Obesity, affecting over one billion individuals globally, is a chronic disease that significantly increases the risk of cardiovascular disease, type 2 diabetes, and sleep apnea. Amycretin, a novel molecule developed by Novo Nordisk, is emerging as a promising therapeutic avenue for weight management. It functions as a unimolecular long-acting glucagon-like peptide-1 (GLP-1) and amylin receptor co-agonist. GLP-1 receptor agonists and amylin receptor agonists have demonstrated clinically relevant weight loss and glucose-lowering effects in people with overweight, obesity, and type 2 diabetes. By acting on both GLP-1 and amylin receptors, amycretin aims to leverage the combined benefits of appetite suppression, slowed gastric emptying and improved metabolic control.
Amycretin's Mechanism of Action
Amycretin is a novel therapy that activates GLP-1 and amylin receptors, two hormones involved in regulating appetite and metabolism. The gut hormone amylin, which suppresses appetite and slows gastric emptying, enhances the effects of GLP-1-based therapies when used in combination.
Phase I Clinical Trial Details
The phase 1 single-center, randomized, placebo-controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses (Part A) and multiple ascending doses (Part B, 10 days of treatment; Part C/D, 12 weeks of treatment) of 144 adult participants with overweight or obesity. The primary endpoint was the number of treatment-emergent adverse events (TEAEs) observed in the trial. Supportive secondary pharmacokinetic endpoints for parts A-D were area under the amycretin plasma concentration-time curve and maximum plasma concentration. Exploratory pharmacodynamic endpoints in part C/D were change in bodyweight (%) and fasting plasma glucose (mmol/L) from before dosing on day 1 until day 85.
Study Participants
Between May 11, 2022, and Jan 9, 2024, 144 participants were enrolled in the study (48 participants in part A, 36 participants in part B, and 60 participants in part C/D). Eligible individuals were men or women (including women of childbearing potential) aged 18-55 years at the time of signing informed consent. For parts A and B, participants had a BMI of 25·0-34·9 kg/m2 and for part C/D, a BMI of 27·0-39·9 kg/m2.
Study Design
In part A, participants were randomly assigned across six treatment groups (single ascending doses of oral amycretin [1 mg, 3 mg, 6 mg, 12 mg, 18 mg (12 + 6 mg per adaptive study design), or 25 mg]) or placebo (6:2 to amycretin groups vs placebo). Part A consisted of a 28-day screening period, a 1-day (single dose) intervention period, and a 21-day follow-up period. In part B, participants were randomly assigned across three treatment groups (multiple ascending doses of oral amycretin [3 mg, 6 mg, or 12 mg once daily]) or placebo (9:3 to amycretin groups vs placebo). Part B consisted of a 28-day screening period, a 10-day intervention period, and a 21-day follow-up period. In part C/D, 60 participants were randomly assigned to one of three dose-escalation treatment groups (multiple ascending doses of oral amycretin in a fixed titration regimen for all participants [part C1: from 3 mg to 50 mg once daily; part C2: from 6 mg to 2 × 50 mg (two tablets in a single daily dose); and part D: from 3 mg to 2 × 25 mg (two tablets in a single daily dose)]), or placebo (16:4 to amycretin groups vs placebo). Part C/D consisted of a 4-week screening period, a 12-week intervention period, and a 3-week follow-up period.
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Safety and Tolerability
Across parts A-D, there were 364 treatment-emergent adverse events in 89 (62%) of 144 participants, all of which were mild or moderate in severity and increased in frequency in a dose-dependent manner. The most common treatment-emergent adverse events were gastrointestinal in nature (180 [49%] of 364 events), observed in 72 (81%) of 89 participants who reported a treatment-emergent adverse event. No deaths were reported. In people with overweight or obesity, amycretin appeared safe and tolerable. Results from the published phase 1 trial of oral amycretin showed that the most common TEAEs were related to gastrointestinal symptoms (mainly nausea and vomiting) and decreased appetite; these were most frequent for the higher doses.
Phase Ib/IIa Trial Results: Subcutaneous Amycretin
In a Phase Ib/IIa study (NCT06064006), amycretin, a glucagon-like peptide-1 (GLP-1) and amylin receptor co-agonist, showed weight-loss outcomes of up to 22% in 36 weeks. The Phase Ia/IIb study investigated three doses of once-weekly subcutaneous amycretin in 125 patients who are overweight or with obesity. In January, Novo recorded 22% weight loss in people who received weekly amycretin injections for 36 weeks in a phase 1b/2a study. The company didn’t mention whether weight loss appeared to plateau after 36 weeks or whether the trends suggest possible improvement over a longer period.
Study Design and Participants
Between September 15, 2023, and April 14, 2024, 198 individuals were assessed for eligibility at a single research center in Texas, USA. Included were patients aged 18-55 years with overweight or obesity (BMI 27.0-39.9 kg/m²) who were randomly allocated to receive either amycretin or placebo. Altogether, 125 patients (101 in amycretin and 24 in placebo) were included in the final analysis. Investigators conducted a five-part, randomized, placebo-controlled Phase 1b/2a trial at a single site in the United States (San Antonio, Texas). Eligible adults (aged 18-55 years) had a body mass index (BMI) of 27.0-39.9 kg/m² and no major illnesses such as diabetes. Part A tested single ascending doses (0.3 mg, 0.6 mg, 1.0 mg). The primary endpoint was the incidence of treatment-emergent adverse events.
Weight Loss Outcomes
Amycretin resulted in significant weight loss across most doses compared to placebo. The secondary outcome of relative change in body weight was significantly greater with amycretin compared to placebo (-24.4% vs. -1.1% in 60 mg, -22.0% vs 1.9% in 20 mg, and -16.2% vs. 2.3% in 5 mg, p<0.0001 for all). Superiority to placebo was evident by week 4 and widened through the study, with no weight-loss plateau observed during the 12-week maintenance phases in any cohort. Participants who received the highest doses (up to 60 mg) reported body weight reductions of up to 24.3% versus 1.1% with placebo after 36 weeks of treatment.
Metabolic Improvements
Metabolic markers showed exploratory improvements in parallel with weight. Fasting plasma glucose levels declined by up to 0.8 mmol/L, and HbA1c levels decreased by 0.6 percentage points in the highest-dose cohort, although statistical significance versus placebo was inconsistent across doses.
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Adverse Events
Most treatment-related adverse events were mild to moderate, being primarily gastrointestinal in nature. Treatment-emergent adverse events occurred in 92% of amycretin users compared with 100% of placebo participants in Parts B-E reporting at least one event. Nausea affected 82%, vomiting 53%, and diarrhea 41% of treated participants, peaking during up-titration and diminishing thereafter. Dysaesthesia incidence varied by dose: 18% in Part B (60 mg), 29% in Part C (20 mg), and 6% in Part D (5 mg), resolving in all but one case.
Planned Phase III Trial
Following a positive end-of-Phase II meeting, Novo Nordisk shared that regulatory authorities have approved the therapy to proceed. Novo Nordisk is hoping to initiate the Phase III trial in Q1 2026. The company plans to initiate the trial in adults who are overweight or with obesity in Q1 2026. Executive vice president for development at Novo Nordisk, Martin Lange said: “We are very pleased that the feedback from regulatory authorities has allowed us to take subcutaneous and oral amycretin in weight management to Phase III. We are excited about the amycretin molecule, and this marks an important step forward. "We are pleased with the promising results of amycretin and the feedback from regulatory authorities and are excited to advance both subcutaneous and oral versions of this molecule into phase 3 development for weight management. At Novo Nordisk, we understand that addressing obesity is a complex challenge that many patients face. These results reflect our robust pipeline in obesity, our focus on progressing scientific innovation and expanding the range of options available to patients and healthcare professionals," said Martin Holst Lange, executive vice president for Development at Novo Nordisk.
Novo Nordisk's Position in the Market
Following all these updates, Novo Nordisk’s share price has now increased, making it the most valuable company in Europe once again. But Novo hasn’t been resting on its laurels, instead doubling down on bolstering its obesity pipeline via licensing deals. Its main competitor, Eli Lilly’s tirzepatide, marketed as Zepbound in weight loss and Mounjaro in type 2 diabetes, is projected to reach sales of $60.8bn. Since Zepbound beat Wegovy in a head-to-head weight loss trial in December 2024, Novo has been searching for ways to dial up efficacy. As well as this, the company has also listed two new studies for CagriSema, another candidate in its pipeline.
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