Highlights
– Amycretin, a novel unimolecular GLP-1 and amylin receptor agonist, achieved up to 24.3% weight loss over 36 weeks in overweight or obese adults.
– The safety profile was consistent with known GLP-1 and amylin agonists, primarily involving mild-to-moderate gastrointestinal events.
– The study supports further investigation of amycretin as a potential anti-obesity therapy, reflecting a new direction in incretin-based pharmacotherapy.
– This trial adds to the dynamic landscape of multi-agonist therapies in metabolic disease management.
Clinical Background and Disease Burden
Obesity remains a global health crisis, contributing to increased morbidity and mortality from metabolic, cardiovascular, and oncological diseases. Despite lifestyle interventions and existing pharmacotherapies, a significant unmet need persists for effective, durable, and tolerable weight loss agents. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide and tirzepatide, have revolutionized obesity care, but limitations around efficacy plateaus and gastrointestinal side effects remain. The integration of amylin receptor agonism, with its complementary appetite-suppressing and gastric emptying effects, represents a promising strategy for enhancing metabolic outcomes.
Methodology
This phase 1b/2a, single-center, randomized, placebo-controlled trial (ClinicalTrials.gov: NCT06064006) aimed to assess the safety, tolerability, pharmacokinetics, and weight loss efficacy of subcutaneously administered amycretin in adults (18–55 years) with overweight or obesity (BMI 27.0–39.9 kg/m²). Participants (n=125) were randomly assigned to amycretin (n=101) or placebo (n=24), with blinding maintained for both investigators and subjects.
The study comprised five parts:
– Part A: Single ascending dose
– Part B: Multiple ascending dose (0.3 mg to 60 mg; 36 weeks)
– Parts C, D, E: Multiple ascending dose with maintenance (20 mg for 36 weeks, 5 mg for 28 weeks, 1.25 mg for 20 weeks; maintenance for final 12 weeks)
Primary endpoint: Number of treatment-emergent adverse events (TEAEs).
Secondary endpoints: Pharmacokinetic parameters (AUC, Cmax), and relative change in bodyweight from baseline.
Key Findings
Among 125 randomized participants, mean baseline weight ranged from 88.3 to 99.1 kg. Amycretin showed dose-dependent and significant weight reduction compared to placebo across all dosing regimens:
– 60 mg (Part B, 36 weeks): -24.3% vs -1.1% (placebo)
– 20 mg (Part C, 36 weeks): -22.0% vs 1.9%
– 5 mg (Part D, 28 weeks): -16.2% vs 2.3%
– 1.25 mg (Part E, 20 weeks): -9.7% vs 2.0%
Statistical significance was robust (Parts A-D: p<0.0001; Part E: p=0.0003). The most common adverse events were gastrointestinal (nausea, vomiting, diarrhea), mostly mild or moderate, mirroring early-phase profiles of established GLP-1 and amylin analogs. Importantly, a notable proportion of discontinuations were unrelated to treatment-emergent adverse events, suggesting other trial or participant factors influenced retention.
Mechanistic Insights and Biological Plausibility
Amycretin’s design as a unimolecular agonist for both GLP-1 and amylin receptors aims to leverage synergistic mechanisms: GLP-1 reduces appetite and enhances insulin secretion; amylin slows gastric emptying and also suppresses food intake. Preclinical and translational studies support this dual targeting as a means to potentiate weight loss beyond GLP-1 agonism alone, possibly addressing the therapeutic ceiling observed with monotherapy. The magnitude of weight loss observed in this study approaches or surpasses that seen in recent phase 3 trials of GLP-1/GIP dual agonists, suggesting a meaningful advance.
Expert Commentary and Current Perspectives in GLP-1 Drug Development
The development of amycretin aligns with a broader trend towards multi-agonist therapies in metabolic disease, as exemplified by the clinical success of tirzepatide (GLP-1/GIP receptor agonist) and the investigational triagonist retatrutide (GLP-1/GIP/glucagon receptor agonist). The impressive weight loss efficacy of amycretin in this early-phase trial is promising, but longer-term data on cardiovascular safety, metabolic improvements (e.g., glycemic control), and real-world tolerability will be essential.
According to the 2023 ADA/EASO guidelines, GLP-1 receptor agonists are recommended as first-line pharmacotherapy for obesity with compelling evidence for weight loss and metabolic benefits. The incremental gains from new multi-agonist strategies, however, could shift the paradigm—particularly if tolerability and adherence are maintained.
Controversies and Limitations
The study’s limitations include its single-center design, relatively small sample size, and short-to-moderate duration (up to 36 weeks). High dropout rates, albeit largely unrelated to adverse events, may affect generalizability. The lack of detailed subgroup analysis (e.g., by sex, race, baseline metabolic status) limits insights into population-specific efficacy or risk. Furthermore, the trial did not address long-term cardiovascular safety or compare amycretin directly with established GLP-1 or GIP/GLP-1 therapies.
Conclusion
Amycretin demonstrated substantial, dose-dependent weight loss and a safety profile consistent with GLP-1 and amylin agonists in overweight and obese adults. These findings support further development of amycretin and reinforce the value of dual or multi-agonist strategies in the evolving pharmacotherapy of obesity. Ongoing and future studies must address durability of effect, broader metabolic endpoints, and comparative effectiveness to solidify amycretin’s clinical role.
References
1. Dahl K, Toubro S, Dey S, Duque do Vale R, Flint A, Gasiorek A, Heydorn A, Jastreboff AM, Key C, Petersen SB, Vegge A, Adelborg K. Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. Lancet. 2025 Jul 12;406(10499):149-162. doi: 10.1016/S0140-6736(25)01185-7 IF: 88.5 Q1 .2. Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384:989-1002.
3. Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387:205-216.
4. Wharton S, et al. EASO Guidelines on Obesity Management. Obes Facts. 2023;16(1):1-21.
