scio-469 and Arthritis--Rheumatoid

SCIO-469 is a small-molecule p38 mitogen-activated protein (MAP) kinase inhibitor under development by Scios Inc as a potential oral therapy for inflammatory disorders. By July 2004, SCIO-469 was in phase lib clinical trials for rheumatoid arthritis.

Topics: Animals; Arthritis, Rheumatoid; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Enzyme Inhibitors; Humans; Indoles; p38 Mitogen-Activated Protein Kinases; Structure-Activity Relationship

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).. 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.. 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.. 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.

Topics: Administration, Oral; Adult; Aged; Arthritis, Rheumatoid; Blood Sedimentation; C-Reactive Protein; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; p38 Mitogen-Activated Protein Kinases; Severity of Illness Index; Treatment Outcome

Topics: Arthritis, Rheumatoid; Chronic Disease; Clinical Trials, Phase II as Topic; Crystallography, X-Ray; Enzyme Inhibitors; Humans; Indoles; Inflammatory Bowel Diseases; Models, Molecular; Molecular Structure; p38 Mitogen-Activated Protein Kinases; Phenylurea Compounds; Protein Binding; Psoriasis; Pyridones; Pyrimidines; Treatment Outcome

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Enzyme Inhibitors; Humans; Indoles; Naphthalenes; p38 Mitogen-Activated Protein Kinases; Phenylurea Compounds; Pyrazoles; Pyridazines; Pyridones; Pyrimidines; Rheumatology