943-P: Role of Model-Informed Drug Development in Confirming Additional Clinical Benefits of Dulaglutide

Throughout the development cycle of dulaglutide, model‐informed drug development (MIDD) was applied to facilitate and accelerate decision‐making. Currently, dulaglutide 0.75 mg and 1.5 mg given subcutaneously once weekly (QW) is approved for the treatment of type 2 diabetes. Post-approval, pharmacokinetic/pharmacodynamic (PKPD) exposure-response and mechanistic quantitative system pharmacology (QSP) models which leveraged accrued phase 1 data led to the hypothesis that additional glycemic control was possible with higher dulaglutide doses of 3.0 mg and 4.5 mg. MIDD was utilized to design a phase 2 study which explored the safety and efficacy for 3.0 mg and 4.5 mg versus 1.5 mg QW doses and tested a dose escalation approach for mitigating gastrointestinal (GI) nausea/vomiting effects for the investigational doses. Phase 2 data enriched understanding of benefit-risk of the extended doses and refined the dose escalation scheme for the pivotal phase 3 trial (AWARD-11). Efficacy and GI tolerability from AWARD-11 closely resembled model-predictions. While MIDD has been most commonly applied in dose-selection, novel MIDD approaches were also adopted for the dulaglutide program to design a dose escalation scheme and evaluate drug-drug interactions (DDI). Acetaminophen PK from previous gastric emptying studies covering a wide range of dulaglutide doses was used to characterize the extent of gastric-emptying delay (GED) related to 4.5 mg of dulaglutide and this extent of GED was then applied to physiologically based pharmacokinetic (PBPK) models of individual commonly co-administered oral agents to simulate effect of delayed gastric emptying on their PK profiles. Overall, a range of quantitative models were successfully employed to predict effects of and inform clinical trial design for higher dulaglutide doses for patients needing additional glycemic control.