Evaluation of the long-term treatment effects of intravenous idursulfase in patients with mucopolysaccharidosis II (MPS II) using statistical modeling: data from the Hunter Outcome Survey (HOS)

Joseph Muenzer,Jaco Botha,Barbara K Burton,Paul Harmatz,Christoph Kampmann,Roberto Giugliani

doi:10.1186/s13023-021-02052-4

Abstract

BackgroundMucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, life-limiting lysosomal storage disease caused by deficient iduronate-2-sulfatase activity. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase can stabilize or improve many somatic manifestations, but there remains a need for further analysis of long-term treatment outcomes. Using data from patients with MPS II enrolled in the Hunter Outcome Survey (HOS), mixed modeling was performed to evaluate and predict the effects of IV idursulfase treatment on selected clinical parameters for up to 8 years following treatment start. The modeling population comprised male patients followed prospectively in HOS who had received IV idursulfase for at least 5 years and who had data available for two or more time points (at least one post-ERT). Age at ERT start and time since ERT start were included as covariates.ResultsIn total, 481 patients were eligible for inclusion in at least one model. At 8 years post-ERT start, improvement from baseline was predicted for each age group (< 18 months, 18 months to < 5 years and ≥ 5 years at treatment start) in the following parameters: mean urinary glycosaminoglycan levels (percentage changes of > –75% in each group), mean left ventricular mass index (decreases of ~ 1 g/m2) and mean palpable liver size (decreases of > 2 cm). Improvements in mean 6-min walk test distance (increase of > 50 m) and stabilization in percent predicted forced vital capacity and forced expiratory volume in 1 s (decreases of ~ 4 and ~ 9 percentage points, respectively) at 8 years post-ERT start were predicted for patients aged ≥ 5 years at ERT start (these assessments are unsuitable for patients aged < 5 years). Predicted changes over time were similar across the three age groups; however, overall outcomes were most favorable in children aged < 18 months at ERT start.ConclusionsThese findings suggest that the previously reported positive effects of IV idursulfase on the somatic manifestations of MPS II are predicted to be maintained for at least 8 years following ERT initiation and highlight the value of statistical modeling to predict long-term treatment outcomes in patients with rare diseases.

Highlights

Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, life-limiting lysosomal storage disease caused by deficient iduronate-2-sulfatase activity
left ventricular mass index (LVMI) In the model of LVMI in the overall patient population, LVMI remained stable for up to 8 years post-Enzyme replacement therapy (ERT) start in all age groups, with decreases of approximately 1 g/m2 at 8 years post-ERT compared with baseline across all ages at treatment start (Fig. 2)
Statistical modeling represents a valuable additional approach for the evaluation of real-world clinical outcomes in these patient populations. In summary, these results provide novel predictions of the expected trends in clinical and biochemical parameters for up to 8 years following the start of ERT and extend the existing evidence that long-term IV idursulfase has a positive effect on urinary glycosaminoglycan (uGAG) levels, LVMI, percent predicted forced vital capacity (FVC) and F EV1, 6-min walk test (6MWT) and liver size in patients with MPS II

Summary

Introduction

Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, life-limiting lysosomal storage disease caused by deficient iduronate-2-sulfatase activity. Using data from patients with MPS II enrolled in the Hunter Outcome Survey (HOS), mixed modeling was performed to evaluate and predict the effects of IV idursulfase treatment on selected clinical parameters for up to 8 years following treatment start. The disease is caused by deficient activity of the lysosomal enzyme iduronate2-sulfatase (I2S), which leads to the accumulation of glycosaminoglycans (GAGs) throughout the body and results in progressive, multisystemic clinical signs and symptoms [2, 3]. Patients with CNS involvement tend to experience a more rapid disease progression and die in the second decade of life, typically with respiratory and/or cardiac complications in addition to severe neurological involvement [2, 6, 7]

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