Abstract / Summary
Low adiponectin levels may contribute to insulin resistance. This first-in-human study evaluated adiponectin receptor agonist (PEG)-BHD1028 in subjects with insulin resistance. 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 multiple-ascending dose (MAD) cohorts for 28 days (8, 16, and 32 μg/kg QD). Each cohort had eight subjects, with two on placebo. Area under the curve (AUC) was 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 measured at regular intervals. Changes were analyzed by the Kruskal-Wallis test (for MMTT) and generalized estimating equations (GEEs). The MAD cohort mean age was 49 years, with a body mass index of 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 (p = 0.116) were also observed, with the greatest percentage change on 8 μg/kg. There were no consistent differences between groups in body weight, triglycerides, and inflammatory markers. Adiponectin agonist (PEG)-BHD1028 was well-tolerated with dose-related increases in exposure. Observed effects on insulin c-peptide and insulin during the MMTT support further development.
Primary Source
Clinical and translational science
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