ARRY-162 is a first-in-class, orally active, MEK inhibitor, that has demonstrated potent anti-inflammatory and bone-protective activity along with synergistic efficacy and a low side effect profile in preclinical models of inflammatory diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). MEK has been demonstrated to regulate the biosynthesis of certain pro-inflammatory cytokines, in particular, TNF, IL-6 and IL-1. We believe the inhibition of MEK will have broad therapeutic applications in the treatment of inflammatory and chronic degenerative diseases driven by these cytokines such as RA, OA, chronic obstructive pulmonary disease, psoriasis and inflammatory bowel disease.
About MEK Inhibition
Pro-inflammatory proteins, or cytokines, have been broadly implicated as playing detrimental roles in a number of inflammatory diseases. MEK is an enzyme that interferes with the biosynthesis process and regulates the production of the inflammatory cytokines TNF, IL-6 and IL-1. Modulation of MEK has been shown to provide clinical benefit in the treatment for a number of inflammatory diseases. Our extensive experience with MEK inhibitors leads us to believe that this target will have a number of applications in cytokine driven diseases and be amenable to chronic modulation that is well tolerated by patients.
Phase 1 Clinical Trial
We initiated Phase 1 clinical testing of ARRY-162 in January 2007 in healthy volunteers. The results were reported at the 2007 European League Against Rheumatism (EULAR) conference and at the International Association of Inflammation Societies’ (IAIS) 8th World Congress on Inflammation. The multiple ascending dose (MAD) study of ARRY-162 showed 50 to 90 percent inhibition of TNF, IL-6 and IL-1 when measured over a 24 hour period with 40 mg daily. The single ascending dose (SAD) study, when administered orally at 5 to 80mg, was shown to also inhibit the production of TNF, IL-6 and IL-1. ARRY-162 did not inhibit anti-inflammatory cytokines IL-1RA or TNFRII, and was well tolerated with no serious adverse affects, showing dose proportional to human pharmacokinetics in both MAD and SAD studies. We completed a Phase 1b 28-day multiple ascending dose trial with ARRY-162 added to methotrexate (MTX) in patients with stable RA.
ARRY-162 Inhibits TNF, IL-1 & IL-6 with a Long Duration of Action
Future Milestones
We have ongoing a Phase 2 trial, which is being performed on three continents: North America, South America and Europe. This 12-week study is enrolling 200 patients with active RA on stable doses of MTX. Based upon the safety, tolerability and pharmacodynamic efficacy we have seen in RA patients in Phase 1, we believe we will see anti-inflammatory efficacy of ARRY-162 in these Phase 2 RA studies. We expect to receive top-line results on the Phase 2 trial during the second half of calendar 2009.
Scientific Posters
|
