Idursulfase

Hunter syndrome is an X-linked disease caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. Iduronate-2-sulfatase functions to catabolize the glycosaminoglycans (GAG) dermatan sulfate and heparan sulfate by cleavage of oligosaccharide-linked sulfate moieties. Due to the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome, glycosaminoglycans progressively accumulate in the cells, leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction.

Idursulfase is a purified form of the lysosomal enzyme iduronate-2-sulfatase, produced in a human cell line providing a human glycosylation profile, which is analogous to the naturally occurring enzyme. Idursulfase is secreted as a 525 amino acid glycoprotein and contains 8 N-linked glycosylation sites that are occupied by complex, hybrid, and high-mannose type oligosaccharide chains. Idursulfase has a molecular weight of approximately 76 kD.

Treatment of Hunter syndrome patients with intravenous idursulfase 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.

Idursulfase is taken up by selective receptor-mediated mechanisms involving binding to mannose 6-phosphate receptors. Upon internalization by cells, it is localized within cellular lysosomes, thereby limiting distribution of the protein. Degradation of idursulfase is achieved by generally well understood protein hydrolysis mechanisms to produce small peptides and amino acids, consequently renal and liver function impairment is not expected to affect the pharmacokinetics of idursulfase. Pharmacokinetic parameters measured during the first infusion at week 1 of studies TKT024 (0.5 mg/kg weekly arm) and HGT-ELA-038 are displayed in table 1 and table 2 below as a function of age and body weight, respectively.

Table 1. Pharmacokinetic parameters at week 1 as a function of age in Studies TKT024 and HGT-ELA-038:

Patients in the TKT024 and HGT-ELA-038 studies were also stratified across five weight categories; as shown in the following table:

Table 2. Pharmacokinetic parameters at week 1 as a function of body weight in studies TKT024 and HGT-ELA-038:

A higher volume of distribution at steady state (V_ss) was observed in the lowest weight groups.

Overall, there was no apparent trend in either systemic exposure or clearance rate of idursulfase with respect to either age or body weight.

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, repeated dose toxicity, toxicity to reproduction and development and to male fertility.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Animal studies have shown excretion of idursulfase in breast milk.