On July 24, 2006, the FDA grantedShire Pharmaceuticals approval tomarket Elaprase (idursulfase), the firstenzyme replacement therapy for thetreatment of Hunter's syndrome.1Hunter's syndrome is an X-linkedrecessive genetic disorder caused by adeficiency of the lysosomal enzymeiduronate-2-sulfatase (I2S). This enzymehydrolyzes the degradation productsof proteoglycans, the constituentsof the extracellular matrix. Thesedegradation products are called glycosaminoglycans(GAGs) or mucopolysaccharides.Hunter's syndrome, alsoreferred to as mucopolysaccharidosistype 2 (MPS II), is one of many lysosomalstorage disorders that affectmetabolism of mucopolysaccharides.2
In severe cases, patients presentwith symptoms of Hunter's syndromearound age 2 to 6 years, as GAGs accumulatein the lysosomes of body cells.2Symptoms may include enlarged skulland forehead, frequent infections,2hearing loss, obstructive airways diseasewith sleep apnea,1 cardiac valveabnormalities,3 organ enlargement, andmental retardation. It is estimated thatHunter's syndrome affects 1 in 100,000people in the United States, the vastmajority of whom are males due to thesex-linked inheritance of the disease.2
Elaprase is an exogenous enzymethat targets intracellular lysosomesand causes catabolism of accumulatedGAGs. This action results from themannose-6-phosphate (M6P) residueson the oligosaccharide chains allowingElaprase to bind to the M6P receptorson the cell surface. This binding allowsthe entry of Elaprase into the cell,where it then targets the GAGs.4
A phase 2/3 randomized, doubleblind,placebo-controlled clinical studyevaluated the safety and efficacy ofrecombinant human I2S (idursulfase)for the treatment of Hunter's syndrome.The study included 96 patientsdiagnosed with Hunter's syndrome,ranging from 5 to 31 years of age.During 53 weeks, patients were administeredinfusions of Elaprase 0.5 mg/kgevery week (n = 32), Elaprase 0.5mg/kg every other week (n = 32), orplacebo (n = 32).
A composite end point consisting of(1) distance walked in 6 minutes and(2) the percentage of predicted forcedvital capacity (FVC) based on the sumof the ranks change from baseline wasused to evaluate efficacy. The resultsshowed a significant improvement inboth treatment groups, compared withplacebo (P = .00049 for weekly and P =.0416 for every-other-week idursulfasegroups) after 1 year. The weekly-dosinggroup had a 2.7% increase in the percentageof predicted FVC (P = .065), a37-m increase in the 6-minute walk (P= .013), and a 160-mL increase inabsolute FVC (P = .001), compared withplacebo at 53 weeks.3,4
Elaprase has a boxed warning due tothe risk of hypersensitivity reactions.The reactions that have been observedin some patients are respiratory distress,hypotension, hypoxia, seizure, andangioedema. Because of the potentialfor these reactions, appropriate medicalsupport should be readily available.During clinical trials, if severe reactionsoccurred, the subsequent doses weremanaged by decreasing the rate ofElaprase and using corticosteroids and/or antihistamines prior to or during infusions.With the above measures, nopatient discontinued permanently dueto a hypersensitivity reaction. Otherinfusion-based reactions included headache,cutaneous reactions, fever, andhypertension. The frequency of thesereactions decreased over time withcontinued use of Elaprase.4
Dosage and Administration
The recommended dose of Elapraseis 0.5 mg/kg given via intravenous infusiononce weekly. Elaprase is suppliedas a concentrated solution (2 mg/mL)in a 3-mL vial, contains no preservatives,and must be diluted in 100 mL of0.9% sodium chloride prior to infusion.The infusion rate should never be lessthan 100 mL/hour or exceed 8 hoursdue to stability concerns.4 Elaprasevials should be stored at between 36?Fand 46?F.
Ms. Domenici and Dr. Patel areboth pharmacists at Brigham andWomen's Hospital, Boston, Mass. Ms.Bunnell is a fourth-year PharmD candidatefrom Northeastern Universitycurrently on co-op clerkship in theInvestigational Drug Service atBrigham 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.