ARRY-797, A SELECTIVE, POTENT INHIBITOR OF P38, PROMOTES DISEASE NORMALIZATION IN ANIMAL MODELS OF RHEUMATOID ARTHRITIS AND SIGNIFICANTLY REDUCES EX VIVO IL-1 BETA, PGE2 AND TNF- ALPHA PRODUCTION IN NORMAL HUMAN SUBJECTS

Background: The p38 MAPK pathway is activated in numerous inflammatory conditions, including RA, IBD asthma, acute coronary syndrome, and chronic obstructive pulmonary disease. Although p38 has been the target of many drug discovery efforts which produced clinical candidates that inhibit TNF-alpha and IL1-β release, very few have moved into late stages of development. ARRY-797 is a potent inhibitor of p38alpha enzyme (IC50<5nM). This compound has physiochemical properties quite distinct from other p38 inhibitors, being very water soluble. In addition, it is selective for inhibition of p38, versus ∼200 other kinases and is extremely potent in human whole blood, blocking LPS-stimulated TNF-alpha production with an IC50<1 nM.Results: In an in vivo mouse model of LPS-induced TNF-alpha, ARRY-797 significantly inhibits TNF-alpha production at doses as low as 1 mg/kg (52% inhibition). In animal models of rheumatoid arthritis (CIA and AIA), ARRY-797 significantly normalizes histologic endpoints, such as inflammation, bone resorption and cartilage damage (ED50∼3 mg/kg in both animal models). In Phase I clinical studies, healthy volunteers were administered a single oral dose of ARRY-797 (25, 50, 100, 200, 300 or 400 mg); blood was drawn at various times after dosing and stimulated ex vivo with LPS. Plasma samples were then analyzed to determine concentrations of various cytokines and inflammatory mediators. ARRY-797 was well-tolerated and drug exposure was dose-proportional. In ex vivo blood samples, there was a significant time- and concentration-dependent inhibition of LPS-induced IL-1"eta, PGE2 and TNF-alpha, with >80% inhibition observed at the 50 mg dose level. Consistent with the robust potency in whole blood, the plasma concentrations of parent drug peaked at ∼20 nM at the 50 mg dose and cytokine inhibition was sustained for >4 hours.Conclusion: Thus, low doses of ARRY-797 produced profound effects on clinical biomarkers. Further clinical evaluation of ARRY-797 in patients with inflammatory diseases is planned.Citation: Ann Rheum Dis, volume 66, supplement II, year 2007, page 445Session: RA – non-biologic treatment