@article{506dd47f739a455399aae81824145cee,
title = "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.",
author = "Krug, {Alexander W.} and Visser, {Sandra A.G.} and Kuenhi Tsai and Bhargava Kandala and Craig Fancourt and Bob Thornton and Linda Morrow and Kaarsholm, {Niels C.} and Bernstein, {Harold S.} and Stoch, {S. Aubrey} and Michael Crutchlow and Kelley, {David E.} and Marian Iwamoto",
note = "Funding Information: Funding for this research was provided in its entirety by Merck Sharp & Dohme, a subsidiary of Merck, Kenilworth, NJ. The sponsor was involved in trial designs; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. MK-2640 has been developed by Merck. The authors thank all participants in the clinical studies. Amy Cheng is acknowledged for operational support. Iris Xie, Sheila Breidinger, Lena Hofer, and Lucy Ghannoum are all acknowledged for bioanalytical support, and Catherine Matthews is acknowledged for noncompartmental analysis. Dan Xiao is acknowledged for programming of final datasets. Ravi Nargund, Songnian Lin, James Mu, Vijay Reddy, Ester Carballo-Jane, Theresa Kelly, and Margaret van Heek are acknowledged for their contribution to the discussion of the trial designs. Funding Information: Funding for this research was provided in its entirety by Merck Sharp & Dohme, a subsidiary of Merck, Kenilworth, NJ. The sponsor was involved in trial designs; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. MK-2640 has been developed by Merck. Publisher Copyright: {\textcopyright} 2018 American Society for Clinical Pharmacology and Therapeutics",
year = "2019",
month = feb,
doi = "10.1002/cpt.1215",
language = "English",
volume = "105",
pages = "417--425",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Wiley-Blackwell",
number = "2",
}