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.
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.
Harmatz
Paul
P
Children's Hospital & Research Center at Oakland, 747 52nd St, Oakland, CA 94609, USA. pharmatz@mail.cho.org
Ketteridge
David
D
Giugliani
Roberto
R
Guffon
Natalie
N
Teles
Elisa Leão
EL
Miranda
M Clara Sá
MC
Yu
Zi-Fan
ZF
Swiedler
Stuart J
SJ
Hopwood
John J
JJ
D000293:Adolescent; D000328:Adult; D000920:Antibody-Dependent Cell Cytotoxicity; D002648:Child; D005260:Female; D006025:Glycosaminoglycans / Q000652:urine; D018737:Hand Strength; D006801:Humans; D007275:Injections, Intravenous; D007518:Isoantibodies / Q000096:biosynthesis / Q000276:immunology; D007596:Joints / Q000503:physiopathology; D008297:Male; D009068:Movement; D009087:Mucopolysaccharidosis VI / Q000188:drug therapy* / Q000503:physiopathology / Q000652:urine; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D010807:Physical Endurance; D016059:Range of Motion, Articular; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D020127:Recovery of Function; D012720:Severity of Illness Index; D016896:Treatment Outcome; D016138:Walking
D006025:Glycosaminoglycans; D007518:Isoantibodies; D011993:Recombinant Fusion Proteins; D020051:N-Acetylgalactosamine-4-Sulfatase