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

Alexander W. Krug, Sandra A.G. Visser, Kuenhi Tsai, Bhargava Kandala, Craig Fancourt, Bob Thornton, Linda Morrow, Niels C. Kaarsholm, Harold S. Bernstein, S. Aubrey Stoch, Michael Crutchlow, David E. Kelley, Marian Iwamoto

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish
Pages (from-to)417-425
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume105
Issue number2
DOIs
StatePublished - Feb 2019
Externally publishedYes

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