A dose-optimization trial of laronidase (Aldurazyme) in patients with mucopolysaccharidosis I.
Author(s): Giugliani R, Rojas VM, Martins AM, Valadares ER, Clarke JT, Goes JE, Kakkis ED, Worden MA, Sidman M, Cox GF
Affiliation(s): Department of Genetics/UFRGS, Medical Genetics Service/HCPA, Postgraduate Program in Medical Sciences, Pediatrics/UFRGS, Porto Alegre, RS, Brazil. firstname.lastname@example.org
Publication date & source: 2009-01, Mol Genet Metab., 96(1):13-9. Epub 2008 Nov 26.
Publication type: Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
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.