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P062 The narrow spectrum kinase inhibitor TOP1288 demonstrates potent anti-inflammatory effects in a T cell adoptive transfer colitis model through a topical mode of action

Solanke Y., Foster M., Fyfe M., Rowley A., Sirohi S., Webber S., Walshe C.

Topivert Pharma Ltd, London, United Kingdom

Background

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 (NSKIs) have been specifically designed to have topical, non-systemic, effects in the colon after oral dosing. TOP1288 has already entered clinical development and is safe and well tolerated in a Phase 1 study. Here we compare the efficacy of an NSKI, TOP1288, to the systemically available immunosuppressant cyclosporine A (CsA) in a preclinical model of colitis.

Methods

In vitro anti-inflammatory 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 who received a single 5 mg/kg dose of TOP1288 by oral gavage. Compound levels in plasma and colon tissue were determined over 24hrs post dose. Compounds were also assessed in an adoptive transfer (AT) colitis model where mice received TOP1288 (3 mg/kg BID) or CsA (75mg/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 colon tissue cytokine levels.

Results

TOP1288 exhibits a broad and potent in vitro anti-inflammatory profile. In a PK study, TOP1288, after a 5mg/ml oral dose, had negligible systemic exposure (below the limit of detection, 1 ng/ml). In contrast, high colon exposure was observed (Cmax 3083 ng/ml and AUC 19841 hr*ng/ml). In an AT model of colitis, TOP1288 was comparable to CsA with marked anti-inflammatory effects on both histological endpoints and inflammatory cytokine release. Inhibition of IL-8 release correlated with a reduction in neutrophil infiltration. TOP1288 systemic exposure in the model was very low and comparable to that in the PK study. In contrast, CsA achieved very high systemic levels (>1.5 μg/ml).

Conclusion

TOP1288 has broad-acting, potent anti-inflammatory activity in vitro and in vivo. PK profiling of TOP1288 following oral dosing indicates that efficacy in the AT model in vivo is through a topical mode of action and is, at a 13 fold lower dose, comparable in effect to systemically available cyclosporine A. This data highlights the therapeutic potential of topical NSKIs, offering an improved efficacy and safety profile over current therapies.