Summary: In adults with overweight or obesity, the oral GLP-1 and amylin receptor co-agonist amycretin was generally safe and well tolerated across single and multiple ascending doses in this first-in-human phase 1 trial, with mostly mild to moderate, dose-dependent gastrointestinal adverse events. Weight and glucose effects were exploratory only and were not formally tested, so efficacy remains unproven.
PICO Summary
| Element | Detail |
|---|---|
| Population | 144 adults aged 18 to 55 with overweight or obesity (BMI 25.0 to 39.9 kg/m2); first-in-human, phase 1, double-blind, randomised, placebo-controlled trial, single centre, USA. |
| Intervention | Oral amycretin, a single-molecule GLP-1 and amylin receptor agonist: single ascending doses 1 to 25 mg (part A, n=48); multiple ascending doses 3 to 12 mg once daily (part B, n=36); 12-week fixed dose-escalation up to 50 to 100 mg daily (part C/D, n=60). |
| Comparison | Matching placebo, randomised 6:2, 9:3, and 16:4 to amycretin versus placebo across the parts. |
| Outcome | Primary safety endpoint: 364 treatment-emergent adverse events occurred in 89 of 144 participants (62%), all mild or moderate and increasing in a dose-dependent manner; gastrointestinal events predominated (180 of 364, 49%, affecting 81% of those with any event); no deaths were reported. Pharmacokinetics were dose-proportional. Bodyweight and fasting plasma glucose were exploratory endpoints in part C/D and were reported without formal significance testing. |
Expert Commentary
This is an early but carefully conducted first-in-human study of a single molecule combining GLP-1 and amylin receptor agonism, and the signal worth noting is tolerability rather than efficacy. The safety profile is reassuring for a phase 1 programme: adverse events were uniformly mild to moderate, predictably gastrointestinal, and clearly dose related, with no deaths across 144 exposed participants. What the trial does not do is demonstrate efficacy. Weight and glucose changes were exploratory endpoints reported without formal statistical testing, so reading amycretin as an established weight loss agent is premature. The central limitation is inherent to the design, since a phase 1 safety study cannot show how a drug performs against active comparators or over a clinically meaningful horizon, and the manufacturer sponsorship warrants the usual caution about framing and emphasis. Can I use this with my patients? No, not yet; amycretin remains investigational and belongs in trials, not clinics. What I would want to see next is adequately powered phase 2 and phase 3 data, with head to head comparison against established incretin therapies and durable metabolic and cardiovascular endpoints, before this molecule earns any place in routine practice.
References
Gasiorek A, Heydorn A, Gabery S, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the first-in-class GLP-1 and amylin receptor agonist, amycretin: a first-in-human, phase 1, double-blind, randomised, placebo-controlled trial. Lancet. 2025;406(10499):135-148. doi:10.1016/S0140-6736(25)01176-6