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Once-Weekly Zenagamtide Reduces HbA1c Across All Doses in Type 2 Diabetes Phase 2 Trial
In a 36-week placebo-controlled trial, once-weekly subcutaneous zenagamtide significantly lowered HbA1c at all tested doses in adults with type 2 diabetes, with estimated treatment differences versus placebo ranging from about 0.77 percentage points at the lowest dose (0.4 mg; 95% CI −1.26 to −0.28; p=0.0021) to about 1.56 percentage points at the highest dose (40 mg; 95% CI −2.05 to −1.07; p<0.0001). These results establish a clear dose-response relationship and support the therapeutic viability of this novel triple-receptor agonist approach.
What Was Studied
The trial investigated the dose-response relationship of once-weekly subcutaneous zenagamtide — a unimolecular agonist of GLP-1, amylin, and calcitonin receptors — with respect to glycaemic efficacy and safety in adults with type 2 diabetes. The primary outcome was change in HbA1c from baseline to week 36, evaluated across six distinct dose levels ranging from 0.4 mg to 40 mg.
How It Was Studied
This was a multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding phase 2 trial conducted at 83 hospital and clinic sites across 11 countries. A total of 262 adults aged 18–75 years with type 2 diabetes (HbA1c 7.0–10.0%), a BMI of 23.0 to below 50.0 kg/m², and stable treatment with metformin with or without an SGLT2 inhibitor were enrolled. Participants were randomly assigned in a 6:1 ratio to zenagamtide or matched placebo, and further allocated equally across six dose groups (0.4, 1.5, 5, 10, 20, or 40 mg), yielding approximately 36–38 participants per active-treatment arm and 37 in the placebo group. Treatment began at a starting dose of 0.2 mg and escalated every four weeks to the assigned maintenance dose, with the full intervention period lasting 36 weeks followed by a four-week follow-up.
What Was Observed
- HbA1c reduction was significant at every dose level. Mean baseline HbA1c across all groups was 7.8% (SD 0.8). At week 36, zenagamtide 0.4 mg produced an estimated HbA1c change of −0.9%, representing a treatment difference of about 0.77 percentage points versus placebo (ETD −0.77%, 95% CI −1.26 to −0.28; p=0.0021), indicating a statistically robust and clinically meaningful reduction even at the lowest dose tested.
- The highest dose produced the largest glycaemic benefit. Zenagamtide 40 mg reduced HbA1c by an estimated −1.7%, yielding a treatment difference of approximately 1.56 percentage points versus placebo (ETD −1.56%, 95% CI −2.05 to −1.07; p<0.0001), with narrow confidence intervals reflecting a reliable estimate of effect at this dose.
- Adverse events were predominantly gastrointestinal and mild to moderate in severity. Serious adverse events occurred in 21 of 261 treated participants (8%), distributed across all dose groups and placebo; no deaths were reported during the trial.
Why This Matters
Zenagamtide represents a mechanistically distinct approach by combining GLP-1, amylin, and calcitonin receptor agonism within a single molecule, and this trial provides proof-of-concept that such unimolecular co-agonism can produce clinically meaningful glycaemic improvements in type 2 diabetes. The well-defined dose-response relationship observed across six dose levels offers a quantitative foundation for selecting optimal dosing regimens in future phase 3 development. The tolerability profile, characterised by predominantly gastrointestinal and mostly mild-to-moderate adverse events, appears consistent with the class effects described by the investigators for GLP-1-based and amylin-based therapies.
How to Read This Result
Although the findings are encouraging and internally consistent across all dose levels, this remains a phase 2 dose-finding trial with small per-arm sample sizes and a 36-week observation window; longer-term efficacy, cardiovascular outcomes, and head-to-head performance relative to established GLP-1 receptor agonists have not yet been evaluated.
Limitations
The abstract does not explicitly report study limitations.