Agalsidase beta

The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to clear the accumulating substrate in the organ tissues; thereby, preventing, stabilizing or reversing the progressive decline in function of these organs before irreversible damage has occurred.

After intravenous infusion, agalsidase beta is rapidly removed from the circulation and taken up by vascular endothelial and parenchymal cells into lysosomes, likely through the mannose-6 phosphate, mannose and asialoglycoprotein receptors.

Fabry disease

Fabry disease is an inherited heterogeneous and multisystemic progressive disease, that affects both males and females. It is characterised by the deficiency of α-galactosidase. Reduced or absent αgalactosidase activity results in the accumulation of GL-3 in the lysosomes of many cell types including the endothelial and parenchymal cells, ultimately leading to life-threatening clinical deteriorations as a result of renal, cardiac and cerebrovascular complications.

Following an intravenous administration of agalsidase beta to adults at doses of 0.3 mg, 1 mg and 3 mg/kg body weight, the AUC values increased more than dose proportional, due to a decrease in clearance, indicating a saturated clearance. The elimination half-life was dose independent and ranged from 45 to 100 minutes.

After intravenous administration of agalsidase beta to adults with an infusion time of approximately 300 minutes and at a dose of 1 mg/kg body weight, biweekly, mean C_max plasma concentrations ranged from 2000-3500 ng/ml, while the AUC_inf ranged from 370-780 µg min/ml. V_ss ranged from 8.3-40.8 l, plasma clearance from 119-345 ml/min and the mean elimination half-life from 80-120 minutes.

Agalsidase beta 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 agalsidase beta in a clinically significant way. Renal elimination of agalsidase beta is considered to be a minor pathway for clearance.

Paediatric population

Agalsidase beta pharmacokinetics was also evaluated in two paediatric studies. In one of these studies, 15 paediatric patients with available pharmacokinetics data, aged 8.5 to 16 years weighing 27.1 to 64.9 kg were treated with 1.0 mg/kg every 2 weeks. Agalsidase beta clearance was not influenced by weight in this population. Baseline CL was 77 ml/min with a V_ss of 2.6 l; half-life was 55 min. After IgG seroconversion, CL decreased to 35 ml/min, V_ss increased to 5.4 l, and half-life increased to 240 min. The net effect of these changes after seroconversion was an increase in exposure of 2- to 3-fold based on AUC and C_max. No unexpected safety issues were encountered in patients with an increase in exposure after seroconversion.

In another study with 30 paediatric patients with available pharmacokinetics data, aged 5 to 18 years, treated with two lower dose regimens of 0.5 mg/kg every 2 weeks and 1.0 mg/kg every 4 weeks, mean CL was 4.6 and 2.3 ml/min/kg, respectively, mean V_ss was 0.27 and 0.22 l/kg, respectively, and mean elimination half-life was 88 and 107 minutes, respectively. After IgG seroconversion, there was no apparent change in CL (+24% and +6%, resp.), while V_ss was 1.8 and 2.2 fold higher, with the net effect being a small decrease in C_max (up to -34% and -11%, resp.) and no change in AUC (-19% and -6%, resp.).

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, single dose toxicity, repeated dose toxicity and embryonal/foetal toxicity. Studies with regard to other stages of the development have not been carried out. Genotoxic and carcinogenic potential are not expected.