ARRY-162, A SELECTIVE, POTENT MEK1/2 INHIBITOR, SIGNIFICANTLY REDUCES EX VIVO IL-1 BETA AND TNF ALPHA; PRODUCTION IN NORMAL SUBJECTS

Background: The MEK-ERK pathway is activated in numerous inflammatory conditions, including RA, IBD and COPD, and activation of this pathway plays a role in the production of inflammatory mediators, such as IL-1β and TNFα.Objectives: To examine the efficacy associated with inhibition of this pathway, we have discovered and are developing ARRY-162, a potent (IC50 = 12 nM), selective, ATP-uncompetitive MEK1/2 inhibitor.Results: Inhibition of the MEK-ERK pathway, as expected, reduces mediator production in vitro: in TPA-stimulated human whole blood, this compound inhibited TNFα, IL-1β, and IL-6 production (IC50s of 23, 21 and 21 nM, respectively). This ability to inhibit mediator production is consistent with preclinical efficacy: ARRY-162 is highly efficacious in CIA and AIA rat models, with ∼ED50s of 3 and 10 mg/kg, respectively, equal to or better than standard agents. Because of its different mechanism of action, addition of ARRY-162 to methotrexate, etanercept, ibuprofen or dexamethasone regimens in these models results in improved efficacy that is at least additive, if not synergistic. As a result of excellent preclinical efficacy, tolerability and development properties, ARRY-162 has moved into clinical trials. In a single ascending dose study, healthy volunteers were administered an oral dose of ARRY-162 (5, 10, 20, 30, 40 or 80 mg); blood was drawn at various times after dosing and stimulated ex vivo with TPA. ARRY-162 was well-tolerated and drug exposure was dose-proportional. In ex vivo samples, there was both a time- and concentration-dependent inhibition of TPA-induced IL-1β and TNFα, with >80% inhibition observed at plasma concentrations of >50 and 150 ng/ml, respectively. Similar inhibition of pERK required 300 ng/ml, demonstrating that inhibition of the pro-inflammatory processes is very sensitive to pERK inhibition. A multiple ascending dose clinical study has confirmed the pharmacokinetics and pharmacodynamics of ARRY-162 and helped define tolerability. Clinical evaluation of ARRY-162 in combination with methotrexate in patients with rheumatoid arthritis is on-going.Citation: Ann Rheum Dis, volume 66, supplement II, year 2007, page 444Session: RA – non-biologic treatment