LAPS Insulin115: 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.
(© 2017 John Wiley & Sons Ltd.)