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Mechanism of Action
Hunter syndrome (Mucopolysaccharidosis II, MPS II) is an X-linked recessive disease caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. This enzyme cleaves the terminal 2-O-sulfate moieties from the glycosaminoglycans (GAG) dermatan sulfate and heparan sulfate. Due to the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome, GAG progressively accumulate in the lysosomes of a variety of cells, leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction.
Treatment of Hunter syndrome patients with ELAPRASE (idursulfase solution) provides exogenous enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow specific binding of the enzyme to the M6P receptors on the cell surface, leading to cellular internalization of the enzyme, targeting to intracellular lysosomes and subsequent catabolism of accumulated GAG.
The pharmacokinetic characteristics of idursulfase were evaluated in several studies in patients with Hunter syndrome. The serum concentration of idursulfase was quantified using an antigen-specific ELISA assay. The area under the concentration-time curve (AUC) increased in a greater than dose proportional manner as the dose increased from 0.15 mg/kg to 1.5 mg/kg following a single 1-hour infusion of ELAPRASE (idursulfase solution) . The pharmacokinetic parameters at the recommended dose regimen (0.5 mg/kg ELAPRASE (idursulfase solution) administered weekly as a 3-hour infusion) were determined at Week 1 and Week 27 in 10 patients ages 7.7 to 27 years (Table 1). There were no apparent differences in PK parameter values between Week 1 and Week 27.
Table 1 - Pharmacokinetic Parameters (Mean, Standard Deviation)
|Pharmacokinetic Parameter||Week 1||Week 27|
|Cmax (µg/mL)||1.5 (0.6)||1.1 (0.3)|
|AUC (min*µg/mL)||206 (87)||169 (55)|
|t1/2 (min)||44 (19)||48 (21)|
|Cl (mL/min/kg)||3.0 (1.2)||3.4 (1.0)|
|Vss (% BW)||21 (8)||25 (9)|
The safety and efficacy of ELAPRASE (idursulfase solution) were evaluated in a randomized, double-blind, placebo-controlled clinical study of 96 patients with Hunter syndrome. The study included patients with a documented deficiency in iduronate-2-sulfatase enzyme activity who had a percent predicted forced vital capacity (%-predicted FVC) less than 80%. The patients' ages ranged from 5 to 31 years. Patients who were unable to perform the appropriate pulmonary function testing, or those who could not follow protocol instructions were excluded from the study. Patients received ELAPRASE (idursulfase solution) 0.5 mg/kg every week (n=32), ELAPRASE (idursulfase solution) 0.5 mg/kg every other week (n=32), or placebo (n=32). The study duration was 53 weeks.
The primary efficacy outcome assessment was a two-component composite score based on the sum of the ranks of the change from baseline to Week 53 in distance walked during a six-minute walk test (6-MWT) and the ranks of the change in %-predicted FVC. This two-component composite primary endpoint differed statistically significantly between the three groups, and the difference was greatest between the placebo group and the weekly treatment group (weekly ELAPRASE (idursulfase solution) vs. placebo, p=0.0049).
Examination of the individual components of the composite score showed that, in the adjusted analysis, the weekly ELAPRASE (idursulfase solution) -treated group experienced a 35 meter greater mean increase in the distance walked in six minutes compared to placebo. The changes in %-predicted FVC were not statistically significant (Table 2).
Table 2 - Clinical Study Results
| ELAPRASE (idursulfase solution) Weekly
| ELAPRASE (idursulfase solution)
|Baseline||Week 53||Changeb||Baseline||Week 53||Changeb|| Difference in
|Results from the 6-Minute Walk Test (Meters)|
|Mean ± SD||392 ± 108||436 ± 138||44 ± 70||393 ± 106||400 ± 106||7 ± 54|| 37 ± 16c
35 ± 14d
|Percentiles (25th, 75th)||316, 488||365, 536||0, 94||341, 469||361, 460||-30, 31|
|Results from the Forced Vital Capacity Test (% of Predicted)|
|Mean ± SD||55.3 ± 15.9||58.7 ± 19.3||3.4 ± 10.0||55.6 ± 12.3||56.3 ± 15.7||0.8 ± 9.6|| 2.7 ± 2.5c
4.3 ± 2.3d
|Percentiles (25th, 75th)||43.6, 69.3||44.4, 70.7||-0.8, 9.5||46.9, 64.4||43.8, 67.5||-5.4, 5.0|
| a One patient in the placebo group and one patient
in the ELAPRASE (idursulfase solution) group died before Week 53; imputation wasby last observation
carried forward in the intent-to-treat analysis
b Change, calculated as Week 53 minus Baseline
c Observed mean ± SE
d ANCOVA model based mean ± SE, adjusted for baseline disease severity, region, and age.
Measures of bioactivity were urinary GAG levels and changes in liver and spleen size. Urinary GAG levels were elevated in all patients at baseline. Following 53 weeks of treatment, mean urinary GAG levels were markedly reduced in the ELAPRASE (idursulfase solution) weekly group, although GAG levels still remained above the upper limit of normal in half of the ELAPRASE (idursulfase solution) -treated patients. Urinary GAG levels remained elevated and essentially unchanged in the placebo group. Sustained reductions in both liver and spleen volumes were observed in the ELAPRASE (idursulfase solution) weekly group through Week 53 compared to placebo. There were essentially no changes in liver and spleen volumes in the placebo group.
Last reviewed on RxList: 11/28/2007
This monograph has been modified to include the generic and brand name in many instances.
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