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The incidence and significance of anti-natalizumab antibodies

Results from AFFIRM and SENTINEL

P. A. Calabresi, MD, G. Giovannoni, MD, C. Confavreux, MD, S. L. Galetta, MD, E. Havrdova, MD, M. Hutchinson, MD, L. Kappos, MD, D. H. Miller, MD, P. W. O'Connor, MD, J. T. Phillips, MD, PhD, C. H. Polman, MD, E. -W. Radue, MD, R. A. Rudick, MD, W. H. Stuart, MD, F. D. Lublin, MD, A. Wajgt, MD, B. Weinstock-Guttman, MD, D. R. Wynn, MD, F. Lynn, MSc, M. A. Panzara, MD, MPH For the AFFIRM and SENTINEL Investigators

From the Johns Hopkins Multiple Sclerosis Center (P.A.C.), Baltimore, MD; Institute of Neurology (G.G., D.H.M.), London, UK; Hôpital Neurologique (C.C.), Lyon, France; University of Pennsylvania School of Medicine (S.L.G.), Philadelphia; Neurological Department (E.H.), General Teaching Hospital, Prague, Czech Republic; St Vincent's University Hospital (M.H.), Dublin, Ireland; University Hospitals Basel (L.K., E.-W.R.), Switzerland; St. Michael's Hospital (P.W.O'C.), Toronto, Ontario, Canada; Texas Neurology (J.T.P.), Dallas; VU Medical Centre (C.H.P.), Amsterdam, the Netherlands; Mellon Center for Multiple Sclerosis Treatment and Research (R.A.R.), Cleveland Clinic Foundation, OH; MS Center of Atlanta (W.H.S.), GA; Mt. Sinai School of Medicine (F.D.L.), New York; Silesian Medical University (A.W.), Katowice, Poland; Jacobs Neurological Institute (B.W.-G.), SUNY University at Buffalo, NY; Consultants in Neurology Multiple Sclerosis Center (D.R.W.), Northbrook, IL; and Biogen Idec, Inc. (F.L., M.A.P.), Cambridge, MA.

Address correspondence and reprint requests to Dr Calabresi, Department of Neurology, Johns Hopkins Hospital, Pathology 627, 600 N. Wolfe St., Baltimore, MD 21287 Calabresi{at}jhmi.edu

Objective: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab.

Methods: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon ß-1a [INFß1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as "transiently positive" if they had detectable antibodies (0.5 µg/mL) at a single time point or "persistently positive" if they had antibodies at two or more time points 6 weeks apart.

Results: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p 0.05), relapse rate (p = 0.009), and MRI (p 0.05) compared with antibody-negative patients. In transiently positive patients, full efficacy was achieved after approximately 6 months of treatment, the time when patients were becoming antibody negative. The incidence of infusion-related adverse events was significantly higher in persistently positive patients. Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and antibody-negative patients were not statistically significant.

Conclusions: The incidence of persistent antibody positivity associated with natalizumab is 6%. Reduced clinical efficacy is apparent in persistently positive patients. Patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for antibody testing.

GLOSSARY: BLQ = below the limit of quantification; EDSS = Expanded Disability Status Scale; Gd+ = gadolinium enhancing; IFNß1a = interferon ß-1a; MS = multiple sclerosis; MSFC = multiple sclerosis functional composite; OD = optical density.

Editorial, see page 1386

Received August 11, 2006. Accepted in final form April 17, 2007.

e-Pub ahead of print on August 29, 2007, at www.neurology.org

*These authors contributed equally.

AFFIRM and SENTINEL investigators are listed in the appendix.

Disclosure: Disclosure information provided after the article text.

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