LAPSInsulin115: A novel ultra-long-acting basal insulin with a unique action profile

Aims: To conduct a comprehensive pre-clinical study of the novel ultra-long acting insulin analogue (LAPS)Insulin115. Methods: Pharmacokinetic/pharmacodynamic studies comparing (LAPS)Insulin115 with other basal insulins were conducted in genetically diabetic (db/db) mice. Insulin signalling in the major target organs was analysed using Western blot after single subcutaneous injection in wild-type male Wistar rats. Using in vitro assays we analysed transendothelial transport, insulin receptor (IR) interaction, and the mitogenic and metabolic properties of (LAPS)Insulin115. Furthermore, IR downregulation after long-term exposure to high concentrations of (LAPS)Insulin115 was analysed using an in vitro desensitization/resensitization model. Results: The novel Fc-conjugated insulin derivative (LAPS)Insulin115 showed an extensively prolonged pharmacokinetic and pharmacodynamic profile in rodents. Despite its size of 59 kDa, (LAPS)Insulin115 passes the vascular endothelial barrier and induces insulin signalling in all major target tissues in rats. In vitro, (LAPS)Insulin115 showed a very slow onset of action because of its reduced IR affinity; however, after long-term stimulation it was equipotent in respect to its metabolic potency and showed no increased mitogenic action when compared with regular insulin. Remarkably, under conditions of chronic exposure, (LAPS)Insulin115 does not induce irreversible desensitization of target cells, which is probably attributable to much less prominent IR downregulation. Conclusion: Thus, (LAPS)Insulin115 exhibits a unique in vivo and in vitro profile and thereby represents an excellent candidate for a once-weekly insulin analogue.