Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter Syndrome)

摘要

Background Mucopolysaccharidosis II (MPS II, Hunter syndrome) is a rare X-linked lysosomal storage disorder caused by the deficiency of iduronate-2-sulfatase (IDS). In affected patients, glycosaminoglycan (GAG) accumulates in the lysosomes of many organs and tissues contributing to the pathology associated with MPS II. The objective of this phase I/II clinical study was to evaluate the efficacy and safety of recombinant human iduronate-2-sulfatase (idursulfase beta, Hunterase?) in the treatment of MPS II. Methods Thirty-one MPS II patients between 6 and 35?years of age were enrolled in a randomized, single-blinded, active comparator-controlled phase I/II trial for 24?weeks. Patients were randomized to active comparator infusions (N=11), 0.5?mg/kg idursulfase beta infusions (N=10), or 1.0?mg/kg idursulfase beta infusions (N=10). The primary efficacy variable was the level of urinary GAG excretion. The secondary variables were changes in the distance walked in 6?minutes (6-minute walk test, 6MWT), echocardiographic findings, pulmonary function tests, and joint mobility. Results Patients in all three groups exhibited reduction in urine GAG and this reduced GAG level was maintained for 24?weeks. Urine GAG was also significantly reduced in the 0.5?mg/kg and 1.0?mg/kg idursulfase beta groups when compared to the active comparator group (P = 0.043, 0.002, respectively). Changes in 6MWT were significantly greater in the 0.5?mg/kg and 1.0?mg/kg idursulfase groups than in the active comparator group (p= 0.003, 0.015, respectively). Both idursulfase beta infusions were generally safe and well tolerated, and elicited no serious adverse drug reactions. The most frequent adverse events were urticaria and skin rash, which were easily controlled with administration of antihistamines. Conclusions This study indicates that idursulfase beta generates clinically significant reduction of urinary GAG, improvements in endurance as measured by 6MWT, and it has an acceptable safety profile for the treatment of MPS II. Trial registration ClinicalTrials.gov: NCT01301898