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On July 24, 2006, the FDA granted Shire Pharmaceuticals approval to market Elaprase (idursulfase), the first enzyme replacement therapy for the treatment of Hunter's syndrome.1 Hunter's syndrome is an X-linked recessive genetic disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S). This enzyme hydrolyzes the degradation products of proteoglycans, the constituents of the extracellular matrix. These degradation products are called glycosaminoglycans (GAGs) or mucopolysaccharides. Hunter's syndrome, also referred to as mucopolysaccharidosis type 2 (MPS II), is one of many lysosomal storage disorders that affect metabolism of mucopolysaccharides.2
In severe cases, patients present with symptoms of Hunter's syndrome around age 2 to 6 years, as GAGs accumulate in the lysosomes of body cells.2 Symptoms may include enlarged skull and forehead, frequent infections,2 hearing loss, obstructive airways disease with sleep apnea,1 cardiac valve abnormalities,3 organ enlargement, and mental retardation. It is estimated that Hunter's syndrome affects 1 in 100,000 people in the United States, the vast majority of whom are males due to the sex-linked inheritance of the disease.2
Elaprase is an exogenous enzyme that targets intracellular lysosomes and causes catabolism of accumulated GAGs. This action results from the mannose-6-phosphate (M6P) residues on the oligosaccharide chains allowing Elaprase to bind to the M6P receptors on the cell surface. This binding allows the entry of Elaprase into the cell, where it then targets the GAGs.4
A phase 2/3 randomized, doubleblind, placebo-controlled clinical study evaluated the safety and efficacy of recombinant human I2S (idursulfase) for the treatment of Hunter's syndrome. The study included 96 patients diagnosed with Hunter's syndrome, ranging from 5 to 31 years of age. During 53 weeks, patients were administered infusions of Elaprase 0.5 mg/kg every week (n = 32), Elaprase 0.5 mg/kg every other week (n = 32), or placebo (n = 32).
A composite end point consisting of (1) distance walked in 6 minutes and (2) the percentage of predicted forced vital capacity (FVC) based on the sum of the ranks change from baseline was used to evaluate efficacy. The results showed a significant improvement in both treatment groups, compared with placebo (P = .00049 for weekly and P = .0416 for every-other-week idursulfase groups) after 1 year. The weekly-dosing group had a 2.7% increase in the percentage of predicted FVC (P = .065), a 37-m increase in the 6-minute walk (P = .013), and a 160-mL increase in absolute FVC (P = .001), compared with placebo at 53 weeks.3,4
Elaprase has a boxed warning due to the risk of hypersensitivity reactions. The reactions that have been observed in some patients are respiratory distress, hypotension, hypoxia, seizure, and angioedema. Because of the potential for these reactions, appropriate medical support should be readily available. During clinical trials, if severe reactions occurred, the subsequent doses were managed by decreasing the rate of Elaprase and using corticosteroids and/ or antihistamines prior to or during infusions. With the above measures, no patient discontinued permanently due to a hypersensitivity reaction. Other infusion-based reactions included headache, cutaneous reactions, fever, and hypertension. The frequency of these reactions decreased over time with continued use of Elaprase.4
Dosage and Administration
The recommended dose of Elaprase is 0.5 mg/kg given via intravenous infusion once weekly. Elaprase is supplied as a concentrated solution (2 mg/mL) in a 3-mL vial, contains no preservatives, and must be diluted in 100 mL of 0.9% sodium chloride prior to infusion. The infusion rate should never be less than 100 mL/hour or exceed 8 hours due to stability concerns.4 Elaprase vials should be stored at between 36?F and 46?F.
Ms. Domenici and Dr. Patel are both pharmacists at Brigham and Women's Hospital, Boston, Mass. Ms. Bunnell is a fourth-year PharmD candidate from Northeastern University currently on co-op clerkship in the Investigational Drug Service at Brigham and Women's Hospital.
1. Shire's ELAPRASE (idursulfase) Approved by the Food and Drug Administration (FDA) for Hunter Syndrome. Press Release. Wayne, PA: Shire PLC; July 24, 2006.
2. R&D Pipeline: Hunter Syndrome. Shire PLC. Available at: www.shire.com/shire/Pipeline/hunter.jsp?tn=5&m1=37. Accessed October 30, 2006.
3. Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006;8(8):465-473.
4. Elaprase package insert. Cambridge, MA: Shire Human Genetic Therapies Inc, July 2006.