A dose-optimization trial of laronidase (Aldurazyme (R)) in patients with mucopolysaccharidosis I

Recombinant human alpha-L-iduronidase (Aldurazyme (R) 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 (1.2 mg/kg every 2 weeks; 1.2 mg/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 1.2 mg/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. (C) 2008 Elsevier Inc. All rights reserved.BioMarin Pharmaceutical Inc.Genzyme CorporationUniv Fed Rio Grande do Sul, Postgrad Program Med Sci Pediat, Med Genet Serv HCPA, Dept Genet, Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Ctr Genet Med, São Paulo, BrazilUniv Fed Minas Gerais, Dept Propedeut Complementar, Belo Horizonte, MG, BrazilHosp Sick Children, Toronto, ON M5G 1X8, CanadaHosp Infantil Joana de Gusmao, Pediat Intens Care Unit, Florianopolis, SC, BrazilBioMarin Pharmaceut Inc, Novato, CA USAGenzyme Corp, Cambridge, MA USAHarvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USAHarvard Univ, Sch Med, Div Genet, Childrens Hosp Boston, Boston, MA 02115 USAUniversidade Federal de São Paulo, Ctr Genet Med, São Paulo, BrazilWeb of Scienc