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Type: Journal article
Title: 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
Author: Harmatz, P.
Ketteridge, D.
Giugliani, R.
Guffon, N.
Teles, E.
Miranda, C.
Yu, Z.
Swiedler, S.
Hopwood, J.
Citation: Pediatrics, 2005; 115(6):E681-E689
Publisher: Amer Acad Pediatrics
Issue Date: 2005
ISSN: 0031-4005
Statement of
Harmatz, Paul ; Ketteridge, David ; Giugliani, Roberto ; Guffon, Natalie ; Teles, Elisa Leão ; Miranda, M Clara Sá ; Yu, Zi-fan ; Swiedler, Stuart J ; Hopwood, John J for the MPS VI Study Group
Abstract: <h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 degrees ) 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.<h4>Conclusions</h4>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.
Keywords: MPS VI Study Group
Mucopolysaccharidosis VI
Recombinant Fusion Proteins
Hand Strength
Range of Motion, Articular
Treatment Outcome
Injections, Intravenous
Severity of Illness Index
Recovery of Function
Antibody-Dependent Cell Cytotoxicity
Physical Endurance
DOI: 10.1542/peds.2004-1023
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Paediatrics publications

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