Half-life prolongation of therapeutic proteins by conjugation to ATIII-binding pentasaccharides: a first-in-human study of CarboCarrier® insulin.

Aim 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 (R) insulin (SCH 900948) as an example. A rising single dose phase 1 study was performed assessing safety, tolerability, pharmacokinetics and relative bioactivity of CarboCarrier (R) insulin. Safety, tolerability and pharmacokinetics (PK) of single doses of CarboCarrier (R) insulin in healthy volunteers were explored, and the doseresponse relationship and relative bioactivity of CarboCarrier (R) 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 72h post-dose. Effects of CarboCarrier (R) insulin were compared with those of NPH-insulin. Results CarboCarrier (R) insulin was safe and well-tolerated and no consistent pattern of adverse events occurred. CarboCarrier (R) insulin exposure (Cmax and AUC) increased proportionally with dose. The mean terminal elimination half-life ranged between 3.11 and 5.28h. All CarboCarrier (R) insulin dose groups showed decreases in the mean change from baseline of plasma glucose concentrations compared with the placebo group. Conclusions CarboCarrier (R) 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 (R) technology by making use of CarboCarrier (R) insulin as an example.