794 - Characterization of ARRY-438162, a Potent MEK Inhibitor in Combination with Methotrexate or Ibuprofen in In Vivo Models of Arthritis.

Jed Pheneger1, Eli Wallace1, Allison Marlow1, Brian Hurley1, Joe Lyssikatos1, Alison M. Bendele2, Patrice A. Lee1. 1Array BioPharma, Boulder, CO; 2Bolder BioPath, Boulder, CO
Presentation Number: 794

New agents being developed to treat rheumatoid arthritis (RA) will likely be used in combination with the current therapies for this disease, i.e., methotrexate and NSAIDs. PURPOSE: The objectives of these studies are to examine the effects of the addition of a selective mitogen-activated protein kinase (MEK) inhibitor, ARRY-438162, to either of these two standard therapies. ARRY-438162 is a potent (IC50=12 nM) inhibitor of MEK. Because it is un-competitive with ATP, it is also potent in cell systems (IC50=11 nM). METHODS: Rat collagen-induced arthritis (CIA) and rat adjuvant-induced arthritis (AIA) models were used to determine efficacy in the subacute inflammation setting. In the CIA studies, rats with established disease, induced by injections of Type II collagen, were treated with 0.3, 1 or 3 mg/kg ARRY-438162 (PO, BID) with or without 30 mg/kg ibuprofen (PO, QD) for six days. Body weight and ankle diameter were used to monitor disease progression on days 0-7. The AIA model was induced by an injection of a lipoidal amine in FCA on day 0. The AIA rats were treated with 1, 3 or 10 mg/kg ARRY-438162 (PO, QD) beginning on day 8 and continuing for 6 days, with or without the addition of 0.05 mg/kg methotrexate (PO, QD) which was dosed days 0-13. Disease progression was monitored on days 7-14 measuring both paw diameter and body weight. RESULTS: Treatment with ARRY-438162 reduced disease severity in a dose-related manner in both animal models. ARRY-438162 in the CIA model inhibited increases in ankle diameter by 27% and 50% at 1 and 3 mg/kg, while ibuprofen had 46% inhibition. When combined with ibuprofen, these same two doses resulted in 74% and 72% inhibition, respectively. Microscopic examination of the ankle joints showed ARRY-438162 significantly inhibited lesions (inflammation, cartilage damage, pannus formation and bone resorption) by 32% and 60% at 1 and 3 mg/kg, while treatment with ibuprofen alone resulted in 17% inhibition, which was not significantly different from the controls. When these two doses of ARRY-438162 were combined with ibuprofen, the result was 54% and 77% inhibition of joint destruction. In AIA, 3 and 10 mg/kg of ARRY-438162 inhibited AIA ankle diameter 11% and 34%, while MTX had 33% inhibition. When combined with MTX, 3 and 10 mg/kg of ARRY-438162 resulted in 55% and 71% inhibition. Microscopic examination of ankle joints for inflammation and bone resorption also showed improved efficacy versus either compound alone.
CONCLUSIONS: We have shown that a potent, selective inhibitor of MEK is additive to currently used therapies for RA with respect to inhibiting inflammation and joint destruction in preclinical models of this disease. This activity is dose-related, potent and extensive, and supports the clinical testing of ARRY-438162 in combination therapy in rheumatoid arthritis.

J. Pheneger, Array BioPharma, 1 Stocks or Stock options (in a for-profit corporation); Array BioPharma, 3 Employment (full or part time).