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

• Published in: Molecular genetics and metabolism Vol. 96; no. 1; pp. 13 - 19
• Main Authors: Giugliani, Roberto, Rojas, Verónica Muñoz, Martins, Ana Maria, Valadares, Eugênia R., Clarke, Joe T.R., Góes, José E.C., Kakkis, Emil D., Worden, Mary Alice, Sidman, Marisa, Cox, Gerald F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2009
• Subjects: Adolescent; Child; Child, Preschool; Clinical trial; Dose-optimization; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme replacement therapy; Female; Glycosaminoglycans; Glycosaminoglycans - urine; Humans; Hurler; Hurler–Scheie; Iduronidase - administration & dosage; Iduronidase - adverse effects; Iduronidase - immunology; Infusions, Intravenous - adverse effects; Laronidase; Male; Mucopolysaccharidosis (MPS) type I; Mucopolysaccharidosis I - drug therapy; Mucopolysaccharidosis I - enzymology; Mucopolysaccharidosis I - immunology; Mucopolysaccharidosis I - physiopathology; Scheie; Young Adult; Hurler–Scheie; Glycosaminoglycans; Enzyme replacement therapy; Hurler; Clinical trial; Laronidase; Dose-optimization; Mucopolysaccharidosis (MPS) type I; Scheie
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2008.10.009

Recombinant human α- 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 (1.2 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 6 h 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.