Published online December 29, 2008
PEDIATRICS Vol. 123 No. 1 January 2009, pp. 229-240 (doi:10.1542/peds.2007-3847)

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ARTICLE

Long-term Efficacy and Safety of Laronidase in the Treatment of Mucopolysaccharidosis I

Lorne A. Clarke, MD^a, J. Edmond Wraith, MB, ChB^b, Michael Beck, MD^c, Edwin H. Kolodny, MD^d, Gregory M. Pastores, MD^d,e, Joseph Muenzer, MD, PhD^f, David M. Rapoport, MD^g, Kenneth I. Berger, MD^g, Marisa Sidman, MS^h, Emil D. Kakkis, MD, PhDⁱ and Gerald F. Cox, MD, PhD^h,j,k

^a Department of Medical Genetics, University of British Columbia and Children's and Women's Health Center of British Columbia, Vancouver, British Columbia, Canada
^b Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester, United Kingdom
^c Department of Pediatrics, Children's Hospital, University of Mainz, Mainz, Germany
^d Departments of Neurology
^e Pediatrics
^g Medicine, New York University School of Medicine, New York, New York
^f Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina
^h Genzyme Corporation, Cambridge, Massachusetts
ⁱ BioMarin Pharmaceutical Inc, Novato, California
^j Division of Genetics, Children's Hospital Boston, Boston, Massachusetts
^k Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

OBJECTIVE. Our goal was to evaluate the long-term safety and efficacy of recombinant human -L-iduronidase (laronidase) in patients with mucopolysaccharidosis I.

PATIENTS AND METHODS. All 45 patients who completed a 26-week, double-blind, placebo-controlled trial of laronidase were enrolled in a 3.5-year open-label extension study. Mean patient age at baseline was 16 (range: 6–43) years. All patients had attenuated disease (84% Hurler-Scheie, 16% Scheie phenotypes). Clinical, biochemical, and health outcomes measures were evaluated through the extension phase. Changes are presented as the mean ± SEM.

RESULTS. All 40 patients (89%) who completed the trial received at least 80% of scheduled infusions. As shown in earlier trials, urinary glycosaminoglycan levels decreased within the first 12 weeks and liver volume decreased within the first year. Percent predicted forced vital capacity remained stable, with a linear slope of –0.78 percentage points per year. The 6-minute walk distance increased 31.7 ± 10.2 m in the first 2 years, with a final gain of 17.1 ± 16.8 m. Improvements in the apnea/hypopnea index (decrease of 7.6 ± 4.5 events per hour among the patients with significant baseline sleep apnea) and shoulder flexion (increase of 17.4° ± 3.6°) were most rapid during the first 2 years. Improvements in the Child Health Assessment Questionnaire/Health Assessment Questionnaire disability index (decrease of 0.31 ± 0.11, signifying a clinically meaningful improvement in activities of daily living) were gradual and sustained over the treatment period. Laronidase infusions were generally well tolerated except in 1 patient who experienced an anaphylactic reaction. Infusion-associated reactions, which occurred in 53% of the patients, were mostly mild, easily managed, and decreased markedly after 6 months. One patient died as a result of an upper respiratory infection unrelated to treatment. Antibodies to laronidase developed in 93% of the patients; 29% of the patients were seronegative at their last assessment.

CONCLUSIONS. This trial demonstrates the long-term clinical benefit and safety of laronidase in attenuated patients with mucopolysaccharidosis I and highlights the magnitude and chronology of treatment effects. Prompt diagnosis and early treatment will maximize treatment outcomes.

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Key Words: clinical trial • enzyme replacement therapy • mucopolysaccharidosis I • laronidase

Abbreviations: MPS I—mucopolysaccharidosis I • FVC—forced vital capacity • 6MWT—6-minute walk test • IAR—infusion-associated reaction • Ig—immunoglobulin • ELISA—enzyme-linked immunosorbent assay • AHI—apnea/hypopnea index • CHAQ/HAQ—Child Health Assessment Questionnaire/Health Assessment Questionnaire • LVH—left ventricular hypertrophy

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Accepted Apr 22, 2008.

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