From In Vitro Efficacy to Long-Term HbA1c Response for GLP-1R/GlucagonR Agonism Using the 4GI-HbA1c Systems Model

For the treatment of Type 2 Diabetes, high efficacy approaches such as Glucagon-like peptide 1 (GLP-1)-based therapies are recommended for glucose control. Prediction of the clinical outcome of these therapies on glucose and hemoglobin A1c (HbA1c), using early available pharmacokinetic and in vitro efficacy information, can be a valuable tool for compound selection and supporting drug development. Our previously developed glucose homeostasis model (the 4GI model) is a systems model that is able to quantify drug effects on glucose based on in vitro potency and PK information. In this research, the model was coupled to an existing integrated glucose-red blood cell-HbA1c (IGRH) model for predicting the effects of GLP-1 and GLP-1/glucagon (dual) receptor agonists, liraglutide and cotadutide, on glucose and HbA1c. The 4GI model was validated for predicting 24-h glucose (C_glc,av) with minimal model calibration using short-term Ph2a continuous glucose monitoring (CGM) data. Subsequently, the predicted C_glc,av served as input for the HbA1c model to assess the predictiveness of the combined 4GI-HbA1c model on HbA1c. The resulting combined model was used in cotadutide's clinical development by providing predictive insights into the 26 weeks glucose and HbA1c dynamics of the Ph2b study prior to its initiation. Retrospective analysis showed that the model adequately predicted the effect of cotadutide and liraglutide on fasting plasma glucose and HbA1c (Root Means Square Percent Error (RMSPE) 5.9% and 13%, respectively). This demonstrates the potential of the 4GI-HbA1c systems model as a valuable tool in supporting the clinical development of novel GLP-1 and/or glucagon agonists.