340-OR: LY3437943 (LY) , a Novel Triple GIP/GLP-1/Glucagon Receptor Agonist, Provides Glucose Lowering and Weight Loss in Patients with T2DM after 12 Weeks of Treatment

Multi-receptor incretin agonists are being developed for several metabolic disorders. LY is an investigational triple agonist with potent activity on glucose-dependent insulinotropic polypeptide (GIP) , glucagon-like polypeptide-1 (GLP-1) , and glucagon receptors. LY was safely studied in a prior first-in-human study and pharmacokinetics properties supported once weekly dosing. The primary objective of this randomized, double-blind, placebo-controlled, Phase 1 proof-of-concept study was to assess the safety and tolerability of multiple ascending doses of LY in patients with type 2 diabetes (T2D) . Seventy-two patients were randomized (9:3:1) to 5 rising dose cohorts of subcutaneous LY, placebo, and dulaglutide 1.5mg, respectively. Within cohort, dose-escalation was implemented at highest 2 cohorts. Vital signs, laboratory data and adverse events (AEs) were monitored to assess safety and tolerability. Efficacy was assessed by monitoring change in glycated hemoglobin (HbA_1c) and body weight at week 12. The most common treatment-emergent AEs were gastrointestinal (nausea and diarrhea) , which were mostly mild in severity. By week 12, mean systolic and diastolic blood pressure decreased from baseline in LY compared to placebo group, while pulse and heart rate increased from baseline within most LY cohorts and dulaglutide, but not with placebo. By week 12, mean HbA_1c decreased from baseline in all groups, with higher doses of LY showing statistically significant placebo-adjusted decreases of up to 1.56%. Except at the initial cohort, dose-dependent decreases in mean placebo-adjusted body weight of up to 8.96 kg were observed with LY. LY3437943 exhibits safety and tolerability profile similar to other incretins. Promising glycemic and body weight loss efficacy within this study highlights the potential for LY to provide additional benefit versus existing therapies in treatment of T2D and obesity.