The incidence and significance of anti-natalizumab antibodies: Results from AFFIRM and SENTINEL

Peter Calabresi, G. Giovannoni, C. Confavreux, S. L. Galetta, E. Havrdova, M. Hutchinson, L. Kappos, D. H. Miller, P. W. O'Connor, J. T. Phillips, C. H. Polman, E. W. Radue, R. A. Rudick, W. H. Stuart, F. D. Lublin, A. Wajgt, B. Weinstock-Guttman, D. R. Wynn, F. Lynn, M. A. Panzara

Research output: Contribution to journalArticle

Abstract

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 β-1a [INFβ1a] 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.

Original languageEnglish (US)
Pages (from-to)1391-1403
Number of pages13
JournalNeurology
Volume69
Issue number14
DOIs
StatePublished - Oct 2007

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Anti-Idiotypic Antibodies
Incidence
Antibodies
Natalizumab
Safety
Relapsing-Remitting Multiple Sclerosis
Interferons
Multiple Sclerosis
Enzyme-Linked Immunosorbent Assay
Placebos
Recurrence
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Calabresi, P., Giovannoni, G., Confavreux, C., Galetta, S. L., Havrdova, E., Hutchinson, M., ... Panzara, M. A. (2007). The incidence and significance of anti-natalizumab antibodies: Results from AFFIRM and SENTINEL. Neurology, 69(14), 1391-1403. https://doi.org/10.1212/01.wnl.0000277457.17420.b5

The incidence and significance of anti-natalizumab antibodies : Results from AFFIRM and SENTINEL. / Calabresi, Peter; Giovannoni, G.; Confavreux, C.; Galetta, S. L.; Havrdova, E.; Hutchinson, M.; Kappos, L.; Miller, D. H.; O'Connor, P. W.; Phillips, J. T.; Polman, C. H.; Radue, E. W.; Rudick, R. A.; Stuart, W. H.; Lublin, F. D.; Wajgt, A.; Weinstock-Guttman, B.; Wynn, D. R.; Lynn, F.; Panzara, M. A.

In: Neurology, Vol. 69, No. 14, 10.2007, p. 1391-1403.

Research output: Contribution to journalArticle

Calabresi, P, Giovannoni, G, Confavreux, C, Galetta, SL, Havrdova, E, Hutchinson, M, Kappos, L, Miller, DH, O'Connor, PW, Phillips, JT, Polman, CH, Radue, EW, Rudick, RA, Stuart, WH, Lublin, FD, Wajgt, A, Weinstock-Guttman, B, Wynn, DR, Lynn, F & Panzara, MA 2007, 'The incidence and significance of anti-natalizumab antibodies: Results from AFFIRM and SENTINEL', Neurology, vol. 69, no. 14, pp. 1391-1403. https://doi.org/10.1212/01.wnl.0000277457.17420.b5
Calabresi, Peter ; Giovannoni, G. ; Confavreux, C. ; Galetta, S. L. ; Havrdova, E. ; Hutchinson, M. ; Kappos, L. ; Miller, D. H. ; O'Connor, P. W. ; Phillips, J. T. ; Polman, C. H. ; Radue, E. W. ; Rudick, R. A. ; Stuart, W. H. ; Lublin, F. D. ; Wajgt, A. ; Weinstock-Guttman, B. ; Wynn, D. R. ; Lynn, F. ; Panzara, M. A. / The incidence and significance of anti-natalizumab antibodies : Results from AFFIRM and SENTINEL. In: Neurology. 2007 ; Vol. 69, No. 14. pp. 1391-1403.
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abstract = "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 β-1a [INFβ1a] 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.",
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T1 - The incidence and significance of anti-natalizumab antibodies

T2 - Results from AFFIRM and SENTINEL

AU - Calabresi, Peter

AU - Giovannoni, G.

AU - Confavreux, C.

AU - Galetta, S. L.

AU - Havrdova, E.

AU - Hutchinson, M.

AU - Kappos, L.

AU - Miller, D. H.

AU - O'Connor, P. W.

AU - Phillips, J. T.

AU - Polman, C. H.

AU - Radue, E. W.

AU - Rudick, R. A.

AU - Stuart, W. H.

AU - Lublin, F. D.

AU - Wajgt, A.

AU - Weinstock-Guttman, B.

AU - Wynn, D. R.

AU - Lynn, F.

AU - Panzara, M. A.

PY - 2007/10

Y1 - 2007/10

N2 - 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 β-1a [INFβ1a] 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.

AB - 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 β-1a [INFβ1a] 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.

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