Purpose: To evaluate the safety and efficacy of recombinant human iduronate-2-sulfatase (idursulfase) in the treatment of mucopolysaccharidosis II. Methods: Ninety-six mucopolysaccharidosis II patients between 5 and 31 years of age were enrolled in a double-blind, placebo-controlled trial. Patients were randomized to placebo infusions, weekly idursulfase (0.5 mg/kg) infusions or every-other-week infusions of idursulfase (0.5 mg/kg).Efficacy was evaluated using a composite endpoint consisting of distance walked in 6 minutes and the percentage of predicted forced vital capacity based on the sum of the ranks of change from baseline. Results: Patients in the weekly and every-other-week idursulfase groups exhibited significant improvement in the composite endpoint compared to placebo (P ϭ 0.0049 for weekly and P ϭ 0.0416 for every-other-week) after one year. The weekly dosing group experienced a 37-m increase in the 6-minute-walk distance (P ϭ 0.013), a 2.7% increase in percentage of predicted forced vital capacity (P ϭ 0.065), and a 160 mL increase in absolute forced vital capacity (P ϭ 0.001) compared to placebo group at 53 weeks. Idursulfase was generally well tolerated, but infusion reactions did occur.

Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

The mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders caused by the absence of functional enzymes that contribute to the degradation of glycosaminoglycans (GAGs). The progressive systemic deposition of GAGs results in multi-organ system dysfunction that varies with the particular GAG deposited and the specific enzyme mutation(s) present. Cardiac involvement has been reported in all MPS syndromes and is a common and early feature, particularly for those with MPS I, II, and VI. Cardiac valve thickening, dysfunction (more severe for left-sided than for right-sided valves), and hypertrophy are commonly present; conduction abnormalities, coronary artery and other vascular involvement may also occur. Cardiac disease emerges silently and contributes significantly to early mortality.The clinical examination of individuals with MPS is often difficult due to physical and, sometimes, intellectual patient limitations. The absence of precordial murmurs does not exclude the presence of cardiac disease. Echocardiography and electrocardiography are key diagnostic techniques for evaluation of valves, ventricular dimensions and function, which are recommended on a regular basis. The optimal technique for evaluation of coronary artery involvement remains unsettled.Standard medical and surgical techniques can be modified for MPS patients, and systemic therapies such as hematopoietic stem cell transplantation and enzyme replacement therapy (ERT) may alter overall disease progression with regression of ventricular hypertrophy and maintenance of ventricular function. Cardiac valve disease is usually unresponsive or, at best, stabilized, although ERT within the first few months of life may prevent valve involvement, a fact that emphasizes the importance of early diagnosis and treatment in MPS.

Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) is a lysosomal storage disease that is characterized by systemic clinical manifestations and significant functional impairment. Diagnosis and management are often challenging because of the considerable variability in symptom presentation and rate of progression. The optimal standard of care should be based on evidence from randomized, controlled trials, meta-analyses, systematic reviews, and expert opinion. In support of this goal, comprehensive management guidelines have been drafted by an international group of experts in the management of patients with mucopolysaccharidosis VI. The guidelines provide a detailed outline of disease manifestations by body system, recommendations for regular assessments, and an overview of current treatment options.

Mucopolysaccharidosis II, also known as Hunter syndrome, is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase, which catalyzes a step in the catabolism of glycosaminoglycans. In patients with mucopolysaccharidosis II, glycosaminoglycans accumulate within tissues and organs, contributing to the signs and symptoms of the disease. Mucopolysaccharidosis II affects multiple organs and physiologic systems and has a variable age of onset and variable rate of progression. Common presenting features include excess urinary glycosaminoglycan excretion, facial dysmorphism, organomegaly, joint stiffness and contractures, pulmonary dysfunction, myocardial enlargement and valvular dysfunction, and neurologic involvement. In patients with neurologic involvement, intelligence is impaired, and death usually occurs in the second decade of life, whereas those patients with minimal or no neurologic involvement may survive into adulthood with normal intellectual development. Enzyme replacement therapy has emerged as a new treatment for mucopolysaccharidosis disorders, including Hunter syndrome. The purpose of this report is to provide a concise review of mucopolysaccharidosis II for practitioners with the hope that such information will help identify affected boys earlier in the course of their disease.

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ObjectiveTo assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA).MethodsPatients with Morquio A aged ≥5 years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated.ResultsAt week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI −17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI −2.1, 4.4; P = 0.494) for weekly and −0.5 stairs/min (95 % CI −3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation.ConclusionsElosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-014-9715-6) contains supplementary material, which is available to authorized users.

Purpose: This study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human iduronate-2-sulfatase) in patients with Hunter syndrome. Methods: All 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed. Results: No change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were observed at most time points. Mean liver and spleen volumes remained reduced throughout the 2-year extension study. Mean joint range of motion improved for the shoulder and remained stable in other joints. Both the parent-and child-assessed Child Health Assessment Questionnaire Disability Index Score demonstrated significant improvement. Infusion-related adverse events occurred in 53% of patients and peaked at Month 3 of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of patients and seemed to attenuate the improvement in pulmonary function. Conclusions: Weekly infusions of idursulfase result in sustained clinical improvement during 3 years of treatment. Genet Med 2011:13(2):95-101.