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Currently Enrolling Trials

General Information

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

Clinical Results

FDA Approval
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

To develop and validate an improved screening assay for detecting total antibodies to Naglazyme.
Protocol Submission: November 30, 2005
To develop and Validate an improved immunogenicity assay for detecting neutralizing antibodies to Naglazyme.
Full Report Submission: November 30, 2005
To develop and evaluate an improved immunogenicity assay for detecting IgE antibodies to Naglazyme.
Full Report Submission: November 30, 2005
To analyze, using the improved and validated immunogenicity assays, archived serum samples from patients in the phase III trials (ASB-03-05) for binding, neutralizing and IgE antibodies to Naglazyme. Analysis will evaluate immunogenicity Rates and individual patient titers to assess how antibody levels increase or decrease as a function of repeated exposure to better evaluate impact of repeated dosing on potential induction of immunological tolerance.
Final Report Submission: May 31, 2006
To develop and validate an improved assay for detecting Naglazyme in human plasma.
Final Report Submission: November 30, 2005
To evaluate the long-term safety and efficacy data in a Clinical Surveillance Program (CSP) of patients being treated with Naglazyme. Detailed clinical status information will be collected at study entry and on an annual basis for 15 years. Serious and severe adverse events among all patients will be collected and submitted through periodic safety update reports as specified by the regulations (21 CFR 600.80). A substudy within the CSP will evaluate the effect of Naglazyme on pregnancy and lactation. A second substudy within the CSP will include the enrollment of at least 10 children less than 5 years of age, to be treated with 1 mg/kg/week Naglazyme for at least 1 year and will report the analysis of these data. CSP data will be analyzed at yearly intervals, and the results will be submitted in annual reports. Information will also be collected on clinical status, adverse events, assessment of immunogenicity, and potential effects of antibody formation.
Protocol Submission: June 30, 2005
Study Start: July 15, 2005
Final Report Submission: December 31, 2020
To conduct a study of no less than 4 infants with MPS VI who are less than one year of age to determine the effects of Naglazyme treatment on the development of skeletal dysplasia. Patients would be randomized in a 1:1 fashion to one of two Naglazyme dose groups (1.0 mg/kg or 2.0 mg/kg). Randomized patients would be followed for at least one year.
Protocol Submission: July 30, 2005
Patient Enrollment Completion: September 30, 2007
Final Report Submission: January 15, 2009

Side Effects

Adverse events associated with the use of Naglazyme may include, but are not limited to, the following:

Abdominal Pain
Ear Pain
Pain
Conjunctivitis
Dyspnea
Rigors
Chest Pain
Pharyngitis

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.

Mechanism of Action

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.

Literature References

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