ARTHRITIS & RHEUMATISM Vol. 60, No. 7, July 2009, pp 1895–1905 DOI 10.1002/art.24567 © 2009, American College of Rheumatology The Safety and Efficacy of a JAK Inhibitor in Patients With Active Rheumatoid Arthritis Results of a Double-Blind, Placebo-Controlled Phase IIa Trial of Three Dosage Levels of CP-690,550 Versus Placebo Joel M. Kremer, 1 Bradley J. Bloom, 2 Ferdinand C. Breedveld, 3 John H. Coombs, 2 Mark P. Fletcher, 4 David Gruben, 2 Sriram Krishnaswami, 2 Rube ´n Burgos-Vargas, 5 Bethanie Wilkinson, 2 Cristiano A. F. Zerbini, 6 and Samuel H. Zwillich 2 Objective. To determine the efficacy, safety, and tolerability of 3 different dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inad- equate or toxic response. Methods. Patients (n  264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks. Results. By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP-690,550–treated patients com- pared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low-density lipoprotein cholesterol and high- density lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04–0.06 mg/dl) were seen in all CP-690,550 treatment arms. Conclusion. Our findings indicate that CP- 690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically mean- ingful reductions in the signs and symptoms of RA. Further studies of CP-690,550 in RA are warranted. ClinicalTrials.gov identifier: NCT00147498. Presented in part at the 70th Annual Scientific Meeting of the American College of Rheumatology, Washington, DC, November 2006. Supported by Pfizer. 1 Joel M. Kremer, MD: Albany Medical College, Albany, New York; 2 Bradley J. Bloom, MD, John H. Coombs, PharmD, MBA (current address: Novartis Pharmaceuticals, Florham Park, New Jer- sey), David Gruben, PhD, Sriram Krishnaswami, PhD, Bethanie Wilkinson, PhD, Samuel H. Zwillich, MD: Pfizer, New London, Connecticut; 3 Ferdinand C. Breedveld, MD: Leiden University Med- ical Centre, Leiden, The Netherlands; 4 Mark P. Fletcher, MD: Pfizer, Ann Arbor, Michigan; 5 Rube ´n Burgos-Vargas, MD: Hospital General de Mexico, Mexico City, Mexico; 6 Cristiano A. F. Zerbini, MD, FACP: Hospital Heliopolis, Sao Paulo, Brazil. Dr. Kremer has received consulting fees from Pfizer (more than $10,000) and from Bristol-Myers Squibb, Centocor, Roche, and UCB (less than $10,000 each), grant support from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, Roche, Pfizer, and UCB, and he served as a paid consultant to Pfizer in connection with this study. Drs. Bloom and Gruben own stock or stock options in Pfizer. Dr. Breedveld has received consulting fees, speaking fees, and/or honoraria from Pfizer, Wyeth, Centocor, Abbott, and Roche (less than $10,000 each) and served as a paid consultant to Pfizer in connection with this study. Dr. Fletcher owns stock or stock options in Pfizer and holds patents related to the experimental therapy described in this report. Dr. Zerbini has received speaking fees from Bristol-Myers Squibb, Sanofi-Aventis, Roche, and Lilly (less than $10,000 each). Dr. Zwillich owns stock or stock options in Pfizer and is named as an inventor on unpublished patent applications assigned to Pfizer Prod- ucts Inc. relating to the subject matter of this study. Address correspondence and reprint requests to Samuel H. Zwillich, MD, Pfizer Global Research and Development, 50 Pequot Avenue, New London, CT 06320. E-mail: samuel.h.zwillich@pfizer.com. Submitted for publication July 15, 2008; accepted in revised form March 9, 2009. 1895