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

Clin Pharmacol Ther. 2019 Feb;105(2):417-425. doi: 10.1002/cpt.1215. Epub 2018 Sep 30.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Adolescent
  • Adult
  • Antigens, CD / drug effects
  • Blood Glucose / drug effects*
  • Cross-Over Studies
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Glucose Clamp Technique
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / adverse effects
  • Insulin / analogs & derivatives*
  • Insulin / pharmacokinetics
  • Insulin / therapeutic use
  • Male
  • Middle Aged
  • Receptor, Insulin / drug effects
  • Young Adult


  • Antigens, CD
  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • MK-2640
  • INSR protein, human
  • Receptor, Insulin