Clinical outcomes in idursulfase-treated patients with mucopolysaccharidosis type II: 3-year data from the hunter outcome survey (HOS)

Abstract

Background: Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare, X-linked disorder caused by deficient activity of the enzyme iduronate-2-sulfatase (I2S). Treatment is available in the form of enzyme replacement therapy (ERT) with recombinant I2S. Clinical outcomes following ≥3 years of ERT with idursulfase were investigated in a broad population of patients with MPS II enrolled in the Hunter Outcome Survey (HOS).

Methods: As of January 2016, 639 patients (excluding female patients, individuals who had received a bone marrow transplant and those enrolled in the phase 1/2 [TKT018] or phase 2/3 [TKT024] clinical trial) followed prospectively in the registry had received idursulfase for ≥6 months. These individuals all had data available for ≥1 clinical parameter at baseline and ≥1 additional time point following treatment initiation. Changes in clinical parameters were assessed in the subcohorts of patients with a measurement at baseline and at year 1, 2 or 3 of treatment. Safety data from patients who started treatment at or after enrollment in HOS (n = 233) were also assessed.

Results: Median (10th, 90th percentiles) age at first treatment was 6.2 (2.1, 18.2) years and median treatment duration was 56.3 (18.2, 97.6) months. Urinary glycosaminoglycan (uGAG) levels decreased from baseline to year 3 in patients with data available at this time point (median change from baseline: -201.0 [-591.4, -21.9] μg/mg creatinine [n = 121]). Improvements in the following parameters were observed at year 3 in the subcohorts: 6-min walking test (6MWT) distance, 10.6 (-33.6, 50.8)% (n = 26); left ventricular mass index (LVMI), -9.3 (-31.5, 19.7)% (n = 52); absolute forced vital capacity (FVC), 29.7 (-13.4, 66.7)% (n = 23); absolute forced expiratory volume in 1 s (FEV₁), 22.8 (-15.2, 62.1)% (n = 22); palpable liver size, -54.5 (-85.7, 50.0)% (n = 53); palpable spleen size, -33.3 (-80.0, 33.3)% (n = 17). No new or unexpected safety concerns were identified in this analysis.

Conclusions: These findings suggest that idursulfase has a positive effect on uGAG levels, 6MWT results, LVMI, FVC, FEV₁ and hepatosplenomegaly after 1, 2 and 3 years treatment.

Keywords: Disease registry; Efficacy; Hunter syndrome; Idursulfase; Lysosomal storage disease.

Fig. 1

Change in urinary glycosaminoglycan (uGAG) levels. a Absolute change and (b) percentage change from baseline^a in uGAG levels in patients with data available after 1, 2 or 3 years of treatment with idursulfase. c Absolute change and (d) percentage change from baseline in uGAG levels in patients with data available at consecutive time points (year 1, year 2 and year 3 of treatment with idursulfase). Box plots illustrate the 25th, 50th (median) and 75th percentiles (boxes) and the 10th and 90th percentiles (whiskers). ^aThe baseline measurement was defined as the last recorded measurement in the 12 months preceding the start of idursulfase treatment. A post-baseline measurement was defined as the value recorded closest to the 1st, 2nd or 3rd-year anniversary of the baseline measurement, within 6 months either side of the anniversary date. If there were two values within equal times of the evaluation visit, the first value was used. uGAG values for each patient may have been determined by different methods; therefore, absolute changes and percentage changes from baseline in uGAG levels are presented to give an indication of general trends

Fig. 2

Distance walked in the 6-min walk test. a Baseline distance walked plotted against reference data [29] by age at assessment (n = 38). b Absolute change from baseline^a in distance walked in patients with data available after 1, 2 or 3 years of treatment with idursulfase. c Percentage change from baseline in distance walked in patients with data available after 1, 2 or 3 years of treatment with idursulfase. Box plots illustrate the 25th, 50th (median) and 75th percentiles (boxes) and the 10th and 90th percentiles (whiskers). ^aThe baseline measurement was defined as the last recorded measurement in the 12 months preceding the start of idursulfase treatment. A post-baseline measurement was defined as the value recorded closest to the 1st, 2nd or 3rd-year anniversary of the baseline measurement, within 6 months either side of the anniversary date. If there were two values within equal times of the evaluation visit, the first value was used

Fig. 3

Change in left ventricular mass index (LVMI). a Absolute change from baseline^a in LVMI in patients with data available after 1, 2 or 3 years of treatment with idursulfase. b Percentage change from baseline in LVMI in patients with data available after 1, 2 or 3 years of treatment with idursulfase. Box plots illustrate the 25th, 50th (median) and 75th percentiles (boxes) and the 10th and 90th percentiles (whiskers). ^aThe baseline measurement was defined as the last recorded measurement in the 12 months preceding the start of idursulfase treatment. A post-baseline measurement was defined as the value recorded closest to the 1st, 2nd or 3rd anniversary of the baseline measurement, within 6 months either side of the anniversary date. If there were two values within equal times of the evaluation visit, the first value was used

Fig. 4

Change in forced vital capacity (FVC). a Absolute change from baseline^a in FVC in patients with data available after 1, 2 or 3 years of treatment with idursulfase. b Percentage change from baseline in FVC in patients with data available after 1, 2 or 3 years of treatment with idursulfase. Box plots illustrate the 25th, 50th (median) and 75th percentiles (boxes) and the 10th and 90th percentiles (whiskers). ^aThe baseline measurement was defined as the last recorded measurement in the 12 months preceding the start of idursulfase treatment. A post-baseline measurement was defined as the value recorded closest to the1st, 2nd or 3rd-year anniversary of the baseline measurement, within 6 months either side of the anniversary date. If there were two values within equal times of the evaluation visit, the first value was used

Fig. 5

Change in forced expiratory volume in 1 s (FEV₁). a Absolute change from baseline^a in FEV₁ in patients with data available after 1, 2 or 3 years of treatment with idursulfase. b Percentage change from baseline in FEV₁ in patients with data available after 1, 2 or 3 years of treatment with idursulfase. Box plots illustrate the 25th, 50th (median) and 75th percentiles (boxes) and the 10th and 90th percentiles (whiskers). ^aThe baseline measurement was defined as the last recorded measurement in the 12 months preceding the start of idursulfase treatment. A post-baseline measurement was defined as the value recorded closest to the 1st, 2nd or 3rd-year anniversary of the baseline measurement, within 6 months either side of the anniversary date. If there were two values within equal times of the evaluation visit, the first value was used

Fig. 6

Change in palpable liver and spleen size. a Absolute change from baseline^a in palpable liver size in patients with data available after 1, 2 or 3 years of treatment with idursulfase. b Absolute change from baseline^a in palpable spleen size in patients with data available after 1, 2 or 3 years of treatment with idursulfase. Box plots illustrate the 25th, 50th (median) and 75th percentiles (boxes) and the 10th and 90th percentiles (whiskers). ^aThe baseline measurement was defined as the last recorded measurement in the 12 months preceding the start of idursulfase treatment. A post-baseline measurement was defined as the value recorded closest to the 1st, 2nd or 3rd-year anniversary of the baseline measurement, within 6 months either side of the anniversary date. If there were two values within equal times of the evaluation visit, the first value was used