Clinical Evaluation of MK‐2640: An Insulin Analog With Glucose‐Responsive Properties

Abstract

The goal of this investigation was to examine clinical translation of glucose responsiveness of MK-2640, which is a novel insulin saccharide conjugate that can bind the insulin receptor or mannose receptor C type 1 (MRC1), the latter dependent upon glucose concentration. In a rising dose study in 36 healthy adults under euglycemic clamp conditions, rising exposures revealed saturation of MK-2640 clearance, likely due to saturation of clearance by MRC1. Potency of MK-2640 was ~25-fold reduced relative to regular human insulin. In a randomized, 2-period crossover trial in 16 subjects with type 1 diabetes mellitus to evaluate glucose-responsiveness of i.v. administered MK-2640, we were unable to demonstrate a glucose-dependent change in MK-2640 clearance, although a significant glucose-dependent augmentation of glucose infusion rate was observed. These pharmacokinetic (PK) and pharmacodynamic (PD) data provide crucial insights into next steps for developing an insulin saccharide conjugate as a clinically effective glucose-responsive insulin analog.

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

“…This finding is unexplained to date as we were not able to discriminate between experimental and mechanistic considerations without doing further studies. At higher MK-2640 concentrations a saturation of MK-2640 clearance was observed ( Figure 3 in Krug et al 21 ), similar to RHI's nonlinear clearance (Figure 2, left upper panel 23 ) but right-shifted by 25-fold. This suggests that the saturation in MK-2640 clearance, similar as for RHI, is driven by the insulin-receptor mediated clearance.…”

“…Based on the observed MK-2640 clearance and potency difference in nondiabetics, the infusion rate for MK-2640 was set in Part 2 in T1DM to 40 pmol/minutes/kg to reach equipotent steady-state levels that can maintain a 90 mg/dL glucose clamp target. In this PoM assessment, MK-2640 displayed a nonsignificant (6%) decrease in clearance at hyperglycemia vs. euglycemia, 21 rather than the predicted 30% based on preclinical studies. 28 Despite its PK limitations, MK-2640 manifested at hyperglycemia vs. euglycemia a modest PD differentiation from regular human insulin, stimulating a greater increase in glucose infusion rate, reflecting that there may be a glucose-dependent change in insulin action but that this is not reflected in systemic clearance change (Figure 4 lower panel).…”

“…In this study, glucose-responsiveness of i.v.-administered MK-2640, where MK-2640 PK, measured as clearance, and PD, measured as GIR, was evaluated at euglycemia (90 mg/dL) vs. hyperglycemia (300 mg/dL) in comparison to RHI. 21 During Part 1, the PK and PD for MK-2640 was assessed at euglycemia. Real-time modeling of the Part 1 data provided estimates of the MK-2640 clearance and the relative potency difference against RHI in nondiabetics based on the literature clinical RHI PKPD model (Fancourt 2015).…”

“…20 MK-2640 has been the first GRI that has advanced to the clinic to examine clinical translation of its glucose responsiveness. 21 The MK-2640 first-in-human study (ClinicalTrials.gov Identifier: NCT02269735) aimed to examine the safety, tolerability, and pharmacokinetic-pharmacodynamic (PKPD) relationship of intravenous (i.v.) administered MK-2640 in healthy nondiabetic subjects under euglycemic clamp conditions, and to examine proof of mechanism (PoM) in type 1 diabetes mellitus (T1DM) subjects by demonstrating a (glucose-responsive) change in clearance between euglycemic and hyperglycemic conditions.…”

Biologically Inspired and Chemically Derived Methods for Glucose‐Responsive Insulin Therapy

“…This strategy provided a means to enhance the activity and bioavailability of insulin upon glucose exposure, but the low K m of GOx for glucose meant that the enzyme would be too easily released from insulin, even in hypoglycemic conditions . These efforts extended to next‐generation efforts to develop saccharide‐modified insulin that would impart glucose‐responsive properties without a need for a protein component that are presently under clinical development …”