Published online June 4, 2007
PEDIATRICS Vol. 120 No. 1 July 2007, pp. e37-e46 (doi:10.1542/peds.2006-2156)
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ARTICLE

Enzyme Replacement Therapy in Patients Who Have Mucopolysaccharidosis I and Are Younger Than 5 Years: Results of a Multinational Study of Recombinant Human {alpha}-L-Iduronidase (Laronidase)

J. Edmond Wraith, MBChBa, Michael Beck, MDb, Roderick Lane, PhDc, Ans van der Ploeg, MD, PhDd, Elsa Shapiro, PhD, ABPPe, Yong Xue, MD, PhDf, Emil D. Kakkis, MD, PhDg and Nathalie Guffon, MDh

a Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester, United Kingdom
b Department of Pediatrics, Children's Hospital, University of Mainz, Mainz, Germany
c Sleep and Respiratory Services, Great Ormond Street Hospital, London, United Kingdom
d Department of Pediatrics, Sophia Children's Hospital, Rotterdam, Netherlands
e Division of Pediatric Clinical Neuroscience, University of Minnesota, Minneapolis, Minnesota
f Genzyme Europe BV, Naarden, Netherlands
g BioMarin Pharmaceutical Inc, Novato, California
h Department of Pediatrics, Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Edouard Herriot, Lyon, France

OBJECTIVE. Our objective was to evaluate the safety, pharmacokinetics, and efficacy of laronidase in young, severely affected children with mucopolysaccharidosis I.

METHODS. This was a prospective, open-label, multinational study of 20 patients who had mucopolysaccharidosis I and were <5 years old (16 with Hurler syndrome, 4 with Hurler-Scheie syndrome) and were scheduled to receive intravenous laronidase at 100 U/kg (0.58 mg/kg) weekly for 52 weeks. Four patients underwent dosage increases to 200 U/kg for the last 26 weeks because of elevated urinary glycosaminoglycan levels at week 22.

RESULTS. Laronidase was well tolerated at both dosages. Investigators reported improved clinical status in 94% of patients at week 52. The mean urinary glycosaminoglycan level declined by ~50% at week 13 and was sustained thereafter. A more robust decrease in urinary glycosaminoglycan was observed in patients with low antibody levels and those who were receiving the 200 U/kg dosage. On examination, the liver edge was reduced by 69.5% in patients with a palpable liver at baseline and week 52 (n = 10). The proportion of patients with left ventricular hypertrophy decreased from 53% to 17%. Global assessment of sleep studies showed improvement or stabilization in 67% of patients, and the apnea/hypopnea index decreased by 5.8 events per hour (–8.5%) in those with abnormal baseline values. The younger patients with Hurler syndrome (<2.5 years) and all 4 patients with Hurler-Scheie syndrome showed normal mental development trajectories during the 1-year treatment period.

CONCLUSIONS. Laronidase seems to be well tolerated and to provide clinical benefit in patients who have severe mucopolysaccharidosis I and are <5 years old. Enzyme replacement therapy is not curative and may not improve all affected organs and systems in individuals when irreversible changes have developed. The long-term clinical outcome and effects of antibodies and laronidase dosing on glycosaminoglycan reduction warrant additional investigation.

Key Words: enzyme replacement therapy • Hurler syndrome • laronidase • MPS I

Abbreviations: MPS I—mucopolysaccharidosis I • HSCT—hematopoietic stem cell transplantation • ERT—enzyme replacement therapy • AE—adverse event • IgG—immunoglobulin G • AHI—apnea/hypopnea index • IAR—infusion-associated reaction

Accepted Dec 13, 2006.