With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multi-receptor agonists in development may provide approaches to fulfill this unmet medical need. LY3437943 is a novel, unimolecular triple agonist peptide at the glucagon receptor, GCGR, glucose-dependent insulinotropic polypeptide receptor, GIPR, and glucagon-like peptide-1 receptor, GLP-1R. In vitro, LY3437943 shows balanced GCGR and GLP-1R activity, but more GIPR activity. In obese mice, administration of LY3437943 decreased body weight and improved glycemic control.

Body weight loss could be attributed to a combination of energy expenditure, primarily mediated by GCGR, and food intake, driven primarily by GLP-1R and GIPR. In a randomized, double-blind, placebo- controlled, Phase 1 proof-of-concept study, we assessed the safety and tolerability of multiple ascending doses of LY in patients with type 2 diabetes, T2D. 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 HbA_1c decreased from baseline in all groups, with higher doses of LY showing statistically significant baseline-adjusted decreases of up to 1.90%. Dose-dependent decreases in mean baseline-adjusted body weight of up to 8.65 kg were observed with LY.

In conclusion, LY3437943 showed a safety and tolerability profile similar to other incretins. Its pharmacokinetic profile supported once-weekly dosing. Promising glycemic and body weight loss efficacy within these studies highlights the potential for LY to provide additional benefit versus existing therapies in treatment of T2D and obesity.