793-P: Biased GLP-1 Analog Ecnoglutide (XW003) Has Improved Efficacy Relative to Unbiased Peptides

Introduction & Objective: Ecnoglutide (XW003) is a cAMP-biased GLP-1 analog being developed for the treatment of type 2 diabetes mellitus (T2DM) and obesity. The objective of this analysis was to compare the preclinical and clinical efficacy of ecnoglutide to unbiased GLP-1 peptides.

Methods: Ecnoglutide was assessed for cAMP production and β-arrestin recruitment in GLP-1R reporter cell lines. Glucose control was tested in db/db mice administered a single subcutaneous dose of GLP-1 analogs, with blood glucose recorded for 144 h. Body weight and insulin response were evaluated in db/db mice dosed with once daily injections of GLP-1 analogs for 42 days. A 20 week Phase 2 study was conducted in 145 patients with T2DM (ecnoglutide 0.4, 0.8, or 1.2 mg). Comparator clinical results were obtained from published reports.

Results: In vitro, cAMP induction was similar for ecnoglutide and semaglutide. EC50 values for β-arrestin recruitment were also similar, however, maximum recruitment and receptor internalization were lower for ecnoglutide. In mice, a single dose of ecnoglutide led to more sustainable decreases in blood glucose compared to semaglutide, extending glucose suppression by up to 48 h. In mice, ecnoglutide also significantly improved weight control and induced higher levels of insulin versus semaglutide. The increased preclinical potency of ecnoglutide translated into clinical efficacy. T2DM patients administered up to 1.2 mg ecnoglutide for 20 weeks had a -2.39% reduction in HbA1c. This compared to -1.14% reported for liraglutide (1.8 mg at 52 weeks), -1.55% to -1.86% for semaglutide (1.0 mg at 30-40 weeks), and -1.46% for dulaglutide (1.5 mg at 26 weeks). Furthermore, 1.2 mg ecnoglutide showed comparable HbA1c reductions to the biased dual GIP/GLP-1 receptor agonist, tirzepatide (15 mg), which reduced HbA1c by -2.30% at 40 weeks.

Conclusion: Bias for the cAMP pathway results in sustained signaling that correlates with increased clinical efficacy compared to unbiased GLP-1 analogs.