Chapter 7:Discovery and Clinical Development of Idursulfase (Elaprase®) for the Treatment of Mucopolysaccharidosis II (Hunter Syndrome)

Mucopolysaccharidosis II (MPS II), also known as Hunter syndrome, is a rare X-linked recessive lysosomal storage disorder with an incidence of 1 in 100 000 to 160 000 live births. The clinical disease is caused by a deficiency of iduronate-2-sulfatase, which results in a chronic and progressive accumulation of glycosaminoglycans or GAGs in nearly all cell types, tissues and organs of the body. Clinical manifestations of MPS II disease include airway obstruction and compromised lung capacity, cardiomyopathy and valvular heart disease, hepatosplenomegaly, severe skeletal deformities, and neurological decline in most patients. The lack of an effective treatment and the successes of enzyme replacement therapies (ERTs) for other lysosomal storage diseases motivated the development of an ERT for MPS II. Iduronate-2-sulfatase (idursulfase) was produced by recombinant DNA technology in a fully human protein production system which, importantly, resulted in the production of idursulfase with human glycosylation. The non-clinical development of idursulfase progressed from proof-of-principle pharmacodynamic studies, to dose and dose-frequency studies, to an analysis of tissue biodistribution of the enzyme, and finally to pharmacokinetic and toxicological assessments. The clinical development of the final drug product, called Elaprase® (Shire Human Genetic Therapies, Inc., Lexington, MA), consisted of an initial Phase I/II study, followed by a Phase II/III pivotal trial. The results of the Phase II/III showed that intravenous infusions of Elaprase were generally well tolerated, and that a weekly dosing regimen provided significant clinical benefit to MPS II patients as demonstrated by improvements in walking ability and pulmonary function. Elaprase received marketing authorisation in the USA in 2006 and in Europe in 2007. During this era, the development of Elaprase as an effective therapy for MPS II patients, was part of a continuum of many important scientific and medical advances in the field of rare genetic diseases.