1871-LB: Phase 1 Topline Safety, Efficacy, and Pharmacokinetics of Oral Ecnoglutide

Introduction & Objective: Ecnoglutide is a cAMP-biased, long-acting GLP-1RA being developed for the treatment of type 2 diabetes mellitus and obesity. Oral ecnoglutide (XW004) is formulated with an absorption enhancer, PNAC (T2026). The objective of this study was to evaluate the safety and tolerability of oral ecnoglutide in healthy adults. Methods: We conducted a randomized, double-blind, placebo-controlled Phase 1 study in healthy (Cohorts 1 to 3) and healthy obese (Cohort 4) adults. Participants (n = 56) were randomized to receive oral ecnoglutide at target doses of 7, 15, or 30 mg QD for up to 6 weeks, with dose escalation. Safety, tolerability, PK, and body weight were assessed. The results of Cohorts 1 to 4 are presented, the study is ongoing to evaluate additional dosing schemes. Results: Oral ecnoglutide was generally safe and well tolerated. The most common AEs were mild to moderate gastrointestinal events that occurred during dose escalation. There were no serious AEs. One participant experienced a Grade 3 AE of diarrhea that led to study drug discontinuation. At baseline, participants had a mean BMI of 25.8 to 26.1 kg/m2 (Cohorts 1 to 3) and 32.9 kg/m2 (Cohort 4). At end of treatment, participants in Cohorts 1 to 3 receiving up to 7, 15, or 30 mg QD oral ecnoglutide for 2 weeks had body weight change from baseline of -3.63, -3.38, and -6.55%, respectively vs -0.85% for placebo. Participants in Cohort 4 receiving up to 30 mg QD for 6 weeks had a body weight reduction of -6.76% vs -0.85% for placebo. At steady state, oral ecnoglutide 30 mg QD resulted in a plasma AUC0-24h of 12,470 h*ng/mL and calculated weekly AUC 0-168h of 87,290 h*ng/mL. Conclusion: Oral ecnoglutide was safe and well tolerated and resulted in pronounced weight loss after 6 weeks of dosing. Improved oral bioavailability enables a daily dose of 30 mg oral ecnoglutide to match or exceed the plasma exposure of weekly subcutaneous GLP-1 analogs. Oral ecnoglutide has a potential to be a best-in-class oral GLP-1RA. Disclosure Z. Zhu: None. Y. Li: Employee; Sciwind Biosciences. G. Wanjun: Employee; Sciwind Biosciences. Q. Zheng: Employee; Sciwind Biosciences. J. Deng: Employee; Sciwind Biosciences. E. Adegbite: Employee; Sciwind Biosciences. S. Ross: None. L. Telusca: None. C.L. Jones: Employee; Sciwind Biosciences. M. Fenaux: None. S. Xu: None. M.K. Junaidi: None. Funding Sciwind Biosciences