Preclinical pharmacology of RA15127343: In vitro and in vivo activity of a novel ultralong-acting basal insulin.

Aim: To report the in vitro and in vivo preclinical pharmacokinetic (PK) and pharmacodynamic (PD) properties of RA15127343, a novel ultralong-acting insulin analogue targeting once-weekly administration, in female Göttingen minipigs.

Methods: In vitro binding and activation of human insulin receptor isoforms (IR-A/IR-B), glucose uptake in rat myocytes, as well as mitogenic activity of RA15127343 were evaluated. In vivo, the PK and PD activities of RA15127343 were assessed in female, normoglycaemic Göttingen minipigs. The half-life (t ) and time to maximum plasma concentration (T ) of subcutaneously (SC) administered RA15127343 (10/30/45/60 nmol/kg) were estimated. In vivo blood glucose and endogenous plasma C-peptide concentrations after single SC administration (10/30/45/60 nmol/kg) or repeated dosing (15 nmol/kg) were analysed.

Results: In comparison to human insulin, RA15127343 showed lower in vitro binding affinity (19.9/6.31 μM vs. 1.10/1.14 nM) and activation (2.054 μM/669.6 nM vs. 26.04/18.24 nM) of IR-A/IR-B, lower potency to activate glucose uptake (855.2 vs. 3.37 nM) and lower mitogenic activity (17.92 μM vs. 10.78 nM; proliferation in MCF7 cells). In vivo, the mean t and T of RA15127343 after SC administration ranged from 48 to 59 and 30 to 39 hours, respectively. Blood glucose and plasma C-peptide concentrations were significantly lower with RA15127343 (single/repeated doses) versus vehicle.

Conclusions: RA15127343 showed an ultra-long t with a slow onset of action. The preclinical pharmacological outcomes suggest RA15127343 could be a potential ultralong-acting insulin analogue with low risk of hypoglycaemia in humans.