Efficacy and safety of once-daily oral zenagamtide, a novel unimolecular GLP-1 and amylin receptor agonist, in adults with type 2 diabetes: a multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial.

内容摘要

Zenagamtide (formerly amycretin) is a unimolecular peptide 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-daily oral 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 [HbA1c] 7&#xb7;0-10&#xb7;0% [53-86 mmol/mol]), treated with stable doses of metformin with or without a SGLT2 inhibitor, and with a BMI of 23&#xb7;0 to <50&#xb7;0 kg/m2 were randomly assigned (5:1) to oral zenagamtide or placebo using a randomisation and trial supplies management system, then further randomly assigned (1:1:1) to one of three dose groups (6, 25, or 50 mg). Participants assigned to placebo were similarly assigned to matched placebo regimens corresponding to each dosing schedule. Randomisation was stratified by HbA1c (<8&#xb7;5% or &#x2265;8&#xb7;5%) at screening and country of residence (Japan or other countries). The starting dose of oral zenagamtide was 1&#xb7;5 mg, with dose escalations every 4 weeks until the maintenance dose was reached (6, 25, or 50 mg). Participants and staff were masked within each dose level to placebo or zenagamtide. The primary outcome was change in HbA1c 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. This trial is registered with ClinicalTrials.gov, NCT06542874, and is completed. Between Aug 7 and Dec 27, 2024, 186 (20%) of 915 screened participants were randomly assigned to oral zenagamtide (54 participants to 6 mg, 51 participants to 25 mg, and 51 participants to 50 mg) or placebo (30 participants) and were included in the full analysis set. At week 36, from baseline (mean range 7&#xb7;9-8&#xb7;1%), estimated mean change in HbA1c was -0&#xb7;9% with zenagamtide 6 mg (estimated treatment difference [ETD] vs placebo -0&#xb7;5% [95% CI -1&#xb7;04 to -0&#xb7;04]; p=0&#xb7;033), -1&#xb7;3% with zenagamtide 25 mg (-0&#xb7;99% [-1&#xb7;49 to -0&#xb7;49]; p=0&#xb7;0001), and -1&#xb7;4% with zenagamtide 50 mg (-1&#xb7;09% [-1&#xb7;59 to -0&#xb7;59]; p<0&#xb7;0001). The most common adverse events were gastrointestinal, occurring in 14 (26%) of 54 participants in the zenagamtide 6 mg group, 21 (41%) of 51 participants in the zenagamtide 25 mg group, 24 (47%) of 51 participants in the zenagamtide 50 mg group, and seven (23%) of 30 participants in the placebo group. Serious adverse events were reported in seven (4%) of 186 participants receiving zenagamtide: two in the 6 mg group, two in the 25 mg group, and three in 50 mg group. No serious adverse events were reported in the placebo group. No deaths occurred during the trial. In people with type 2 diabetes, once-daily oral zenagamtide showed clinically meaningful and significant improvements in HbA1c from baseline to week 36 compared with placebo at all three dose levels (6, 25, and 50 mg). The safety and tolerability of oral zenagamtide was consistent with other GLP-1 and amylin receptor agonists. Novo Nordisk.