Immunogenicity of Alemtuzumab Treatment in Relapsing-Remitting Multiple Sclerosis (RRMS) Patients in the CARE-MS II Study (P07.101)

OBJECTIVE: To assess effects of anti-alemtuzumab antibodies on efficacy and safety of alemtuzumab in RRMS patients who relapsed on prior therapy. BACKGROUND: In CARE-MS II, alemtuzumab reduced relapse rate by 49% (p DESIGN/METHODS: 840 patients were randomized to alemtuzumab (12 or 24 mg intravenously on 5 days initially and 3 days one year later) or IFNB-1a (44 µg subcutaneously 3-times weekly). Serum samples were collected before and 1, 3 and 12 months after each course and screened for alemtuzumab-binding antibodies using a validated MSD technology platform. Specificity was confirmed using a competitive-binding assay. Positive samples were tested for inhibitory antibodies using a cell-based flow cytometry assay. Effects of antibody status on efficacy, safety, and pharmacodynamics were assessed. RESULTS: Anti-alemtuzumab antibodies were detected in 80.2% of alemtuzumab-treated patients. Titers generally increased during first 3 months of each course, declining by Month 12. At Month 12, 29.3% of patients remained positive for anti-alemtuzumab antibodies. Antibody development was more pronounced after the second course. Most patients with binding antibodies tested positive for anti-alemtuzumab inhibitory antibodies. While patterns were similar between groups, fewer alemtuzumab 24 mg (70.8%) than 12 mg patients (83.7%) had positivity. Antibody status did not correlate with any impact on efficacy, overall safety, or infusion-associated reactions. Presence of anti-alemtuzumab or inhibitory antibodies did not lead to clinically meaningful alterations in pharmacodynamic responses to alemtuzumab and had no effect on the pattern of lymphocyte depletion and repopulation. CONCLUSIONS: Anti-alemtuzumab and inhibitory antibodies were commonly detected, with no apparent impact on alemtuzumab efficacy, safety or T and B cell pharmacodynamics in a 2-year study. Supported by: Genzyme, a Sanofi company and Bayer Healthcare Pharmaceuticals. Disclosure: Dr. Soelberg-Sorensen has received personal compensation for activities with Biogen Idec, Merck Serono, Novartis, Genmab, TEVA, Elan, GlaxoSmithKline as a member of scientific advisory boards, from Merck Serono, Genmab, TEVA for steering committees or independent data monitoring boards in clinical trials. Dr. Soelberg-Sorensen has received research support Biogen Idec, Bayer Schering, Merck Serono, TEVA, Baxter, Sanofi-Aventis, BioMS, Novartis, Bayer, RoFAR, Roche, Genzyme, the Danish Multiple Sclerosis Society, the Danish Medic. Dr. Arnold has received personal compensation or research support from Bayer Healthcare, Biogen Idec, Genetech, NeuroRx Research, Roche, Schering, Serono, and Teva Neuroscience. Dr. Arnold has received personal compensation or research support for Bayer Healthcare, Biogen Idec, Genetech, NeuroRx Research, Roche, Schering, Serono, and Teva Neuroscience. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen9s institution has received research support from Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience. Dr. Coles has received personal compensation for activities with Genzyme Corporation, GlaxoSmithKline, Inc., and Merck Serono as a consultant and/or speaker. Dr. Coles has received research support from Genzyme Corportation. Dr. Confavreux has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavreux has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Fox has received personal compensation from Bayer, Biogen Idec, EMD Serono, Genzyme Corporation, Novartis, Opexa Therapeutics, and Teva Neuroscience. Dr. Fox has received research support from Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Ono Pharmaceutical, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Hartung has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Bayer, Novartis, and Merck Serono. Dr. Havrodova has received personal compensation for activities with Bayer, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck & Co., Inc., Sanofi-Aventis Pharmaceuticals, Inc., Serono, and Teva Neuroscience. Dr. Selmaj has received personal compensation for activities with Biogen Idec, Genzyme, Ono Pharmaceutical, Novartis, Bayer, Hoffmann LaRoche, Merck, Serono and Synthon. Dr. Weiner has received personal compensation for activities with Biogen Idec, Novartis, Serono, Inc., Teva Neuroscience, GlaxoSmithKline, Inc., Nasvax, Xenoport and Genzyme Corporation as a consultant, speaker and/or participant on an advisory board. Dr. Weiner has received research support from Merck Serono. Dr. Miller has received personal compensation for activities with Allergan, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Forest, Novartis, Sanofi Aventis, and Teva as a speaker. Dr. Miller has received research support from Allergan, Biogen Idec, Genzyme, Elan, Teva, Novartis, Ono, Sanofi Aventis, EMD Serono, and Roche-Genetech. Dr. Twyman has received personal compensation for activities with Genzyme Corporation. Dr. Twyman has received research support from Genzyme Corporation. Dr. Lake receives personal compensation as an employee of Genzyme. Dr. Margolin has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Richards has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Sung has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Panzara has received personal compensation for activities with Genzyme an employee. Dr. Panzara holds stock options in Genzyme. Dr. Compston has received personal compensation for activities with Genzyme Corporation as a speaker. Dr. Compston has received research support from Genzyme Corporation.