ARRY-162, A NOVEL INHIBITOR OF MEK KINASE: PHASE 1A-1B PHARMACOKINETIC AND PHARMACODYNAMIC RESULTS

Background: MEK is a MAPKK involved in growth factor signal transduction and cytokine production. Hence, this kinase plays a critical role in mediating and propagating the effects of pro-inflammatory cytokines in the disease state. ARRY-162 is an orally available, potent and selective allosteric inhibitor of MEK in development for treatment of inflammatory diseases such as rheumatoid arthritis (RA). The safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of ARRY-162 have been assessed in double-blind, placebo-controlled, escalating dose studies for 14 days in healthy normal volunteers (HNV; n = 50) and for 28 days in RA patients taking stable doses of methotrexate (MTX; n = 30).Methods: Subjects received oral doses of ARRY-162 (NHV: 5, 10, 20, 40, 60, 80 mg QD or 20 mg BID; RA patients: 10, 20, 40 mg QD or 10, 20 mg BID). Blood was collected at various time points on the first and last day of dosing for each cohort in both studies and stimulated ex vivo with 12-O-tetradecanoylphorbol-13-acetate (TPA). After 24 hours, plasma was prepared and analyzed for levels of IL-1β, TNF and IL-6 by ELISA. For each subject, data were normalized to percentage of Day 1 pre-dose response. Plasma concentrations of ARRY-162 and MTX were also determined using LC-MS/MS methods.Results: ARRY-162 was generally well-tolerated for 14 and 28 days. Dose-dependent inhibition of TPA-induced IL-1β, TNF and IL-6 was observed with the higher dose cohorts having near complete inhibition of these biomarkers for at least 4 hours. For example, in the 40 mg QD cohort after 14 days of dosing, there was >97% inhibition of IL-1β, >75% inhibition of TNF and >85% inhibition of IL-6. In the 40 mg QD cohort after 28 days of dosing in RA patients, there was >90% inhibition of IL-1β, >95% inhibition of TNF and >95% inhibition of IL-6. Each of these cytokine levels remained suppressed throughout each 24 hours following 40 mg QD. ARRY-162 exhibited dose-proportional PK consistent with prior single-agent results. There was no indication of PK drug-drug interactions between ARRY-162 and MTX. Levels of the ex vivo biomarkers were closely linked to plasma concentrations of ARRY-162.Conclusion: In these Phase 1a and 1b studies, ARRY-162 was well tolerated and significantly inhibited the production of clinically relevant biomarkers such as IL-1, TNF and IL-6. Based on these encouraging data, a 12-week Phase 2 study of ARRY-162 in patients with RA has been initiated.Citation: Ann Rheum Dis, volume 67, supplement II, year 2008, page 87Session: RA: new targets, new bullets – early clinical experience