Naglazyme (galsufase) is a variant form of the polymorphic human enzyme N-acetylgalactosamine 4-sulfatase of recombinant DNA origin. It is designed to replace the natural enzyme, increasing the catabolism of glycosaminoglycans (GAG), which abnormally accumulate in multiple tissue types in patients with mucopolysaccharidosis VI (MPS-VI, or Maroteaux-Lamy syndrome).
Naglazyme is specifically indicated for the treatment of adults and children with MPS-VI.
Naglazyme is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution for intravenous injection. Recommended dosing is 1 mg/kg once weekly via 4+ hour infusion, with pretreatment 30 to 60 minutes prior with antihistamines (with or without antipyretics) to reduce potential infusion reactions
Approval of Naglazyme was based on 3 clinical studies enrolling a total of 56 patients: 39 received the drug in a double-blind, placebo-controlled study followed by an open-label extension, and 17 received the drug in a pair of long-term open-label studies for up to 144 weeks. In the double blind studies, subjects were treated with 1 mg/kg of the drug or placebo via once-weekly infusion for 24 weeks. At the end of treatment, Naglazyme was seen to significantly increased baseline-adjusted mean 12-minute walk distance compared to placebo, the study's primary endpoint (+92 meters; p=0.025). A positive, non-significant trend was observed in increasing performance in a 3 minute stair climb test, vs. placebo (+5.7 stairs/minute; p=0.053). Also, patients receiving Naglazyme showed significant reductions in urinary GAG secretion compared to placebo, though reductions were not sufficient to reach normal, healthy-patient levels
In an open-label extension to the double blind study, all 38 patients completing the initial study received the drug for an additional 24 weeks. Subjects who had received Naglazyme in the initial study showed additional improvements in mean 12-minute walk distance and rate of stair climbing (+36 meters, +3 stairs/minute); subjects who had received placebo in the initial study experienced larger mean improvements (+66 meters, +6 stairs/minute).
In the pair of long-term open label studies, 17 subjects received the drug for up to 144 weeks. These trials confirmed that reductions in urinary GAG levels were maintained throughout administration.
Ongoing Study Commitments
Adverse events associated with the use of Naglazyme may include, but are not limited to, the following:
Infusion of Naglazyme produced infusion reactions, some of which were severe. It is recommended that patients receive treatment with antihistamines with or without antipyretics prior to infusion, but this pretreatment is not entirely effective in eliminating reactions. Severe infusion-reaction symptoms included angioneurotic edema, hypotension, dyspnea, bronchospasm, respiratory distress, apnea, and urticaria. Infusion symptoms generally resolved with slowing or temporary interruption of the infusion and administration of additional antihistamines, antipyretics and corticosteroids (as needed).
In addition, 98% of patients treated with the drug developed anti-Naglazyme IgG antibodies, typically within 4-8 weeks of treatment. 5 patients with high antibody response experienced changes in the pharmacokinetic parameters of the drug; some evidence of inhibition of efficacy was observed, though the extent of this effect is unclear.
Naglazyme supplies recombinant-engineered galsulfase, a normal variant form of the polymorphic human enzyme, N-acetylgalactosamine 4-sulfatase. It is a lysosomal hydrolase that catalyzes the cleavage of the sulfate ester from terminal N-acetylgalactosamine 4-sulfate residues of GAG chondroitin 4-sulfate and dermatan sulfate. Increased catabolism of GAG in turn reduces systemic dermatan sulfate accumulation, thereby reducing the primary symptoms of MPS VI.
Harmatz P, Ketteridge D, Giugliani R, Guffon N, Teles EL, Miranda MC, Yu ZF, Swiedler SJ, Hopwood JJ; MPS VI Study Group. 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
Harmatz P, Kramer WG, Hopwood JJ, Simon J, Butensky E, Swiedler SJ; Mucopolysaccharidosis VI Study Group. Pharmacokinetic profile of recombinant human N-acetylgalactosamine 4-sulphatase enzyme replacement therapy in patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): a phase I/II study. Acta Paediatrica Supplement 2005 Mar;94(447):61-8; discussion 57.
Swiedler SJ, Beck M, Bajbouj M, Giugliani R, Schwartz I, Harmatz P, Wraith JE, Roberts J, Ketteridge D, Hopwood JJ, Guffon N, Sa Miranda MC, Teles EL, Berger KI, Piscia-Nichols C. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). American Journal of Medical Genetics Part A 2005 Apr 15;134(2):144-50
Harmatz P, Whitley CB, Waber L, Pais R, Steiner R, Plecko B, Kaplan P, Simon J, Butensky E, Hopwood JJ. Enzyme replacement therapy in mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Journal of Pediatrics 2004 May;144(5):574-80
For additional information regarding Naglazyme or MPS-VI, please visit the Naglazyme web page.