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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.
Pediatrics. 2005 Jun; 115(6):e681-9.Ped

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.

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 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.

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.

Authors+Show Affiliations

Children's Hospital & Research Center at Oakland, 747 52nd St, Oakland, CA 94609, USA. pharmatz@mail.cho.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15930196

Citation

Harmatz, Paul, et al. "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." Pediatrics, vol. 115, no. 6, 2005, pp. e681-9.
Harmatz P, Ketteridge D, Giugliani R, et al. 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. Pediatrics. 2005;115(6):e681-9.
Harmatz, P., Ketteridge, D., Giugliani, R., Guffon, N., Teles, E. L., Miranda, M. C., Yu, Z. F., Swiedler, S. J., & Hopwood, J. J. (2005). 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. Pediatrics, 115(6), e681-9.
Harmatz P, et al. 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. Pediatrics. 2005;115(6):e681-9. PubMed PMID: 15930196.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Harmatz,Paul, AU - Ketteridge,David, AU - Giugliani,Roberto, AU - Guffon,Natalie, AU - Teles,Elisa Leão, AU - Miranda,M Clara Sá, AU - Yu,Zi-Fan, AU - Swiedler,Stuart J, AU - Hopwood,John J, AU - ,, PY - 2005/6/3/pubmed PY - 2005/11/11/medline PY - 2005/6/3/entrez SP - e681 EP - 9 JF - Pediatrics JO - Pediatrics VL - 115 IS - 6 N2 - 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 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. 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. SN - 1098-4275 UR - https://www.unboundmedicine.com/medline/citation/15930196/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_ L2 - http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&amp;pmid=15930196 DB - PRIME DP - Unbound Medicine ER -