Galsulfase

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). MPS VI is a heterogeneous and multisystemic disorder characterized by the deficiency of N-acetylgalactoasamine 4-sulfatase, a lysosomal hydrolase which catalyses the hydrolysis of sulfate moiety of the glycosaminoglycan, dermatan sulfate. Reduced or absent N-acetylgalactosamine 4-sulfatase activity results in the accumulation of dermatan sulfate in many cell types and tissues.

The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to hydrolyze the accumulated substrate and to prevent further accumulation.

Purified galsulfase, a recombinant form of human N-acetylgalactosamine 4-sulfatase, is a glycoprotein with a molecular weight of approximately 56 kD. Galsulfase is comprised of 495 amino acids after cleavage of the N-terminus. The molecule contains 6 N-linked oligosaccharide modification sites. After intravenous infusion, galsulfase is rapidly removed from the circulation and taken up by cells into lysosomes, most likely via mannose-6 phosphate receptors.

The pharmacokinetics of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg/kg of galsulfase as a 4 hour infusion. After 24 weeks of treatment the mean (± Standard Deviation [SD]) maximum plasma concentration (C_max) was 2,357 (± 1,560) ng/ml and the mean (± SD) area under the plasma concentration-time curve (AUC_0-t) was 5,860 (± 4,184) h x ng/ml. The mean (± SD) volume of distribution (Vz) was 316 (± 752) ml/kg and the mean (± SD) plasma clearance (CL) was 7.9 (± 14.7) ml/min/kg. The mean (± SD) elimination half-life (t_1/2) was 22.8 (± 10.7) minutes at Week 24.

Pharmacokinetic parameters in Phase 1 patients have remained stable over the long term (through at least 194 weeks).

Galsulfase is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of galsulfase in a clinically significant way. Renal elimination of galsulfase is considered a minor pathway for clearance.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, single-dose toxicity, repeated-dose toxicity or on general reproductive performance or embryo-foetal development in rats or rabbits. Peri- and post-natal toxicity has not been investigated. Genotoxic and carcinogenic potential are not expected.

The cause of clinical relevance of the hepatic toxicity (bile duct hyperplasia/periportal inflammation) seen at clinically relevant doses in the repeated dose monkey toxicity study is not known.