Evaluation of idursulfase for the treatment of mucopolysaccharidosis II (Hunter syndrome)

Figures & data

Box 1. Drug summary.

Drug name	Idursulfase (recombinant human iduronate-2-sulfatase)
Phase	Phase IV
Indication	Patients with mucopolysaccharidosis II (Hunter syndrome)
Pharmacology description/mechanism of action	Idursulfase acts by cleaving the terminal 2-O-sulfate moieties from dermatan sulfate and heparan sulfate, which are abnormally stored in the lysosomes of cells in patients with mucopolysaccharidosis II
Route of administration	Intravenous infusion
Pivotal trials	The Phase II/III pivotal trial (NCT 00069641) was a randomized, double-blind, placebo-controlled, multicenter, international study enrolling 96 attenuated male patients aged 5.0 to 30.9 years with mucopolysaccharidosis II. Patients received either infusions of idursulfase (0.5 mg/kg every week or every other week [EOW]), or placebo for 53 weeks. Patients were stratified by age, six-minute walk test (6MWT) distance, and percent predicted forced vital capacity (%FVC) at baseline. The primary efficacy endpoint was a two-component score generated by summing the rank scores for change from baseline in the 6MWT distance and %FVC. Secondary endpoints included changes in 6MWT distance, %FVC, absolute FVC, liver and spleen volumes, excretion of dermatan sulfate and heparan sulfate in urine, and passive joint range-of-motion (JROM). After 53 weeks, the primary efficacy endpoint score was significantly improved in both idursulfase groups compared with placebo. Liver and spleen volume and urine levels of dermatan sulfate and heparan sulfate decreased significantly from baseline in both treatment groups when compared with placebo. Improvements were greater in the weekly treated group; thus, 0.5 mg/kg weekly is the recommended dose

Table 1. Pharmacokinetic parameters in 10 human patients receiving idursulfase (0.5 mg/kg weekly as a 3-hour infusion).

Pharmacokinetic Parameter (units)	Week 1 (mean, standard deviation)	Week 27 (mean, standard deviation)
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)

AUC: Area under the serum concentration-time curve; C_max: Maximal concentration; t_1/2: Serum terminal elimination half-life; Cl: Normalized serum clearance; V_ss: Apparent volume of distribution at steady state normalized to body weight.

Figure 1. Treatment efficacy in the Phase II/III clinical trial for change in 6MWT distance and change in %FVC from baseline (components of the primary composite endpoint score).

Figure 2. A. The effect of idursulfase on %FVC. Baseline %FVC = 56.2% ± 1.5% (mean ± SE). **p < 0.01. B. The effect of idursulfase on absolute FVC (p < 0.001 compared with baseline for each value of the total population). No statistical testing was performed on the subgroups. Baseline FVC was 1.18 ± 0.055 L (mean ± SE) for the total population.

Figure 3. Effect of idursulfase on 6MWT distance in the Phase II/III extension study. Baseline 6MWT distance = 400 ± 10 m (mean ± SE). The dotted horizontal line represents the baseline.

Figure 4. Growth charts for MPS II patients A. under 10 years of age at the start of enzyme replacement therapy (ERT) with idursulfase and B. 10 years of age or older at the start of ERT. The dotted lines illustrate the growth before ERT and the continuous lines the growth on ERT. The shaded area represents the 3rd to the 97th percentiles of height in boys based on United States Centers for Disease Control and Prevention growth charts. With kind permission from Springer Science+Business Media: [38].

Table 2. Summary of safety data in the Phase I/II, Phase II/III, and Phase II/III extension studies, and the HOS under 6 year analysis.

Number of patients who experienced	Phase I/II [36]	Phase II/III [34]	Phase II/III EXT [37]	HOS Under 6 yrs [39]
Any AE (possibly or probably drug-related)	NR	NR	56/94 (59.6%)	NR
≥ 1 serious AE (related or unrelated to study drug)	1/12 (8.3%)	26/96 (27.1%)	27/94 (28.7%)	16/124 (12.9%) < 6 yrs 58/287 (20.2%) ≥ 6 yrs
≥ 1 IRR	0/4 placebo 6/8 (75%) idursulfase	21/32 (65.6%) placebo 22/32 (68.8%) weekly 22/32 (68.8%) EOW	50/94 (53%)	34/124 (27%) < 6 yrs 56/287 (20%) ≥ 6 yrs
≥ 1 serious IRR	1/12 (8.3%)	NR	NR	1/124 (0.8%) < 6 yrs 6/287 (2.1%) ≥ 6 yrs
Death	0	2*	1*	5*
IgG antibodies to idursulfase at ≥ 1 time point	6/12 (50%)	30/64 (46.9%) idursulfase 0/32 placebo	47/94 (50%)	38/71 (53.5%) < 6 yrs 71/166 (42.8%) ≥ 6 yrs
IgE antibodies to idursulfase at ≥ 1 time point	0	0	0	0

*Unrelated to study medication.

AE: Adverse event; EOW: Every other week dosing; NR: Not reported.

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