General Information

Fabrazyme is a recombinant form of human alpha-galactosidase A, which is administered intravenously to the patient in order to replace the deficient enzyme and initiate the breakdown of stored lipids.

Fabrazyme is intended for intravenous infusion. The recommended dosage of Fabrazyme is 1.0 mg/kg body weight infused every 2 weeks as an IV.

Clinical Results

FDA approval of Fabrazyme was based on a randomized, double-blind, placebo-controlled, multinational, multicenter study of 58 Fabry subjects, ages 16 to 61 years, all naïve to enzyme replacement therapy. 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 zero was achieved in 20 of 29 (69%) subjects treated with Fabrazyme compared to zero of 29 treated with placebo.

All 58 subjects in the randomized study participated in an open-label extension study of Fabrazyme 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. 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.

All subjects 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.

Mechanism of Action

Fabrazyme is recombinant human á-galactosidase A enzyme with the same amino acid sequence as the native enzyme. Purified agalsidase beta is a homodimeric glycoprotein. It is produced by recombinant DNA technology in a Chinese Hamster Ovary mammalian cell expression

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

Literature References

Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill, 2001;3733-3774.

MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38:750-760.

MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet. 2001;38:769-775.

Peters FP, Sommer A, Vermeulen A, Cheriex EC, Kho TL. Fabry's disease: a multidisciplinary disorder. Postgrad Med J. 1997;73:710-712.