Elaprase (Idursulfase) - Description and Clinical Pharmacology

DESCRIPTION

ELAPRASE is a formulation of idursulfase, a purified form of human iduronate-2-sulfatase, a lysosomal enzyme. Idursulfase is produced by recombinant DNA technology in a human cell line. Idursulfase is an enzyme that hydrolyzes the 2-sulfate esters of terminal iduronate sulfate residues from the glycosaminoglycans dermatan sulfate and heparan sulfate in the lysosomes of various cell types.

Idursulfase is a 525-amino acid glycoprotein with a molecular weight of approximately 76 kilodaltons. The enzyme contains eight asparagine-linked glycosylation sites occupied by complex oligosaccharide structures. The enzyme activity of idursulfase is dependent on the post-translational modification of a specific cysteine to formylglycine. Idursulfase has a specific activity ranging from 41 to 77 U/mg of protein (one unit is defined as the amount of enzyme required to hydrolyze 1 µmole of heparin disaccharide substrate per hour under the specified assay conditions).

ELAPRASE is intended for intravenous infusion and is supplied as a sterile, nonpyrogenic clear to slightly opalescent, colorless solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP. Each vial contains an extractable volume of 3.0 mL with an idursulfase concentration of 2.0 mg/mL at a pH of approximately 6, providing 6.0 mg idursulfase, 24.0 mg sodium chloride, 6.75 mg sodium phosphate monobasic monohydrate, 2.97 mg sodium phosphate dibasic heptahydrate, and 0.66 mg polysorbate 20. ELAPRASE does not contain preservatives; vials are for single use only.

CLINICAL PHARMACOLOGY

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 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.

Pharmacokinetics

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. The pharmacokinetic parameters at the recommended dose regimen (0.5 mg/kg ELAPRASE 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 2). There were no apparent differences in PK parameter values between Week 1 and Week 27.

Table 2 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)

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with ELAPRASE.

ELAPRASE at intravenous doses up to 5 mg/kg, administered twice weekly (about 1.6 times the recommended human weekly dose based on body surface area) had no effect on fertility and reproductive performance in male rats.

CLINICAL STUDIES

The safety and efficacy of ELAPRASE 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 0.5 mg/kg every week (n=32), ELAPRASE 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 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 meter greater mean increase in the distance walked in six minutes compared to placebo. The changes in %-predicted FVC were not statistically significant (Table 3).

Table 3 Clinical Study Results

	ELAPRASE Weekly n=32 1			Placebo n=32			ELAPRASE Weekly — Placebo
	Baseline	Week 53	Change 2	Baseline	Week 53	Change	Difference in Change
Results from the 6-Minute Walk Test (Meters)
Mean ± SD	392 ± 108	436 ± 138	44 ± 70	393 ± 106	400 ± 106	7 ± 54	37 ± 16 3 35 ± 14 4 (p=0.01)
Median	397	429	31	403	412	-4
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 ± 2.5 4.3 ± 2.3 (p=0.07)
Median	54.9	59.2	2.1	57.4	54.6	-2.5
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

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 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 weekly group through Week 53 compared to placebo. There were essentially no changes in liver and spleen volumes in the placebo group.