title: Long-term Immunogenicity of Elosulfase Alfa in the Treatment of Morquio A Syndrome: Results From MOR-005, a Phase III Extension Study.
abstract: Elosulfase alfa is an enzyme replacement therapy for the treatment of Morquio A syndrome (mucopolysaccharidosis IVA), a lysosomal storage disorder caused by a deficiency of the enzyme N-acetylgalactose-amine-6-sulfatase. We previously reported immunogenicity data from our 24-week placebo-controlled Phase III study, MOR-004. Here, we report the long-term immunogenicity profile of elosulfase alfa from MOR-005, the Phase III extension trial to assess potential correlations between antidrug antibodies and efficacy and safety profile outcomes throughout 120 weeks of treatment.
  
  
  
  The long-term immunogenicity of elosulfase alfa was evaluated in patients with Morquio A syndrome in an open-label extension study for a total of 120 weeks. All patients received 2.0 mg/kg elosulfase alfa either weekly or every other week before establishment of 2.0 mg/kg/wk as the recommended dose, at which time all patients received weekly treatment. Efficacy measures were compared with those from the MOR-004 baseline, enabling analysis of changes over 120 weeks. The primary efficacy measure was the change from baseline in 6-minute walk test. Secondary measures included changes from baseline in 3-minute stair climb test and normalized urine keratan sulfate, a pharmacodynamic metric.
  
  
  
  All patients treated with elosulfase alfa developed antidrug total antibodies (TAb) by week 24 of MOR-004. In the extension study, all patients, including those who had previously received placebo, were TAb positive by study week 36 (MOR-005 week 12). All patients remained TAb positive throughout the study, and TAb titers were similar across treatment groups at week 120. Nearly all patients tested positive for neutralizing antibodies (NAb) at least once, with incidence of NAb positivity peaking at 85.9% at study week 36, then steadily declining to 66.0% at study week 120. In all treatment groups, mean urine keratan sulfate remained below treatment-naive baseline despite the presence of antidrug antibodies. No relationship was observed between TAb titers or NAb positivity and changes in urine keratan sulfate, 6-minute walk test, or 3-minute stair climb test from baseline to week 120. No consistent associations were detected between antidrug antibodies and the occurrence of hypersensitivity adverse events or anaphylaxis over the course of the study.
  
  
  
  Immunogenicity results from this long-term study are consistent with previously reported 24-week results. Despite the sustained presence of antidrug antibodies, elosulfase alfa was well tolerated, and patients continued to benefit from treatment through week 120. No associations were detected between higher TAb titers or NAb positivity and reduced treatment effect or worsened safety profile measures. ClinicalTrials.gov identifier: NCT01415427.
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, California. Electronic address: Brian.Long@bmrn.com.
authors.forename: Brian
authors.initials: B
authors.lastname: Long
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: Celeste
authors.initials: C
authors.lastname: Decker
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: Shahid
authors.initials: S
authors.lastname: Khan
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, California.
authors.forename: Peter
authors.initials: P
authors.lastname: Slasor
authors.affiliation: Department of Gestroenterology, UCSF Benioff Children's Hospital Oakland, Children's Hospital and Research Center Oakland, Oakland, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Harmatz
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, California.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Neill
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, California.
authors.forename: Becky
authors.initials: B
authors.lastname: Schweighardt
mesh_terms: D000328:Adult; D057134:Antibodies, Neutralizing; D002648:Child; D002811:Chondroitinsulfatases / Q000627:therapeutic use*; D004311:Double-Blind Method; D056947:Enzyme Replacement Therapy / Q000009:adverse effects / Q000379:methods*; D005260:Female; D006801:Humans; D007632:Keratan Sulfate / Q000652:urine; D008297:Male; D008875:Middle Aged; D009043:Motor Activity; D009085:Mucopolysaccharidosis IV / Q000188:drug therapy*
chemical_list: D057134:Antibodies, Neutralizing; D007632:Keratan Sulfate; D002811:Chondroitinsulfatases; C102295:GALNS protein, human
keywords: Morquio A; Vimizim; elosulfase alfa; immunogenicity; mucopolysaccharidosis IVA