Immunogenicity of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients With Morquio A Syndrome: Results From MOR-004, a Phase III Trial

Abstract Purpose Morquio A syndrome ( mucopolysaccharidosisIVA [MPS IVA]) is a lysosomal storage disordercaused by deficiency of the enzyme N- acetylgalactosamine-6- sulfatase, which is required to degrade the glycosaminoglycan keratan sulfate. Morquio A is associated with extensive morbidity and early mortality. Elosulfase alfais an enzyme replacement therapythat provides a treatment option for patients with Morquio A. We examined the immunogenicity profile of elosulfase alfa, assessing any correlations between antidrug antibodies and the efficacy and safety outcomes in 176 patients with Morquio A from a 24-week international Phase III trial. Methods Patients were randomized to placebo (n = 59) or elosulfase alfa2.0 mg/kg administered weekly (n = 58) or every other week (n = 59) as an ~4-hour infusion. Blood samples were routinely tested to determine drug-specific total antibody titerand neutralizing antibody (NAb) positivity. Drug-specific immunoglobulin Epositivity was tested routinely and in response to severe hypersensitivity adverse events (AEs). Antidrug antibody positivity and titer were compared with efficacy and safety metrics to assess possible correlations. Findings The 176 patients in the trial were 54% female, with a mean age of 11.9 years. In all patients treated with elosulfase alfaantidrug antibodies developed, and in the majority, antibodies capable of interfering with cation-independent mannose-6-phosphate receptorbinding in vitro (NAb) developed. Less than 10% of patients tested positive for drug-specific IgE during the study. Despite the high incidence of anti– elosulfase alfaantibodies, no correlations were detected between higher total antibody titersor NAb positivity and worsened 6-minute walk test results, urine keratin sulfate levels, or hypersensitivity AEs. Drug-specific IgE pos i tivity had no apparent association with the occurrence of anaphylaxis, other hypersensitivity AEs, and/or treatment withdrawal. Implications Despite the universal development of antidrug antibodies, elosulfase alfatreatment was both safe and well tolerated and immunogenicity was not associated with reduced treatment effect. ClinicalTrials.gov identifier: NCT01275066. ( Clin Ther.