title: Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I.
abstract: OBJECTIVE
  Our goal was to evaluate the long-term safety and efficacy of recombinant human alpha-l-iduronidase (laronidase) in patients with mucopolysaccharidosis I.
  
  
  METHODS
  All 45 patients who completed a 26-week, double-blind, placebo-controlled trial of laronidase were enrolled in a 3.5-year open-label extension study. Mean patient age at baseline was 16 (range: 6-43) years. All patients had attenuated disease (84% Hurler-Scheie, 16% Scheie phenotypes). Clinical, biochemical, and health outcomes measures were evaluated through the extension phase. Changes are presented as the mean +/- SEM.
  
  
  RESULTS
  All 40 patients (89%) who completed the trial received at least 80% of scheduled infusions. As shown in earlier trials, urinary glycosaminoglycan levels decreased within the first 12 weeks and liver volume decreased within the first year. Percent predicted forced vital capacity remained stable, with a linear slope of -0.78 percentage points per year. The 6-minute walk distance increased 31.7 +/- 10.2 m in the first 2 years, with a final gain of 17.1 +/- 16.8 m. Improvements in the apnea/hypopnea index (decrease of 7.6 +/- 4.5 events per hour among the patients with significant baseline sleep apnea) and shoulder flexion (increase of 17.4 degrees +/- 3.6 degrees) were most rapid during the first 2 years. Improvements in the Child Health Assessment Questionnaire/Health Assessment Questionnaire disability index (decrease of 0.31 +/- 0.11, signifying a clinically meaningful improvement in activities of daily living) were gradual and sustained over the treatment period. Laronidase infusions were generally well tolerated except in 1 patient who experienced an anaphylactic reaction. Infusion-associated reactions, which occurred in 53% of the patients, were mostly mild, easily managed, and decreased markedly after 6 months. One patient died as a result of an upper respiratory infection unrelated to treatment. Antibodies to laronidase developed in 93% of the patients; 29% of the patients were seronegative at their last assessment.
  
  
  CONCLUSIONS
  This trial demonstrates the long-term clinical benefit and safety of laronidase in attenuated patients with mucopolysaccharidosis I and highlights the magnitude and chronology of treatment effects. Prompt diagnosis and early treatment will maximize treatment outcomes.
authors.affiliation: University of British Columbia, Department of Medical Genetics, Vancouver, British Columbia, Canada. lclarke@cw.bc.ca
authors.forename: Lorne A
authors.initials: LA
authors.lastname: Clarke
authors.forename: J Edmond
authors.initials: JE
authors.lastname: Wraith
authors.forename: Michael
authors.initials: M
authors.lastname: Beck
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Kolodny
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Pastores
authors.forename: Joseph
authors.initials: J
authors.lastname: Muenzer
authors.forename: David M
authors.initials: DM
authors.lastname: Rapoport
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Berger
authors.forename: Marisa
authors.initials: M
authors.lastname: Sidman
authors.forename: Emil D
authors.initials: ED
authors.lastname: Kakkis
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Cox
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004311:Double-Blind Method; D005076:Exanthema / Q000139:chemically induced / Q000175:diagnosis; D005260:Female; D006261:Headache / Q000139:chemically induced / Q000175:diagnosis; D006801:Humans; D007068:Iduronidase / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D008297:Male; D008059:Mucopolysaccharidosis I / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D013995:Time; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; D007068:Iduronidase