title: A dose-optimization trial of laronidase (Aldurazyme) in patients with mucopolysaccharidosis I.
abstract: Recombinant human alpha-l-iduronidase (Aldurazyme), laronidase) is approved as an enzyme replacement therapy to treat the lysosomal storage disorder, mucopolysaccharidosis type I (MPS I) at a dose of 0.58 mg/kg by once-weekly intravenous infusion. To assess whether alternate dosing regimens might provide a better reduction in lysosomal storage, a 26-week, randomized, open-label, multinational dose-optimization trial was conducted. The pharmacodynamic effect and safety of the approved laronidase dose was compared to three alternative regimens (1.2mg/kg every 2 weeks; 1.2mg/kg every week; 1.8 mg/kg every 2 weeks) among 33 MPS I patients. The four treatment regimens showed no significant differences in the reduction of urinary glycosaminoglycan excretion or liver volume. Laronidase had an acceptable safety profile in all dose regimen groups. Infusion-associated reactions were the most common drug-related adverse events across dose regimens (by patient incidence), and included pyrexia (21%), vomiting (15%), rash (15%), and urticaria (12%). Patients in the approved dose group had the lowest incidence of drug-related adverse events (38% vs. 63-75%) and infusion-associated reactions (25% vs. 25-63%). There was one death: a patient with acute bronchitis died of respiratory failure 6h after completing the first laronidase infusion. The approved 0.58 mg/kg/week laronidase dose regimen provided near-maximal reductions in glycosaminoglycan storage and the best benefit-to-risk ratio. The 1.2mg/kg every 2 weeks regimen may be an acceptable alternative for patients with difficulty receiving weekly infusions, but the long-term effects of this regimen are unknown.
authors.affiliation: Department of Genetics/UFRGS, Medical Genetics Service/HCPA, Postgraduate Program in Medical Sciences, Pediatrics/UFRGS, Porto Alegre, RS, Brazil. rgiugliani@hcpa.ufrgs.br
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.forename: Verónica Muñoz
authors.initials: VM
authors.lastname: Rojas
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Martins
authors.forename: Eugênia R
authors.initials: ER
authors.lastname: Valadares
authors.forename: Joe T R
authors.initials: JT
authors.lastname: Clarke
authors.forename: José E C
authors.initials: JE
authors.lastname: Góes
authors.forename: Emil D
authors.initials: ED
authors.lastname: Kakkis
authors.forename: Mary Alice
authors.initials: MA
authors.lastname: Worden
authors.forename: Marisa
authors.initials: M
authors.lastname: Sidman
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Cox
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006025:Glycosaminoglycans / Q000652:urine; D006801:Humans; D007068:Iduronidase / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D007262:Infusions, Intravenous / Q000009:adverse effects; D008297:Male; D008059:Mucopolysaccharidosis I / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D055815:Young Adult
chemical_list: D006025:Glycosaminoglycans; D007068:Iduronidase