Fabrazyme Pharmacology, Pharmacokinetics, Studies, Metabolism - Agalsidase Beta

Fabrazyme Pharmacology, Pharmacokinetics, Studies, Metabolism - Agalsidase Beta

CLINICAL PHARMACOLOGY

Fabry disease is an X-linked genetic disorder of glycosphingolipid metabolism. Deficiency of the lysosomal enzyme a-galactosidase A leads to progressive accumulation of glycosphingolipids, predominantly GL-3, in many body tissues, occurring over a period of years or decades. Clinical manifestations of Fabry disease include renal failure, cardiomyopathy, and cerebrovascular accidents. Accumulation of GL-3 in renal endothelial cells may play a role in renal failure.

Fabrazyme^Ò is intended to provide an exogenous source of a-galactosidase A in Fabry disease patients. Preclinical and clinical studies evaluating a limited number of cell types indicate that Fabrazyme^Ò will catalyze the hydrolysis of glycosphingolipids including GL-3.

Plasma profiles of Fabrazyme^Ò were studied at 0.3, 1.0 and 3.0 mg/kg in 15 patients with Fabry disease. The area under the plasma concentration-time curve (AUC¥) and the clearance did not increase proportionately with increasing doses, demonstrating that the enzyme follows non-linear pharmacokinetics. Terminal half-life was dose independent with a range of 45 - 102 minutes.

In 11 patients with Fabry disease given 1.0 mg/kg Fabrazyme^Ò every 14 days for a total of 11 infusions, the pharmacokinetic responses following repeated dosing fell into three categories. In some patients, pharmacokinetic responses were maintained with repeated dosing, whereas in other patients, pharmacokinetic values decreased at infusion seven relative to baseline and returned to baseline values by infusion 11. In the remaining patients, AUC declined and failed to return to baseline by infusion 11. In these patients, the average AUC was 25% of its initial level. Some patients with elevated titers of antibody to agalsidase were among those with decreased AUC. The development of antibodies to agalsidase did not influence half-life, but reduced both apparent Cmax and AUC. The long-term consequence of antibody development to the pharmacokinetics of agalsidase has not been established.

The safety and efficacy of Fabrazyme^Ò were assessed in a randomized, double-blind, placebo-controlled, multinational, multicenter study of 58 Fabry patients (56 males and two females), ages 16 to 61 years, all naïve to enzyme replacement therapy. Patients received either 1.0 mg/kg of Fabrazyme^Ò or placebo every two weeks for five months (20 weeks) for a total of 11 infusions. All patients were pretreated with acetaminophen and an antihistamine to decrease or prevent infusion associated reactions. Oral steroids were an additional option to the pretreatment regimen for patients who exhibited severe or recurrent infusion reactions. The primary efficacy endpoint of GL-3 inclusions in renal interstitial capillary endothelial cells, was assessed by light microscopy and was graded on an inclusion severity score ranging from 0 (normal or near normal) to 3 (severe inclusions).

A GL-3 inclusion score of 0 was achieved in 20 of 29 (69%) patients treated with Fabrazyme^Ò compared to 0 of 29 treated with placebo (p<0.001). Similar reductions in GL-3 inclusions were observed in the capillary endothelium of the heart and skin (Table 1). No differences between groups in symptoms or renal function were observed during this five month study.

All 58 patients in the randomized study participated in an open-label extension study of Fabrazyme^Ò at 1.0 mg/kg every two weeks indefinitely. At the end of six months of open-label treatment, most patients achieved a GL-3 inclusion score of 0 in capillary endothelium (Table 1). GL-3 was decreased to normal or near normal levels in mesangial cells, glomerular capillary endothelium, interstitial cells and non-capillary endothelium. GL-3 deposition was still present in vascular smooth muscle cells, tubular epithelium and podocytes, at variably reduced levels. Plasma GL-3 levels were reduced to levels below the limit of detection and remained so up to 18 months of treatment.

The reduction of GL-3 inclusions suggests that Fabrazyme^Ò may ameliorate disease expression; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.