Elsevier

The Journal of Pediatrics

Volume 148, Issue 4, April 2006, Pages 533-539.e6
The Journal of Pediatrics

Original article
Enzyme replacement therapy for mucopolysaccharidosis VI: A phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study

https://doi.org/10.1016/j.jpeds.2005.12.014Get rights and content

Objective

The objective of this Phase 3 study was to confirm the efficacy and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome), a rare, fatal lysosomal storage disease with no effective treatment.

Study design

Thirty-nine patients with MPS VI were evaluated in a randomized, double-blind, placebo-controlled, multicenter, multinational study for 24 weeks. The primary efficacy variable was the distance walked in a 12-minute walk test (12MWT), whereas the secondary efficacy variables were the number of stairs climbed in a 3-minute stair climb (3MSC) and the level of urinary glycosaminoglycan (GAG) excretion. All patients received drug in an open-label extension period for an additional 24 weeks.

Results

After 24 weeks, patients receiving rhASB walked on average 92 meters (m) more in the 12MWT (p = .025) and 5.7 stairs per minute more 3MSC (p = .053) than patients receiving placebo. Continued improvement was observed during the extension study. Urinary GAG declined by -227 ± 18 μg/mg more with rhASB than placebo (p <.001). Infusions were generally safe and well tolerated. Patients exposed to drug experienced positive clinical benefit despite the presence of antibody to the protein.

Conclusion

rhASB significantly improves endurance, reduces GAG, and has an acceptable safety profile.

Section snippets

Study Design

This was a randomized, double-blind, multicenter, placebo-controlled, 24-week Phase 3 study of rhASB followed by a 24-week extension period. Following screening eligibility assessments, eligible patients completed baseline assessments, and they were randomized in a 1:1 ratio to receive weekly intravenous infusions of either rhASB 1.0 mg/kg or placebo solution for 24 consecutive weeks. After 24 weeks, all patients completing treatment were enrolled in the open-label extension. The investigator

Characteristics of Patients

Characteristics of the study patients are shown in Table I. Although those in the placebo group were, on average, younger, shorter, and weighed less than those in the rhASB group, none of these differences was statistically significant. All 28 eligible patients were randomized, as were 11 patients who did not fulfill inclusion criteria. Seven of these exceeded the walk distance eligibility entry criteria at screening, 3 were <7 years of age, and 1 had experienced a failed bone marrow transplant

Discussion

Mucopolysaccharidosis VI is a rare, fatal lysosomal storage disease with no effective treatment. Administration of 1.0 mg/kg rhASB led to a statistically significant improvement in endurance, as measured by the 12MWT and 3MSC; and in a statistically significant decline in urinary GAG excretion. rhASB was well tolerated, with most AEs attributable to manifestations of the MPS VI disease. IARs related to study drug administration were readily managed and did not result in discontinuation of the

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This study was sponsored by BioMarin Pharmaceutical Inc., and it was supported, in part, with funds provided by the National Center for Research Resources, 5 M01 RR-01271 (Dr Harmatz).

List of the investigators for the MPS VI Phase 3 Study Group is available at www.jpeds.com.

1

Drs Harmatz, Wittes, Lowe, Berger, and Yu have provided consulting support to BioMarin Pharmaceutical Inc., Novato, California.

2

Drs Swiedler, Kakkis, and Ms Newman are employees and stockholders of BioMarin Pharmaceutical, Inc.

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