ARRY-797 is a selective, orally active, inhibitor of p38, a mitogen-activated protein kinase family member activated by cytokines and growth factors that have been broadly implicated as playing a detrimental role in a number of inflammatory diseases and post-operative pain. By targeting p38, which regulates the production of TNF, IL-6, IL-1 and PGE2, we believe that the inhibition of p38 will provide efficacy in regulating inflammatory cytokine production and benefit patients with a number of inflammatory diseases and pain.
About p38 Inhibition for Inflammation and Pain
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 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, including COX inhibitors. Many forms of acute and chronic pain have inflammatory origins, therefore pan-cytokine suppression may treat both the inflammation and the resulting pain. We believe modulation of all three cytokines plus PGE2 may be more effective than inhibition of any one in isolation.
Phase 1 Clinical Trial
We initiated Phase 1 clinical testing of ARRY-797 in October 2006. The trial was designed to assess the preliminary safety, exposure and inhibition of mechanism-related biomakers in a dose escalation study in normal, healthy volunteers. ARRY-797 demonstrated good tolerability and significant efficacy in preclinical models of human inflammatory disease and certain cytokine-driven cancers. At the 2007 Annual European Congress of Rheumatology (EULAR), and at the International Association of Inflammation Societies' (IAIS) 8th World Congress on Inflammation, we reported results from a single ascending dose (SAD) study in healthy volunteers with ARRY-797. The drug met the study objectives, showing inhibition of IL-1, TNF and PGE2 production (>90% inhibition, with >50% inhibition at 24hrs at the highest dose) and a linear increase in exposure and increased oral dose (25-400 mg). ARRY-797 completed a multiple ascending dose (MAD) study in normal volunteers and we expect to present those results during 2008.
Phase 2 Clinical Trial
We initiated Phase 2 clinical testing of ARRY-797 in November 2007. This acute pain trial was designed to assess the tolerability, safety and analgesic efficacy in a randomized, double blind, parallel-group, placebo-controlled study in dental patients undergoing third molar extraction. ARRY-797 reached its primary and secondary endpoints for analgesic efficacy and was well-tolerated with no SAEs. 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 than 0.0001), and statistically significant for total pain relief over three, eight, twelve and 24 hours post dose.
ARRY-797 demonstrated significant differentiation from placebo in all time periods studied using a visual analog pain intensity scale measured from 0 to 100 mm. Pain intensity between zero and six hours was significantly lower for patients receiving 200 mg of ARRY-797 both before and after surgery, and 400 mg after surgery vs. placebo (p=0.0020 and p=0.0013, respectively). Pain intensity three hours after surgery was 31.5 mm lower in the group receiving 400 mg of ARRY-797 compared to placebo. Patients in this group also reported faster time to meaningful pain relief (p=0.006) and time to onset of analgesia (p=0.0017) relative to placebo.
Future Milestones
Based on study results, we have initiated a second Phase 2 acute inflammatory pain trial in 250 patients comparing three doses of ARRY-797 (200, 400 and 600 mg) with both placebo and with an active comparator, celecoxib (400 mg). We will also be initiating a 12-week study in 140 patients with ankylosing spondylitis, which will help determine the potential efficacy of this compound in chronic inflammatory disorders known to respond to biologic TNF inhibitors, during the second half of 2008. In addition, we are initiating a 28-day study of ARRY-797 in 30 rheumatoid arthritis patients on stable doses of methotrexate with the primary endpoints of safety, tolerability and pharmacokinetics.
Scientific Posters
|
