Mechanism of Action

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of GAG. Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome) is characterized by the absence or marked reduction in N-acetylgalactosamine 4-sulfatase. The sulfatase activity deficiency results in the accumulation of the GAG substrate dermatan sulfate, throughout the body. This accumulation leads to widespread cellular, tissue, and organ dysfunction.

NAGLAZYME is intended to provide an exogenous enzyme that will be taken up into lysosomes and increase the catabolism of GAG. Galsulfase uptake by cells into lysosomes is most likely mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of galsulfase to specific mannose-6- phosphate receptors.

Pharmacokinetics

The pharmacokinetic parameters of galsulfase were evaluated in 13 patients with MPS VI who received mg/g of NAGLAZYME as a 4-hour infusion weekly for 24 weeks. The pharmacokinetic parameters at Week 1 and Week 24 are shown in Table 1.

Nearly all patients who receive treatment with NAGLAZYME develop antibodies to galsulfase. Of 30 patients with MPS VI who received weekly NAGLAZYME infusions and had pharmacokinetics evaluated, 29 developed antibodies to galsulfase. Four patients with high antibody titers had decreases in plasma AUC between Weeks 1 and 24. One patient with high antibody titers had an increase in plasma AUC between Weeks 1 and 24.

A total of 56 patients with MPS VI were enrolled in three clinical studies. The majority of patients had severe manifestations of the disease as evidenced. by poor performance on a test of physical endurance.

In the randomized, double-blind, multicenter, placebo-controlled clinical trial, 39 patients with MPS VI received either NAGLAZYME, 1 mg/kg, or placebo, once-weekly for 24 weeks. The patients' ages ranged from 5 to 29 years. Enrollment was restricted to patients with a 12-minute walk distance of 5 to 400 meters. All patients were treated with antihistamines prior to each infusion.

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