ARRY-162, A POTENT AND SELECTIVE INHIBITOR OF THE MEK 1/2, INHIBITS OSTEOCLAST DIFFERENTIATION AND BONE RESORPTION IN ADJUVANT-INDUCED ARTHRITIS

Background: Rheumatoid arthritis is a chronic disease, characterized by inflammation of the synovium, resulting in pain, loss of movement, and bone destruction. We have shown that the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK) kinase (MEK) plays an important role in regulating the inflammatory response in preclinical animal models of arthritis. However, the exact mechanism of how MEK regulates bone function is not well defined. We hypothesize that inhibition of MEK 1/2 would lead to the prevention of osteoclast (OCL) differentiation and modulates bone resorption. ARRY-162 is a potent and selective oral inhibitor of mitogen-activated protein kinase (MEK1/2) which has been shown to inhibit inflammation and joint destruction in preclinical models of disease as a single agent and in combination with current human standard-of-care therapies. Results: Here, we further investigated the effect of ARRY-162 on osteoclast and osteoblast (OCB) differentiation and function. Human pre-osteoclasts were stimulated with M-CSF (33 ng/mL) and RANKL (66 ng/mL) ± ARRY-162 for 7 days. TRAP staining (tartrate-resistant acid phosphatase) revealed that ARRY-162 inhibits OCL differentiation in a dose-dependent manner (IC50 = 39 nM). To assess bone resorption activity, fully differentiated OCL were cultured on a human bone plate. Resorption was determined by the measurement of free calcium in the cell supernatants, a direct indicator of osteoclast-mediated resorptive activity. ARRY-162 demonstrated potent inhibition of OCL-mediated resorption (IC50 = 625 nM). In contrast, ARRY-162 was shown to be a weak inhibitor of OCB differentiation; inhibiting OCB differentiation at doses 64-fold above the IC50 for OCL differentiation. To further characterize the effects of ARRY-162 in vivo, ARRY-162 was dosed using a therapeutic regimen (delayed dosing until after the onset of disease) in a rat model of adjuvant-induced arthritis, to determine if ARRY-162 has the ability to halt and/or reverse bone resorption and disease progression. ARRY-162, at all doses (3 to 30 mg/kg) and in a dose-related manner, inhibited both signs of inflammation (paw swelling, spleen weights) and bone density loss (as measured by CT and histopathology). Conclusion: These data indicate that ARRY-162 directly inhibits OCL differentiation and function with only minor effects of osteoblast differentiation, and has effective anti-inflammatory and bone protective effects in a therapeutic dosing regimen in AIA. These results suggest that ARRY-162 would be a very effective DMARD, controlling inflammation and blocking additional bone damage in arthritis. ARRY-162 is being evaluated in Phase II clinical trials of rheumatoid arthritis. Disclosure of Interest: A. Wright, Employee of Array BioPharma J. Pheneger, Employee of Array BioPharma A. Gomez, Employee of Array BioPharma J. Winkler, Employee of Array BioPharma E. Wallace, Employee of Array BioPharma P. Lee, Employee of Array BioPharmaCitation: Annals of the Rheumatic Diseases, volume 68, supplement 3, year 2009, page 379Session: Arthritis etiology, pathogenesis and animal models (Poster Presentations )