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Oral Zenagamtide Reduces HbA1c Significantly Across All Three Doses in Type 2 Diabetes
A phase 2 randomised controlled trial found that once-daily oral zenagamtide produced significant reductions in HbA1c compared with placebo at all tested doses over 36 weeks, with estimated treatment differences of approximately 0.5 percentage points at 6 mg, 1.0 percentage point at 25 mg, and 1.1 percentage points at 50 mg. These results establish a clear dose-response relationship and support further development of this novel oral multi-receptor peptide agonist as a candidate treatment for type 2 diabetes.
What Was Studied
This trial investigated the dose-response relationship between once-daily oral zenagamtide — a unimolecular peptide agonist targeting GLP-1, amylin, and calcitonin receptors — and glycaemic control in adults with type 2 diabetes, with change in HbA1c from baseline to week 36 as the primary outcome. Understanding how different oral doses of this novel multi-receptor agonist affect blood glucose is a critical step before designing larger confirmatory trials.
How It Was Studied
This was a 36-week, multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding phase 2 trial conducted across 83 hospital and clinic sites in 11 countries. A total of 216 adults aged 18 to 75 years with type 2 diabetes (HbA1c 7.0–10.0%), a BMI between 23.0 and less than 50.0 kg/m², and stable treatment with metformin with or without an SGLT2 inhibitor were enrolled. Participants were randomly assigned in a 5:1 ratio to oral zenagamtide or matched placebo, then further allocated equally across three dose groups (6 mg, 25 mg, or 50 mg). Dosing began at 1.5 mg with escalations every four weeks until each participant’s assigned maintenance dose was reached, with randomisation stratified by baseline HbA1c and country.
What Was Observed
- All three zenagamtide doses significantly reduced HbA1c versus placebo at week 36. The 6 mg dose produced a mean HbA1c reduction of approximately 0.9 percentage points from a baseline of around 7.9–8.1%, yielding an estimated treatment difference (ETD) versus placebo of about 0.5 percentage points — a statistically significant but relatively modest and imprecise effect (ETD −0.5%, 95% CI −1.04 to −0.04; p=0.033).
- Higher doses showed progressively larger and more precisely estimated reductions. The 25 mg dose achieved a mean HbA1c reduction of approximately 1.3 percentage points (ETD −0.99%, 95% CI −1.49 to −0.49; p=0.0001), and the 50 mg dose approximately 1.4 percentage points (ETD −1.09%, 95% CI −1.59 to −0.59; p<0.0001), with both demonstrating a consistent and meaningful separation from placebo.
- Gastrointestinal adverse events were the most frequently reported side effects and increased with dose. They were reported in 26% of participants receiving 6 mg, 41% receiving 25 mg, and 47% receiving 50 mg, compared with 23% in the placebo group — a pattern consistent with GLP-1 receptor-based therapies.
- Serious adverse events were uncommon and no deaths occurred. Seven participants (4%) receiving zenagamtide across all dose groups experienced serious adverse events, distributed across all three dose levels, while none were reported in the placebo group. The trial was completed without fatalities.
Why This Matters
Zenagamtide represents a pharmacologically novel approach: a single oral peptide molecule that simultaneously engages GLP-1, amylin, and calcitonin receptors, offering a potential new class of oral agents for type 2 diabetes management. The trial demonstrates that meaningful glycaemic reductions are achievable with oral administration of a multi-receptor peptide agonist — a formulation and mechanistic combination not previously established in this setting. The dose-response data generated here provide the quantitative foundation needed to design future pivotal trials.
How to Read This Result
Although findings are consistently positive across all dose groups, the relatively small number of participants per arm (51–54 active participants) and the phase 2 dose-finding design mean that these results should be considered hypothesis-generating rather than definitive, with long-term efficacy and safety remaining to be established in larger trials.
Limitations
The abstract does not explicitly report study limitations.