Efficacy and safety of GLP-1 analog ecnoglutide in adults with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 2 trial

Abstract

Glucagon-like peptide-1 (GLP-1) analogs are important therapeutics for type 2 diabetes and obesity. Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog. We conducted a Phase 2, randomized, double-blind, placebo-controlled study enrolling 145 adults with T2DM. Participants were randomized to 0.4, 0.8, or 1.2 mg ecnoglutide or placebo as once-weekly injections for 20 weeks. The primary objective was to evaluate the efficacy of ecnoglutide, as measured by HbA1c change from baseline at Week 20. Secondary endpoints included body weight, glucose and lipid parameters, as well as safety. We show that, at end of treatment, the 0.4, 0.8, and 1.2 mg groups had statistically significant HbA1c reductions from baseline of -1.81%, -1.90%, and -2.39%, respectively, compared to -0.55% for placebo (P < 0.0001). At end of treatment, 71.9% of the 1.2 mg group had HbA1c ≤ 6.5% versus 9.1% on placebo, and 33.3% had body weight reductions ≥5% versus 3.0% for placebo. Ecnoglutide was generally safe and well tolerated. China Drug Trials Registry CTR20211014.

Fig. 1. Participant disposition.

Screening cases are defined as participants who signed the informed consent. Early withdrawal includes participants who withdrew prior to the end of study visit on Day 169.

Fig. 2. HbA1c changes from baseline in participants treated with ecnoglutide or placebo.

a HbA1c change from baseline to end of treatment (Day 134), derived from mixed model for repeated measures (MMRM) analysis. Least squares mean and SE are shown. Numbers of participants (n) for the 0.4, 0.8, 1.2 mg ecnoglutide and placebo groups, respectively, are as follows: BL, 37, 36, 36, 36; Day 22, 36, 35, 35, 36; Day 50, 35, 34, 35, 36; Day 92, 35, 34, 33, 34; and Day 134, 33, 31, 32, 33. b HbA1c change from baseline at Day 134 and difference from placebo, derived from MMRM analysis, with n = 33, 31, 32, 33 participants in the 0.4, 0.8, 1.2 mg ecnoglutide and placebo groups, respectively. Least squares mean and SE are shown, as well as mean difference from placebo and 95% confidence interval. All ecnoglutide treatment groups were significantly different from placebo (P < 0.0001) using σ = 0.3 superiority margin. c, d The proportion of participants with HbA1c values of ≤6.5% and <7%, respectively, at Day 134. Intent to treat (ITT) population is shown for all analyses. BL baseline. Source data are provided as a Source Data file.

Fig. 3. Changes in glucose and glucagon from baseline.

a Fasting blood glucose (FBG) change from baseline to end of treatment (Day 134), using mixed model for repeated measures (MMRM) analysis. Least squares mean and SE are shown. Numbers of participants (n) for the 0.4, 0.8, 1.2 mg ecnoglutide and placebo groups, respectively, are as follows: BL, 37, 34, 34, 36; Day 22, 36, 35, 35, 36; Day 50, 35, 34, 35, 36; Day 92, 36, 34, 34, 36; and Day 134, 33, 31, 32, 34. P < 0.0001 for all ecnoglutide cohorts compared to placebo at Days 22, 50, 92, and 134. b Glucagon change from baseline to end of treatment (Day 134), using MMRM analysis. Least squares mean and SE are shown. Numbers of participants (n) for the 0.4, 0.8, 1.2 mg ecnoglutide and placebo groups, respectively, are as follows: BL, 37, 36, 36, 36; Day 22, 36, 35, 35, 36; Day 50, 36, 35, 35, 36; Day 92, 36, 34, 34, 36; and Day 134, 34, 31, 32, 34. P < 0.0001 for ecnoglutide 1.2 mg compared to placebo at Day 92. P < 0.002 for ecnoglutide 0.4 and 0.8 mg on Day 92. P < 0.02 for ecnoglutide 1.2 mg on Day 134. c Self-monitored blood glucose pre- and post-meals at baseline and end of treatment (sampled between Days 135–140). Means and SE are shown. d SMBG average change from baseline to Week 20, derived from analysis of variance (one-way ANOVA). Least squares mean and SE are shown, as well as mean difference from placebo and 95% confidence interval. P values were 0.0002, 0.0002, and <0.0001, for 0.4, 0.8, 1.2 mg ecnoglutide compared to placebo, respectively. Numbers of participants (n) for SMBG for the 0.4, 0.8, 1.2 mg ecnoglutide and placebo groups, respectively, are BL, 34, 35, 35, 34; Week 20, 29, 30, 28, 30. BL baseline. Source data are provided as a Source Data file.

Fig. 4. Mean change in body weight from baseline.

a Body weight change (kg) from baseline to end of treatment (Day 134), derived from mixed model for repeated measures (MMRM) analysis. Least squares mean and SE are shown. Numbers of participants (n) for the 0.4, 0.8, 1.2 mg ecnoglutide and placebo groups, respectively, are as follows: BL, 37, 36, 36, 36; Day 8, 36, 36, 35, 36; Day 15, 36, 34, 35, 35; Day 22, 36, 35, 35, 36; Day 29, 36, 35, 33, 36; Day 36, 36, 33, 34, 36; Day 43, 35, 35, 35, 36; Day 50, 36, 34, 33, 36; Day 57, 36, 34, 33, 36; Day 64, 35, 34, 34, 32; Day 71, 35, 33, 32, 36; Day 78, 35, 33, 32, 34; Day 85, 35, 34, 33, 36; Day 92, 36, 34, 34, 34; Day 99, 35, 34, 33, 36; Day 106, 35, 33, 32, 34; Day 113, 36, 33, 33, 35; Day 120, 35, 33, 33, 35; Day 127, 35, 29, 33, 35; Day 134, 35, 34, 33, 33. P < 0.0001 for all ecnoglutide cohorts compared to placebo at Days 106, 120, 127, and 134. b Change in body weight compared to baseline (kg) and difference from placebo, derived from MMRM analysis. Least squares mean and SE are shown, with n = 35, 34, 33, 33 participants for the 0.4, 0.8, 1.2 mg ecnoglutide and placebo groups, respectively. Mean difference from placebo and 95% confidence interval for mean difference are indicated. P < 0.0001 for all ecnoglutide cohorts compared to placebo. c Proportion of participants with body weight loss ≥5% from baseline at Day 134. BL baseline. Source data are provided as a Source Data file.

Fig. 5. Pharmacokinetics of ecnoglutide.

a Linear and b semilog plots of ecnoglutide concentrations (ng/mL) over time. Mean and standard deviation (SD) are shown. Numbers of participants (n) for the 0.4, 0.8, 1.2 mg ecnoglutide groups, respectively, are as follows: Day 1, 37, 36, 36; Day 22, 36, 35, 35; Day 50, 36, 34, 35; Day 92, 36, 34, 34; Day 134, 33, 31, 32; Day 137, 31, 28, 29; Day 148, 33, 28, 29; Day 169, 35, 34, 34. Source data are provided as a Source Data file.