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

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 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article 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phase 3 trial shaohui Bing, Dalong Zhu, Weimin Wang, Guoyu Tong, Jianhua Ma, and 29 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6342890/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Jan, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version 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. Health sciences/Endocrinology/Endocrine system and metabolic diseases/Diabetes/Type 2 diabetes Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity Figures Figure 1 Figure 2 INTRODUCTION 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. RESULTS Study participants Between 29 December 2022 and 12 June 2024, 300 participants were assessed for eligibility and 211 of them were randomly assigned to receive 0.6 mg ecnoglutide (n = 69), 1.2 mg ecnoglutide (n = 71), placebo volume-matched to 0.6 mg ecnoglutide (n = 36), or placebo volume-matched to 1.2 mg ecnoglutide (n = 35) (Fig. 1 ). All randomised participants received ≥ 1 dose of the assigned treatment, and 9 (4%) of them discontinued treatment prematurely in the double-blind period, including 3 from the 0.6 mg ecnoglutide group, 4 from the 1.2 mg ecnoglutide group, and 2 from the placebo group. Out of the 211 randomised participants, 195 (92.4%) entered the open-label period and received treatment with ecnoglutide (0.6 or 1.2 mg) and 5 (2.6%) of them discontinued treatment prematurely, including 2 from the 0.6 mg ecnoglutide group and 3 from the 1.2 mg ecnoglutide group. Across the two periods, the reasons for treatment discontinuation included physicians’ decisions and participants’ own requests among others. Time to study drug discontinuation is shown in Kaplan-Meier plots in Supplementary Fig. 1 . During the double-blind treatment period, 3 participants in the placebo group received rescue therapy because of hyperglycaemia, and none in the ecnoglutide groups required rescue therapy. During the open-label treatment period, 3 participants, with one each from the two ecnoglutide groups and the 0.6 mg placebo group, required rescue therapy because of hyperglycaemia. All 211 participants were included in full analysis set (FAS) and safety set. Baseline characteristics were similar across the three groups (Table 1 ). At baseline, the mean standard deviation (SD) age was 52.0 (10.9) years, 127 (60.2%) were male, with an average (SD) of 8.52% (0.81) for HbA 1c , 26.93 kg/m 2 (3.40) for body mass index (BMI), and 3.58 years (3.78) for T2DM duration. Table 1 Baseline characteristics (full analysis set) Characteristic Ecnoglutide 1.2 mg (N = 71) Ecnoglutide 0.6 mg (N = 69) Placebo (N = 71) Total (N = 211) Age (years) 52.5 (11.5) 52.1 (10.8) 51.4 (10.4) 52.0 (10.9) Sex Female 28 (39%) 30 (43%) 26 (37%) 84 (40%) Male 43 (61%) 39 (57%) 45 (63%) 127 (60%) Bodyweight (kg) 71.53 (12.05) 74.25 (15.20) 73.69 (11.31) 73.14 (12.93) Height (cm) 165.30 (8.03) 164.83 (9.80) 165.22 (9.34) 165.12 (9.04) BMI (kg/m 2 ) 26.35 (3.31) 27.23 (3.65) 27.23 (3.20) 26.93 (3.40) Waist circumference (cm) 93.26 (8.94) 94.02 (10.55) 94.60 (8.36) 93.96 (9.29) Diabetes duration (years) 3.66 (3.99) 4.10 (4.20) 3.00 (3.02) 3.58 (3.78) Prior antihyperglycemic medication use 35 (49) 41 (59) 26 (37) 102 (48) HbA 1c In % 8.51 (0.83) 8.54 (0.80) 8.51 (0.81) 8.52 (0.81) In mmol/mol 69.51 (9.10) 69.84(8.72) 69.51 (8.89) 69.62 (8.86) ≤ 8.5% 38 (54%) 36 (52%) 37 (52%) 111 (53%) > 8.5% 33 (46%) 33 (48%) 34 (48%) 100 (47%) Fasting plasma glucose (mmol/L) 9.67 (1.86) 9.67 (1.76) 9.81 (1.82) 9.72 (1.81) eGFR MDRD (ml/min/1.73m 2 ) 124.7 (35.1) 122.0 (29.9) 113.5 (25.9) 120.0 (30.8) Notes: Data are mean (SD) or n (%). Data are for all randomised participants. N = all randomly assigned participants who took at least one dose of study drug. BMI = body mass index. eGFR MDRD =estimated glomerular filtration rate based on the Modification of Diet in Renal Disease equation. HbA 1c = glycated haemoglobin. Primary outcome The primary endpoint was met, and both doses of ecnoglutide significantly reduced HbA 1c more than placebo for both primary and secondary efficacy estimands. At week 24, the least squares mean (LSM) change (95% CI) from baseline in HbA 1c as per the treatment policy estimand was − 1.96% (-2.18 to -1.73) with 0.6 mg ecnoglutide, -2.43% (-2.65 to -2.20) with 1.2 mg ecnoglutide, and − 0.87% (-1.09 to -0.65) with placebo (Fig. 2 , Table 2 ). The estimated treatment difference (ETD) versus placebo was − 1.09% (95% CI -1.40 to -0.77; p = 0.0003) with 0.6 mg ecnoglutide and − 1.56% (95% CI -1.87 to -1.24; p < 0.0001) with 1.2 mg ecnoglutide (Fig. 2 , Table 2 ). Significantly greater decreases from baseline in HbA 1c with both 0.6 mg and 1.2 mg ecnoglutide versus placebo were evident since the first assessment at week 4 (Fig. 2 ). The cumulative distribution of change from baseline in HbA 1c at week 24 is presented in Supplementary Fig. 2 . At week 24, the LSM change (95% CI) from baseline in HbA 1c as per the hypothetical estimand was − 1.96% (-2.18 to -1.73) with 0.6 mg ecnoglutide, -2.43% (-2.65 to -2.20) with 1.2 mg ecnoglutide, and − 0.85% (-1.07 to -0.62) with placebo. The ETD versus placebo was − 1.11% (95% CI -1.43 to -0.79; p = 0.0002) with 0.6 mg ecnoglutide and − 1.58% (95% CI -1.90 to -1.26; p < 0.0001) with 1.2 mg ecnoglutide. Table 2 Efficacy measures at week 24 (full analysis set) Ecnoglutide 1.2 mg (N = 71) Ecnoglutide 0.6 mg (N = 69) Placebo (N = 71) LSM change from baseline (95% CI) ETD vs placebo (95% CI) p value LSM change from baseline (95% CI) ETD vs placebo (95% CI) p value LSM change from baseline (95% CI) HbA 1c (%) -2.43 (-2.65 to -2.20) -1.56 (-1.87 to -1.24) < 0.0001 -1.96 (-2.18 to -1.73) -1.09 (-1.40 to -0.77) 0.0003 -0.87 (-1.09 to -0.65) HbA 1c (mmol/mol) -50.0 (-52.44 to -47.59) -17.01 (-20.43 to -13.57) < 0.0001 -44.89 (-47.34 to -42.43) -11.88 (-15.32 to -8.44) 0.0003 -33.01 (-35.42 to -30.59) Fasting plasma glucose (mmol/L) -3.32 (-3.68 to -2.97) -2.11 (-2.61 to -1.62) < 0.0001 -2.89 (-3.24 to -2.53) -1.68 (-2.17 to -1.18) < 0.0001 -1.21 (-1.56 to -0.86) 2h-postprandial plasma glucose (mmol/L) -7.42 (-8.17 to -6.67) -5.61 (-6.66 to -4.56) < 0.0001 -5.95 (-6.69 to -5.21) -4.14 (-5.18 to -3.10) < 0.0001 -1.81 (-2.54 to -1.08) 7-Point SMBG (mmol/L) Mean Glucose -3.99 (-4.43 to -3.54) -2.81 (-3.45 to -2.17) < 0.0001 -3.36 (-3.81 to -2.91) -2.18 (-2.82 to -1.55) < 0.0001 -1.18 (-1.63 to -0.72) Postprandial glucose excursion -1.58 (-1.91 to -1.24) -1.03 (-1.50 to -0.55) < 0.0001 -1.38 (-1.72 to -1.04) -0.83 (-1.31 to -0.35) 0.0008 -0.55 (-0.89 to -0.21) Bodyweight (kg) -3.21 (-3.84 to -2.58) -1.76 (-2.65 to -0.87) 0.0001 -3.04 (-3.68 to -2.40) -1.59 (-2.48 to -0.69) 0.0005 -1.45 (-2.08 to -0.82) Bodyweight (%) -4.74 (-5.65 to -3.82) -2.72 (-4.01 to -1.43) < 0.0001 -4.51 (-5.43 to -3.58) -2.490 (-3.79 to -1.20) 0.0002 -2.02 (-2.92 to -1.11) Waist circumference (cm) -3.35 (-4.13 to -2.57) -2.15 (-3.25 to -1.06) 0.0001 -2.75 (-3.54 to -1.97) -1.56 (-2.66 to -0.46) 0.0058 -1.19 (-1.97 to -0.42) Hip circumference (cm) -2.96 (-3.55 to -2.37) -1.34 (-2.17 to -0.50) 0.0018 -2.49 (-3.09 to -1.89) -0.87 (-1.71 to -0.03) 0.0425 -1.62 (-2.21 to -1.03) CI = confidence interval. ETD = estimated treatment difference. HbA 1c = glycated haemoglobin. LSM = least square mean. SMBG = self-monitoring of blood glucose. Prespecified sensitivity analyses all supported the conclusions of the primary analysis for the primary efficacy endpoint, showing similar and significant ETDs with both 0.6 and 1.2 mg ecnoglutide versus placebo ( Supplementary Fig. 3 ). Subgroup analysis also showed that both 0.6 and 1.2 mg ecnoglutide consistently reduced HbA 1c versus placebo to a larger extent across subgroups stratified by sex, age, baseline HbA 1c , and BMI ( Supplementary Fig. 4 ). Secondary outcomes At week 24, the proportion of participants who achieved HbA 1c < 7.0% was 68.1% with 0.6 mg ecnoglutide and 80.3% with 1.2 mg ecnoglutide, both significantly higher than 21.1% with placebo (p < 0.0001 for both); the proportion of participants who achieved HbA 1c ≤ 6.5% was 52.2% with 0.6 mg ecnoglutide and 76.1% with 1.2 mg ecnoglutide, both significantly higher than 12.7% with placebo (p < 0.0001 for both); the proportion of participants who achieved normoglycaemia (HbA 1c ≤ 5.7%) was 10.1% with 0.6 mg ecnoglutide and 35.2% with 1.2 mg ecnoglutide, compared to 0% with placebo ( Supplementary Table.1 ). Similarly, more participants achieved the composite endpoint of HbA 1c < 7.0% without severe hypoglycaemia and without bodyweight gain in both the 0.6 mg and 1.2 mg ecnoglutide groups than in the placebo group (58.0% and 71.8% versus 18.3%, p < 0.0001 for both) (Fig. 2 , Supplementary Table.1 ). At week 24, the LSM change (95% CI) from baseline in fasting plasma glucose (FPG) was − 2.89 mmol/L (-3.24 to -2.53) with 0.6 mg ecnoglutide, -3.32 mmol/L (-3.68 to -2.97) with 1.2 mg ecnoglutide, and − 1.21 mmol/L (-1.56 to -0.86) with placebo (Table 2 ). The ETD versus placebo was − 1.68 mmol/L (95% CI -2.17 to -1.18; p < 0.0001) with 0.6 mg ecnoglutide and − 2.11 mmol/L (95% CI -2.61 to -1.62; p < 0.0001) with 1.2 mg ecnoglutide (Fig. 2 , Table 2 ). The LSM change (95% CI) from baseline in 2h-postprandial plasma glucose was − 5.95 mmol/L (-6.69 to -5.21) with 0.6 mg ecnoglutide, -7.42 mmol/L (-8.17 to -6.67) with 1.2 mg ecnoglutide, and − 1.81 mmol/L (-2.54 to -1.08) with placebo. The ETD versus placebo was − 4.14 mmol/L (95% CI -5.18 to -3.10; p < 0.0001) with 0.6 mg ecnoglutide and − 5.61 mmol/L (95% CI -6.66 to -4.56; p < 0.0001) with 1.2 mg ecnoglutide (Table 2 ). Significantly larger reductions in mean seven-point self-monitored blood glucose (SMBG) and mean postprandial glucose excursion were also observed with 0.6 mg and 1.2 mg ecnoglutide versus placebo (p < 0.0001 for all; Fig. 2 , Table 2 ). At week 24, the LSM change (95% CI) from baseline in bodyweight was − 3.04 kg (-3.68 to -2.40) with 0.6 mg ecnoglutide, -3.21 kg (-3.84 to -2.58) with 1.2 mg ecnoglutide, and − 1.45 kg (-2.08 to -0.82) with placebo. The ETD versus placebo was − 1.59 kg (95% CI -2.48 to -0.69; p = 0.0005) with 0.6 mg ecnoglutide and − 1.76 kg (95% CI -2.65 to -0.87; p = 0.0001) with 1.2 mg ecnoglutide (Table 2 ). The cumulative distribution of change from baseline in bodyweight at week 24 is presented in Supplementary Fig. 5 . The LSM percentage change (95% CI) from baseline in bodyweight was − 4.51% (-5.43 to -3.58) with 0.6 mg ecnoglutide, -4.74% (-5.65 to -3.82) with 1.2 mg ecnoglutide, and − 2.02% (-2.92 to -1.11) with placebo. The ETD versus placebo was − 2.49% (95% CI -3.79 to -1.20; p = 0.0002) with 0.6 mg ecnoglutide and − 2.72% (95% CI -4.01 to -1.43; p < 0.0001) with 1.2 mg ecnoglutide (Table 2 ). At week 24, a bodyweight reduction of ≥ 5% from baseline was achieved by significantly more participants in the 0.6 mg and 1.2 mg ecnoglutide groups than in the placebo group (39.1% and 43.7% versus 11.3%, p = 0.0002 and p < 0.0001, respectively); more participants achieved a ≥ 10% bodyweight reduction in the 0.6 mg and 1.2 mg ecnoglutide groups than in the placebo group, although the differences were not statistically significant ( Supplementary Table.1 ). At week 24, waist circumference decreased from baseline by an LSM of 2.75 cm with 0.6 mg ecnoglutide, 3.35 cm with 1.2 mg ecnoglutide, and 1.19 cm with placebo. The ETDs versus placebo were significant for both ecnoglutide groups (Table 2 ). Hip circumference also significantly decreased from baseline with both doses of ecnoglutide versus placebo (Table 2 ). At week 24, homeostasis model assessments of β-cell function (HOMA-β) significantly increased with both doses of ecnoglutide than with placebo. homeostasis model assessments of insulin resistance HOMA-IR decreased with ecnoglutide versus increased with placebo, though the differences did not reach statistical significance. No significant changes compared to placebo were observed for fasting insulin levels for either of the ecnoglutide dose group ( Supplementary Table.1 ). At week 24, decreases from baseline in LDL cholesterol were observed with ecnoglutide groups, these changes were not significantly different from that with placebo; and significant decrease from baseline in triglycerides versus placebo was observed with 1.2 mg ecnoglutide group, not with 0.6 mg ecnoglutide ( Supplementary Table.1 ). Efficacy data at week 52 are summarised in Supplementary Table.2 . In the two groups who received ecnoglutide throughout, improvements in glycaemia control and bodyweight in the double-blind treatment period were maintained during the open-label treatment period (Fig. 2 ). In each placebo group, improvements in glycaemia control and bodyweight among other efficacy measures were observed after switching to ecnoglutide ( Supplementary Table.2 ). Safety outcomes During the double-blinded treatment period, treatment-emergent adverse events (TEAEs) occurred in 78.3% of the 0.6 mg ecnoglutide group, 77.5% of the 1.2 mg ecnoglutide group, and 63.4% of the placebo group (Table 3 ). Serious TEAEs were reported in 2.9% of the 0.6 mg ecnoglutide group, 4.2% of the 1.2 mg ecnoglutide group, and 5.6% of the placebo group. TEAEs led to premature treatment discontinuation in 1 (1.4%) participant in each treatment group (Table 3 ). No deaths occurred in any group. The most frequently reported TEAEs by system organ class were gastrointestinal, metabolic, and nutritional disorders. The most commonly reported gastrointestinal events for ecnoglutide were diarrhoea and nausea (Table 3 ). Other TEAEs with a > 5% incidence included decreased appetite, lipase increased, upper respiratory tract infection, urinary tract infection, and asthenia among others. Most adverse events in the ecnoglutide groups were mild to moderate in severity and the incidence was the highest during the dose-escalation period and decreased over time ( Supplementary Fig. 6 ). Table 3 Treatment-emergent adverse events (TEAEs) during the double-blind treatment period (safety set a ) Participants, n (%) Ecnoglutide 1.2 mg (N = 71) Ecnoglutide 0.6 mg (N = 69) Placebo (N = 71) Any TEAEs 55 (77.5%) 54 (78.3%) 45 (63.4%) Treatment-related 44 (62.0%) 40 (58.0%) 20 (28.2%) Grade ≥ 3 TEAEs 5 (7.0%) 3 (4.3%) 20 (28.2%) Treatment-related 3 (4.2%) 1 (4.1%) 0 Serious TEAEs 3 (4.2%) 2 (2.9%) 4 (5.6%) Treatment-related 1 (1.4%) 0 0 TEAEs leading to treatment discontinuation 1 (1.4%) 1 (1.4%) 1 (1.4%) TEAEs leading to death 0 0 0 TEAEs occurring in ≥ 5% of participants in any treatment group (preferred term) Decreased appetite 19 (26.8%) 15 (21.7%) 3 (4.2%) Asthenia 10 (14.1%) 1 (1.4%) 2 (2.8%) Lipase increased 9 (12.7%) 8 (11.6%) 2 (2.8%) Nausea 9 (12.7%) 5 (7.2%) 7 (9.9%) diarrhoea 8 (11.3%) 17 (24.6%) 4 (5.6%) Abdominal distension 6 (8.5%) 3 (4.3%) 1 (1.4%) Dizziness 5 (7.0%) 2 (2.9%) 0 Upper respiratory tract infection 5 (7.0%) 7 (10.1%) 3 (4.2%) Sinus tachycardia 4 (5.6%) 1 (1.4%) 1 (1.4%) Hyperlipidaemia 2 (2.8%) 3 (4.3%) 5 (7.0%) Urine leukocyte positive 2 (2.8%) 2 (2.9%) 5 (7.0%) Anaemia 1 (1.4%) 4 (5.8%) 2 (2.8%) Flatulence 1 (1.4%) 0 4 (5.6%) Urinary tract infection 1 (1.4%) 6 (8.7%) 7 (9.9%) TEAEs of special interests 36 (50.7%) 37 (53.6%) 20 (28.2%) Hypoglycaemia (blood glucose < 3.9 mmol/L) 4 (5.6%) 2 (2.9%) 1 (1.4%) Hypoglycaemia (blood glucose < 3.0 mmol/L) 0 0 0 Severe hypoglycaemia 0 0 0 Note: a The safety set comprised all participants who received ≥ 1 dose of study treatment and safety evaluation after treatment initiation. Hypoglycaemia (identified via scheduled laboratory visit) was reported in 2 (2.9%) participants in the 0.6 mg ecnoglutide group, 5 (5.6%) in the 1.2 mg ecnoglutide group, and 1 (1.4%) in the placebo group (Table 3 ). No severe hypoglycaemia, pancreatitis, or gallbladder-related disorders were reported with ecnoglutide in this study. Elevated lipase and amylase levels were reported by more participants in the ecnoglutide groups (11.6%/4.3% in the 0.6 mg group and 12.7%/2.8% in the 1.2 mg group) than in the placebo group (2.8%/0). These elevations did not appear to be dose-related ( Supplementary Fig. 8 ), and were not associated with clinical symptoms or signs, pancreatitis, or hepatic disorders. Pulse rate increased by a mean of 3.0 beats/min with ecnoglutide 0.6 mg and 5.4 beats/min with 1.2 mg ecnoglutide versus a mean decrease of 1.6 beats/min with placebo at week 24. Mean systolic blood pressure decreased by 4.4 mmHg with 0.6 mg ecnoglutide and a mean of 5.2 mmHg with 1.2 mg ecnoglutide versus 2.1 mmHg with placebo. Changes in diastolic blood pressure from baseline were similar across the three groups at week 24 ( Supplementary Tables.3 ). During the open-label period, the proportions of participants reporting TEAEs in the two ecnoglutide groups were lower than their counterparts in the double-blind period, and the incidences of TEAEs in the two groups switching from placebo to ecnoglutide were similar to what was reported by the two ecnoglutide groups in the double-blind period ( Supplementary Table.4 ). Across the four treatment groups, gastrointestinal disorders were still the most frequently reported events, which were mostly transient, and mild to moderate in severity. No pancreatitis or severe hypoglycaemic events were reported. DISCUSSION In this phase 3 trial, compared with placebo, once-weekly injections of ecnoglutide at doses of 1.2 mg and 0.6 mg demonstrated significant improvement in glycaemic control in participants with T2DM inadequately controlled with diet and exercise alone or with a single oral hypoglycaemic agent. Both doses of ecnoglutide were superior to placebo in reducing HbA 1c , without increasing the risk of hypoglycaemia. Reductions in HbA 1c were observed by the first study assessment at week 4 and sustained until the end of treatment at week 52. The magnitude of the reductions in HbA 1c observed for ecnoglutide was dose-dependent. At week 24, up to 80.3% in the 1.2 mg ecnoglutide group and 68.1% in the 0.6 mg ecnoglutide group versus 21.1% in the placebo group reached the HbA 1c target of < 7.0% as recommended by the American Diabetes Association (ADA) 19 , and up to 35.2% of participants in the 1.2 mg ecnoglutide group reached normoglycaemia (HbA 1c < 5.7%). More importantly, the proportion of participants who achieved the composite endpoint of HbA 1c < 7.0% without severe glycaemia and without bodyweight gain was also significantly higher in the ecnoglutide groups than in the placebo group at week 24 (71.8% with 1.2 mg and 58.0% with 0.6 mg versus 18.3% with placebo). The beneficial effect on glycaemic control was further supported by the significant improvements in FPG, 2-h postprandial plasma glucose (2h-PPG), 7-Point SMBG profiles, and the β cell function. These results agree to the findings in the phase 2 trial of ecnoglutide in participants with T2DM that was uncontrolled with diet, exercise, or single oral glucose-lowering medication. 18 In this phase 2 study, the HbA 1c target of < 7.0% was achieved in 84% on ecnoglutide 1.2 mg and 68% on ecnoglutide 0.8 mg versus 21% on placebo at week 20. Although indirect cross-trial comparisons should be viewed with caution due to differences in trial designs, populations, and analysis methods, ecnoglutide showed comparable or greater HbA 1c reductions versus other GLP-1 based therapies including selective GLP-1 receptor agonists dulaglutide and semaglutide as well as the dual GIP/GLP1 receptor agonist tirzepatide. The decreases from baseline in HbA 1c were 1.96% and 2.43% with ecnoglutide (0.6 mg and 1.2 mg at week 24) in the current study, compared to 1.25% and 1.46% for dulaglutide (0.75 mg and 1.5 mg at week 26) in the Chinese subgroup of an East Asian trial, 1.45% and 1.55% with semaglutide (0.5 mg and 1.0 mg at week 30) in SUSTAIN-1 among global participants, and 1.87%, 1.89%, and 2.07% for tirzepatide (5 mg, 10 mg, and 15 mg at week 40) in SURPASS-1 among global participants. 8 , 9 , 20 The greater decreases with ecnoglutide compared with semaglutide and dulaglutide may be largely attributed to the fact that ecnoglutide is a cAMP signalling biased GLP-1 analogue, which is anticipated to have enhanced efficacy than unbiased GLP-1 receptor agonists like semaglutide and dulaglutide. A preclinical study has showed that at the same dose level, ecnoglutide significantly reduced blood glucose and HbA 1c more than semaglutide. 16 Ecnoglutide showed comparable but slightly greater HbA 1c reductions compared with the dual GIP/GLP-1 receptor agonist tirzepatide, which also favours the cAMP signalling pathway. In addition to glycaemic effects, significant and sustained bodyweight reductions were observed over 52 weeks of treatment with ecnoglutide. The average bodyweight loss was 3.04 and 3.21 kg for ecnoglutide in the current study, compared to 1.0 and 1.5 kg for dulaglutide (0.75 and 1.5 mg at week 26) in the Chinese subgroup of the East Asian trial, and 3.73 and 4.53 kg for semaglutide (0.5 and 1.0 mg at week 30) in SUSTAIN-1. 8 , 20 More importantly, at week 24, 39.1–43.7% in the ecnoglutide groups versus 11.3% in the placebo group achieved a bodyweight loss of ≥ 5%, the ADA-recommended target. 21 Favourable changes in waist and hip circumferences with ecnoglutide versus placebo were also observed at week 24, providing further evidence for the beneficial effects of ecnoglutide in bodyweight management. In addition, favourable changes in systolic blood pressure, lipids, and insulin sensitivity were observed with ecnoglutide, suggesting potential cardiovascular benefits. The observed safety profile of ecnoglutide in this study population was consistent with the known class effects of GLP-1 receptor agonists, with transient, mild to moderate gastrointestinal events as the most frequently reported TEAEs. Gastrointestinal adverse events mainly occurred in the dose escalation period and diminished over time. No new safety signals were detected in this study. No cases of severe hypoglycaemia were reported throughout the study. Slight increases in pulse rate were noted for ecnoglutide in this study, which were consistent with observations for other GLP-1 receptor agonists. 8 , 9 , 22 Both doses of ecnoglutide were well-tolerated, which was evident in the very low rate of treatment discontinuation. Only 1.4% of participants in the two groups discontinued ecnoglutide due to TEAEs. This study has several strengths, including the randomised, placebo-controlled design with the use of a volume-matched placebo for masking within each dose and a switch-over design to allow for minimised exposure to placebo treatment and long-term efficacy evaluation. Additionally, a relatively high proportion of participants completed the study, giving fairly complete data. This study also has limitations. Firstly, it was conducted in China only, so the observed findings may not be fully translatable to other ethnic/racial populations. However, since GLP-1 receptor agonists have been shown to be efficacious in both Asian and non-Asian populations, 23 similar efficacy and safety of ecnoglutide are expected in non-Asian populations as well. Secondly, although the trial duration was sufficiently long to assess the primary and secondary endpoints, the long-term impact of ecnoglutide on cardiovascular and renal outcomes require longer studies to assess fully. This study observed a good placebo effect in efficacy measures such as changes from baseline in HbA 1c , FPG, and bodyweight, similar to the placebo effects observed in another reported phase 3 trial conducted in China. 24 This placebo effect might be due to the relatively shorter diabetic history and more treatment-naive participants in the placebo group, which may contribute to more responsiveness to therapy. This effect could also be due to randomisation, participants’ adherence to treatment as well as guidance from their healthcare professionals, and participants’ continued lifestyle modifications during the trial. Another phase 3 study is being conducted to assess the long-term efficacy and safety of ecnoglutide as an add-on to metformin in patients with T2DM (NCT05680129). In conclusion, ecnoglutide, a cAMP signalling-biased GLP-1 receptor agonist, administered at doses of 0.6 and 1.2 mg once weekly as monotherapy for T2DM, significantly improved glycaemic control, with up to 35.2% of participants achieving normoglycaemia, and robustly reduced bodyweight versus placebo, without increasing the risk of severe hypoglycaemia. Ecnoglutide was well-tolerated, with a very low rate of treatment discontinuation and a safety profile consistent with other GLP-1 receptor agonists. The favourable efficacy and safety profiles indicate that ecnoglutide is a promising initial treatment option for T2DM early in the course of the disease. METHODS Study design We conducted a randomised, double-blind, placebo-controlled, phase 3 trial across 32 sites in China. This trial was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice Guidelines, and all applicable local laws and regulations. This study protocol was approved by institutional review boards or ethics committees of all participating sites and written informed consent was obtained from all participants prior to study entry. The study comprised 2-week screening, 4-week run-in, 24-week double-blind core treatment, 28-week open-label extended treatment, and 5-week safety follow-up ( Supplementary Fig. 8 ). Participants were randomly assigned (2:2:1:1) to receive once-weekly subcutaneous injections of ecnoglutide (0.6 or 1.2 mg) or volume-matched placebo (0.6 or 1.2 mg), with stratification according to baseline HbA 1c (≤ 8.5% or > 8.5%), via an interactive web response system. All investigators, participants, and the sponsor remained blinded to treatment assignment. Placebo and active drug were provided in injector pens, identical in appearance. After a 2-week screening and 4-week run-in period, participants were re-assessed for eligibility. Eligible participants received once weekly subcutaneous injections of study drugs in a double-blind manner for 24 weeks. At the end of 24 weeks, participants were unblinded one by one and all switched to open-label treatment. They either continued to receive ecnoglutide at the respective maintenance doses or started receiving ecnoglutide for 28 weeks, followed by a 5-week safety follow-up period. Study drug was administered once weekly via subcutaneous injection using injector pens with a pre-set volume, following a slow dose-escalation regimen, starting at 0.3 mg (equivalent to 0.15 mL injection) with fixed double-dose increments every 4 weeks until the allocated maintenance dose was reached. The maintenance doses of 0.6 and 1.2 mg were reached at 4 and 8 weeks in respective ecnoglutide groups. Participants who switched from placebo to ecnoglutide during the open-label treatment period underwent the same dose-escalation procedure. If intolerable symptoms or events occurred and persisted, a lower tolerated dose could be used at the investigator’s discretion. More details on the dosing regimen are available in the supplementary (p 2–3). Initiation of new antihyperglycemic medications, with metformin as the first choice, was only allowed for rescue therapy for persistent hyperglycaemia on the basis of prespecified criteria ( supplementary , p 4). Participants Key inclusion criteria included adults aged 18–75 years (inclusive) with T2DM inadequately controlled with diet and exercise alone or with only one oral hypoglycaemic agent. Eligible participants had a BMI of 20.0–35.0 kg/m² (inclusive), an HbA 1c level of 7.5–11.0% (inclusive) at screening, and an HbA 1c level of 7.0–10.5% (inclusive) at randomisation, and a FPG level of ≤ 13.9 mmol/L at both screening and randomisation. Participants were excluded if they had type 1 diabetes mellitus or other diabetes mellitus, received any GLP-1 drug or dipeptidyl peptidase-4 inhibitor within the preceding 3 months or insulin within the preceding 6 months (except for the ≤ 14-day use of insulin for co-morbidities), or experienced diabetic ketoacidosis, hyperosmolar hyperglycaemic state, lactic acidosis in diabetes, or severe chronic complications of diabetes within the prior 6 months. Full list of eligibility criteria is provided in the supplementary (p 3–4). Study endpoints and assessments The primary efficacy endpoint was change from baseline in HbA 1c at week 24, assessed by the central laboratory. The secondary efficacy endpoints included proportions of participants who achieved an HbA 1c level of < 7.0% and ≤ 6.5% at weeks 24 and 52; proportion of participants who achieved a composite endpoint of HbA 1c < 7.0%, no severe hypoglycaemia, and no bodyweight gain at week 24; changes from baseline at weeks 24 and 52 in FPG, 2h-PPG, seven-point SMBG profiles, fasting insulin, HOMA-β and HOMA-IR, blood lipids, bodyweight, waist circumference, and hip circumference. Safety endpoints included the incidences of TEAEs, serious TEAEs, and TEAEs of special interest (hypoglycaemia, cardiovascular events, gastrointestinal events, pancreatitis, and gallbladder-related disorders). Other safety measurements included vital signs, physical examinations, 12-lead electrocardiograms (ECG), and laboratory assessments. Statistical analyses The study was designed to establish superiority for each dose of ecnoglutide versus placebo for the primary endpoint at week 24. The sample size calculation assumed at least a -1.2% difference in mean change from baseline in HbA 1c at week 24 between ecnoglutide groups and the pooled placebo group, a common SD of 1.1%, and a drop-out rate of 20%. A sample size of 210 participants provided at least 90% power to establish superiority for an ecnoglutide dose compared with placebo (superiority margin of 0.5%) at a one-sided significance level of 0.025. Full details of type I error control strategy are provided in the supplementary (p 5). Efficacy analyses were performed in the FAS, comprised all randomised participants who received ≥ 1 dose of study treatment. Safety analyses were conducted in the safety set, comprising all participants who received ≥ 1 dose of study treatment and safety evaluation after treatment initiation. The primary efficacy endpoint was evaluated using two estimands. For the primary efficacy estimand, the treatment policy strategy was used to assess the treatment effect between ecnoglutide and placebo among all randomised participants regardless of intercurrent events (early treatment discontinuation and rescue therapy). For the secondary efficacy estimand, the hypothetical strategy was used to assess the treatment effect between ecnoglutide and placebo among all participants without intercurrent events, i.e., data collected after intercurrent events were excluded from analysis. For the primary endpoint analysis, a mixed model for repeated measures (MMRM) was used, in which the change from baseline in HbA 1c was used as the dependent variable, categorical baseline HbA 1c level, visit time points, treatment grouping, and treatment by visit interaction were used as the explanatory variables. The model was used to calculate covariate-adjusted mean change from baseline in HbA 1c of each group at week 24 and its standard error, its 95% confidence interval (CI), as well as inter-group mean difference between each ecnoglutide group and the placebo group and its 95% CI. For missing HbA 1c values at week 24 in participants who experienced intercurrent events, imputation was performed using the retrieved dropout-based multiple imputation, or the missing at random approach if the former was not appropriate. Prespecified sensitivity analyses were conducted to assess the robustness of results for the primary endpoint by the use of alternative data selections and methods for handling missing data, including analysis of covariance (ANCOVA), which considered baseline HbA 1c and treatment group as exploratory variables, and the jump to reference (J2R) assumption, in which missing data was imputed based on the reference group data. Subgroup analysis was also conducted for the primary endpoint. For the analysis of the secondary efficacy endpoints, change from baseline in FPG at week 24, and change and percentage change from baseline in bodyweight at week 24 were analysed by strategies and methods consistent to those for the primary endpoint. The proportions of participants who achieved prespecified targets of bodyweight loss or HbA 1c reductions were analysed and compared using the logistic regressions and the 95% CIs for these proportions were calculated using the Clopper-Pearson method, with missing data imputed using the non-response imputation method. Results for the other secondary efficacy endpoints were summarised descriptively without data imputation. Safety endpoints were summarised descriptively by the use of data for all randomised participants who received at least one dose of study drug (safety set). Statistical analyses were performed using SAS version 9.4. See Protocol for extended statistical methods. This study was registered with both ClinicalTrials.gov (NCT05680155) and China Drug Trials Registry ( www.chinadrugtrials.org.cn , CTR20223156). Reproting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Declarations Competing Interests D. Z., W. W., G. T., J. M., B. W., X. Z., B. S., S. P., K. W., X. S., X. Z., L. F., Y. L., Y. L., D. H., C. J., T. P., H. X., J. H., H. D. received funding from Sciwind Biosciences to their institutions as trial investigators. S. B., F. J., Q. Z., M. Y., L. G., X. L., Y. B., M. G., J. N., L. Y., W. G., Y. L., H. P. are employees of Hangzhou Sciwind Biosciences. S X. is an employee of Sciwind Biosciences. Author Contributors D. Z., W. W., H. P., Y. L., S. X., S. B., Q. Z., J. N., L. Y., W. G., L. G., X. L., Y. B., M. G., G. T., J. M., B. W., X. Z., B. S., S. P., K. W., X. S., X. Z., L. F., Y. L., Y. L., D. H., C. J., T. P., H. X., J. H., and H. D. designed and performed the study. D. Z., H. P., M. Y., S. X., S. B., Q. Z., and F. J. analysed and interpreted the data. D. Z., S. B., and S. X. drafted the manuscript. All authors approved the final submitted paper. Acknowledgements We thank the participants, the investigators and their teams who took part in this study. This study was funded by Hangzhou Sciwind Biosciences Co., Ltd. The study sponsor was involved in study design and protocol development and responsible for data collection, data analysis, data interpretation, and writing of the report. The decision to submit the report for publication was made by all authors, who had full access to the data. Part of the data from this study were presented at the American Diabetes Association’s 84th Scientific Sessions, June 2024. Data availability The full dataset and protocol are not publicly available due to data privacy laws and contractual obligations. Sciwind Biosciences will provide de-identified individual participant data underlying the reported results upon request. Data are available after acceptance of this article with no expiration of data requests currently set. Requests should be made by contacting corresponding authors and will be evaluated within 6 months of receipt. Access will be provided after the proposed use of the data has been approved by a review committee and receipt of a signed data access agreement with Sciwind Biosciences. Code availability Code supporting this Article is available within the Supplementary Information. References Collaborators GD (2023) Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. 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Circulation 146:1882–1894 Granata A, Maccarrone R, Anzaldi M et al (2022) GLP-1 receptor agonists and renal outcomes in patients with diabetes mellitus type 2 and diabetic kidney disease: state of the art. Clin Kidney J 15:1657–1665 Holst JJ (2024) GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management. Nat Metab 6:1866–1885 American Diabetes Association Professional Practice Committee (2024) 9. Pharmacologic approaches to glycemic treatment: Standards of care in diabetes – 2024. Diabetes Care 47:S158–S178 Davies MJ, Aroda VR, Collins BS et al (2022) Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). 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JCI Insight 5:e140532 Zhu D, Wang W, Tong G et al (2024) Efficacy and safety of GLP-1 analog ecnoglutide in adults with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 2 trial. Nat Commun 15:8408 American Diabetes Association Professional Practice Committee. 6. Glycemic goals and hypoglycemia: Standards of care in diabetes – 2024. Diabetes Care. 47, S111-S125 (2024) Shi LX, Liu XM, Shi YQ et al (2020) Efficacy and safety of dulaglutide monotherapy compared with glimepiride in Chinese patients with type 2 diabetes: Post-hoc analyses of a randomized, double-blind, phase III study. J Diabetes Investig. 11, 142 – 50 American Diabetes Association Professional Practice Committee. 8. Obesity and weight management for the prevention and treatment of type 2 diabetes: Standards of care in diabetes – 2024. Diabetes Care. 47, S145-S157 (2024) Wysham C, Blevins T, Arakaki R et al (2014) Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care 37:2159–2167 Gan S, Dawed AY, Donnelly LA et al (2020) Efficacy of modern diabetes treatments DPP-4i, SGLT-2i, and GLP-1RA in White and Asian patients with diabetes: A systematic review and meta-analysis of randomized controlled trials. Diabetes Care 43:1948–1957 Yan X, Ma J, Liu Y et al (2024) Efficacy and safety of visepegenatide, a long-acting weekly GLP-1 receptor agonist as monotherapy in type 2 diabetes mellitus: a randomised, double-blind, parallel, placebo-controlled phase 3 trial. Lancet Reg Health West Pac 7:101101 Supplementary Material The Supplementary Figures and Tables are not available with this version. Additional Declarations Yes there is potential Competing Interest. D. Z., W. W., G. T., J. M., B. W., X. Z., B. S., S. P., K. W., X. S., X. Z., L. F., Y. L., Y. L., D. H., C. J., T. P., H. X., J. H., H. D. received funding from Sciwind Biosciences to their institutions as trial investigators. S. B., F. J., Q. Z., M. Y., L. G., X. L., Y. B., M. G., J. N., L. Y., W. G., Y. L., H. P. are employees of Hangzhou Sciwind Biosciences. S X. is an employee of Sciwind Biosciences. Supplementary Files StatisticalAnalysisPlan.docx Statistical Analysis Plan CONSORTchecklist.doc CONSORT checklist Clinicaltrialprotocol.docx Clinical trial protocol Cite Share Download PDF Status: Published Journal Publication published 07 Jan, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Yang","email":"","orcid":"","institution":"Hangzhou Sciwind Biosciences Co., Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Liu","middleName":"","lastName":"Yang","suffix":""},{"id":451075573,"identity":"8f5a2ff6-abe4-4100-93cc-e9e5bff946ac","order_by":30,"name":"Wanjun Guo","email":"","orcid":"","institution":"Hangzhou Sciwind Biosciences Co., Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Wanjun","middleName":"","lastName":"Guo","suffix":""},{"id":451075574,"identity":"bf0a6a02-c806-454f-9e8b-e9ad0e4baf9a","order_by":31,"name":"Yao Li","email":"","orcid":"","institution":"Sciwind Biosciences","correspondingAuthor":false,"prefix":"","firstName":"Yao","middleName":"","lastName":"Li","suffix":""},{"id":451075575,"identity":"d66581e4-1d95-4ba8-a015-86401862912b","order_by":32,"name":"Susan Xu","email":"","orcid":"","institution":"Sciwind Biosciences","correspondingAuthor":false,"prefix":"","firstName":"Susan","middleName":"","lastName":"Xu","suffix":""},{"id":451075576,"identity":"97f1d132-5ac4-4491-a15a-43bd184d5836","order_by":33,"name":"Hai Pan","email":"","orcid":"","institution":"Sciwind Biosciences","correspondingAuthor":false,"prefix":"","firstName":"Hai","middleName":"","lastName":"Pan","suffix":""}],"badges":[],"createdAt":"2025-03-31 08:20:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6342890/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6342890/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-68165-7","type":"published","date":"2026-01-07T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83291884,"identity":"e609b1b3-8160-4c45-8fd0-b27ac603cebf","added_by":"auto","created_at":"2025-05-22 13:14:02","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":98215,"visible":true,"origin":"","legend":"\u003cp\u003eTrial profile\u003c/p\u003e\n\u003cp\u003eNotes: \u003csup\u003ea\u003c/sup\u003eOne participant who had a pre-dose adverse event during the run-in period and was not randomised. \u003csup\u003eb\u003c/sup\u003eThree participants who did not enter open-label study after 24 weeks of the double-blind treatment due to rescue therapy were considered as completing the trial according to the protocol. \u003csup\u003ec\u003c/sup\u003eOne participant discontinued treatment because of decreased appetite.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6342890/v1/138565f3a65fb3cb2ddaf898.jpg"},{"id":83292941,"identity":"057ecc72-1f8c-4386-b32f-39f73cb74ed2","added_by":"auto","created_at":"2025-05-22 13:22:02","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":120478,"visible":true,"origin":"","legend":"\u003cp\u003eEfficacy outcomes of 0.6 mg and 1.2 mg ecnoglutide once weekly versus placebo at weeks 24 and 52\u003c/p\u003e\n\u003cp\u003eData are LSM (SE), unless otherwise noted. Estimated treatment differences are LSM (95% CI) at week 24 (full analysis set). (A) Change from baseline in HbA\u003csub\u003e1c \u003c/sub\u003eover time from MMRM analysis. (B) Change from baseline in HbA\u003csub\u003e1c\u003c/sub\u003e at week 24 from MMRM analysis. (C) Proportion of participants reaching HbA\u003csub\u003e1c\u003c/sub\u003e targets (\u0026lt;7.0%, ≤6.5%, and \u0026lt;5.7%) and the composite endpoint (HbA\u003csub\u003e1c\u003c/sub\u003e\u0026lt;7.0%, no severe hypoglycaemia, and no bodyweight gain) from logistic regression analysis. (D) Change from baseline in FPG over time from MMRM analysis. (E) Seven-point SMBG profiles at baseline and week 24. (F) Change from baseline in bodyweight over time from MMRM analysis. CI=confidence interval. FPG=fasting plasma glucose. HbA\u003csub\u003e1c\u003c/sub\u003e=glycated haemoglobin. LSM=least squares mean. MMRM=mixed model repeated measures. SE=standard error. SMBG=self-monitored blood glucose.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6342890/v1/50a61e4c1e3dc828083691c8.jpg"},{"id":102094983,"identity":"d2fffe50-1fef-4fa2-8046-b4723c09ce52","added_by":"auto","created_at":"2026-02-07 08:11:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1480260,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6342890/v1/a349fd4d-067e-4cd5-9428-92254e6a0f7a.pdf"},{"id":83291887,"identity":"56b48e13-c7f8-46a5-bf14-24c5a98f50d9","added_by":"auto","created_at":"2025-05-22 13:14:02","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":230673,"visible":true,"origin":"","legend":"Statistical Analysis Plan","description":"","filename":"StatisticalAnalysisPlan.docx","url":"https://assets-eu.researchsquare.com/files/rs-6342890/v1/d3ef56968500045ab15165b3.docx"},{"id":83291886,"identity":"9a9a2ba6-dc73-4ef9-87f7-5b6a588efc2c","added_by":"auto","created_at":"2025-05-22 13:14:02","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":235008,"visible":true,"origin":"","legend":"CONSORT checklist","description":"","filename":"CONSORTchecklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-6342890/v1/bedab7ef34111b2619bc65bb.doc"},{"id":83292942,"identity":"de3415a8-6454-4e93-9976-c154783600ee","added_by":"auto","created_at":"2025-05-22 13:22:02","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1157445,"visible":true,"origin":"","legend":"Clinical trial protocol","description":"","filename":"Clinicaltrialprotocol.docx","url":"https://assets-eu.researchsquare.com/files/rs-6342890/v1/d4916258a1c3f28a4dab37b7.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nD. Z., W. W., G. T., J. M., B. W., X. Z., B. S., S. P., K. W., X. S., X. Z., L. F., Y. L., Y. L., D. H., C. J., T. P., H. X., J. H., H. D. received funding from Sciwind Biosciences to their institutions as trial investigators. S. B., F. J., Q. Z., M. Y., L. G., X. L., Y. B., M. G., J. N., L. Y., W. G., Y. L., H. P. are employees of Hangzhou Sciwind Biosciences. S X. is an employee of Sciwind Biosciences.","formattedTitle":"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","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eType 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.\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e-\u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e The goal of T2DM management is to reduce the risk of\u0026nbsp;associated\u0026nbsp;complications through\u0026nbsp;optimal\u0026nbsp;glycaemic control. Despite a wide range of available treatment options, a large proportion of patients still cannot achieve glycated haemoglobin\u0026nbsp;(HbA\u003csub\u003e1c\u003c/sub\u003e) treatment targets.\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e Furthermore,\u0026nbsp;glycaemic management should consider\u0026nbsp;minimising undesired effects\u0026nbsp;such as\u0026nbsp;hypoglycaemia\u0026nbsp;and bodyweight gain,\u003csup\u003e6\u003c/sup\u003e which has proven to be challenging with traditional glucose-lowering medications.\u003c/p\u003e\n\u003cp\u003eThe 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.\u003csup\u003e7\u003c/sup\u003e\u003csup\u003e-\u003c/sup\u003e\u003csup\u003e9\u003c/sup\u003e Apart from glycaemic control, GLP-1 receptor agonists provide other\u0026nbsp;clinical\u0026nbsp;benefits,\u0026nbsp;including\u0026nbsp;bodyweight loss, cardiovascular\u0026nbsp;risk reduction, and improvement in\u0026nbsp;renal outcomes\u0026nbsp;among others.\u003csup\u003e10\u003c/sup\u003e\u003csup\u003e-\u003c/sup\u003e\u003csup\u003e12\u003c/sup\u003e Therefore, they are\u0026nbsp;an effective treatment option for T2DM and have been\u0026nbsp;recommended\u0026nbsp;by various guidelines.\u003csup\u003e13\u003c/sup\u003e\u003csup\u003e-\u003c/sup\u003e\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eEcnoglutide, 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.\u003csup\u003e16\u003c/sup\u003ecAMP bias is hypothesised to enhance the clinical efficacy of GLP-1 receptor agonists\u0026nbsp;through reducing internalisation of the GLP-1 receptor and enhancing insulin secretion.\u003csup\u003e17\u003c/sup\u003e In a preclinical study,\u0026nbsp;ecnoglutide\u0026nbsp;showed a\u0026nbsp;stronger\u0026nbsp;binding affinity\u0026nbsp;towards the GLP-1 receptor\u0026nbsp;and\u0026nbsp;more\u0026nbsp;potent efficacy\u0026nbsp;in reducing blood glucose and bodyweight than semaglutide, an unbiased\u0026nbsp;GLP-1\u0026nbsp;receptor agonist.\u003csup\u003e16\u003c/sup\u003e In phase 1 trials among healthy volunteers, once-weekly injections\u0026nbsp;of ecnoglutide\u0026nbsp;exhibited favourable\u0026nbsp;safety\u0026nbsp;and\u0026nbsp;tolerability\u0026nbsp;profiles and a half-life ranging from 124 to 138 h, indicating its potential as a long-acting regimen.\u003csup\u003e16\u003c/sup\u003e In a phase 2 trial among\u0026nbsp;individuals with T2DM, once-weekly injections\u0026nbsp;of ecnoglutide\u0026nbsp;at doses of 0.4, 0.8, and 1.2 mg resulted in more pronounced\u0026nbsp;improvements\u0026nbsp;versus placebo\u0026nbsp;in glycaemic control and bodyweight, supporting its potential as a treatment option for T2DM.\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eHere 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.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy participants\u003c/h2\u003e\n \u003cp\u003eBetween 29 December 2022 and 12 June 2024, 300 participants were assessed for eligibility and 211 of them were randomly assigned to receive 0.6 mg ecnoglutide (n\u0026thinsp;=\u0026thinsp;69), 1.2 mg ecnoglutide (n\u0026thinsp;=\u0026thinsp;71), placebo volume-matched to 0.6 mg ecnoglutide (n\u0026thinsp;=\u0026thinsp;36), or placebo volume-matched to 1.2 mg ecnoglutide (n\u0026thinsp;=\u0026thinsp;35) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). All randomised participants received\u0026thinsp;\u0026ge;\u0026thinsp;1 dose of the assigned treatment, and 9 (4%) of them discontinued treatment prematurely in the double-blind period, including 3 from the 0.6 mg ecnoglutide group, 4 from the 1.2 mg ecnoglutide group, and 2 from the placebo group. Out of the 211 randomised participants, 195 (92.4%) entered the open-label period and received treatment with ecnoglutide (0.6 or 1.2 mg) and 5 (2.6%) of them discontinued treatment prematurely, including 2 from the 0.6 mg ecnoglutide group and 3 from the 1.2 mg ecnoglutide group. Across the two periods, the reasons for treatment discontinuation included physicians\u0026rsquo; decisions and participants\u0026rsquo; own requests among others. Time to study drug discontinuation is shown in Kaplan-Meier plots in \u003cstrong\u003eSupplementary Fig.\u0026nbsp;1\u003c/strong\u003e.\u003c/p\u003e\n \u003cp\u003eDuring the double-blind treatment period, 3 participants in the placebo group received rescue therapy because of hyperglycaemia, and none in the ecnoglutide groups required rescue therapy. During the open-label treatment period, 3 participants, with one each from the two ecnoglutide groups and the 0.6 mg placebo group, required rescue therapy because of hyperglycaemia.\u003c/p\u003e\n \u003cp\u003eAll 211 participants were included in full analysis set (FAS) and safety set.\u003c/p\u003e\n \u003cp\u003eBaseline characteristics were similar across the three groups (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). At baseline, the mean standard deviation (SD) age was 52.0 (10.9) years, 127 (60.2%) were male, with an average (SD) of 8.52% (0.81) for HbA\u003csub\u003e1c\u003c/sub\u003e, 26.93 kg/m\u003csup\u003e2\u003c/sup\u003e (3.40) for body mass index (BMI), and 3.58 years (3.78) for T2DM duration.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline characteristics (full analysis set)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEcnoglutide\u003c/p\u003e\n \u003cp\u003e1.2 mg\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;71)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEcnoglutide\u003c/p\u003e\n \u003cp\u003e0.6 mg\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;69)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;71)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;211)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52.5 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52.1 (10.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51.4 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52.0 (10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (39%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (37%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (61%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39 (57%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e127 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBodyweight (kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71.53 (12.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e74.25 (15.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73.69 (11.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73.14 (12.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeight (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e165.30 (8.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e164.83 (9.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e165.22 (9.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e165.12 (9.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.35 (3.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.23 (3.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.23 (3.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.93 (3.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWaist circumference (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e93.26 (8.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e94.02 (10.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e94.60 (8.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e93.96 (9.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiabetes duration (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.66 (3.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.10 (4.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.00 (3.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.58 (3.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior antihyperglycemic medication use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e102 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHbA\u003csub\u003e1c\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIn %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.51 (0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.54 (0.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.51 (0.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.52 (0.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIn mmol/mol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69.51 (9.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69.84(8.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69.51 (8.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69.62 (8.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;8.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (54%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e111 (53%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;8.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFasting plasma glucose (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.67 (1.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.67 (1.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.81 (1.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.72 (1.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eeGFR\u003csub\u003eMDRD\u003c/sub\u003e (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e124.7 (35.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e122.0 (29.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e113.5 (25.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e120.0 (30.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eNotes: Data are mean (SD) or n (%). Data are for all randomised participants. N\u0026thinsp;=\u0026thinsp;all randomly assigned participants who took at least one dose of study drug. BMI\u0026thinsp;=\u0026thinsp;body mass index. eGFR\u003csub\u003eMDRD\u003c/sub\u003e=estimated glomerular filtration rate based on the Modification of Diet in Renal Disease equation. HbA\u003csub\u003e1c\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;glycated haemoglobin.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003ePrimary outcome\u003c/h2\u003e\n \u003cp\u003eThe primary endpoint was met, and both doses of ecnoglutide significantly reduced HbA\u003csub\u003e1c\u003c/sub\u003e more than placebo for both primary and secondary efficacy estimands. At week 24, the least squares mean (LSM) change (95% CI) from baseline in HbA\u003csub\u003e1c\u003c/sub\u003e as per the treatment policy estimand was \u0026minus;\u0026thinsp;1.96% (-2.18 to -1.73) with 0.6 mg ecnoglutide, -2.43% (-2.65 to -2.20) with 1.2 mg ecnoglutide, and \u0026minus;\u0026thinsp;0.87% (-1.09 to -0.65) with placebo (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The estimated treatment difference (ETD) versus placebo was \u0026minus;\u0026thinsp;1.09% (95% CI -1.40 to -0.77; p\u0026thinsp;=\u0026thinsp;0.0003) with 0.6 mg ecnoglutide and \u0026minus;\u0026thinsp;1.56% (95% CI -1.87 to -1.24; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) with 1.2 mg ecnoglutide (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Significantly greater decreases from baseline in HbA\u003csub\u003e1c\u003c/sub\u003e with both 0.6 mg and 1.2 mg ecnoglutide versus placebo were evident since the first assessment at week 4 (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The cumulative distribution of change from baseline in HbA\u003csub\u003e1c\u003c/sub\u003e at week 24 is presented in \u003cstrong\u003eSupplementary Fig.\u0026nbsp;2\u003c/strong\u003e. At week 24, the LSM change (95% CI) from baseline in HbA\u003csub\u003e1c\u003c/sub\u003e as per the hypothetical estimand was \u0026minus;\u0026thinsp;1.96% (-2.18 to -1.73) with 0.6 mg ecnoglutide, -2.43% (-2.65 to -2.20) with 1.2 mg ecnoglutide, and \u0026minus;\u0026thinsp;0.85% (-1.07 to -0.62) with placebo. The ETD versus placebo was \u0026minus;\u0026thinsp;1.11% (95% CI -1.43 to -0.79; p\u0026thinsp;=\u0026thinsp;0.0002) with 0.6 mg ecnoglutide and \u0026minus;\u0026thinsp;1.58% (95% CI -1.90 to -1.26; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) with 1.2 mg ecnoglutide.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eEfficacy measures at week 24 (full analysis set)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"8\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eEcnoglutide 1.2 mg\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;71)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eEcnoglutide 0.6 mg\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;69)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;71)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLSM change from baseline (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eETD vs placebo\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLSM change from baseline (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eETD vs placebo\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLSM change from baseline (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHbA\u003csub\u003e1c\u003c/sub\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.43\u003c/p\u003e\n \u003cp\u003e(-2.65 to -2.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.56\u003c/p\u003e\n \u003cp\u003e(-1.87 to -1.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.96\u003c/p\u003e\n \u003cp\u003e(-2.18 to -1.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.09\u003c/p\u003e\n \u003cp\u003e(-1.40 to -0.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.87\u003c/p\u003e\n \u003cp\u003e(-1.09 to -0.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHbA\u003csub\u003e1c\u003c/sub\u003e (mmol/mol)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-50.0\u003c/p\u003e\n \u003cp\u003e(-52.44 to -47.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-17.01\u003c/p\u003e\n \u003cp\u003e(-20.43 to -13.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-44.89\u003c/p\u003e\n \u003cp\u003e(-47.34 to -42.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-11.88\u003c/p\u003e\n \u003cp\u003e(-15.32 to -8.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-33.01\u003c/p\u003e\n \u003cp\u003e(-35.42 to -30.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFasting plasma glucose (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.32\u003c/p\u003e\n \u003cp\u003e(-3.68 to -2.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.11\u003c/p\u003e\n \u003cp\u003e(-2.61 to -1.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.89\u003c/p\u003e\n \u003cp\u003e(-3.24 to -2.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.68\u003c/p\u003e\n \u003cp\u003e(-2.17 to -1.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.21\u003c/p\u003e\n \u003cp\u003e(-1.56 to -0.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2h-postprandial plasma glucose (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-7.42\u003c/p\u003e\n \u003cp\u003e(-8.17 to -6.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-5.61\u003c/p\u003e\n \u003cp\u003e(-6.66 to -4.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-5.95\u003c/p\u003e\n \u003cp\u003e(-6.69 to -5.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-4.14\u003c/p\u003e\n \u003cp\u003e(-5.18 to -3.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.81\u003c/p\u003e\n \u003cp\u003e(-2.54 to -1.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"8\"\u003e\n \u003cp\u003e7-Point SMBG (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean Glucose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.99\u003c/p\u003e\n \u003cp\u003e(-4.43 to -3.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.81\u003c/p\u003e\n \u003cp\u003e(-3.45 to -2.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.36\u003c/p\u003e\n \u003cp\u003e(-3.81 to -2.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.18\u003c/p\u003e\n \u003cp\u003e(-2.82 to -1.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.18\u003c/p\u003e\n \u003cp\u003e(-1.63 to -0.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePostprandial glucose excursion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.58\u003c/p\u003e\n \u003cp\u003e(-1.91 to -1.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.03\u003c/p\u003e\n \u003cp\u003e(-1.50 to -0.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.38\u003c/p\u003e\n \u003cp\u003e(-1.72 to -1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.83\u003c/p\u003e\n \u003cp\u003e(-1.31 to -0.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.55\u003c/p\u003e\n \u003cp\u003e(-0.89 to -0.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBodyweight (kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.21\u003c/p\u003e\n \u003cp\u003e(-3.84 to -2.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.76\u003c/p\u003e\n \u003cp\u003e(-2.65 to -0.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.04\u003c/p\u003e\n \u003cp\u003e(-3.68 to -2.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.59\u003c/p\u003e\n \u003cp\u003e(-2.48 to -0.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.45\u003c/p\u003e\n \u003cp\u003e(-2.08 to -0.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBodyweight (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-4.74\u003c/p\u003e\n \u003cp\u003e(-5.65 to -3.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.72\u003c/p\u003e\n \u003cp\u003e(-4.01 to -1.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-4.51\u003c/p\u003e\n \u003cp\u003e(-5.43 to -3.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.490\u003c/p\u003e\n \u003cp\u003e(-3.79 to -1.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.02\u003c/p\u003e\n \u003cp\u003e(-2.92 to -1.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWaist circumference (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.35\u003c/p\u003e\n \u003cp\u003e(-4.13 to -2.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.15\u003c/p\u003e\n \u003cp\u003e(-3.25 to -1.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.75\u003c/p\u003e\n \u003cp\u003e(-3.54 to -1.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.56\u003c/p\u003e\n \u003cp\u003e(-2.66 to -0.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.19\u003c/p\u003e\n \u003cp\u003e(-1.97 to -0.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHip circumference (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.96\u003c/p\u003e\n \u003cp\u003e(-3.55 to -2.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.34\u003c/p\u003e\n \u003cp\u003e(-2.17 to -0.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.49\u003c/p\u003e\n \u003cp\u003e(-3.09 to -1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.87\u003c/p\u003e\n \u003cp\u003e(-1.71 to -0.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0425\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.62\u003c/p\u003e\n \u003cp\u003e(-2.21 to -1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eCI\u0026thinsp;=\u0026thinsp;confidence interval. ETD\u0026thinsp;=\u0026thinsp;estimated treatment difference. HbA\u003csub\u003e1c\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;glycated haemoglobin. LSM\u0026thinsp;=\u0026thinsp;least square mean. SMBG\u0026thinsp;=\u0026thinsp;self-monitoring of blood glucose.\u003c/p\u003e\n \u003cp\u003ePrespecified sensitivity analyses all supported the conclusions of the primary analysis for the primary efficacy endpoint, showing similar and significant ETDs with both 0.6 and 1.2 mg ecnoglutide versus placebo (\u003cstrong\u003eSupplementary Fig.\u0026nbsp;3\u003c/strong\u003e). Subgroup analysis also showed that both 0.6 and 1.2 mg ecnoglutide consistently reduced HbA\u003csub\u003e1c\u003c/sub\u003e versus placebo to a larger extent across subgroups stratified by sex, age, baseline HbA\u003csub\u003e1c\u003c/sub\u003e, and BMI (\u003cstrong\u003eSupplementary Fig.\u0026nbsp;4\u003c/strong\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSecondary outcomes\u003c/h3\u003e\n\u003cp\u003eAt week 24, the proportion of participants who achieved HbA\u003csub\u003e1c\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;7.0% was 68.1% with 0.6 mg ecnoglutide and 80.3% with 1.2 mg ecnoglutide, both significantly higher than 21.1% with placebo (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for both); the proportion of participants who achieved HbA\u003csub\u003e1c\u003c/sub\u003e\u0026thinsp;\u0026le;\u0026thinsp;6.5% was 52.2% with 0.6 mg ecnoglutide and 76.1% with 1.2 mg ecnoglutide, both significantly higher than 12.7% with placebo (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for both); the proportion of participants who achieved normoglycaemia (HbA\u003csub\u003e1c\u003c/sub\u003e\u0026thinsp;\u0026le;\u0026thinsp;5.7%) was 10.1% with 0.6 mg ecnoglutide and 35.2% with 1.2 mg ecnoglutide, compared to 0% with placebo (\u003cstrong\u003eSupplementary Table.1\u003c/strong\u003e). Similarly, more participants achieved the composite endpoint of HbA\u003csub\u003e1c\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;7.0% without severe hypoglycaemia and without bodyweight gain in both the 0.6 mg and 1.2 mg ecnoglutide groups than in the placebo group (58.0% and 71.8% versus 18.3%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for both) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cstrong\u003eSupplementary Table.1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAt week 24, the LSM change (95% CI) from baseline in fasting plasma glucose (FPG) was \u0026minus;\u0026thinsp;2.89 mmol/L (-3.24 to -2.53) with 0.6 mg ecnoglutide, -3.32 mmol/L (-3.68 to -2.97) with 1.2 mg ecnoglutide, and \u0026minus;\u0026thinsp;1.21 mmol/L (-1.56 to -0.86) with placebo (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The ETD versus placebo was \u0026minus;\u0026thinsp;1.68 mmol/L (95% CI -2.17 to -1.18; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) with 0.6 mg ecnoglutide and \u0026minus;\u0026thinsp;2.11 mmol/L (95% CI -2.61 to -1.62; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) with 1.2 mg ecnoglutide (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The LSM change (95% CI) from baseline in 2h-postprandial plasma glucose was \u0026minus;\u0026thinsp;5.95 mmol/L (-6.69 to -5.21) with 0.6 mg ecnoglutide, -7.42 mmol/L (-8.17 to -6.67) with 1.2 mg ecnoglutide, and \u0026minus;\u0026thinsp;1.81 mmol/L (-2.54 to -1.08) with placebo. The ETD versus placebo was \u0026minus;\u0026thinsp;4.14 mmol/L (95% CI -5.18 to -3.10; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) with 0.6 mg ecnoglutide and \u0026minus;\u0026thinsp;5.61 mmol/L (95% CI -6.66 to -4.56; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) with 1.2 mg ecnoglutide (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Significantly larger reductions in mean seven-point self-monitored blood glucose (SMBG) and mean postprandial glucose excursion were also observed with 0.6 mg and 1.2 mg ecnoglutide versus placebo (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for all; Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eAt week 24, the LSM change (95% CI) from baseline in bodyweight was \u0026minus;\u0026thinsp;3.04 kg (-3.68 to -2.40) with 0.6 mg ecnoglutide, -3.21 kg (-3.84 to -2.58) with 1.2 mg ecnoglutide, and \u0026minus;\u0026thinsp;1.45 kg (-2.08 to -0.82) with placebo. The ETD versus placebo was \u0026minus;\u0026thinsp;1.59 kg (95% CI -2.48 to -0.69; p\u0026thinsp;=\u0026thinsp;0.0005) with 0.6 mg ecnoglutide and \u0026minus;\u0026thinsp;1.76 kg (95% CI -2.65 to -0.87; p\u0026thinsp;=\u0026thinsp;0.0001) with 1.2 mg ecnoglutide (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The cumulative distribution of change from baseline in bodyweight at week 24 is presented in \u003cstrong\u003eSupplementary Fig.\u0026nbsp;5\u003c/strong\u003e. The LSM percentage change (95% CI) from baseline in bodyweight was \u0026minus;\u0026thinsp;4.51% (-5.43 to -3.58) with 0.6 mg ecnoglutide, -4.74% (-5.65 to -3.82) with 1.2 mg ecnoglutide, and \u0026minus;\u0026thinsp;2.02% (-2.92 to -1.11) with placebo. The ETD versus placebo was \u0026minus;\u0026thinsp;2.49% (95% CI -3.79 to -1.20; p\u0026thinsp;=\u0026thinsp;0.0002) with 0.6 mg ecnoglutide and \u0026minus;\u0026thinsp;2.72% (95% CI -4.01 to -1.43; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) with 1.2 mg ecnoglutide (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eAt week 24, a bodyweight reduction of \u0026ge;\u0026thinsp;5% from baseline was achieved by significantly more participants in the 0.6 mg and 1.2 mg ecnoglutide groups than in the placebo group (39.1% and 43.7% versus 11.3%, p\u0026thinsp;=\u0026thinsp;0.0002 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, respectively); more participants achieved a\u0026thinsp;\u0026ge;\u0026thinsp;10% bodyweight reduction in the 0.6 mg and 1.2 mg ecnoglutide groups than in the placebo group, although the differences were not statistically significant (\u003cstrong\u003eSupplementary Table.1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAt week 24, waist circumference decreased from baseline by an LSM of 2.75 cm with 0.6 mg ecnoglutide, 3.35 cm with 1.2 mg ecnoglutide, and 1.19 cm with placebo. The ETDs versus placebo were significant for both ecnoglutide groups (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Hip circumference also significantly decreased from baseline with both doses of ecnoglutide versus placebo (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eAt week 24, homeostasis model assessments of \u0026beta;-cell function (HOMA-\u0026beta;) significantly increased with both doses of ecnoglutide than with placebo. homeostasis model assessments of insulin resistance HOMA-IR decreased with ecnoglutide versus increased with placebo, though the differences did not reach statistical significance. No significant changes compared to placebo were observed for fasting insulin levels for either of the ecnoglutide dose group (\u003cstrong\u003eSupplementary Table.1\u003c/strong\u003e). At week 24, decreases from baseline in LDL cholesterol were observed with ecnoglutide groups, these changes were not significantly different from that with placebo; and significant decrease from baseline in triglycerides versus placebo was observed with 1.2 mg ecnoglutide group, not with 0.6 mg ecnoglutide (\u003cstrong\u003eSupplementary Table.1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eEfficacy data at week 52 are summarised in \u003cstrong\u003eSupplementary Table.2\u003c/strong\u003e. In the two groups who received ecnoglutide throughout, improvements in glycaemia control and bodyweight in the double-blind treatment period were maintained during the open-label treatment period (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). In each placebo group, improvements in glycaemia control and bodyweight among other efficacy measures were observed after switching to ecnoglutide (\u003cstrong\u003eSupplementary Table.2\u003c/strong\u003e).\u003c/p\u003e\n\u003ch3\u003eSafety outcomes\u003c/h3\u003e\n\u003cp\u003eDuring the double-blinded treatment period, treatment-emergent adverse events (TEAEs) occurred in 78.3% of the 0.6 mg ecnoglutide group, 77.5% of the 1.2 mg ecnoglutide group, and 63.4% of the placebo group (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Serious TEAEs were reported in 2.9% of the 0.6 mg ecnoglutide group, 4.2% of the 1.2 mg ecnoglutide group, and 5.6% of the placebo group. TEAEs led to premature treatment discontinuation in 1 (1.4%) participant in each treatment group (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). No deaths occurred in any group. The most frequently reported TEAEs by system organ class were gastrointestinal, metabolic, and nutritional disorders. The most commonly reported gastrointestinal events for ecnoglutide were diarrhoea and nausea (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Other TEAEs with a\u0026thinsp;\u0026gt;\u0026thinsp;5% incidence included decreased appetite, lipase increased, upper respiratory tract infection, urinary tract infection, and asthenia among others. Most adverse events in the ecnoglutide groups were mild to moderate in severity and the incidence was the highest during the dose-escalation period and decreased over time (\u003cstrong\u003eSupplementary Fig.\u0026nbsp;6\u003c/strong\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTreatment-emergent adverse events (TEAEs) during the double-blind treatment period (safety set\u003csup\u003ea\u003c/sup\u003e)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParticipants, n (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEcnoglutide 1.2 mg\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;71)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEcnoglutide 0.6 mg\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;69)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;71)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny TEAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55 (77.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54 (78.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (63.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment-related\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44 (62.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 (58.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (28.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 TEAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (7.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (28.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment-related\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerious TEAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (5.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment-related\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTEAEs leading to treatment discontinuation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTEAEs leading to death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eTEAEs occurring in \u0026ge;\u0026thinsp;5% of participants in any treatment group (preferred term)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDecreased appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (26.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (21.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsthenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (14.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLipase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (12.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (11.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (12.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (7.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (9.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ediarrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (11.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (24.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (5.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal distension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (8.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (7.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUpper respiratory tract infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (7.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (10.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSinus tachycardia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (5.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyperlipidaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (7.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUrine leukocyte positive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (7.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (5.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFlatulence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (5.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUrinary tract infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (8.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (9.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTEAEs of special interests\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (50.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (53.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (28.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypoglycaemia\u003c/p\u003e\n \u003cp\u003e(blood glucose\u0026thinsp;\u0026lt;\u0026thinsp;3.9 mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (5.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypoglycaemia\u003c/p\u003e\n \u003cp\u003e(blood glucose\u0026thinsp;\u0026lt;\u0026thinsp;3.0 mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSevere hypoglycaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eNote: \u003csup\u003ea\u003c/sup\u003e The safety set comprised all participants who received\u0026thinsp;\u0026ge;\u0026thinsp;1 dose of study treatment and safety evaluation after treatment initiation.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eHypoglycaemia (identified via scheduled laboratory visit) was reported in 2 (2.9%) participants in the 0.6 mg ecnoglutide group, 5 (5.6%) in the 1.2 mg ecnoglutide group, and 1 (1.4%) in the placebo group (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). No severe hypoglycaemia, pancreatitis, or gallbladder-related disorders were reported with ecnoglutide in this study. Elevated lipase and amylase levels were reported by more participants in the ecnoglutide groups (11.6%/4.3% in the 0.6 mg group and 12.7%/2.8% in the 1.2 mg group) than in the placebo group (2.8%/0). These elevations did not appear to be dose-related (\u003cstrong\u003eSupplementary Fig.\u0026nbsp;8\u003c/strong\u003e), and were not associated with clinical symptoms or signs, pancreatitis, or hepatic disorders.\u003c/p\u003e\n\u003cp\u003ePulse rate increased by a mean of 3.0 beats/min with ecnoglutide 0.6 mg and 5.4 beats/min with 1.2 mg ecnoglutide versus a mean decrease of 1.6 beats/min with placebo at week 24. Mean systolic blood pressure decreased by 4.4 mmHg with 0.6 mg ecnoglutide and a mean of 5.2 mmHg with 1.2 mg ecnoglutide versus 2.1 mmHg with placebo. Changes in diastolic blood pressure from baseline were similar across the three groups at week 24 (\u003cstrong\u003eSupplementary Tables.3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eDuring the open-label period, the proportions of participants reporting TEAEs in the two ecnoglutide groups were lower than their counterparts in the double-blind period, and the incidences of TEAEs in the two groups switching from placebo to ecnoglutide were similar to what was reported by the two ecnoglutide groups in the double-blind period (\u003cstrong\u003eSupplementary Table.4\u003c/strong\u003e). Across the four treatment groups, gastrointestinal disorders were still the most frequently reported events, which were mostly transient, and mild to moderate in severity. No pancreatitis or severe hypoglycaemic events were reported.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this phase 3 trial, compared with placebo, once-weekly injections of ecnoglutide at doses of 1.2 mg and 0.6 mg demonstrated significant improvement in glycaemic control in participants with T2DM inadequately controlled with diet and exercise alone or with a single oral hypoglycaemic agent. Both doses of ecnoglutide were superior to placebo in reducing HbA\u003csub\u003e1c\u003c/sub\u003e, without increasing the risk of hypoglycaemia. Reductions in HbA\u003csub\u003e1c\u003c/sub\u003e were observed by the first study assessment at week 4 and sustained until the end of treatment at week 52. The magnitude of the reductions in HbA\u003csub\u003e1c\u003c/sub\u003e observed for ecnoglutide was dose-dependent. At week 24, up to 80.3% in the 1.2 mg ecnoglutide group and 68.1% in the 0.6 mg ecnoglutide group versus 21.1% in the placebo group reached the HbA\u003csub\u003e1c\u003c/sub\u003e target of \u0026lt;\u0026thinsp;7.0% as recommended by the American Diabetes Association (ADA)\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, and up to 35.2% of participants in the 1.2 mg ecnoglutide group reached normoglycaemia (HbA\u003csub\u003e1c\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;5.7%). More importantly, the proportion of participants who achieved the composite endpoint of HbA\u003csub\u003e1c\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;7.0% without severe glycaemia and without bodyweight gain was also significantly higher in the ecnoglutide groups than in the placebo group at week 24 (71.8% with 1.2 mg and 58.0% with 0.6 mg versus 18.3% with placebo). The beneficial effect on glycaemic control was further supported by the significant improvements in FPG, 2-h postprandial plasma glucose (2h-PPG), 7-Point SMBG profiles, and the β cell function.\u003c/p\u003e \u003cp\u003eThese results agree to the findings in the phase 2 trial of ecnoglutide in participants with T2DM that was uncontrolled with diet, exercise, or single oral glucose-lowering medication.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e In this phase 2 study, the HbA\u003csub\u003e1c\u003c/sub\u003e target of \u0026lt;\u0026thinsp;7.0% was achieved in 84% on ecnoglutide 1.2 mg and 68% on ecnoglutide 0.8 mg versus 21% on placebo at week 20.\u003c/p\u003e \u003cp\u003eAlthough indirect cross-trial comparisons should be viewed with caution due to differences in trial designs, populations, and analysis methods, ecnoglutide showed comparable or greater HbA\u003csub\u003e1c\u003c/sub\u003e reductions versus other GLP-1 based therapies including selective GLP-1 receptor agonists dulaglutide and semaglutide as well as the dual GIP/GLP1 receptor agonist tirzepatide. The decreases from baseline in HbA\u003csub\u003e1c\u003c/sub\u003e were 1.96% and 2.43% with ecnoglutide (0.6 mg and 1.2 mg at week 24) in the current study, compared to 1.25% and 1.46% for dulaglutide (0.75 mg and 1.5 mg at week 26) in the Chinese subgroup of an East Asian trial, 1.45% and 1.55% with semaglutide (0.5 mg and 1.0 mg at week 30) in SUSTAIN-1 among global participants, and 1.87%, 1.89%, and 2.07% for tirzepatide (5 mg, 10 mg, and 15 mg at week 40) in SURPASS-1 among global participants.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e The greater decreases with ecnoglutide compared with semaglutide and dulaglutide may be largely attributed to the fact that ecnoglutide is a cAMP signalling biased GLP-1 analogue, which is anticipated to have enhanced efficacy than unbiased GLP-1 receptor agonists like semaglutide and dulaglutide. A preclinical study has showed that at the same dose level, ecnoglutide significantly reduced blood glucose and HbA\u003csub\u003e1c\u003c/sub\u003e more than semaglutide.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Ecnoglutide showed comparable but slightly greater HbA\u003csub\u003e1c\u003c/sub\u003e reductions compared with the dual GIP/GLP-1 receptor agonist tirzepatide, which also favours the cAMP signalling pathway.\u003c/p\u003e \u003cp\u003eIn addition to glycaemic effects, significant and sustained bodyweight reductions were observed over 52 weeks of treatment with ecnoglutide. The average bodyweight loss was 3.04 and 3.21 kg for ecnoglutide in the current study, compared to 1.0 and 1.5 kg for dulaglutide (0.75 and 1.5 mg at week 26) in the Chinese subgroup of the East Asian trial, and 3.73 and 4.53 kg for semaglutide (0.5 and 1.0 mg at week 30) in SUSTAIN-1.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e More importantly, at week 24, 39.1\u0026ndash;43.7% in the ecnoglutide groups versus 11.3% in the placebo group achieved a bodyweight loss of \u0026ge;\u0026thinsp;5%, the ADA-recommended target.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Favourable changes in waist and hip circumferences with ecnoglutide versus placebo were also observed at week 24, providing further evidence for the beneficial effects of ecnoglutide in bodyweight management. In addition, favourable changes in systolic blood pressure, lipids, and insulin sensitivity were observed with ecnoglutide, suggesting potential cardiovascular benefits.\u003c/p\u003e \u003cp\u003eThe observed safety profile of ecnoglutide in this study population was consistent with the known class effects of GLP-1 receptor agonists, with transient, mild to moderate gastrointestinal events as the most frequently reported TEAEs. Gastrointestinal adverse events mainly occurred in the dose escalation period and diminished over time. No new safety signals were detected in this study. No cases of severe hypoglycaemia were reported throughout the study. Slight increases in pulse rate were noted for ecnoglutide in this study, which were consistent with observations for other GLP-1 receptor agonists.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Both doses of ecnoglutide were well-tolerated, which was evident in the very low rate of treatment discontinuation. Only 1.4% of participants in the two groups discontinued ecnoglutide due to TEAEs.\u003c/p\u003e \u003cp\u003eThis study has several strengths, including the randomised, placebo-controlled design with the use of a volume-matched placebo for masking within each dose and a switch-over design to allow for minimised exposure to placebo treatment and long-term efficacy evaluation. Additionally, a relatively high proportion of participants completed the study, giving fairly complete data. This study also has limitations. Firstly, it was conducted in China only, so the observed findings may not be fully translatable to other ethnic/racial populations. However, since GLP-1 receptor agonists have been shown to be efficacious in both Asian and non-Asian populations,\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e similar efficacy and safety of ecnoglutide are expected in non-Asian populations as well. Secondly, although the trial duration was sufficiently long to assess the primary and secondary endpoints, the long-term impact of ecnoglutide on cardiovascular and renal outcomes require longer studies to assess fully.\u003c/p\u003e \u003cp\u003eThis study observed a good placebo effect in efficacy measures such as changes from baseline in HbA\u003csub\u003e1c\u003c/sub\u003e, FPG, and bodyweight, similar to the placebo effects observed in another reported phase 3 trial conducted in China.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e This placebo effect might be due to the relatively shorter diabetic history and more treatment-naive participants in the placebo group, which may contribute to more responsiveness to therapy. This effect could also be due to randomisation, participants\u0026rsquo; adherence to treatment as well as guidance from their healthcare professionals, and participants\u0026rsquo; continued lifestyle modifications during the trial. Another phase 3 study is being conducted to assess the long-term efficacy and safety of ecnoglutide as an add-on to metformin in patients with T2DM (NCT05680129).\u003c/p\u003e \u003cp\u003eIn conclusion, ecnoglutide, a cAMP signalling-biased GLP-1 receptor agonist, administered at doses of 0.6 and 1.2 mg once weekly as monotherapy for T2DM, significantly improved glycaemic control, with up to 35.2% of participants achieving normoglycaemia, and robustly reduced bodyweight versus placebo, without increasing the risk of severe hypoglycaemia. Ecnoglutide was well-tolerated, with a very low rate of treatment discontinuation and a safety profile consistent with other GLP-1 receptor agonists. The favourable efficacy and safety profiles indicate that ecnoglutide is a promising initial treatment option for T2DM early in the course of the disease.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy design\u003c/h2\u003e\n \u003cp\u003eWe conducted a randomised, double-blind, placebo-controlled, phase 3 trial across 32 sites in China. This trial was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice Guidelines, and all applicable local laws and regulations. This study protocol was approved by institutional review boards or ethics committees of all participating sites and written informed consent was obtained from all participants prior to study entry.\u003c/p\u003e\n \u003cp\u003eThe study comprised 2-week screening, 4-week run-in, 24-week double-blind core treatment, 28-week open-label extended treatment, and 5-week safety follow-up (\u003cstrong\u003eSupplementary Fig.\u0026nbsp;8\u003c/strong\u003e).\u003c/p\u003e\n \u003cp\u003eParticipants were randomly assigned (2:2:1:1) to receive once-weekly subcutaneous injections of ecnoglutide (0.6 or 1.2 mg) or volume-matched placebo (0.6 or 1.2 mg), with stratification according to baseline HbA\u003csub\u003e1c\u003c/sub\u003e (\u0026le;\u0026thinsp;8.5% or \u0026gt;\u0026thinsp;8.5%), via an interactive web response system. All investigators, participants, and the sponsor remained blinded to treatment assignment. Placebo and active drug were provided in injector pens, identical in appearance.\u003c/p\u003e\n \u003cp\u003eAfter a 2-week screening and 4-week run-in period, participants were re-assessed for eligibility. Eligible participants received once weekly subcutaneous injections of study drugs in a double-blind manner for 24 weeks. At the end of 24 weeks, participants were unblinded one by one and all switched to open-label treatment. They either continued to receive ecnoglutide at the respective maintenance doses or started receiving ecnoglutide for 28 weeks, followed by a 5-week safety follow-up period.\u003c/p\u003e\n \u003cp\u003eStudy drug was administered once weekly via subcutaneous injection using injector pens with a pre-set volume, following a slow dose-escalation regimen, starting at 0.3 mg (equivalent to 0.15 mL injection) with fixed double-dose increments every 4 weeks until the allocated maintenance dose was reached. The maintenance doses of 0.6 and 1.2 mg were reached at 4 and 8 weeks in respective ecnoglutide groups. Participants who switched from placebo to ecnoglutide during the open-label treatment period underwent the same dose-escalation procedure. If intolerable symptoms or events occurred and persisted, a lower tolerated dose could be used at the investigator\u0026rsquo;s discretion. More details on the dosing regimen are available in the \u003cstrong\u003esupplementary\u003c/strong\u003e (p 2\u0026ndash;3). Initiation of new antihyperglycemic medications, with metformin as the first choice, was only allowed for rescue therapy for persistent hyperglycaemia on the basis of prespecified criteria (\u003cstrong\u003esupplementary\u003c/strong\u003e, p 4).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eKey inclusion criteria included adults aged 18\u0026ndash;75 years (inclusive) with T2DM inadequately controlled with diet and exercise alone or with only one oral hypoglycaemic agent. Eligible participants had a BMI of 20.0\u0026ndash;35.0 kg/m\u0026sup2; (inclusive), an HbA\u003csub\u003e1c\u003c/sub\u003e level of 7.5\u0026ndash;11.0% (inclusive) at screening, and an HbA\u003csub\u003e1c\u003c/sub\u003e level of 7.0\u0026ndash;10.5% (inclusive) at randomisation, and a FPG level of \u0026le;\u0026thinsp;13.9 mmol/L at both screening and randomisation. Participants were excluded if they had type 1 diabetes mellitus or other diabetes mellitus, received any GLP-1 drug or dipeptidyl peptidase-4 inhibitor within the preceding 3 months or insulin within the preceding 6 months (except for the \u0026le;\u0026thinsp;14-day use of insulin for co-morbidities), or experienced diabetic ketoacidosis, hyperosmolar hyperglycaemic state, lactic acidosis in diabetes, or severe chronic complications of diabetes within the prior 6 months. Full list of eligibility criteria is provided in the \u003cstrong\u003esupplementary\u003c/strong\u003e (p 3\u0026ndash;4).\u003c/p\u003e\n\u003ch3\u003eStudy endpoints and assessments\u003c/h3\u003e\n\u003cp\u003eThe primary efficacy endpoint was change from baseline in HbA\u003csub\u003e1c\u003c/sub\u003e at week 24, assessed by the central laboratory. The secondary efficacy endpoints included proportions of participants who achieved an HbA\u003csub\u003e1c\u003c/sub\u003e level of \u0026lt;\u0026thinsp;7.0% and \u0026le;\u0026thinsp;6.5% at weeks 24 and 52; proportion of participants who achieved a composite endpoint of HbA\u003csub\u003e1c\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;7.0%, no severe hypoglycaemia, and no bodyweight gain at week 24; changes from baseline at weeks 24 and 52 in FPG, 2h-PPG, seven-point SMBG profiles, fasting insulin, HOMA-\u0026beta; and HOMA-IR, blood lipids, bodyweight, waist circumference, and hip circumference.\u003c/p\u003e\n\u003cp\u003eSafety endpoints included the incidences of TEAEs, serious TEAEs, and TEAEs of special interest (hypoglycaemia, cardiovascular events, gastrointestinal events, pancreatitis, and gallbladder-related disorders). Other safety measurements included vital signs, physical examinations, 12-lead electrocardiograms (ECG), and laboratory assessments.\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analyses\u003c/h2\u003e\n \u003cp\u003eThe study was designed to establish superiority for each dose of ecnoglutide versus placebo for the primary endpoint at week 24. The sample size calculation assumed at least a -1.2% difference in mean change from baseline in HbA\u003csub\u003e1c\u003c/sub\u003e at week 24 between ecnoglutide groups and the pooled placebo group, a common SD of 1.1%, and a drop-out rate of 20%. A sample size of 210 participants provided at least 90% power to establish superiority for an ecnoglutide dose compared with placebo (superiority margin of 0.5%) at a one-sided significance level of 0.025. Full details of type I error control strategy are provided in the \u003cstrong\u003esupplementary\u003c/strong\u003e (p 5).\u003c/p\u003e\n \u003cp\u003eEfficacy analyses were performed in the FAS, comprised all randomised participants who received\u0026thinsp;\u0026ge;\u0026thinsp;1 dose of study treatment. Safety analyses were conducted in the safety set, comprising all participants who received\u0026thinsp;\u0026ge;\u0026thinsp;1 dose of study treatment and safety evaluation after treatment initiation.\u003c/p\u003e\n \u003cp\u003eThe primary efficacy endpoint was evaluated using two estimands. For the primary efficacy estimand, the treatment policy strategy was used to assess the treatment effect between ecnoglutide and placebo among all randomised participants regardless of intercurrent events (early treatment discontinuation and rescue therapy). For the secondary efficacy estimand, the hypothetical strategy was used to assess the treatment effect between ecnoglutide and placebo among all participants without intercurrent events, i.e., data collected after intercurrent events were excluded from analysis.\u003c/p\u003e\n \u003cp\u003eFor the primary endpoint analysis, a mixed model for repeated measures (MMRM) was used, in which the change from baseline in HbA\u003csub\u003e1c\u003c/sub\u003e was used as the dependent variable, categorical baseline HbA\u003csub\u003e1c\u003c/sub\u003e level, visit time points, treatment grouping, and treatment by visit interaction were used as the explanatory variables. The model was used to calculate covariate-adjusted mean change from baseline in HbA\u003csub\u003e1c\u003c/sub\u003e of each group at week 24 and its standard error, its 95% confidence interval (CI), as well as inter-group mean difference between each ecnoglutide group and the placebo group and its 95% CI. For missing HbA\u003csub\u003e1c\u003c/sub\u003e values at week 24 in participants who experienced intercurrent events, imputation was performed using the retrieved dropout-based multiple imputation, or the missing at random approach if the former was not appropriate.\u003c/p\u003e\n \u003cp\u003ePrespecified sensitivity analyses were conducted to assess the robustness of results for the primary endpoint by the use of alternative data selections and methods for handling missing data, including analysis of covariance (ANCOVA), which considered baseline HbA\u003csub\u003e1c\u003c/sub\u003e and treatment group as exploratory variables, and the jump to reference (J2R) assumption, in which missing data was imputed based on the reference group data. Subgroup analysis was also conducted for the primary endpoint.\u003c/p\u003e\n \u003cp\u003eFor the analysis of the secondary efficacy endpoints, change from baseline in FPG at week 24, and change and percentage change from baseline in bodyweight at week 24 were analysed by strategies and methods consistent to those for the primary endpoint. The proportions of participants who achieved prespecified targets of bodyweight loss or HbA\u003csub\u003e1c\u003c/sub\u003e reductions were analysed and compared using the logistic regressions and the 95% CIs for these proportions were calculated using the Clopper-Pearson method, with missing data imputed using the non-response imputation method. Results for the other secondary efficacy endpoints were summarised descriptively without data imputation. Safety endpoints were summarised descriptively by the use of data for all randomised participants who received at least one dose of study drug (safety set). Statistical analyses were performed using SAS version 9.4. See Protocol for extended statistical methods. This study was registered with both ClinicalTrials.gov (NCT05680155) and China Drug Trials Registry (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.chinadrugtrials.org.cn\u003c/span\u003e\u003c/span\u003e, CTR20223156).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eReproting summary\u003c/h2\u003e\n \u003cp\u003eFurther information on research design is available in the Nature Portfolio Reporting Summary linked to this article.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eD. Z., W. W., G. T., J. M., B. W., X. Z., B. S., S. P., K. W., X. S., X. Z., L. F., Y. L., Y. L., D. H., C. J., T. P., H. X., J. H., H. D. received funding from Sciwind Biosciences to their institutions as trial investigators. S. B., F. J., Q. Z., M. Y., L. G., X. L., Y. B., M. G., J. N., L. Y., W. G., Y. L., H. P. are employees of Hangzhou Sciwind Biosciences. S X. is an employee of Sciwind Biosciences.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contributors\u003c/h2\u003e \u003cp\u003eD. Z., W. W., H. P., Y. L., S. X., S. B., Q. Z., J. N., L. Y., W. G., L. G., X. L., Y. B., M. G., G. T., J. M., B. W., X. Z., B. S., S. P., K. W., X. S., X. Z., L. F., Y. L., Y. L., D. H., C. J., T. P., H. X., J. H., and H. D. designed and performed the study. D. Z., H. P., M. Y., S. X., S. B., Q. Z., and F. J. analysed and interpreted the data. D. Z., S. B., and S. X. drafted the manuscript. All authors approved the final submitted paper.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe thank the participants, the investigators and their teams who took part in this study. This study was funded by Hangzhou Sciwind Biosciences Co., Ltd. The study sponsor was involved in study design and protocol development and responsible for data collection, data analysis, data interpretation, and writing of the report. The decision to submit the report for publication was made by all authors, who had full access to the data. Part of the data from this study were presented at the American Diabetes Association\u0026rsquo;s 84th Scientific Sessions, June 2024.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eThe full dataset and protocol are not publicly available due to data privacy laws and contractual obligations. Sciwind Biosciences will provide de-identified individual participant data underlying the reported results upon request. Data are available after acceptance of this article with no expiration of data requests currently set. Requests should be made by contacting corresponding authors and will be evaluated within 6 months of receipt. Access will be provided after the proposed use of the data has been approved by a review committee and receipt of a signed data access agreement with Sciwind Biosciences.\u003c/p\u003e \u003cp\u003eCode availability\u003c/p\u003e \u003cp\u003eCode supporting this Article is available within the Supplementary Information.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCollaborators GD (2023) Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet 402:203\u0026ndash;234\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMauricio D, Meneghini L, Seufert J et al (2017) Glycaemic control and hypoglycaemia burden in patients with type 2 diabetes initiating basal insulin in Europe and the USA. Diabetes Obes Metab 19:1155\u0026ndash;1164\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu J, Liu M, Chai Z et al (2023) Projected rapid growth in diabetes disease burden and economic burden in China: a spatio-temporal study from 2020 to 2030. Lancet Reg Health West Pac 33:100700\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFang M, Wang D, Coresh J, Selvin E (2021) Trends in diabetes treatment and control in U.S. adults, 1999\u0026ndash;2018. N Engl J Med 384:2219\u0026ndash;2228\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi J, Chattopadhyay K, Xu M et al (2018) Glycaemic control in type 2 diabetes patients and its predictors: a retrospective database study at a tertiary care diabetes centre in Ningbo, China. BMJ Open 8:e019697\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHypoglycaemia cardiovascular (2019) disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol 7:385\u0026ndash;396\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDrucker DJ (2024) Efficacy and safety of GLP-1 medicines for type 2 diabetes and obesity. Diabetes Care 47:1873\u0026ndash;1888\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSorli C, Harashima SI, Tsoukas GM et al (2017) Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol 5:251\u0026ndash;260\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosenstock J, Wysham C, Fr\u0026iacute;as JP et al (2021) Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet 398:143\u0026ndash;155\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarx N, Husain M, Lehrke M, Verma S, Sattar N (2022) GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 diabetes. Circulation 146:1882\u0026ndash;1894\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGranata A, Maccarrone R, Anzaldi M et al (2022) GLP-1 receptor agonists and renal outcomes in patients with diabetes mellitus type 2 and diabetic kidney disease: state of the art. Clin Kidney J 15:1657\u0026ndash;1665\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolst JJ (2024) GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management. Nat Metab 6:1866\u0026ndash;1885\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Diabetes Association Professional Practice Committee (2024) 9. Pharmacologic approaches to glycemic treatment: Standards of care in diabetes \u0026ndash;\u0026thinsp;2024. Diabetes Care 47:S158\u0026ndash;S178\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavies MJ, Aroda VR, Collins BS et al (2022) Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). \u003cem\u003eDiabetes Care\u003c/em\u003e. 45, 2753\u0026thinsp;\u0026ndash;\u0026thinsp;2586\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChinese Elderly Type 2 Diabetes Prevention and Treatment of Clinical Guidelines Writing Group, Geriatric Endocrinology and Metabolism Branch of Chinese Geriatric Society, Geriatric Endocrinology and Metabolism Branch of Chinese Geriatric Health Care Society, Geriatric Professional Committee of Beijing Medical Award Foundation, National Clinical Medical Research Center for Geriatric Diseases (PLA General Hospital) (2022) Clinical guidelines for prevention and treatment of type 2 diabetes mellitus in the elderly in China (2022 edition). Zhonghua nei ke za zhi 61:12\u0026ndash;50\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo W, Xu Z, Zou H et al (2023) Discovery of ecnoglutide - A novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog. Mol Metab 75:101762\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWillard FS, Douros JD, Gabe MB et al (2020) Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight 5:e140532\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhu D, Wang W, Tong G et al (2024) Efficacy and safety of GLP-1 analog ecnoglutide in adults with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 2 trial. Nat Commun 15:8408\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Diabetes Association Professional Practice Committee. 6. Glycemic goals and hypoglycemia: Standards of care in diabetes \u0026ndash;\u0026thinsp;2024. Diabetes Care. 47, S111-S125 (2024)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShi LX, Liu XM, Shi YQ et al (2020) Efficacy and safety of dulaglutide monotherapy compared with glimepiride in Chinese patients with type 2 diabetes: Post-hoc analyses of a randomized, double-blind, phase III study. \u003cem\u003eJ Diabetes Investig.\u003c/em\u003e 11, 142\u0026thinsp;\u0026ndash;\u0026thinsp;50\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Diabetes Association Professional Practice Committee. 8. Obesity and weight management for the prevention and treatment of type 2 diabetes: Standards of care in diabetes \u0026ndash;\u0026thinsp;2024. Diabetes Care. 47, S145-S157 (2024)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWysham C, Blevins T, Arakaki R et al (2014) Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care 37:2159\u0026ndash;2167\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGan S, Dawed AY, Donnelly LA et al (2020) Efficacy of modern diabetes treatments DPP-4i, SGLT-2i, and GLP-1RA in White and Asian patients with diabetes: A systematic review and meta-analysis of randomized controlled trials. Diabetes Care 43:1948\u0026ndash;1957\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYan X, Ma J, Liu Y et al (2024) Efficacy and safety of visepegenatide, a long-acting weekly GLP-1 receptor agonist as monotherapy in type 2 diabetes mellitus: a randomised, double-blind, parallel, placebo-controlled phase 3 trial. Lancet Reg Health West Pac 7:101101\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Supplementary Material","content":"\u003cp\u003eThe Supplementary Figures and Tables are not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6342890/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6342890/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEcnoglutide 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\u003csub\u003e1c\u003c/sub\u003e) from baseline at week 24. 211 participants were randomised to receive ecnoglutide 1.2 mg (n\u0026thinsp;=\u0026thinsp;71), 0.6 mg(n\u0026thinsp;=\u0026thinsp;69), or placebo(n\u0026thinsp;=\u0026thinsp;71). At week 24, HbA\u003csub\u003e1c\u003c/sub\u003e changed from baseline by -1.96%, -2.43% with 0.6 mg, 1.2 mg ecnoglutide, and \u0026minus;\u0026thinsp;0.87 with placebo. Bodyweight changed by -3.04 kg, -3.21 kg with 0.6 mg, 1.2 mg ecnoglutide, and \u0026minus;\u0026thinsp;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.\u003c/p\u003e \u003cp\u003eType 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.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e 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\u003csub\u003e1c\u003c/sub\u003e) treatment targets.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Furthermore, glycaemic management should consider minimising undesired effects such as hypoglycaemia and bodyweight gain,\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e which has proven to be challenging with traditional glucose-lowering medications.\u003c/p\u003e \u003cp\u003eThe 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.\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e 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.\u003csup\u003e\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Therefore, they are an effective treatment option for T2DM and have been recommended by various guidelines.\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eEcnoglutide, 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.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e 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.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e 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.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e 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.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e 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.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHere 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.\u003c/p\u003e","manuscriptTitle":"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","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-22 13:13:57","doi":"10.21203/rs.3.rs-6342890/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f5557a61-863f-4373-8ac2-0842485217b6","owner":[],"postedDate":"May 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":47991823,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases/Diabetes/Type 2 diabetes"},{"id":47991824,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity"}],"tags":[],"updatedAt":"2026-02-07T08:10:44+00:00","versionOfRecord":{"articleIdentity":"rs-6342890","link":"https://doi.org/10.1038/s41467-025-68165-7","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2026-01-07 05:00:00","publishedOnDateReadable":"January 7th, 2026"},"versionCreatedAt":"2025-05-22 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