Summary: In 144 adults with overweight or obesity, oral amycretin, a first-in-class single-molecule GLP-1 and amylin receptor agonist, was evaluated against placebo in a first-in-human phase 1 trial. The primary endpoint was safety. Treatment-emergent adverse events occurred in 89 of 144 participants (62%), were all mild or moderate, increased dose-dependently, and were predominantly gastrointestinal. Weight loss was an exploratory endpoint only.
PICO Summary
| Element | Detail |
|---|---|
| Population | 144 adults aged 18 to 55 years with overweight or obesity (BMI 25.0 to 39.9 kg/m2 depending on study part); single-centre, San Antonio, Texas, USA. |
| Intervention | Oral amycretin, a single-molecule GLP-1 and amylin receptor agonist, given as single ascending doses (part A, 1 to 25 mg) and multiple ascending doses (part B, 3 to 12 mg once daily; part C/D, fixed titration up to 2 x 50 mg once daily over 12 weeks). Amycretin arms total n=110. |
| Comparison | Matching placebo within each part (randomisation 6:2, 9:3, or 16:4 amycretin vs placebo). Placebo arms total n=34. |
| Outcome | Primary endpoint (safety): 364 treatment-emergent adverse events in 89 of 144 participants (62%), all mild or moderate and dose-dependent; gastrointestinal events were most common (180 of 364, 49%), reported by 72 of 89 affected participants (81%); no deaths. Plasma concentrations showed dose proportionality. Exploratory pharmacodynamic endpoints (part C/D, change to day 85): weight and fasting plasma glucose reduction reported, with no confidence intervals, p values, or formal efficacy testing in the abstract. The published report describes estimated mean weight loss of 13.1% versus 1.2% with placebo at the highest oral dose, framed as exploratory. |
Expert Commentary
This is a first-in-human phase 1 trial, and its conclusions should be read accordingly. The primary objective was safety and tolerability, and on that measure oral amycretin behaved as expected for an incretin-based agent: adverse events were entirely mild or moderate, rose with dose, and were dominated by gastrointestinal symptoms, with no deaths reported. The weight and glucose changes that have attracted attention were exploratory pharmacodynamic endpoints confined to part C/D, and the abstract reports no confidence intervals, p values, or formal efficacy analysis. The often-quoted figure of roughly 13 percent weight loss at the highest dose is drawn from a small, open-titration arm and must be treated as hypothesis-generating rather than established efficacy. Two cautions are worth stating plainly. The trial was funded and conducted by the manufacturer, Novo Nordisk, and the headline weight numbers are strikingly large for a 12-week phase 1 exposure, which invites scrutiny rather than enthusiasm. The single weighed limitation is the absence of any powered efficacy comparison: dose-escalation safety studies are not designed to quantify benefit, and small arms inflate apparent effects. Can I use this with my patients? Not yet. Amycretin is investigational and unavailable, and these data justify only continued trial development, not clinical use. The appropriate next step is the adequately powered phase 2 and 3 programme already under way, which should report efficacy with proper statistical inference.
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