Objective: To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA).
Methods: Patients were randomized to receive SCIO-469 at either 30 or 60 mg three times daily in an immediate-release (IR) formulation or at 100 mg once daily in an extended-release (ER) formulation, or placebo for 24 weeks. The primary endpoint was American College of Rheumatology (ACR)20 response at Week 12. Safety was monitored through Week 26.
Results: Overall, 302 patients were randomized: 76 to placebo, 75 to 30 mg IR, 73 to 60 mg IR, and 78 to 100 mg ER. There were no significant differences in ACR20 responses at Week 12 between SCIO-469 and placebo. Declines in C-reactive protein and erythrocyte sedimentation rate during early treatment did not persist to Week 12 and were not a consequence of decreased SCIO-469 plasma levels. The 60 mg IR regimen showed a dose-limiting toxicity manifested by elevations in alanine aminotransferase. Adverse events were common in all groups (79.7% and 86.7% through 13 and 26 weeks, respectively). Twenty-one patients reported 28 serious adverse events (SAE). SAE were more common with IR SCIO-469 than with placebo (7% vs 4%) but were not reported with ER SCIO-469.
Conclusion: In all regimens tested, SCIO-469 showed no greater efficacy compared to placebo in patients with RA. The transient effect of SCIO-469 on acute-phase reactants suggests a complex role of p38 MAPK in inflammation.