Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study.

BACKGROUND: Amycretin is a novel, unimolecular GLP-1 and amylin receptor agonist. The aim of this study was to investigate the safety, tolerability, pharmacokinetics, and effects on bodyweight of subcutaneous amycretin administered over a treatment period of up to 36 weeks in participants with overweight or obesity. METHODS: In this randomised, placebo-controlled, phase 1b/2a study, we investigated the safety, tolerability, pharmacokinetics, and effects on bodyweight of subcutaneous injection of amycretin in participants aged 18-55 years with overweight or obesity (BMI 27·0-39·9 kg/m). The study took place at a single clinical research centre in San Antonio, TX, USA. Participants were randomly allocated to receive amycretin or placebo, with participants and investigators masked to trial product allocation. There were five parts: Part A (single ascending dose); Part B (multiple ascending dose [MAD]-dose escalation), once-weekly amycretin escalated from 0·3 mg to 60 mg for a total treatment duration of 36 weeks; and Parts C, D, and E (MAD-dose response), once-weekly amycretin escalated from 0·3 mg up to maintenance doses of 20 mg for a total treatment duration of 36 weeks, 5 mg for a total of 28 weeks, or 1·25 mg for a total of 20 weeks (maintenance dose sustained for the last 12 weeks). The primary endpoint was the number of treatment-emergent adverse events measured from baseline to end of study (Parts A-E). Secondary endpoints were area under the plasma concentration-time curve, maximum plasma concentration, and relative change in bodyweight from baseline. The safety analysis set comprised all participants exposed to treatment, and the full analysis set comprised all randomly allocated participants. This study is registered with ClinicalTrials.gov, NCT06064006. FINDINGS: Between Sept 15, 2023, and April 24, 2024, 125 participants were randomly allocated to amycretin (n=101) or placebo (n=24). Mean baseline bodyweight was 88·3-99·1 kg across Parts B-E. The most common treatment-emergent adverse events were gastrointestinal, and the majority were mild to moderate in severity and resolved by the end of the study. A large number of participants withdrew from the study, with a high proportion of discontinuations occurring due to reasons unrelated to treatment-emergent adverse events. Estimated mean bodyweight change from baseline was significantly (Parts A-D: p<0·0001; Part E: p=0·0003) higher with amycretin versus placebo in Part B (60 mg, -24·3% vs -1·1%; week 36), Part C (20 mg, -22·0% vs 1·9%; week 36), Part D (5 mg, -16·2% vs 2·3%; week 28), and Part E (1·25 mg, -9·7% vs 2·0%; week 20). INTERPRETATION: In people with overweight or obesity, once-weekly subcutaneous amycretin up to 60 mg had a safety and tolerability profile consistent with GLP-1 and amylin agonists. Although a high frequency of gastrointestinal events was reported, rates were similar to those seen in early-phase studies of these molecules. These results support further investigation into the weight loss properties of amycretin. FUNDING: Novo Nordisk.