vx-702 and Arthritis--Rheumatoid

To assess the efficacy and safety of VX-702, a p38 MAPK inhibitor, in patients with active, moderate-to-severe rheumatoid arthritis (RA).. Two 12-week, double-blind, placebo-controlled studies of VX-702 were conducted in patients with active, moderate-to-severe RA. In the VeRA study, 313 patients received placebo or 2 daily doses of VX-702. In Study 304, 117 patients received placebo, daily VX-702, or twice weekly VX-702 in addition to concomitant methotrexate (MTX). Study end points included the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (an ACR20 response), ACR50 and ACR70 responses, changes in the serum levels of biomarkers of inflammation, and safety assessments.. The numerically superior ACR20 response rates among patients receiving VX-702 compared with those receiving placebo in both studies did not reach pairwise statistical significance at the highest doses in either study. At week 12 in the VeRA study, ACR20 response rates were 40%, 36%, and 28% among patients receiving 10 mg of VX-702, 5 mg of VX-702, and placebo, respectively. In Study 304, the response rates were 40%, 44%, and 22% for patients receiving 10 mg VX-702 daily plus MTX, 10 mg VX-702 twice weekly plus MTX, and placebo, respectively. Reductions in the levels of C-reactive protein, soluble tumor necrosis factor receptor p55, and serum amyloid A were observed as early as week 1 in both studies, but these levels rapidly returned to baseline values by week 4. The overall frequency of adverse events was similar between the VX-702 and placebo groups. In the VeRA study, serious infections were more frequent in the VX-702 groups compared with the placebo group (2.4% versus 0%) but not in Study 304 (2.6% versus 4.9%).. The modest clinical efficacy plus the transient suppression of biomarkers of inflammation observed in this study suggest that p38 MAPK inhibition may not provide meaningful, sustained suppression of the chronic inflammation seen in RA.

Topics: Adolescent; Adult; Aged; Arthritis, Rheumatoid; C-Reactive Protein; Double-Blind Method; Female; Humans; Male; Methotrexate; Middle Aged; p38 Mitogen-Activated Protein Kinases; Phenylurea Compounds; Receptors, Tumor Necrosis Factor, Type I; Serum Amyloid A Protein; Treatment Outcome; Tumor Necrosis Factor Decoy Receptors

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

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Isoenzymes; p38 Mitogen-Activated Protein Kinases; Phenylurea Compounds; Protein Kinase Inhibitors; Signal Transduction; Treatment Outcome

Vertex Pharmaceuticals Inc, in collaboration with Kissei Pharmaceutical Co Ltd, is developing VX-702, one of a series of second-generation, orally active p38 MAP kinase inhibitors, for the potential treatment of inflammation, rheumatoid arthritis and cardiovascular diseases. In June 2005, a phase II clinical trial of VX-702 was initiated in rheumatoid arthritis. In July 2006, Vertex was planning to file an IND in the second half of 2006.

Topics: Acute Disease; Administration, Oral; Arthritis, Rheumatoid; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Coronary Disease; Drug Evaluation; Enzyme Inhibitors; Humans; p38 Mitogen-Activated Protein Kinases; Patents as Topic; Phenylurea Compounds; Syndrome