P064 TOP1210 narrow spectrum kinase inhibitor demonstrates superior activity and improved safety profile potential compared with corticosteroid and immunomodulators in preclinical models of colitis
C. A. Walshe*, A. Rowley, M. R. Foster, Y. Solanke, S. Sirohi, M. C. Fyfe, S. Webber
Topivert Pharma Ltd, London, United Kingdom
Unwanted systemic side effects are often associated with current therapies for inflammatory bowel disease, particularly corticosteroids, immunomodulators, and tofacitinib. A series of narrow spectrum kinase inhibitors (NSKI) have been specifically designed to have topical, non-systemic, effects in the colon after oral dosing. These novel NSKIs target key kinases involved in inflammatory signalling cascades. Here we compare the efficacy of an NSKI, TOP1210, to either corticosteroid or cyclosporine A in preclinical models of colitis.
In-vitro activity was assessed in lipopolysaccharide stimulated peripheral blood mononuclear cells (PBMCs) and anti-CD3/anti-CD28 stimulated PBMCs. Pharmacokinetic profiling was performed in C57BL/6 mice. Mice received a single 5 mg/kg dose of TOP1210 by oral gavage. Compound levels in plasma and colon tissue were determined at over 24 hrs after dose. Compounds were also assessed in adoptive transfer colitis model where animals received TOP1210 (0.04mg/kg–5mg/kg BID), Budesonide (1 mg/kg BID) or cyclosporine A (75 mg/kg QD), by oral gavage, for 28 days. Plasma exposure was measured on days 22 and 38. Efficacy was assessed on measures of colon oedema, histopathology, and colonic cytokine levels.
TOP1210 exhibited a broader and more potent in-vitro anti-inflammatory profile compared with corticosteroid and cyclosporine A. In a naïve mice PK study, TOP1210 had minimal systemic exposure after a 5 mg/kg oral dose (Cmax 11.7 ng/ml, AUC 48.9 hr*ng/ml). In contrast, high colonic exposure was achieved (Cmax 13671.2 ng/ml and AUC 117472.9 hr*ng/ml). In the adoptive transfer model of colitis, TOP1210 achieved dose-dependent anti-inflammatory effects on both histological endpoints and IL-8 cytokine release. Inhibition of IL-8 release correlated with a reduction in neutrophil infiltration. TOP1210 systemic exposure in the model was comparable with exposure in naïve mice. Efficacy of TOP1210 was superior to the maximum tolerated dose of Budesonide (1mg/kg). Cyclosporine A had very high systemic levels (> 1.5 µg/ml), where TOP1210 achieves comparable efficacy but at a 15-fold lower dose and with only minimal systemic exposure.
TOP1210 has broad-acting, potent anti-inflammatory effects in preclinical models of colitis. PK profiling of TOP1210 indicates these effects are achieved by a topical mode of action. The anti-inflammatory effects of TOP1210 are superior to Budesonide and comparable with systemically acting cyclosporine A. These data highlight the therapeutic potential of topical NSKIs, offering an improved efficacy and safety profile over current therapies.