Zenagamtide (formerly amycretin) is a unimolecular agonist targeting GLP-1 and amylin receptors, with activity also at the calcitonin receptor. The compound was developed to combine incretin and amylin receptor effects in a single molecule and administered once weekly by subcutaneous injection. The trial aimed to define the dose–response relationship for efficacy and safety of once-weekly subcutaneous zenagamtide compared with placebo in adults with type 2 diabetes inadequately controlled on oral therapy.
This was a 36-week, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial conducted at 83 hospitals and clinics across 11 countries. The study comprised a 3-week screening period, a 36-week intervention period, and a 4-week follow-up period.
Eligible participants were adults aged 18–75 years with type 2 diabetes, glycated haemoglobin (HbA1c) 7.0–10.0% (53–86 mmol/mol), on stable metformin with or without a sodium–glucose cotransporter 2 (SGLT2) inhibitor, and a body-mass index (BMI) of 23.0 to <50.0 kg/m2. The trial completed recruitment and follow-up as reported.
Randomisation assigned participants 6:1 to receive either subcutaneous zenagamtide or placebo using a randomisation and trial supplies management system. Participants allocated to active treatment or to placebo were then equally assigned (1:1:1:1:1:1) to one of six maintenance-dose regimens (0.4, 1.5, 5, 10, 20, or 40 mg). Randomisation was stratified by screening HbA1c (<8.5% vs ≥8.5%) and by country of residence (Japan vs other countries).
Participants and site staff were masked within each dose level to whether the assigned regimen was active drug or matching placebo.
The starting dose of subcutaneous zenagamtide was 0.2 mg, with planned dose escalations every 4 weeks until reaching the assigned maintenance dose (range 0.4–40 mg). Placebo recipients were allocated to matched dosing schedules corresponding to the active dose groups. The assigned treatment period was 36 weeks.
The prespecified primary outcome was change in HbA1c from baseline to week 36. The primary analysis used an efficacy estimand based on on-treatment data without rescue medication. Safety outcomes were assessed in all participants exposed to treatment and included adverse events, serious adverse events, and deaths.
The primary efficacy estimand reported was based on data collected while participants were on treatment and without rescue medication. The source reports estimated treatment differences (ETDs) versus placebo with associated 95% confidence intervals and p values for the change in HbA1c at week 36. Detailed statistical methods beyond the estimand description are reported in the source.
Between Aug 7 and Dec 27, 2024, 915 individuals were screened and 262 (29%) were randomised. Of those randomised, 225 were assigned to zenagamtide and 37 to placebo. Random assignment to the six dose levels produced groups of size 36–38 participants: 38 to 0.4 mg, 36 to 1.5 mg, 37 to 5 mg, 38 to 10 mg, 38 to 20 mg, and 38 to 40 mg. One randomised participant did not receive treatment, leaving 261 exposed to study medication.
Baseline mean HbA1c across participants was 7.8% (SD 0.8). Further baseline demographic and clinical characteristics are described in the source.
At week 36, reductions in HbA1c from baseline demonstrated a dose-related pattern across the evaluated maintenance doses. The reported mean change in HbA1c ranged from −0.9% with zenagamtide 0.4 mg to −1.7% with 40 mg. Specifically, the estimated treatment difference versus placebo was −0.77% (95% CI −1.26 to −0.28; p=0.0021) for the 0.4 mg group and −1.56% (95% CI −2.05 to −1.07; p<0.0001) for the 40 mg group using the on-treatment efficacy estimand.
These results were interpreted by the authors as clinically meaningful and statistically significant improvements in HbA1c versus placebo across the evaluated dose range.
Safety findings were reported for all 261 participants exposed to treatment. Most adverse events were gastrointestinal in nature and classified as mild to moderate in severity. A total of 21 participants (8% of those treated) experienced serious adverse events: four with 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 were reported during the trial.
The overall tolerability profile was described as consistent with that of other GLP-1-based and amylin-based therapies.
In this phase 2 dose-finding trial, once-weekly subcutaneous zenagamtide at maintenance doses from 0.4 mg to 40 mg produced dose-dependent, clinically relevant reductions in HbA1c at 36 weeks compared with placebo. The safety and tolerability profile observed, predominantly gastrointestinal adverse events and a modest proportion of serious adverse events, was reported to be consistent with expectations for combined GLP-1 and amylin receptor agonism. The investigators concluded the results support further development of the compound.
The trial was funded by Novo Nordisk. The source provides detailed conflict-of-interest disclosures for the authors, including consultancy, advisory roles, research grants, and employment relationships; several authors are employees and shareholders of Novo Nordisk.
The trial is registered on ClinicalTrials.gov with identifier NCT06542874 and is reported as completed. The source article and supplementary materials (including full methods and additional data) are available through the cited Lancet publication and PubMed entry.