878-P: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study of Adiponectin Agonist (PEG)-BHD1028 in Subjects with Insulin Resistance

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Introduction and Objective: Low adiponectin levels may contribute to insulin resistance. This first-in-human study evaluated adiponectin receptor agonist (PEG)-BHD1028 in subjects with insulin resistance. Methods: Adults with BMI ≥27 kg/m2, HOMA-IR ≥ 1.8, and HbA1c < 6.5% received subcutaneous injections of (PEG)-BHD1028 or placebo in single-ascending dose (SAD) cohorts (4, 8, 16, 32, and 64 μg/kg) and 28-day multiple-ascending dose (MAD) cohorts (8, 16, and 32 μg/kg QD). Each cohort had 8 subjects, with 2 on placebo. Areas under the curve (AUC) were obtained for insulin c-peptide, insulin, and glucose in a mixed meal tolerance test (MMTT) at Day -1 and Day 28. Body weight, triglycerides, and inflammatory markers were followed. Changes were analyzed by ANOVA (for MMTT) and generalized estimating equations (GEE). Results: The MAD cohort mean age was 49 years, with a body mass index 32, baseline HOMA-IR 3.8, and 42% female. Mild gastrointestinal adverse events occurred on (PEG)-BHD1028 (50%) and placebo (33%) without discontinuations. Drug exposure was proportional to dose. Insulin c-peptide AUC changes were +25% on placebo and -63%, +24%, and +2% on (PEG)-BHD1028 8, 16, and 32 μg/kg doses, p<0.001). Reductions in insulin AUC (p=0.116) and glucose AUC (p<0.001) were also observed, with the greatest percentage change on 8 μg/kg. There were no significant differences between groups in body weight, triglycerides, and inflammatory markers. Conclusion: Adiponectin agonist (PEG)-BHD1028 was well-tolerated with dose-related increases in exposure. Observed effects on insulin c-peptide, insulin, and glucose during the MMTT support further development. Disclosure P. Lapuerta: Consultant; Regeneron Pharmaceuticals, ViaCyte, Inc, Vertex Pharmaceuticals Incorporated, Youngene Therapeutics. B. Kim: Employee; EncuraGen, Inc.

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