Amelia: The short answer is that 9% develop antibodies at least once and 6% develop persistent antibodies.
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Hypersensitivity
TYSABRI® has been associated with hypersensitivity reactions, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%. These reactions usually occur within 2 hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain. Generally, these reactions are associated with antibodies to TYSABRI®.
If a hypersensitivity reaction occurs, discontinue administration of TYSABRI® and initiate appropriate therapy (see ADVERSE REACTIONS, Infusion-related Reactions). Patients who experience a hypersensitivity reaction should not be re-treated with TYSABRI®. The possibility of antibodies to TYSABRI® should be considered in patients who have hypersensitivity reactions (see ADVERSE REACTIONS, Immunogenicity).
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Infusion-related Reactions (see WARNINGS, Hypersensitivity)
An infusion-related reaction was defined in clinical trials as any adverse event occurring within 2 hours of the start of an infusion. Approximately 24% of TYSABRI®-treated multiple sclerosis patients experienced an infusion-related reaction, compared to 18% of placebo-treated patients. Events more common in the TYSABRI®-treated patients included headache, dizziness, fatigue, urticaria, pruritus, and rigors. Acute urticaria was observed in approximately 2% of patients. Other hypersensitivity reactions were observed in 1% of patients receiving TYSABRI®. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients. All patients recovered with treatment and/or discontinuation of the infusion.
Patients who became persistently positive for antibodies to TYSABRI® were more likely to have an infusion-related reaction than those who were antibody-negative (see ADVERSE REACTIONS, Immunogenicity).
Immunogenicity
Patients in Study 1 were tested for antibodies to natalizumab every 12 weeks. The assays used were unable to detect low to moderate levels of antibodies to natalizumab. Approximately 9% of patients receiving TYSABRI® developed detectable antibodies at least once during treatment. Approximately 6% of patients had positive antibodies on more than one occasion. Approximately 82% of patients who became persistently antibody-positive developed detectable antibodies by 12 weeks. Anti-natalizumab antibodies were neutralizing in vitro.
The presence of anti-natalizumab antibodies was correlated with a reduction in serum natalizumab levels. In Study 1, the Week 12 pre-infusion mean natalizumab serum concentration in antibody-negative patients was 14.9 mcg/mL compared to 1.3 mcg/mL in antibody-positive patients. Persistent antibody-positivity was associated with a substantial decrease in the effectiveness of TYSABRI®. The risk of increased disability and the annualized relapse rate were similar in persistently antibody-positive TYSABRI®-treated patients and patients who received placebo. A similar phenomenon was also observed in Study 2.
Infusion-related reactions most often associated with persistent antibody-positivity included urticaria, rigors, nausea, vomiting, headache, flushing, dizziness, pruritus, tremor, feeling cold, and pyrexia. Additional adverse events more common in persistently antibody-positive patients included myalgia, hypertension, dyspnea, anxiety, and tachycardia.
If the presence of persistent antibodies is suspected, antibody testing should be performed. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies detected early in the treatment course (e.g., within the first 6 months) may be transient and disappear with continued dosing. Repeat testing at 3 months after the initial positive result is recommended in patients in whom antibodies are detected to confirm that antibodies are persistent. Prescribers should consider the overall benefits and risks of TYSABRI® in a patient with persistent antibodies.
The long-term immunogenicity of TYSABRI® and the effects of low to moderate levels of antibody to natalizumab are unknown. Experience with other monoclonal antibodies suggests that patients who receive therapeutic antibodies after an extended period without treatment may be at higher risk of hypersensitivity reactions than patients who received regularly scheduled treatment. It is not known if this will occur with TYSABRI (see WARNINGS, Hypersensitivity and ADVERSE REACTIONS, Infusion-related Reactions).
Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody-positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TYSABRI® with the incidence of antibodies to other products may be misleading.
