Efficacy and safety of once-weekly subcutaneous zenagamtide, a novel unimolecular GLP-1 and amylin receptor agonist, in type 2 diabetes: a multicentre, randomised, parallel, double-blind, placebo-cont

Zenagamtide (formerly amycretin) is a unimolecular agonist of GLP-1, amylin, and calcitonin receptors. We aimed to investigate the dose-response relationship with respect to the efficacy and safety of once-weekly subcutaneous zenagamtide compared with placebo in adults with type 2 diabetes. This 36-week, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial was conducted at 83 hospital and clinic sites across 11 countries. The trial consisted of a 3-week screening period, a 36-week intervention period, and a 4-week follow-up period. Adults (aged 18-75 years) with type 2 diabetes (glycated haemoglobin [HbA 1c ] 7·0-10·0% [53-86 mmol/mol]), treated with stable doses of metformin with or without a SGLT2 inhibitor, and with a BMI of 23·0 to <50·0 kg/m 2 were randomly assigned (6:1) to once-weekly subcutaneous zenagamtide or placebo using a randomisation and trial supplies management system, before being further randomly assigned to one of six dose groups (1:1:1:1:1:1; 0·4, 1·5, 5, 10, 20, or 40 mg). Participants assigned to placebo were similarly allocated to matched placebo regimens corresponding to each dosing schedule. Randomisation was stratified by HbA 1c (<8·5% or ≥8·5%) at screening and country of residence (Japan or other countries). The starting dose of subcutaneous zenagamtide was 0·2 mg, with dose escalations every 4 weeks until the maintenance dose was reached (0·4-40 mg). Participants and staff were masked within each dose level to placebo or zenagamtide. The primary outcome was change in HbA 1c from baseline to week 36. The primary outcome was assessed in all randomly assigned participants using the efficacy estimand based on on-treatment data without rescue medication. Safety outcomes were assessed in all randomly assigned participants exposed to treatment. The trial is registered with ClinicalTrials.gov, NCT06542874, and is completed. Between Aug 7 and Dec 27, 2024, 262 (29%) of 915 screened individuals were randomly assigned to subcutaneous zenagamtide (n=225) or placebo (n=37). Participants were further randomly assigned (1:1:1:1:1:1) to one of six doses (38 participants to 0·4 mg, 36 participants to 1·5 mg, 37 participants to 5 mg, 38 participants to 10 mg, 38 participants to 20 mg, and 38 participants to 40 mg) or placebo (37 participants). 261 participants were exposed to treatment. At week 36, estimated change in HbA 1c (mean across all groups at baseline 7·8% [SD 0·8]) ranged from -0·9% with zenagamtide 0·4 mg (estimated treatment difference vs placebo: -0·77% [95% CI -1·26 to -0·28]; p=0·0021) to -1·7% with zenagamtide 40 mg (-1·56% [-2·05 to -1·07]; p<0·0001). Most adverse events were gastrointestinal and mild to moderate in severity. 21 (8%) of 261 participants reported serious adverse events (four with zenagamtide 0·4 mg, three with 1·5 mg, two with 5 mg, five with 10 mg, three with 20 mg, one with 40 mg, and three with placebo). No deaths occurred. In people with type 2 diabetes, once-weekly subcutaneous zenagamtide 0·4-40 mg demonstrated clinically meaningful and significant improvements in change in HbA 1c from baseline to week 36 compared with placebo, with a safety and tolerability profile consistent with that of other GLP-1-based and amylin-based therapies. Novo Nordisk.