106-OR: A First-in-Human Single Ascending Dose Study of Oxyntomodulin Analog LY3305677 in Healthy Subjects

LY3305677 (LY) is an acylated single chain peptide analog of mammalian oxyntomodulin designed for once weekly dosing. It has dual pharmacology of GLP-1 and glucagon and has therapeutic potential for T2D, obesity and NASH. This randomized, double blind, placebo-controlled phase 1 study assessed safety and tolerability of single ascending doses of LY. Healthy subjects (N=48) were randomized (6:2) and 47 received subcutaneous LY (6 doses: 0.03 mg to 5.0 mg) or placebo. Safety biomarkers, LY pharmacokinetics (PK), and key exploratory pharmacodynamic (PD) biomarkers were assessed including fasting insulin, glucagon, triglyceride levels, and body weight. Most common LY-related AEs were gastrointestinal events. Dose-dependent increase in nausea, decreased appetite, and vomiting were seen. Most of the events were mild and transient. Increase in heart rate was noted, which returned to baseline for most groups at follow-up visit. No injection site reactions were seen. Median time to maximum LY concentration ranged from 18.2 to 72.1 h, and geometric mean half-life ranged from 7.5 to 9.8 days. Generally, mean fasting insulin level increased within 24 h and lasted over 8 days. At Day 8, LY 2.5 mg and 5.0 mg reduced mean fasting glucagon levels by 2.33 pmol/L and 2.67 pmol/L, respectively as compared with placebo. At Day 5, mean fasting triglyceride levels reduced from baseline by 0.5 mmol/L with LY 5.0 mg as compared to 0.1 mmol/L with placebo. Change from baseline in body weight reached a maximum -2.4 kg with the 5 mg dose, versus -0.5 kg for placebo at Day 8 and this effect was sustained through Day 29 at 5 mg. LY3305677 PK properties are suitable for once-weekly dosing with a safety and tolerability profile similar to other incretins in Phase 1 trials, supporting future clinical evaluation.