Elaprase Mechanism of Action

Pharmacology: Pharmacodynamics: Decreases in urinary GAG levels were observed following treatment with Elaprase. The responsiveness of urinary GAG to dosage alterations of Elaprase is unknown, and the relationship of urinary GAG to other measures of clinical response has not been established. Patients who tested positive for anti-idursulfase antibodies (Ab) experienced a less pronounced decrease in urinary GAG levels (see Clinical Studies as follows and Adverse Reactions).
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 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 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.
Clinical Studies: Clinical Trials in Patients ≥5 Years: The safety and efficacy of Elaprase were evaluated in a 53-week, randomized, double-blind, placebo-controlled clinical trial of 96 patients with Hunter syndrome. The trial included patients with a documented deficiency in iduronate-2-sulfatase enzyme activity who had a percent-predicted forced vital capacity (percent-predicted FVC) <80%. The patients' ages ranged from 5-31 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 0.5 mg/kg every week (n=32), Elaprase 0.5 mg/kg every other week (n=32) or placebo (n=32).
The primary efficacy outcome assessment was a 2-component composite score based on the sum of the ranks of the change from baseline to week 53 in distance walked during a 6-min walk test (6-MWT) and the ranks of the change in percent-predicted FVC. This 2-component composite primary endpoint differed statistically significantly between the 3 groups, and the difference was greatest between the placebo group and the once weekly treatment group (once weekly Elaprase vs placebo, p=0.0049).
Examination of the individual components of the composite score showed that, in the adjusted analysis, the weekly Elaprase-treated group experienced a 35-m greater mean increase in the distance walked in 6 min compared to placebo. The changes in percent-predicted FVC were not statistically significant. (See Table 1.)

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Pharmacodynamic assessments included 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 once-weekly group, although GAG levels still remained above the upper limit of normal in half of the Elaprase-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 once-weekly group through week 53 compared to placebo. There were essentially no changes in liver and spleen volumes in the placebo group.
Extension Trial: Patients who participated in the placebo-controlled trial were eligible to continue treatment in an open-label extension trial. During the extension trial, all patients received Elaprase 0.5 mg/kg once-weekly for 24 months.
Patients who were treated with Elaprase once weekly and every other week in the placebo-controlled trial demonstrated improvement in distance walked in the 6-MWT for an additional 8 months of treatment in the extension trial. There was no change in mean percent-predicted FVC in all Hunter syndrome patients after 6 months of treatment in the extension trial; however, a slight decrease in mean percent-predicted FVC was demonstrated through to month 24 of the extension trial. The long-term effect of Elaprase on pulmonary function in Hunter syndrome patients is unclear.
There were no further reductions in mean urinary GAG levels in patients initially treated with Elaprase once weekly; however, the patients treated with Elaprase every other week during the placebo-controlled trial experienced further reductions in mean urinary GAG levels after changing to a more frequent dosing regimen during the extension trial. The persistence of reduced urinary GAG levels did not correlate with the long term effect demonstrated by the 6-MWT distance or percent-predicted FVC.
Clinical Trial in Patients ≤7 Years: A 53-week, open-label, multicentre, single-arm trial was conducted to assess the safety, pharmacokinetics and pharmacodynamics of Elaprase 0.5 mg/kg once weekly in male Hunter syndrome patients ≤7 years. Safety results demonstrated that patients with complete gene deletion or large gene rearrangement mutations are more likely to develop Ab, including neutralizing antibodies (NAbs), and to experience hypersensitivity reactions with Elaprase administration (see Adverse Reactions). In patients who remained Ab-negative, the pharmacokinetic profile, reduction in urinary GAG excretion levels and reduction in spleen volume were similar to those of adults and children ≥5 years. In patients who were persistently Ab-positive, the presence of anti-idursulfase antibody was associated with reduced systemic exposure of idursulfase and a less pronounced decrease in urinary GAG levels (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
Pharmacokinetics: CLinical Trials in Patients ≥5 Years: The pharmacokinetic characteristics of idursulfase were evaluated in 59 patients with Hunter syndrome. The serum concentration of idursulfase was quantified using an antigen-specific enzyme-linked immunosorbent assay (ELISA). The area under the concentration-time curve (AUC) increased in a greater than dose proportional manner as the dose increased from 0.15-1.5 mg/kg following a single 1-hr infusion of Elaprase. The pharmacokinetic parameters at the recommended dose regimen (Elaprase 0.5 mg/kg administered weekly as a 3-hr infusion) were determined at weeks 1 and 27 in 10 patients 7.7-27 years (see Table 2). There were no apparent differences in pharmacokinetics parameter values between weeks 1 and 27 regardless of the Ab status in these patients.

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Clinical Trial in Patients ≤7 Years: Idursulfase pharmacokinetics was evaluated in 27 patients with Hunter syndrome 16 months-7.5 years who received Elaprase 0.5 mg/kg once weekly as a 3-hr infusion. The presence of anti-idursulfase Ab was associated with a reduced systemic exposure of idursulfase. Eight (8) of the 18 Ab-positive patients had no measurable idursulfase concentrations. An additional 9 Ab-positive patients had decreased peak plasma concentration (C_max), AUC and half-life (t_½) at week 27 compared to week 1 (see Table 3). Idursulfase pharmacokinetics was similar between weeks 1 and 27 in Ab-negative patients (see Table 3).

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All patients with the complete gene deletion or large gene rearrangement genotype (n=8) developed Ab at week 27. Five (5) of these 8 patients had no measurable idursulfase concentrations at week 27, and 3 had a lower systemic exposure at week 27 compared to week 1.