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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.
- Source :
-
Pediatrics [Pediatrics] 2005 Jun; Vol. 115 (6), pp. e681-9. - Publication Year :
- 2005
-
Abstract
- 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.<br />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.<br />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 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.<br />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.
- Subjects :
- Adolescent
Adult
Antibody-Dependent Cell Cytotoxicity
Child
Female
Glycosaminoglycans urine
Hand Strength
Humans
Injections, Intravenous
Isoantibodies biosynthesis
Isoantibodies immunology
Joints physiopathology
Male
Mucopolysaccharidosis VI physiopathology
Mucopolysaccharidosis VI urine
N-Acetylgalactosamine-4-Sulfatase administration & dosage
N-Acetylgalactosamine-4-Sulfatase genetics
N-Acetylgalactosamine-4-Sulfatase immunology
Recombinant Fusion Proteins administration & dosage
Recombinant Fusion Proteins therapeutic use
Recovery of Function
Severity of Illness Index
Treatment Outcome
Walking
Movement
Mucopolysaccharidosis VI drug therapy
N-Acetylgalactosamine-4-Sulfatase therapeutic use
Physical Endurance
Range of Motion, Articular
Subjects
Details
- Language :
- English
- ISSN :
- 1098-4275
- Volume :
- 115
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Pediatrics
- Publication Type :
- Academic Journal
- Accession number :
- 15930196
- Full Text :
- https://doi.org/10.1542/peds.2004-1023