BOULDER, Colorado—The first new rheumatoid arthritis (RA) drug aimed at the MEK pathway failed to meet efficacy endpoints in Phase 2 studies. The drug, Array BioPharma's ARRY-162, is a small molecule MEK inhibitor.

In a 12-week Phase 2 clinical trial with 201 patients with active, methotrexate-resistant RA, researchers studied a placebo group and three different dose groups of ARRY-162, all on a stable background of methotrexate.

After 12 weeks of treatment, none of the treatment groups were significantly better than placebo for ACR20 response rates (p=0.459).

The company noted that the placebo response rates in this study were higher than expected for this patient population and showed regional differences, with patients in South America (99 patients) having substantially higher placebo response rates than those in Eastern Europe (101 patients). There was a trend toward ARRY-162 efficacy in Eastern Europe when patients in the three active treatment arms were combined, as measured by DAS28-4(CRP) (p=0.067), "good" EULAR response (p=0.105), and ACR20 response rate (p=0.115).

MEK is a key protein kinase in the RAS/RAF/MEK/ERK pathway, which mediates production of key proinflammatory cytokines, including TNFα, IL-1β and IL-6, as well as cellular proliferation and survival. It also has a role in pathogenic bone remodeling through direct effects on osteoclasts, the cells responsible for bone resorption. MEK inhibition therefore has the potential to be a novel and safe approach to treating chronic, progressive inflammatory diseases because of its observed anti-inflammatory and bone anti-resorptive effects.

"This is the first clinical trial evaluating the modulation of the MEK pathway for the treatment of chronic inflammatory disease," said Kevin Koch, PhD, President and Chief Scientific Officer of Array Biopharma. "While we are disappointed in the overall efficacy outcome, we were pleased with the confirmation of the favorable safety profile and are continuing to evaluate the regional results. Previously we announced our strategy to rapidly advance ARRY-162 for the treatment of cancer patients. We initiated a Phase 1 oncology trial last month and patient dosing is underway."

About ARRY-162 in inflammatory diseases

ARRY-162, an orally active MEK inhibitor, has shown significant efficacy and is well-tolerated in preclinical models of human arthritis and other inflammatory diseases. In preclinical combination studies with standard of care RA treatments, including methotrexate, dexamethasone, ibuprofen, and etanercept, ARRY-162 was well tolerated and demonstrated at least additive efficacy, even with the maximally efficacious dose of etanercept. ARRY-162 was well-tolerated in preclinical studies for up to 9 months of daily dosing. Phase 1 clinical trials with ARRY-162 have demonstrated selective and dose-dependant inhibition of IL-1, IL-6, and TNF with convenient oral dosing, as well as good tolerability when used in combination with methotrexate.