Home » Drug Information » FDA Approved Drugs » 2005
Medical Areas: Musculoskeletal
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The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
Company: BioMarin Pharmaceuticals
Approval Status: Approved May 2005
Treatment Area: Mucopolysaccharidosis VI
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
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,
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
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
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
Protocol Submission: June 30, 2005
- Study Start: July 15,
- Final Report Submission: December
- 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
Adverse events associated with the use of Naglazyme may include,
but are not limited to, the following:
- Abdominal Pain
- Ear Pain
- Chest Pain
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.
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
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;
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
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
For additional information regarding Naglazyme or MPS-VI, please
visit the Naglazyme web page.