Published online June 1, 2005
PEDIATRICS Vol. 115 No. 6 June 2005, pp. e681-e689 (doi:10.1542/peds.2004-1023)

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ELECTRONIC ARTICLE

Direct Comparison of Measures of Endurance, Mobility, and Joint Function During Enzyme-Replacement Therapy of Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome): Results After 48 Weeks in a Phase 2 Open-Label Clinical Study of Recombinant Human N-Acetylgalactosamine 4-Sulfatase

Paul Harmatz, MD^*, David Ketteridge, MBBS, Roberto Giugliani, MD, PhD, Natalie Guffon, MD^||, Elisa Leão Teles, MD^¶, M. Clara Sá Miranda, PhD^#, Zi-Fan Yu, ScD^**, Stuart J. Swiedler, MD, PhD, John J. Hopwood, PhD for the MPS VI Study Group

^* Children's Hospital & Research Center, Oakland, California
Department of Genetic Medicine, Women's and Children's Hospital Adelaide, North Adelaide, Australia
Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
^|| Hôpital Edouard Herriot Pavillon S, Maladies Metaboliques, Lyon, France
^¶ Unidade de Doencas Metabolicas, Departmento Pediatria, Hospital de Sao João, Porto, Portugal
^# Instituto de Biologia Moleculare Celular, Porto, Portugal
^** Statistics Collaborative, Inc, Washington, DC
BioMarin Pharmaceutical, Inc, Novato, California

Objective. Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme N-acetylgalactosamine 4-sulfatase (ASB). This enzyme deficiency leads to a progressive disorder with multiple tissue and organ involvement. The disease is rare and is heterogeneous in its clinical presentation and progression. A potential treatment for this disease exists in the form of enzyme-replacement therapy (ERT) with recombinant human ASB (rhASB), and a phase 1/2 randomized, double-blind, 2-dose (0.2 and 1 mg/kg) study in 6 patients showed the treatment at 48 weeks to be well tolerated. Greater biochemical efficacy based on a urine glycosaminoglycan occurred in the high-dose (1 mg/kg) group, and functional improvement seemed greater in patients in the high-dose group with rapidly advancing disease. On the basis of the phase 1/2 results, a phase 2, open-label study in patients with rapidly advancing disease was initiated primarily to evaluate efficacy variables that measure endurance, mobility, and joint function in a larger group of patients.

Methods. This was an open-label, multinational study of 10 MPS VI patients who received 48 weekly intravenous treatments with 1.0 mg/kg rhASB and had assessments of biochemical and clinical responses at regular intervals.

Results. After 24 weeks of treatment, each patient on average experienced a 155-m (98%) improvement in the 12-minute walk, a 64-m (62%) improvement at the 6-minute time point of the 12-minute walk, and a 48-stair (110%) gain in the 3-minute stair climb versus the baseline mean values. Additional improvements after 48 weeks of treatment were observed, including mean values of 211 m (138%) in the 12-minute walk, 75 m (80%) at the 6-minute time point of the 12-minute walk, and 61-stair (147%) gain in the 3-minute stair climb versus the baseline mean values. Joint Pain and Stiffness Questionnaire scores improved by at least 50% by week 24 and were maintained at week 48, whereas there were only small improvements in active shoulder range of motion (<10°) and in the time taken to stand, walk, and turn starting from a seated position (Expanded Timed Get-Up and Go test). Improvement in pulmonary function based on forced vital capacity and forced expiratory volume at 1 minute in the absence of growth was observed in 3 of 6 patients, and the observed gains occurred in the 24- to 48-week treatment interval. A mean decrease of 76% in urinary excretion of glycosaminoglycans indicated that a satisfactory biochemical response was achieved and the ERT was well tolerated.

Conclusions. The results suggest that a 12-minute walk extends the dynamic range of the conventional 6-minute walk and, along with the 3-minute stair climb, provide a robust approach to documenting the improvement in endurance in MPS VI patients who undergo ERT with rhASB.

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Key Words: mucopolysaccharidosis VI • N-acetylgalactosamine 4-sulfatase • enzyme-replacement therapy • glycosaminoglycans • clinical trial

Abbreviations: MPS, mucopolysaccharidosis • ASB, N-acetylgalactosamine 4-sulfatase • GAG, glycosaminoglycan • ERT, enzyme-replacement therapy • rhASB, recombinant N-acetylgalactosamine 4-sulfatase • ETGG, Expanded Timed Get-Up and Go • ROM, range of motion • FVC, forced vital capacity • FEV₁, forced expiratory volume at 1 minute • SpO₂, oxygen saturation by pulse oximeter • HAQ, Health Assessment Questionnaire • CHAQ, Childhood Health Assessment Questionnaire

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Accepted Dec 16, 2004.

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