Effect of anti-laronidase antibodies on efficacy and safety of laronidase enzyme replacement therapy for MPS I: A comprehensive meta-analysis of pooled data from multiple studies.

Enzyme replacement therapy (ERT) with laronidase has an important role in the treatment of patients with mucopolysaccharidosis type I (MPS I). Laronidase is safe and has demonstrated effectiveness in terms of stabilizing or improving conventional clinical and laboratory markers of the disease. However, like most ERTs, laronidase produces an anti-drug IgG antibody response in more than 90% of patients during the first few months of treatment. Preclinical data from the MPS I canine model suggest that anti-drug antibodies (ADA) impair enzyme uptake in target tissues. In patients, the effects on tissue glycosaminoglycan (GAG) clearance are difficult to assess directly but data from clinical studies have suggested an association between ADA and both a reduced pharmacodynamic response and hypersensitivity reactions. This comprehensive meta-analysis of pooled data from patients in three clinical studies of laronidase (including one study with an extension) was undertaken to provide a more robust assessment of the relationship between the ADA response to laronidase, clinical and laboratory markers of MPS I, and hypersensitivity reactions. The meta-analysis demonstrated an inverse relationship between the ADA response and the percent reduction in urinary GAG (uGAG) levels. However, no relationships between the ADA response and changes in percent predicted forced vital capacity and six-minute walk test were seen. The study also re-assayed stored serum samples from the original trials with a novel method to determine the inhibitory effect of ADA. Patients with higher ADA exposure over time were found to have higher inhibition of enzyme uptake into cells. High ADA exposure can result in a commensurate level of enzyme uptake inhibition that decreases the pharmacodynamic effect of the exogenously administered therapeutic enzyme, but with no clear effect on clinical efficacy.