Amycretin Data at ADA Highlight Efficacy, Safety of Dual-Agonist Obesity Therapy

New data from the 85th Scientific Sessions of the American Diabetes Association (ADA 2025) highlight the potential of amycretin, in both the oral and subcutaneous formulations, for inducing weight loss in people with overweight or obesity.1,2

Coming less than 2 weeks after sponsoring company Novo Nordisk announced plans to advance amycretin programs for weight management into phase 3 clinical development, results of the studies, which were also simultaneously published in The Lancet, offer insight from a phase 1 trial of oral amycretin and a phase 1b/2a of subcutaneous amycretin.1,2,3

“Amycretin is the first investigational treatment that combines GLP-1 and amylin receptor agonism biology in one molecule, working on distinct pathways and offering complementary effects on appetite control,” said Martin Holst Lange, executive vice president for Development at Novo Nordisk.4 “The findings published and presented today are encouraging. We are excited to advance the clinical development of subcutaneous and oral amycretin into phase 3 to assess its potential as a therapeutic option for weight management.”

Phase 1 Trial of Oral Amycretin

The phase 1, first-in-human study evaluating amycretin, a novel dual GLP-1 and amylin receptor agonist, was a randomized, double-blind, placebo-controlled trial conducted in a single US center. The trial included 144 participants who were randomized in a 6:2 ratio to amycretin or placebo therapy.1

Per trial protocol, participants were divided into parts A, B, and C/D, receiving oral amycretin in doses ranging from 1 mg to 100 mg via titration. In part A, patients received single ascending doses. In part B, investigators included multiple ascending doses over 10 days. In part C/D, fixed titration regimens administered once daily for 12 weeks. Of note, patients in parts A and B had a BMI of 25.0 to 34.9 kg/m and those in part C/D had a BMI of 27.0 to 39.9 kg/m.1

The primary endpoint was safety, with secondary pharmacokinetic and exploratory pharmacodynamic endpoints including changes in body weight and fasting plasma glucose.1

Across all parts, 364 treatment-emergent adverse events (TEAEs) were reported in 62% of participants. According to investigators, all events were mild or moderate in severity, with a dose-dependent increase in frequency. The most common adverse events were gastrointestinal events, including nausea and vomiting, which accounted for 49% of events and affected 81% of participants who reported any event. Investigators highlighted there were no deaths during the study.1

Additionally, investigators pointed out pharmacokinetic analysis indicated amycretin plasma exposure increased proportionally with dose and exploratory pharmacodynamic findings from part C/D suggested potential benefits on body weight and fasting glucose.1

Phase 1/2a Trial of Subcutaneous Amycretin

The trial of subcutaneous amycretin from ADA 2025 was a phase 1b/2a randomized, placebo-controlled study conducted at a single site in the US. The trial enrolled 125 participants aged 18 to 55 years with BMIs between 27.0 to 39.9 kg/m². Participants were randomized to amycretin (n=101) or placebo (n=24), with investigators and participants blinded to treatment allocation.2

The study included five parts: Part A assessed single ascending doses, while Parts B through E tested multiple ascending doses with various titration schedules and maintenance doses (ranging from 1.25 mg to 60 mg once weekly) over periods up to 36 weeks.2

The primary endpoint was the number of TEAEs, with secondary endpoints including pharmacokinetics and bodyweight change from baseline.2

Gastrointestinal side effects were the most common TEAEs, consistent with known profiles of GLP-1 and amylin agonists. Most events were mild to moderate in severity and resolved by study completion. While discontinuations occurred across the trial, most were unrelated to adverse events.2

Secondary outcomes analysis indicated amycretin led to significant weight loss across all dose levels compared to placebo, with investigators calling specific attention to the following results in their abstract:2

• Part B (60 mg, week 36): –24.3% vs –1.1% (P <.0001)
• Part C (20 mg, week 36): –22.0% vs 1.9% (P <.0001)
• Part D (5 mg, week 28): –16.2% vs 2.3% (P <.0001)
• Part E (1.25 mg, week 20): –9.7% vs 2.0% (P = .0003)

In a linked editorial in The Lancet, Tricia Tan, MBChB, PhD, of Imperial College London, and Bernard Khoo, PhD, of University College London, commended the investigators of these studies for their efforts and contributions, but also underlined how the goalposts in obesity management have changed in recent years and the challenge it presents for newer agents like amycretin.5

“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,” concluded the pair.5

References:

1. 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. The Lancet. Published online June 2025. doi: 10.1016/s0140-6736(25)01176-6

2. Dahl K, Toubro S, Dey S, et al. Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. The Lancet. Published online June 2025. doi: 10.1016/s0140-6736(25)01185-7

3. Novo Nordisk. Novo Nordisk to advance subcutaneous and oral amycretin for weight management into phase 3 clinical development. Novo Nordisk. Published June 12, 2025. Accessed June 21, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916348

4. Novo Nordisk. Novo Nordisk’s subcutaneous and oral amycretin data published in The Lancet and presented at ADA 2025. Novo Nordisk. Published June 20, 2025. Accessed June 21, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916351

5. Khoo B, Tan TM-M. GLP-1 and amylin receptor multiagonism with amycretin for obesity management. The Lancet. Published online June 20, 2025. doi: 10.1016/s0140-6736(25)01250-4