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The effect of recombinant human iduronate-2-sulfatase (Idursulfase) on growth in young patients with mucopolysaccharidosis type II.

ABSTRACT: Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked, recessive, lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase. Early bone involvement leads to decreased growth velocity and short stature in nearly all patients. Our analysis aimed to investigate the effects of enzyme replacement therapy (ERT) with idursulfase (Elaprase) on growth in young patients with mucopolysaccharidosis type II. Analysis of longitudinal anthropometric data of MPS II patients (group 1, n?=?13) who started ERT before 6 years of age (range from 3 months to 6 years, mean 3.6 years, median 4 years) was performed and then compared with retrospective analysis of data for MPS II patients naïve to ERT (group 2, n?=?50). Patients in group 1 received intravenous idursulfase at a standard dose of 0.58 mg/kg weekly for 52-288 weeks. The course of average growth curve for group 1 was very similar to growth pattern in group 2. The average value of body height in subsequent years in group 1 was a little greater than in group 2, however, the difference was not statistically significant. In studied patients with MPS II, idursulfase did not appear to alter the growth patterns.

SUBMITTER: Zuber Z

PROVIDER: S-EPMC3890314 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The effect of recombinant human iduronate-2-sulfatase (Idursulfase) on growth in young patients with mucopolysaccharidosis type II.

Żuber Zbigniew Z Różdżyńska-Świątkowska Agnieszka A Jurecka Agnieszka A Tylki-Szymańska Anna A

PloS one 20140113 1

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked, recessive, lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase. Early bone involvement leads to decreased growth velocity and short stature in nearly all patients. Our analysis aimed to investigate the effects of enzyme replacement therapy (ERT) with idursulfase (Elaprase) on growth in young patients with mucopolysaccharidosis type II. Analysis of longitudinal anthropometric data of MPS II patients (grou ...[more]

PMID: 24454794

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Project description:Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare, multisystemic, progressive lysosomal storage disease caused by deficient activity of the iduronate-2-sulfatase (I2S) enzyme. Accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate results in a broad range of disease manifestations that are highly variable in presentation and severity; notably, approximately two-thirds of individuals are affected by progressive central nervous system involvement. Historically, management of this disease was palliative; however, during the 1990s, I2S was purified to homogeneity for the first time, leading to cloning of the corresponding gene and offering a means of addressing the underlying cause of MPS II using enzyme replacement therapy (ERT). Recombinant I2S (idursulfase) was produced for ERT using a human cell line and was shown to be indistinguishable from endogenous I2S. Preclinical studies utilizing the intravenous route of administration provided valuable insights that informed the design of the subsequent clinical studies. The pivotal Phase II/III clinical trial of intravenous idursulfase (Elaprase®; Shire, Lexington, MA, USA) demonstrated improvements in a range of clinical parameters; based on these findings, intravenous idursulfase was approved for use in patients with MPS II in the USA in 2006 and in Europe and Japan in 2007. Evidence gained from post-approval programs has helped to improve our knowledge and understanding of management of patients with the disease; as a result, idursulfase is now available to young pediatric patients, and in some countries patients have the option to receive their infusions at home. Although ERT with idursulfase has been shown to improve somatic signs and symptoms of MPS II, the drug does not cross the blood-brain barrier and so treatment of neurological aspects of the disease remains challenging. A number of novel approaches are being investigated, and these may help to improve the care of patients with MPS II in the future.

Project description:BackgroundTwenty-eight treatment-naïve mucopolysaccharidosis II patients (16 months-7.5 years) received 0.5 mg/kg idursulfase weekly for one year in NCT00607386. Serum anti-idursulfase immunoglobulin G antibodies (Abs) were seen in 68% of patients.MethodsThis post hoc analysis examined the relationship between Ab status, genotype, adverse events (AEs), and efficacy. Event rate analyses, time-varying proportional hazards (Cox) modeling, and landmark analyses were performed to evaluate the relationship between Ab status and safety. We calculated the cumulative probability of AEs by genotype to evaluate the relationship between genotype and safety. Urinary glycosaminoglycan (uGAG) concentration, index of liver size, and spleen volume were compared by Ab status and genotype.Safety resultsThe overall infusion-related AE (IRAE) rate was higher in Ab+ patients than in Ab- ones. However, the rate was highest before Abs developed, then decreased over time, suggesting that Abs did not confer the risk. A landmark analysis of patients who were IRAE-naïve at the landmark point found that Ab+ patients were no more likely to experience post-landmark IRAEs than were Ab- patients. In the genotype analysis, all patients in the complete deletion/large rearrangement (CD/LR) and frame shift/splice site mutation (FS/SSM) groups seroconverted, compared with only one-third of patients in the missense mutation (MS) group (p < 0.001). The cumulative probability of having ≥1 IRAE was 87.5% in the CD/LR group and 46.2% in the MS group, with a shorter time to first IRAE in the CD/LR group (p = 0.004).Efficacy resultsAb+ patients had a reduced response to idursulfase for liver size and uGAG concentration, but not for spleen size. However, when percent change from baseline in liver size and in uGAG level at Week 53 were adjusted for genotype, the difference was significant only for neutralizing Ab+ groups. In the genotype analysis, the CD/LR and FS/SSM groups had a reduced response in liver size and uGAG concentration compared with the MS group.ConclusionsSafety outcomes and spleen size response on idursulfase treatment appeared to be associated with genotype, not Ab status. Liver size and uGAG response on idursulfase treatment at Week 53 appeared to be associated with both neutralizing Ab status and genotype.

Dataset Information

The effect of recombinant human iduronate-2-sulfatase (Idursulfase) on growth in young patients with mucopolysaccharidosis type II.

Publications

The effect of recombinant human iduronate-2-sulfatase (Idursulfase) on growth in young patients with mucopolysaccharidosis type II.

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