Enzyme replacement therapy with laronidase (Aldurazyme(®)) for treating mucopolysaccharidosis type I.

BACKGROUND: Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler syndrome, Hurler-Scheie syndrome and Scheie syndrome, with the scale of severity being such that Hurler syndrome is the most severe and Scheie syndrome the least severe. It is a rare, autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. Deficiency of this enzyme results in the accumulation of glycosaminoglycans within the tissues. The clinical manifestations are facial dysmorphism, hepatosplenomegaly, upper airway obstruction, skeletal deformity and cardiomyopathy. If Hurler syndrome is left untreated, death ensues by adolescence. There are more attenuated variants termed Hurler-Scheie or Scheie syndrome, with those affected potentially not presenting until adulthood. Enzyme replacement therapy has been used for a number of years in the treatment of Hurler syndrome, although the current gold standard would be a haemopoietic stem cell transplant in those diagnosed by 2.5 years of age.

OBJECTIVES: To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, MEDLINE via OVID and EMBASE.Date of most recent search: 08 February 2013.

SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of laronidase enzyme replacement therapy compared to placebo.

DATA COLLECTION AND ANALYSIS: Two authors independently screened the identified trials. The authors then appraised and extracted data.

MAIN RESULTS: One study of 45 patients met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational trial looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in patients with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this trial. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned analysis of covariance). The levels of urinary glycoaminoglycans were also significantly reduced. In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all patients in the treatment group with no apparent clinical effect and titres were reducing by the end of the study. Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation.

AUTHORS' CONCLUSIONS: The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included trial was comprehensive and of good quality, although there were few participants. The trial included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters (reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute-walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those patients diagnosed under 2.5 years of age.