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

Abstract

BackgroundMucopolysaccharidosis 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.MethodsThirty-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.ResultsPatients 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.ConclusionsThis 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 registrationClinicalTrials.gov: NCT01301898

An overview of Korean patients with mucopolysaccharidosis and collaboration through the Asia Pacific MPS Network

“…A 24-week randomized, single-blinded, active comparator-controlled, phase I/II clinical trial of idursulfase beta was conducted to evaluate its efficacy and safety in the treatment of MPS type II patients. This study (31) was the first active comparator-controlled clinical trial of idursulfase beta for Korean male patients with MPS type II. The idursulfase beta treatment was well tolerated by Korean patients with MPS type II and resulted in a significant reduction in urinary GAG excretion as well as an improvement in the distance on the six-minute walking test when compared to the active comparator.…”

Clinical Presentation of Mucopolysaccharidosis Type II (Hunter’s Syndrome)

“…The common clinical presentations are a large head (dolicocephalic), short stature, mental retardation, coarse facial features, a proturbent abdomen, a broad nose with flared nostril, large tongue and musculoskeletal deformities. Other features include upper respiratory infections, valvular heart diseases, enlarged liver and spleen, umbilical as well as inguinal hernia, skin lesions, hypoplastic enamel and carious teeth [1,3,4,6,7,8]. Most of the signs were present in our case.…”

“…Diagnosis is usually made in the second decade of life. Death usually occurs in the fourth decade and the main cause of death is cardiac failure [3,7].…”

“…Weekly intravenous infusion is given over 3 hours at a dose 0.5mg per kg, diluted in saline [1,7]. Bone marrow transplantation and umbilical cord blood transplantation are definitive treatments for MPS.…”

Profile of idursulfase for the treatment of Hunter syndrome

“…15 A second recombinant enzyme, idursulfase beta (Hunterase ® , Green Cross Corp, Yongin, Korea), has been produced from the Chinese hamster ovary cell line by genetic engineering yielding a glycosylated protein analogous to the native human enzyme. 16,17 Its safety and a similar efficacy compared to idursulfase had been demonstrated by a successful clinical trial 16 in Korean patients with MPS II older than 6 years, leading to the recent approval of idursulfase beta by the Korean Ministry of Food and Drug Safety. A second clinical trial demonstrated that the safety and efficacy profile of 0.5 mg/kg/week of idursulfase beta infusion in patients younger than 6 years was similar to that previously reported for older Hunter syndrome patients.…”