Pharmacology Update

Idursulfase Solution for Intravenous Infusion (Elaprase)

By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.

The FDA has approved the first product for the treatment of Hunter syndrome. Idursulfase is a purified form of iduronate-2-sulfase, a 525-amino acid glycoprotein, produced by recombinant DNA technology. Shire Human Genetic Therapies, Inc. markets it as Elaprase.

Indications

Idursulfase is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II).

Dosage

The recommended dose is 0.5 mg/kg of body weight administered every week as an intravenous infusion. The initial rate should be 8 mL/hr for the first 15 minutes. The rate may be increased by 8 mL/hr every 15 minutes if tolerated. The infusion should be over a period of 1 to 3 hours. The rate should not exceed 100 mL/hr. Some patients may require a slower infusion rate but the infusion should not exceed 8 hours, as the diluted preparation should not be stored at room temperature for longer than 8 hours.

Potential Advantages

Idursulfase has demonstrated a significant improvement in walking distance and a trend toward an improvement in predicted forced vital capacity.1,2

Potential Disadvantages

Life threatening anaphylactoid reactions have been reported during infusion. Eleven of 108 patients experienced significant hypersensitivity reactions. Most common infusion reactions include headache, fever, rash, pruritus, erythema, urticaria, and hypertension. Fifty-one percent of patients develop IgG antibodies and those who develop antibodies had an increased incidence of infusion reactions.1

Comments

Mucopolysaccharidosis type II (Hunter syndrome) is a X-linked recessive lysosomal storage disease that primarily affects males. Iduronate-2-sulfase catalyzes the breakdown of glycosaminoglycans (dermatan and heparin sulfate). The deficiency of this enzyme results in accumulation and deposition of glycosaminoglycans fragments in various tissues. This results in psychomotor retardation, facial dysmorphism, dysostosis multiplex with arthrogryposis of fingers and toes, gibbus, hepatosplenomegaly, cardiomyopathy, chronic diarrhea, obstructive airway disease, joint stiffness and limited motion, and hearing impairment.3,4 The disease may vary in severity from mild to severe but is always progressive and life limiting. Idursulfase was approved based on a randomized, double-blind, placebo-controlled, 53-week study of 96 patients with Hunter syndrome.1,2 These patients, ages 5-31 years of age, were randomized to idursulfase (0.5 mg/kg every week or every other week) or placebo. The primary end points were 6-minute walk test and forced vital capacity test. At the end of the study, patients on weekly dosing showed a significant adjusted mean increase of 35 (±14) meters in walking distance (P = 0.01) and an adjusted difference of 4.3 (±2.3) in FVC (% of predicted) (P = 0.07) compared to placebo. There is a potential for serious hypersensitivity reactions. Patients with compromised respiratory function may be at risk for serious acute respiratory reaction due to infusion reactions. Idursulfase is very expensive, with an estimated cost of $300,000 per patient annually for a 20 kg patient.

Clinical Implications

Hunter syndrome is a rare genetic disorder. It is diagnosed in approximately one out of 65,000 to 132,000 births.5 Idursulfase is the first treatment of Hunter syndrome that addresses the underlying cause. Clinical data suggest some improvement in endurance and pulmonary function but the drug is not expected to affect CNS impairment.2 Benefit will also vary depending on each patient's disease burden.

References

1. Elaprase Product Information. Shire Human Genetic Technologies, Inc. July 2006.

2. Muenzer J, et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006;8:465-473.

3. Tushl K, et al. Mucopolysaccharidosis type II in females: case report and review of literature. Pediatr Neurol. 2005;32:270-272.

4. Neufeld PN, Meuenzer J. The Mucopolysaccharideosis. In: Scriver CR, et al, eds. The Metabolic and Molecular Basis of Inherited Diseases. 8th ed. New York, NY: McGraw-Hill; 2001:3421-3452.

5. www.fda.gov/bbs/topics/NEWS/2006/NEW01418.html.