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

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.