Efficacy and safety of cAMP signalling-biased GLP-1 analogue ecnoglutide monotherapy versus placebo in patients with type 2 diabetes (EECOH-1): a multi-centre, randomised, double-blind, placebo-controlled, phase 3 trial

Abstract Ecnoglutide is a cAMP biased GLP-1 analogue developed for the treatment of type 2 diabetes mellitus (T2DM) and obesity. We conducted a randomised, double-blind, placebo-controlled, phase 3 trial (NCT05680155) in Chinese participants with T2DM. Participants were randomised (2:2:1:1) to receive ecnoglutide 0.6 mg or ecnoglutide 1.2 mg or volume-matched placebo for 24 weeks, then all receive ecnoglutide for 28 weeks. The primary endpoint was change in glycated haemoglobin (HbA 1c ) from baseline at week 24. 211 participants were randomised to receive ecnoglutide 1.2 mg (n = 71), 0.6 mg(n = 69), or placebo(n = 71). At week 24, HbA 1c changed from baseline by -1.96%, -2.43% with 0.6 mg, 1.2 mg ecnoglutide, and − 0.87 with placebo. Bodyweight changed by -3.04 kg, -3.21 kg with 0.6 mg, 1.2 mg ecnoglutide, and − 1.45 kg with placebo. Ecnoglutide was safe and well tolerated, with a safety profile consistent with other approved GLP-1 receptor agonists, representing a potential monotherapy option for T2DM. Type 2 diabetes mellitus (T2DM), a progressive metabolic disease primarily characterised by abnormal glucose metabolism, poses an enormous burden on individuals as well as health systems across the world. 1–3 The goal of T2DM management is to reduce the risk of associated complications through optimal glycaemic control. Despite a wide range of available treatment options, a large proportion of patients still cannot achieve glycated haemoglobin (HbA 1c ) treatment targets. 4,5 Furthermore, glycaemic management should consider minimising undesired effects such as hypoglycaemia and bodyweight gain, 6 which has proven to be challenging with traditional glucose-lowering medications. The advert of single glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist tirzepatide has transformed the treatment landscape of T2DM. They can control glycaemia effectively without inducing severe hypoglycaemia or bodyweight gain. 7–9 Apart from glycaemic control, GLP-1 receptor agonists provide other clinical benefits, including bodyweight loss, cardiovascular risk reduction, and improvement in renal outcomes among others. 10–12 Therefore, they are an effective treatment option for T2DM and have been recommended by various guidelines. 13–15 Ecnoglutide, also known as XW003, is a novel, potent cyclic adenosine monophosphate (cAMP)-biased GLP-1 analogue, containing an alanine-to-valine substitution at position 8 as well as an 18-C fatty acid conjugation at the lysine 30 side chain. 16 cAMP bias is hypothesised to enhance the clinical efficacy of GLP-1 receptor agonists through reducing internalisation of the GLP-1 receptor and enhancing insulin secretion. 17 In a preclinical study, ecnoglutide showed a stronger binding affinity towards the GLP-1 receptor and more potent efficacy in reducing blood glucose and bodyweight than semaglutide, an unbiased GLP-1 receptor agonist. 16 In phase 1 trials among healthy volunteers, once-weekly injections of ecnoglutide exhibited favourable safety and tolerability profiles and a half-life ranging from 124 to 138 h, indicating its potential as a long-acting regimen. 16 In a phase 2 trial among individuals with T2DM, once-weekly injections of ecnoglutide at doses of 0.4, 0.8, and 1.2 mg resulted in more pronounced improvements versus placebo in glycaemic control and bodyweight, supporting its potential as a treatment option for T2DM. 18 Here we report the findings from a phase 3 trial, EECOH-1, which investigated the efficacy and safety of once-weekly injections of ecnoglutide at doses of 0.6 mg and 1.2 mg versus placebo in adults with T2DM inadequately controlled with diet and exercise alone or with a single oral hypoglycaemic agent.