title: Half-life prolongation of therapeutic proteins by conjugation to ATIII-binding pentasaccharides: a first-in-human study of CarboCarrier® insulin.
abstract: OBJECTIVE
  Conjugation to antithrombin III ATIII-binding pentasaccharides has been proposed as a novel method to extend the half-life of therapeutic proteins. We aim to validate this technological concept in man by performing a first-in-human study using CarboCarrier® insulin (SCH 900948) as an example. A rising single dose phase 1 study was performed assessing safety, tolerability, pharmacokinetics and relative bioactivity of CarboCarrier® insulin. Safety, tolerability and pharmacokinetics (PK) of single doses of CarboCarrier® insulin in healthy volunteers were explored, and the dose-response relationship and relative bioactivity of CarboCarrier® insulin in subjects with type 2 diabetes were investigated.
  
  
  METHODS
  After an overnight fast, subjects were randomized to a treatment sequence. PK and pharmacodynamic (glucose, insulin and C-peptide) samples were obtained for up to 72 h post-dose. Effects of CarboCarrier® insulin were compared with those of NPH-insulin.
  
  
  RESULTS
  CarboCarrier® insulin was safe and well-tolerated and no consistent pattern of adverse events occurred. CarboCarrier® insulin exposure (Cmax and AUC) increased proportionally with dose. The mean terminal elimination half-life ranged between 3.11 and 5.28 h. All CarboCarrier® insulin dose groups showed decreases in the mean change from baseline of plasma glucose concentrations compared with the placebo group.
  
  
  CONCLUSIONS
  CarboCarrier® insulin is pharmacologically active showing features of insulin action in man. The elimination half-life of the molecule was clearly extended compared with endogenous insulin, indicating that conjugation to ATIII-binding pentasaccharides is a viable approach to extend the half-life of therapeutic proteins in humans. This is an important step towards validation of the CarboCarrier® technology by making use of CarboCarrier® insulin as an example.
authors.affiliation: Early Stage Development, MSD (NV Organon), PO Box 20, 5340 BH, Oss, The Netherlands. a.miltenburg@merck.com
authors.forename: André M M
authors.initials: AM
authors.lastname: Miltenburg
authors.forename: Marita
authors.initials: M
authors.lastname: Prohn
authors.forename: Jacqueline H M
authors.initials: JH
authors.lastname: van Kuijk
authors.forename: Renger G
authors.initials: RG
authors.lastname: Tiessen
authors.forename: Martin
authors.initials: M
authors.lastname: de Kort
authors.forename: Rob J W
authors.initials: RJ
authors.lastname: Berg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood; D049528:Insulin, Long-Acting / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009844:Oligosaccharides / Q000737:chemistry; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D004337:Drug Carriers; D006442:Glycated Hemoglobin; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D009844:Oligosaccharides; C583717:SCH 900948; C517652:hemoglobin A1c protein, human