A Model‐Informed Drug Discovery and Development Strategy for the Novel Glucose‐Responsive Insulin MK‐2640 Enabled Rapid Decision Making

Abstract

A model-informed drug discovery and development strategy played a key role in the novel glucose-responsive insulin MK-2640's early clinical development strategy and supported a novel clinical trial paradigm to assess glucose responsiveness. The development and application of in silico modeling approaches by leveraging substantial published clinical insulin pharmacokinetic-pharmacodynamic (PKPD) data and emerging preclinical and clinical data enabled rapid quantitative decision making. Learnings can be applied to define PKPD properties of novel insulins that could become therapeutically meaningful for diabetic patients.

Review: Glucose-sensitive insulin

“…The main problem was too low insulin potency, likely because of high background clearance via mannose receptor. MK-2640 showed approximately 25-fold lower glucodynamic potency than regular insulin [ 88 ], which is not surprising since similar lower potency had been observed in animal models. Elegant clinical clamp studies showed a 44% change in the glucose infusion rate when comparing MK-2640 vs human insulin, but there was no change in the insulin clearance rate at high blood glucose vs normoglycemia, which contrasts with a 30% difference observed for MK-2640 in preclinical studies [ 85 ].…”

‘Smart’ insulin-delivery technologies and intrinsic glucose-responsive insulin analogues

“…Although animal-based and pilot clinical studies were pursued, this approach is no longer under development. These challenges to create a modified insulin with an improved therapeutic index that enables tighter glycaemic control with a reduced risk for hypoglycaemia, as well as the challenges of translating in vivo animal models and data for application in humans, highlight the importance of developing better in silico GRI modelling in the developmental pipeline [23,[103][104][105].…”

“…In addition to the elegance of the associated chemistries and macromolecular structures, ongoing research has a compelling clinical motivation: to enhance the health and quality of life of patients with type 1 diabetes and of patients with type 2 diabetes refractory to oral therapy-and with less burden on patients [136]. To bridge the valley between basic science and clinical applications, in silico simulations of animal physiology and human patients are likely to provide key guidance [23,[103][104][105].…”

The future of insulin therapy

“…Glucose clamp studies in healthy dogs showed that when glucose levels were lowered to euglycaemic levels, MK-2640 was pre-dominantly cleared via MRC-1 reducing its availability for clearance through the insulin receptor. While hypoglycaemia could be induced with MK-2640 in mini-pigs, this required considerably higher doses than with regular human insulin even when taking the lower affinity of MK-2640 with an approximately 25-fold lower glucodynamic potency [47] into account. These results could partly be confirmed in a glucose clamp study in people with type 1 diabetes [45] showing significantly higher glucose infusion rates (GIR) with MK-2640 than with human regular insulin at hyperglycaemic levels (plasma glucose target 16.7 mmol/l) whereas GIR at euglycaemia were comparable (Fig.…”