title: Multi-domain impact of elosufase alfa in Morquio A syndrome in the pivotal phase III trial.
abstract: OBJECTIVE
  To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double-blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA).
  
  
  METHODS
  Patients with Morquio A syndrome aged ≥5 years were randomized 1:1:1 to elosulfase alfa 2.0mg/kg/week (qw; N=58), elosulfase alfa 2.0mg/kg/every other week (qow; N=59), or placebo (N=59) for 24 weeks. Primary and secondary efficacy measures were 6-minute walk test (6MWT; primary), 3-minute stair climb test (3-MSCT) and urinary keratan sulfate (KS). Safety was also evaluated. Tertiary efficacy measures included respiratory function measures, activities of daily living (MPS Health Assessment Questionnaire [MPS-HAQ]), anthropometric, echocardiographic and radiographic measures, hearing and corneal clouding assessment. In order to fully characterize treatment impact in this heterogeneous disorder, the effect of elosulfase alfa on composite efficacy measures was evaluated as well.
  
  
  RESULTS
  The study was not designed to have sufficient power for any of the tertiary outcomes. For most tertiary endpoints, subjects treated with the weekly dose of elosulfase alfa improved more than those receiving placebo. The largest treatment effects were seen in maximal voluntary ventilation (MVV), MPS-HAQ, height, and growth rate. The qow group appeared similar to placebo. The analysis of a pre-specified composite endpoint (combining changes from baseline in 6MWT, 3MSCT and MVV z-scores equally weighted) showed a modest positive impact of elosulfase alfa qw versus placebo group (P=0.053). As a pre-specified supportive analysis, the O'Brien Rank Sum composite endpoint (changes from baseline in 6MWT, 3MSC, and MVV), analysis also showed that the qw group performed better than the placebo group (P=0.011). In post-hoc analyses, combinations of other endpoints were also explored using the O'Brien Rank Sum test and showed statistically significant differences between elosulfase alfa qw and placebo favoring elosulfase alfa qw. Differences between elosulfase alfa qow and placebo were not statistically significant. Positive changes were observed in most tertiary variables, demonstrating the efficacy of weekly treatment with elosulfase alfa.
  
  
  CONCLUSIONS
  Treatment with weekly elosulfase alfa led to improvements across most efficacy measures, resulting in clinically meaningful benefits in a heterogeneous study population.
authors.affiliation: Salford Royal NHS Foundation Trust, Salford, UK. Electronic address: chris.hendriksz@srft.nhs.uk.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Hendriksz
authors.affiliation: Medical Genetics Service/HCPA, Department of Genetics/UFRGS and INAGEMP, Porto Alegre, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.affiliation: UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Harmatz
authors.affiliation: Villa Metabolica, Centre for Pediatric and Adolescent Medicine, MC University of Mainz, Mainz, Germany.
authors.forename: Eugen
authors.initials: E
authors.lastname: Mengel
authors.affiliation: Hôpital Femme Mère Enfant Centre de référence des maladies héréditaires du metabolism, Bron Cedex, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Guffon
authors.affiliation: Reference Center for Inherited Metabolic Disease, Hôpital Necker-Enfants Malades and IMAGINE Institute, Paris, France.
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.affiliation: Unita Operativa Semplice Malattie Metaboliche Rare, Azienda Ospedaliera San Gerardo, Monza, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Parini
authors.affiliation: Royal Free London NHS Foundation Trust & University College, London, UK.
authors.forename: Derralynn
authors.initials: D
authors.lastname: Hughes
authors.affiliation: New York University School of Medicine, New York, NY, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Pastores
authors.affiliation: New York University School of Medicine, New York, NY, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Lau
authors.affiliation: King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Moeenaldeen D
authors.initials: MD
authors.lastname: Al-Sayed
authors.affiliation: Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Julian
authors.initials: J
authors.lastname: Raiman
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mealiffe
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Haller
mesh_terms: D000203:Activities of Daily Living; D000293:Adolescent; D000328:Adult; D001827:Body Height / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D002811:Chondroitinsulfatases / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D056947:Enzyme Replacement Therapy; D006801:Humans; D008451:Maximal Voluntary Ventilation; D008875:Middle Aged; D009085:Mucopolysaccharidosis IV / Q000188:drug therapy* / Q000503:physiopathology; D012129:Respiratory Function Tests; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D002811:Chondroitinsulfatases; C102295:GALNS protein, human
keywords: Elosulfase alfa; Enzyme replacement therapy; Lysosomal storage disorder; Morquio A syndrome; Mucopolysaccharidosis IVA; Randomized controlled trial