This multicentre, randomised, parallel, double‑blind, placebo‑controlled, dose‑finding phase 2 trial evaluated once‑daily oral zenagamtide, a unimolecular peptide agonist of GLP‑1 and amylin receptors (and calcitonin receptor activity), in adults with type 2 diabetes. The primary objective was to characterise the dose–response relationship for efficacy and safety compared with placebo over a 36‑week intervention period.
The trial enrolled adults aged 18–75 years with type 2 diabetes, baseline glycated haemoglobin (HbA1c) 7.0–10.0% (53–86 mmol/mol), treated with stable doses of metformin with or without an SGLT2 inhibitor, and body‑mass index (BMI) between 23.0 and <50.0 kg/m2. The study included a 3‑week screening period, a 36‑week intervention period, and a 4‑week follow‑up period, and was conducted at 83 sites across 11 countries.
Participants were randomised 5:1 to oral zenagamtide or placebo using a central randomisation and trial supplies management system. Those randomised to active treatment were further assigned 1:1:1 to one of three maintenance dose groups: 6 mg, 25 mg, or 50 mg. Placebo participants were assigned to matched placebo regimens corresponding to each dosing schedule. Randomisation was stratified by screening HbA1c (<8.5% vs ≥8.5%) and country of residence (Japan vs other countries).
The dosing regimen used a starting dose of 1.5 mg with dose escalations every 4 weeks until the assigned maintenance dose (6, 25, or 50 mg) was reached. Participants and site staff were masked within each dose level to active drug versus placebo.
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 randomly assigned participants who were exposed to treatment. The abstract reports primary efficacy and selected safety outcomes; details on secondary efficacy outcomes and additional metabolic measures were not included in the abstract.
Randomised participants were analysed in the full analysis set for the primary efficacy estimand. The primary outcome reporting used estimated mean changes and estimated treatment differences (ETD) versus placebo with 95% confidence intervals and p values. The safety population included all participants exposed to study treatment. The abstract does not provide the full statistical plan or multiplicity adjustments.
Of 915 participants screened between Aug 7 and Dec 27, 2024, 186 (20%) were randomised and included in the full analysis set: 54 participants to zenagamtide 6 mg, 51 to 25 mg, 51 to 50 mg, and 30 to placebo.
Baseline mean HbA1c ranged approximately 7.9–8.1% across groups. At week 36, the estimated mean changes in HbA1c from baseline were:
All three dose levels produced statistically significant and clinically meaningful reductions in HbA1c compared with placebo by week 36 as reported in the abstract.
The most commonly reported adverse events were gastrointestinal in nature. Reported incidence by group was 26% (14/54) in the zenagamtide 6 mg group, 41% (21/51) in the 25 mg group, 47% (24/51) in the 50 mg group, and 23% (7/30) in the placebo group, indicating a dose‑related increase in GI events.
Serious adverse events occurred in seven of 186 participants receiving zenagamtide: two in the 6 mg group, two in the 25 mg group, and three in the 50 mg group. No serious adverse events were reported in the placebo group, and there were no deaths during the trial. The investigators stated that overall safety and tolerability were consistent with other GLP‑1 and amylin receptor agonists.
In adults with type 2 diabetes treated with metformin with or without an SGLT2 inhibitor, once‑daily oral zenagamtide demonstrated clinically meaningful and statistically significant reductions in HbA1c at maintenance doses of 6, 25, and 50 mg compared with placebo at 36 weeks. Gastrointestinal adverse events were the most frequent safety signal and increased with dose; serious adverse events were reported in a small number of participants receiving active drug. The abstract concludes the safety profile aligns with expectations for GLP‑1 and amylin receptor agonists.
The trial was funded by Novo Nordisk and is registered at ClinicalTrials.gov (NCT06542874). The publication includes detailed conflict‑of‑interest declarations: several investigators reported consultancy fees, honoraria, research funding, or employment and shareholdings related to pharmaceutical companies, including Novo Nordisk. The abstract and author disclosures are those reported on PubMed; the full paper likely contains more extensive methodological and conflict‑of‑interest details.
Note: The abstract provides primary efficacy and selected safety results. Additional data on secondary outcomes, patient‑level characteristics, duration of on‑treatment exposure, rescue medication use, and detailed adverse event descriptions were not reported in the abstract and would require consultation of the full article for comprehensive assessment.