ARTHRITIS & RHEUMATISM Vol. 62, No. 8, August 2010, pp 2227–2238 DOI 10.1002/art.27524 © 2010, American College of Rheumatology Ofatumumab, a Human Anti-CD20 Monoclonal Antibody, for Treatment of Rheumatoid Arthritis With an Inadequate Response to One or More Disease-Modifying Antirheumatic Drugs Results of a Randomized, Double-Blind, Placebo-Controlled, Phase I/II Study Mikkel Østergaard, 1 Bo Baslund, 2 William Rigby, 3 Bernadette Rojkovich, 4 Christian Jorgensen, 5 Peter T. Dawes, 6 Charlotte Wiell, 7 Daniel J. Wallace, 8 Søren C. Tamer, 9 Helle Kastberg, 9 Jørgen Petersen, 9 and Stanislaw Sierakowski 10 Objective. To investigate the safety and efficacy of ofatumumab, a novel human anti-CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to >1 disease-modifying antirheumatic drug. Methods. This combined phase I/II study investi- gated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (IV) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell phar- macodynamics were also investigated. Results. AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell deple- tion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had signifi- cantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24. Conclusion. Our findings indicate that ofatu- mumab, administered as 2 IV infusions of doses up to 1,000 mg, is clinically effective in patients with active RA. Rheumatoid arthritis (RA) is a chronic, inflam- matory autoimmune disease characterized by symmetric inflammation of synovial joints, leading to progressive ClinicalTrials.gov identifier: NCT00291928. Supported by Genmab, Copenhagen, Denmark. 1 Mikkel Østergaard, MD, PhD, DMSc: Copenhagen Univer- sity Hospitals at Hvidovre and Glostrup, Copenhagen, Denmark; 2 Bo Baslund, MD, PhD: The National University Hospital, Copenhagen, Denmark; 3 William Rigby, MD: Dartmouth-Hitchcock Medical Cen- ter, Lebanon, New Hampshire; 4 Bernadette Rojkovich, MD, PhD: Polyclinic of the Hospital Brothers of St. John of God in Budapest, Budapest, Hungary; 5 Christian Jorgensen, MD, PhD: Lapeyronie University Hospital, Montpellier, France; 6 Peter T. Dawes, MB, MRCP, FRCP: The Haywood Hospital, Stoke on Trent, UK; 7 Char- lotte Wiell, MD, PhD: Copenhagen University Hospital at Hvidovre, Copenhagen, Denmark; 8 Daniel J. Wallace, MD: Wallace Rheumatic Study Center, Los Angeles, California; 9 Søren C. Tamer, MSc, Helle Kastberg, MSc, Jørgen Petersen, MD, DMSc: Genmab, Copenhagen, Denmark; 10 Stanislaw Sierakowski, MD, PhD, DSc (Med): Medical Academy of Bialystok, Bialystok, Poland. Dr. Østergaard has received consulting fees, speaking fees, and/or honoraria from Genmab (less than $10,000). Mr. Tamer, Ms Kastberg, and Dr. Petersen own stock or stock options in Genmab. Genmab holds patent rights on which Dr. Petersen is listed as an inventor. Address correspondence and reprint requests to Mikkel Østergaard, MD, PhD, DMSc, Department of Rheumatology, Copen- hagen University Hospitals at Hvidovre and Glostrup, Kettegaard Alle 30, DK-2650 Hvidovre, Denmark. E-mail: mo@dadlnet.dk. Submitted for publication March 16, 2009; accepted in revised form April 13, 2010. 2227