The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of ALDURAZYME or of other laronidase products.

In clinical studies 1, 2, 3 [see Clinical Studies (14.1, 14.2)] and a dose-ranging clinical study that enrolled 8 patients between 3 to 17 years old who received once weekly intravenous doses of 0.58 mg/kg of ALDURAZYME, 70 of 73 (96%) of ALDURAZYME-treated patients developed IgG anti-laronidase antibodies (referred to as ADA). The 3 patients who did not develop ADA were patients with Hurler-Scheie forms of MPS I. In the 70 patients who developed ADA, the onset of ADA positivity in most patients occurred within 2 months after starting ALDURAZYME treatment. ADA titers peaked at approximately 4 months and generally declined over time. Higher ADA titers were observed in patients with Hurler forms of MPS I. Neutralizing antibodies that inhibited cellular uptake of laronidase were detected in 38 of 70 (54%) patients who developed ADA. Neutralizing antibodies that inhibited laronidase enzyme activity were detected in 1 of 70 (1.4%) patients who developed ADA.

Anti-Drug Antibody Effects on Pharmacokinetics

In Study 1, in some ALDURAZYME-treated patients who developed ADA the plasma clearance of laronidase at Week 12 was higher than that at Week 1, and patients with higher ADA titer had higher clearance. At Week 26, plasma clearance of laronidase was comparable to that at Week 1.

Anti-Drug Antibody Effects on Pharmacodynamics

Among the 70 ALDURAZYME-treated patients who developed ADA described above, patients with lower ADA titers tended to have greater than 50% reduction in urinary GAG (uGAG) levels at Week 26, while patients with higher ADA titers tended to have less than 50% reduction in uGAG levels. This correlation was observed in patients with Hurler-Scheie or Scheie form of MPS I. There was no clear correlation in patients with Hurler form of MPS I because these patients had high ADA titers and variable urinary GAG reductions. In postmarketing studies, an inverse correlation between percent uGAG reduction and ADA titer was observed in ALDURAZYME-treated patients who developed ADA. Patients with sustained ADA titers were more likely to have high ADA titers and tended to have less reduction in uGAG.

Anti-Drug Antibody Effects on Efficacy and Safety

In clinical studies, no correlation was demonstrated between the presence of ADA and therapeutic response for FVC or 6MWT.

In Study 1 and Study 2, 9 ALDURAZYME-treated patients who experienced severe infusion-associated reactions were tested for laronidase-specific IgE antibodies. One of the 9 patients tested positive for laronidase-specific IgE antibodies.

In the MPS I Registry, laronidase-specific IgE and IgG antibodies were evaluated in 10 ALDURAZYME-treated patients who had suspected hypersensitivity reactions and had an immunogenicity sample collected within seven days of event onset [see Adverse Reactions (6.1)]. Of the 10 patients, 9 tested positive for laronidase-specific IgE and/or IgG antibodies and 1 patient tested negative for both IgE and IgG antibodies.

In the postmarketing setting, five ALDURAZYME-treated patients who experienced anaphylaxis had ADA results available within seven days of event onset. Of these 5 patients, 3 patients tested positive for laronidase-specific IgE and/or IgG antibodies and in the other 2 patients, IgE antibodies were not detected and IgG antibody results were not reported.