adult age, and the specified metabolic and treatment requirements.

This is a phase III, randomized, controlled, double-blind clinical trial evaluating once-weekly subcutaneous zenagamtide compared with once-weekly subcutaneous semaglutide in participants with overweight or obesity and type 2 diabetes. The trial is planned to run from 20 May 2026 to 29 December 2028. Study participation begins with a screening visit to assess eligibility, including demographic and clinical criteria, body mass index, diabetes history, glycated haemoglobin, and stability of background antidiabetic treatment. Eligible participants then enter the treatment period, during which study visits are performed according to the protocol to monitor efficacy and safety outcomes, including body weight, glycaemic control, metabolic variables, adverse events, and hypoglycaemic episodes. An end-of-study visit is conducted at the end of participant follow-up to complete final assessments. The expected duration of participation is not specified. Early termination may occur because of withdrawal of consent, discontinuation of study treatment, occurrence of adverse events, or other protocol-defined reasons.

The investigational treatment consisted of zenagamtide, supplied as a solution for injection in a pre-filled pen and administered subcutaneously once weekly. The study included multiple test products identified as 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. The comparator treatment was semaglutide, supplied as Wegovy solution for injection in a pre-filled pen and administered subcutaneously once weekly. Comparator strengths included 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, and 2.4 mg. Placebo treatments included Placebo Semaglutide and Placebo NNC0487 0111 B. Dosing was aligned with the once-weekly study regimen, and participant compliance monitoring was incorporated as part of the trial administration process.

Efficacy will be assessed by relative change in body weight as the primary endpoint. Secondary efficacy assessments will include change in body weight, change in HbA1c, change in waist circumference, change in BMI, change in systolic blood pressure, change in diastolic blood pressure, change in fasting plasma glucose, change in fasting insulin, change in urinary albumin-to-creatinine ratio, and change in lipids, including total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, non-HDL cholesterol, and triglycerides. Change in high-sensitivity C-reactive protein will also be assessed. Glycaemic response will further be evaluated by the proportion of participants achieving HbA1c < 7.0%, HbA1c ≤ 6.5%, and HbA1c < 5.7%.

Additional efficacy-related assessments will include the number of treatment-emergent clinically significant hypoglycaemic episodes, confirmed by a blood glucose meter, and the number of treatment-emergent severe hypoglycaemic episodes. In the extension phase, change in body weight, change in BMI, and the same hypoglycaemia and treatment-emergent adverse event endpoints will be evaluated.