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Qu, Hongchang

Hongchang Qu

Eli Lilly

Talk Title

The Novel GIP, GLP-1, and Glucagon Triple Receptor Agonist LY3437943: From Discovery to Clinical Proof-of-Concept

Presentation Time

Monday, June 26, 2023, at 03:20 pm - 03:40 pm

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, HbA1c, 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 HbA1c 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.

Dr. Hongchang Qu is currently the Senior Director of the Peptide Therapeutic Group at Eli Lilly. Since he joined Lilly in 2013, he has led multiple preclinical peptide research projects and advanced them into clinical development to establish proof of concept. Prior to joining Eli Lilly, Dr. Qu was a Process Development Scientist for two years at the Polypeptide Laboratories. Dr. Qu holds a Ph.D. degree in organic chemistry from the University of Arizona and had postdoctoral training at University of Pennsylvania.

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