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-controlled, dose-finding, phase 2 trial.
Zenagamtide demonstrated statistically significant reductions in HbA1c in adults with type 2 diabetes, but the clinical relevance of these findings, particularly at lower doses, remains uncertain.
Where it sits
this study against the rest of the zenagamtide corpusSummary and findings
This study measured the efficacy and safety of once-weekly subcutaneous zenagamtide in adults with type 2 diabetes over 36 weeks. Participants were assigned to various doses of zenagamtide or placebo. The primary outcome was the change in HbA1c from baseline to week 36.
Abstract
<h4>Background</h4>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.<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 (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<sub>1c</sub> (<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<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. The trial is registered with ClinicalTrials.gov, NCT06542874, and is completed.<h4>Findings</h4>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<sub>1c</sub> (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.<h4>Interpretation</h4>In people with type 2 diabetes, once-weekly subcutaneous zenagamtide 0·4-40 mg demonstrated clinically meaningful and significant improvements in change in HbA<sub>1c</sub> 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.<h4>Funding</h4>Novo Nordisk.
Background
This paper investigates the efficacy and safety of zenagamtide, a unimolecular agonist of GLP-1 and amylin receptors, in adults with type 2 diabetes. Prior studies have established the role of GLP-1 receptor agonists in managing diabetes, but the specific effects of zenagamtide were not well understood. This study aims to fill that gap by assessing a dose-response relationship in a diverse population.
Methods
The study was a 36-week, multicenter, randomized, parallel, double-blind, placebo-controlled trial involving 915 screened individuals. Adults aged 18-75 with type 2 diabetes were randomly assigned to receive zenagamtide at doses of 0.4, 1.5, 5, 10, 20, or 40 mg, or placebo. The primary outcome was the change in HbA1c from baseline to week 36, assessed in all randomly assigned participants.
Results
At week 36, the estimated change in HbA1c ranged from -0.9% with zenagamtide 0.4 mg to -1.7% with zenagamtide 40 mg. The treatment difference for the 0.4 mg group was -0.77% (95% CI -1.26 to -0.28; p=0.0021) and for the 40 mg group was -1.56% (95% CI -2.05 to -1.07; p<0.0001). Most adverse events reported were gastrointestinal and mild to moderate in severity.
Interpretation
The findings indicate that zenagamtide may lead to statistically significant reductions in HbA1c compared to placebo, particularly at higher doses. However, while the changes are statistically significant, the clinical significance of the reductions, especially at lower doses, may be limited. The study's limitations, including small sample sizes for each dose and potential bias from industry funding, should be considered when interpreting the results.
Key findings
- Estimated change in HbA1c at week 36 ranged from -0.9% with zenagamtide 0.4 mg to -1.7% with zenagamtide 40 mg.
- Estimated treatment difference vs placebo for zenagamtide 0.4 mg was -0.77% (95% CI -1.26 to -0.28; p=0.0021).
- Estimated treatment difference vs placebo for zenagamtide 40 mg was -1.56% (95% CI -2.05 to -1.07; p<0.0001).
- 21 (8%) of 261 participants reported serious adverse events.
- No deaths occurred during the trial.
Limitations
- Small sample sizes for each dose group.
- Industry-funded by Novo Nordisk.
- Short follow-up duration of 36 weeks.
- Potential bias due to unblinded staff in dose allocation.