Array BioPharma Inc. posted positive top-line results from a phase II clinical trial evaluating the efficacy of ARRY-797, a novel, orally administered, small molecule pan-cytokine inhibitor, in patients with post-surgical dental pain.

ARRY-797 achieved its primary and secondary endpoints for analgesic efficacy and was well tolerated. Based on these results, Array is moving forward with a second phase II acute inflammatory pain trial comparing various doses of ARRY-797 to placebo and to celecoxib. Array also plans to initiate a phase II study of ARRY-797 in ankylosing spondylitis, a chronic, painful, inflammatory disorder known to respond to biologic TNF inhibitors.

The analgesic effect of 400 mg of ARRY-797, compared to placebo, was statistically significant based upon the primary endpoint of total pain relief over six hours post dose (p less than0.0001). The analgesic effect was also statistically significant for total pain relief over three, eight, twelve and 24 hours post dose. Other analgesic endpoints, including total pain intensity, time to meaningful pain relief and time to analgesia were also significantly improved versus placebo. Peri-operative dosing with 200 mg before and 200 mg after surgery also resulted in a substantial reduction in total pain intensity. Array believes the efficacy observed in this study is due to the simultaneous inhibition of the pain mediator PGE2 and the inflammatory mediators TNF, IL-1 and IL-6. No serious adverse events were reported and non-serious adverse events were evenly balanced across the three groups.

"These results demonstrate efficacy of ARRY-797 in the management of inflammatory pain," said John Yates, MD, chief medical officer, Array BioPharma. "Together with our multiple-dose, 14-day trial in healthy volunteers, these data confirm the good safety and tolerability profile of ARRY-797. In particular, we have observed no evidence of any gastrointestinal, hepatic or skin toxicity due to ARRY-797. Therefore, we remain very excited about the potential of ARRY-797 to provide clinical benefit in a variety of inflammatory pain conditions."

The phase II trial was a randomized, double-blind, placebo-controlled, parallel-group efficacy study of ARRY-797 in patients undergoing third molar extraction. This is a standard model for testing efficacy of analgesic agents. The study objective was to assess the analgesic efficacy, safety and tolerability of ARRY-797 dosed either after the operation (400 mg) or both before and after surgery (200 mg twice). The trial enrolled 103 patients and was conducted at two centers in the United States.

ARRY-797 is a highly selective p38-alpha inhibitor, which modulates the production of TNF, IL-1, IL-6 and PGE2 in human whole blood with nanomolar potency. ARRY-797 has unique properties, including high water solubility and tissue penetration, and was designed to limit distribution to the central nervous system.

In phase I studies in healthy volunteers of up to 14 days dosing, ARRY-797 demonstrated linear increases in exposure with increasing oral doses from 25 to 400 mg. The drug was well-tolerated at all doses tested with no serious adverse events. In blood samples taken from these volunteers and with LPS, ARRY-797 dose-dependently inhibited the stimulated production of TNF, IL-1, IL-6 and PGE2.

P38 is a kinase target that regulates the production TNF, IL-1 and IL-6 as well as PGE2. TNF, IL-1 and IL-6 are all clinically validated cytokines for controlling inflammation in rheumatoid arthritis and are prevalent in many forms of inflammation. PGE2 is an important mediator of inflammatory pain and the target of NSAIDs. Many forms of acute and chronic pain have inflammatory origins, and pan-cytokine suppression may treat both the inflammation and the resulting pain. Array believes modulation of all three cytokines plus PGE2 may be more effective than inhibition of any one in isolation for controlling both the underlying inflammation and the resulting symptoms such as pain.