title: Immunogenicity of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients With Morquio A Syndrome: Results From MOR-004, a Phase III Trial.
abstract: OBJECTIVE
  Morquio A syndrome (mucopolysaccharidosis IVA [MPS IVA]) is a lysosomal storage disorder caused 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 alfa is an enzyme replacement therapy that 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 alfa 2.0 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 titer and neutralizing antibody (NAb) positivity. Drug-specific immunoglobulin E positivity 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.
  
  
  RESULTS
  The 176 patients in the trial were 54% female, with a mean age of 11.9 years. In all patients treated with elosulfase alfa antidrug antibodies developed, and in the majority, antibodies capable of interfering with cation-independent mannose-6-phosphate receptor binding 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 alfa antibodies, no correlations were detected between higher total antibody titers or NAb positivity and worsened 6-minute walk test results, urine keratin sulfate levels, or hypersensitivity AEs. Drug-specific IgE positivity had no apparent association with the occurrence of anaphylaxis, other hypersensitivity AEs, and/or treatment withdrawal.
  
  
  CONCLUSIONS
  Despite the universal development of antidrug antibodies, elosulfase alfa treatment was both safe and well tolerated and immunogenicity was not associated with reduced treatment effect. ClinicalTrials.gov identifier: NCT01275066. (Clin Ther.
authors.affiliation: BioMarin Pharmaceutical Inc, Novato, California. Electronic address: BSchweighardt@bmrn.com.
authors.forename: Becky
authors.initials: B
authors.lastname: Schweighardt
authors.affiliation: BioMarin Pharmaceutical Inc, Novato, California.
authors.forename: Troy
authors.initials: T
authors.lastname: Tompkins
authors.affiliation: BioMarin Pharmaceutical Inc, Novato, California.
authors.forename: Kelly
authors.initials: K
authors.lastname: Lau
authors.affiliation: BioMarin Pharmaceutical Inc, Novato, California.
authors.forename: Lynne
authors.initials: L
authors.lastname: Jesaitis
authors.affiliation: BioMarin Pharmaceutical Inc, Novato, California.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Qi
authors.affiliation: BioMarin Pharmaceutical Inc, Novato, California.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Musson
authors.affiliation: BioMarin Pharmaceutical Inc, Novato, California.
authors.forename: Pamela
authors.initials: P
authors.lastname: Farmer
authors.affiliation: BioMarin Pharmaceutical Inc, Novato, California.
authors.forename: Christine
authors.initials: C
authors.lastname: Haller
authors.affiliation: BioMarin Pharmaceutical Inc, Novato, California.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Shaywitz
authors.affiliation: BioMarin Pharmaceutical Inc, Novato, California.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: BioMarin Pharmaceutical Inc, Novato, California.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Neill
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood; D002648:Child; D002675:Child, Preschool; D002811:Chondroitinsulfatases / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004342:Drug Hypersensitivity / Q000209:etiology / Q000276:immunology; D056947:Enzyme Replacement Therapy / Q000009:adverse effects / Q000379:methods*; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007632:Keratan Sulfate / Q000652:urine; D008297:Male; D008875:Middle Aged; D009085:Mucopolysaccharidosis IV / Q000188:drug therapy* / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use
chemical_list: D057134:Antibodies, Neutralizing; D011994:Recombinant Proteins; D007073:Immunoglobulin E; D007632:Keratan Sulfate; D002811:Chondroitinsulfatases; C102295:GALNS protein, human
keywords: Morquio A; antibody; efficacy; enzyme replacement therapy; immunogenicity; mucopolysaccharidosis IVA