medwireNews: The novel, single-molecule, dual glucagon-like peptide (GLP)-1 and amylin receptor agonist amycretin has shown promising tolerability with effective weight loss when given either orally or subcutaneously to adults with overweight or obesity.
Data from the two early-phase clinical trials were presented at the 85th ADA Scientific Sessions in Chicago, Illinois, USA, and published simultaneously in The Lancet.
For the first-in-human phase 1 trial, a total of 144 people aged 18–55 years (mean 39 years) with a BMI of 25.0–39.9 kg/m2 and no history of diabetes were randomly assigned to receive oral amycretin at single and multiple ascending doses ranging from 1 mg/day to 2x50 mg/day (in a single dose) or were given placebo for up to 12 weeks.
Agnes Gasiorek (Novo Nordisk, Måløv, Denmark) and co-authors report that, across all groups, there were 364 treatment-emergent adverse events (TEAEs) in 89 (62%) participants. None were unexpected, and all were mild or moderate in severity and occurred in a dose-dependent manner.
The most common TEAEs were gastrointestinal in nature (49% of events). These events, including loss of appetite, nausea, and vomiting, occurred in 81% of the 89 participants who reported a TEAE. There were no deaths during the study.
The researchers also note that there were no significant differences among the treatment groups in clinical safety laboratory parameters, such as electrolytes, kidney function, hematology, and electrocardiogram results. There was, however, a transient increase in heart rate with amycretin that returned to baseline during the follow-up period.
Exploratory analyses of changes in bodyweight and other metabolic parameters from baseline to 12 weeks showed that patients taking amycretin at a single daily dose of 50 mg, two doses of 50 mg, and two doses of 25 mg for 12 weeks had significant mean reductions in bodyweight of 10.4%, 13.1%, and 12.2%, respectively. By comparison, the mean reduction with placebo was 1.2%.
In addition, BMI, waist circumference, fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) were all reduced in the active treatment groups compared with placebo at 12 weeks.
Gasiorek et al say that although these findings are exploratory, they highlight “the potential benefits of GLP-1 and amylin receptor agonism beyond weight loss.”
In the second trial, by Kirsten Dahl (Novo Nordisk, Måløv, Denmark) and colleagues, 125 participants aged 18–55 years with a BMI of 27.0–39.9 kg/m2 and no diabetes were randomly assigned to receive once-weekly subcutaneous amycretin in ascending doses ranging from 0.3 mg to 60 mg for 20–36 weeks, or placebo.
They report that 86 (85%) of 101 participants in the amycretin groups experienced at least one TEAE. As with the phase 1 trial, the most common TEAEs in this phase 1b/2a study were mild-to-moderate gastrointestinal events that increased with dose intensity and had resolved by the end of treatment. Fourteen patients given amycretin experienced the skin reaction dysesthesia, which resolved by the end of the study. Increased heart rate was also reported in some participants.
Of note, 33% of participants withdrew from the study, but more than half (59%) of these discontinuations were for reasons unrelated to TEAEs.
Estimated mean bodyweight change from baseline was significantly higher across amycretin doses compared with placebo. Specifically, the mean bodyweight reductions were 24.3%, 22.0%, 16.2%, and 9.7% with amycretin 60 mg (week 36), 20 mg (week 36), 5 mg (week 28), and 1.25 mg (week 20), respectively. With placebo, the change in bodyweight ranged from a decrease of 1.1% to an increase of 2.0%.
Changes in FPG, HbA1c, lipid levels, and high-sensitivity C-reactive protein levels also favoured amycretin over placebo.
Dahl et al say that the safety, tolerability, and efficacy of oral and subcutaneous amycretin is now being evaluated in an ongoing phase 2 study among people with type 2 diabetes.
In an accompanying comment, Bernard Khoo (University College London, UK) and Tricia Tan (Imperial College London, UK) say the findings indicate that “amycretin, whether given orally or subcutaneously, is generally well tolerated, is associated with promising weight loss, and shows some favourable changes in glycaemia and lipid profiles in the context of non-diabetic overweight and obesity.”
However, they caution that the researchers “used small populations and tested widely varying dose regimens, so the headline weight losses and the frequency of adverse events might not be eventually realised in finalised dose schedules.”
Khoo and Tan also highlight the need to look beyond weight loss to understand whether amycretin reduces the risk for cardiovascular disease and other conditions linked to obesity.
They say: “Head-to-head outcome studies comparing GLP-1 receptor monoagonists with GLP-1 plus amylin receptor multiagonists are required to definitively establish their added value and, hence, their place in obesity management.”
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Lancet 2025; doi:10.1016/S0140-6736(25)01176-6
Lancet 2025; doi:10.1016/S0140-6736(25)01185-7
Lancet 2025; doi:10.1016/S0140-6736(25)01250-4
ADA 85th Scientific Sessions; Chicago, Illinois, USA: 20–23 June