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.
Zenagamtide showed significant reductions in HbA1c levels in adults with type 2 diabetes at all tested doses, but the clinical relevance of these changes should be carefully evaluated.
Where it sits
this study against the rest of the zenagamtide corpusSummary and findings
This study investigated the efficacy and safety of once-daily oral zenagamtide in adults with type 2 diabetes over 36 weeks. Participants were randomly assigned to receive zenagamtide at doses of 6 mg, 25 mg, or 50 mg, or placebo. The primary outcome measured was the change in HbA1c from baseline to week 36.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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<sub>1c</sub>] 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<sup>2</sup> 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 HbA<sub>1c</sub> (<8·5% or ≥8·5%) at screening and country of residence (Japan or other countries). The starting dose of oral zenagamtide was 1·5 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 HbA<sub>1c</sub> 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.<h4>Findings</h4>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 7·9-8·1%), estimated mean change in HbA<sub>1c</sub> was -0·9% with zenagamtide 6 mg (estimated treatment difference [ETD] vs placebo -0·5% [95% CI -1·04 to -0·04]; p=0·033), -1·3% with zenagamtide 25 mg (-0·99% [-1·49 to -0·49]; p=0·0001), and -1·4% with zenagamtide 50 mg (-1·09% [-1·59 to -0·59]; p<0·0001). 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.<h4>Interpretation</h4>In people with type 2 diabetes, once-daily oral zenagamtide showed clinically meaningful and significant improvements in HbA<sub>1c</sub> 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.<h4>Funding</h4>Novo Nordisk.
Background
This paper addresses the efficacy and safety of zenagamtide, a unimolecular peptide agonist of GLP-1 and amylin receptors, in adults with type 2 diabetes. Previous studies have shown the potential of GLP-1 receptor agonists in managing diabetes, but there is limited data on the specific effects of zenagamtide. Understanding its dose-response relationship is important for determining its clinical utility.
Methods
This was a 36-week, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial conducted at 83 sites across 11 countries. A total of 915 participants were screened, with 186 randomly assigned to zenagamtide (6 mg, 25 mg, or 50 mg) or placebo. The primary outcome was the change in HbA1c from baseline to week 36, assessed using on-treatment data without rescue medication.
Results
At week 36, the estimated mean change in HbA1c was -0.9% for zenagamtide 6 mg, -1.3% for 25 mg, and -1.4% for 50 mg, with p-values indicating statistical significance at all doses. The most common adverse events were gastrointestinal, with varying incidence rates across the zenagamtide groups. Serious adverse events were reported in 4% of participants receiving zenagamtide, but none in the placebo group.
Interpretation
The findings indicate that zenagamtide may provide statistically significant reductions in HbA1c levels compared to placebo, particularly at the 50 mg dose. However, the clinical significance of these reductions, especially the small effect sizes at lower doses, should be considered in the context of overall diabetes management. Limitations such as industry funding and a relatively short follow-up period may affect the robustness of the conclusions.
Key findings
- Estimated mean change in HbA1c was -0.9% with zenagamtide 6 mg (ETD vs placebo -0.5%, 95% CI -1.04 to -0.04; p=0.033).
- Estimated mean change in HbA1c was -1.3% with zenagamtide 25 mg (ETD vs placebo -0.99%, 95% CI -1.49 to -0.49; p=0.0001).
- Estimated mean change in HbA1c was -1.4% with zenagamtide 50 mg (ETD vs placebo -1.09%, 95% CI -1.59 to -0.59; p<0.0001).
- Gastrointestinal adverse events occurred in 14 (26%) of 54 participants in the zenagamtide 6 mg group, 21 (41%) of 51 participants in the zenagamtide 25 mg group, and 24 (47%) of 51 participants in the zenagamtide 50 mg group.
- Serious adverse events were reported in seven (4%) of 186 participants receiving zenagamtide, with no serious adverse events in the placebo group.
- No deaths occurred during the trial.
Limitations
- funded by Novo Nordisk
- small sample sizes for each dose group
- short follow-up period of 36 weeks
- no long-term efficacy data reported