CAMBRIDGE, MA -- July 5, 2001 -- Genzyme General reported that a paper published in today's New England Journal of Medicine shows that Fabrazyme™ (agalsidase beta) can clear the lipid globotriaosylceramide (GL-3) from the plasma and the blood vessels of the kidneys, heart and skin in patients with Fabry disease.
The results come from Genzyme's Phase III trial of Fabrazyme, an investigational enzyme replacement therapy for patients with Fabry disease. The results show that Fabrazyme addresses the major pathology underlying Fabry disease: the accumulation of GL-3 in the blood vessels of the major affected organs. In patients with Fabry disease, this buildup often leads to reduced blood flow and organ failure, particularly in the kidneys, heart, and brain.
The results were achieved in a double-blind, placebo-controlled, multicenter trial that enrolled 58 patients at eight medical centers in Europe and the United States. It was the largest clinical trial ever conducted for Fabry disease or any lysosomal storage disorder.
The pivotal trial's primary end point was the clearance of GL-3 from the microvascular endothelial cells in the kidney. After 20 weeks of treatment, 20 of 29 patients (69 percent) who received Fabrazyme had achieved complete or almost complete clearance, as compared with none in the placebo group. In addition, Fabrazyme was able to bring about clearance of GL-3 to near-normal levels from the capillaries of the heart, kidney and skin, and a reduction of GL-3 in kidney tissue and urine.
Previously elevated plasma GL-3 levels were consistently reduced to undetectable levels in the Fabrazyme-treated group, and plasma levels correlated with the clearance of GL-3 from tissues. A statistically significant decrease from baseline in pain was noted for both treatment groups.
All patients continued therapy in the open-label extension trial. Complete vascular clearance to near normal levels was achieved in 98 percent of patients who underwent a repeat kidney biopsy six months into the extension trial, demonstrating that the clearance achieved in the first five months was maintained, and that the placebo patients could achieve the same response when crossed over to Fabrazyme treatment. Similarly, complete or near complete vascular clearance was seen in 96 percent of the skin biopsies, and 75 percent of the heart biopsies. Of note, kidney function remained essentially normal in these patients during the year of follow-up.
"The results published today offer tremendous hope for meeting the needs of patients with Fabry disease," said Robert J. Desnick, M.D., Ph.D, of Mount Sinai School of Medicine, an author of the study and an eminent leader in the development of therapies for lysosomal storage disorders. "We have shown it is possible to reliably achieve total or near-total clearance of GL-3 through a
precise dose of Fabrazyme. This achievement is a validation of our meticulous approach to developing the best possible protein and determining the optimal dose for patients, and the culmination of the work of the many investigators in this trial."
In an editorial accompanying the paper, William A. Gahl, M.D., Ph.D. of the National Institutes of Health, said that "an intimate knowledge" of Fabry disease enabled the study's investigators to select "an appropriate outcome measure and to perform serial renal biopsies for proof of efficacy. Thus, Fabry's disease now joins Gaucher's disease ... as a lysosomal storage disorder that is treatable by enzyme replacement."
The vascular clearance of GL-3 observed in the Phase III trial was achieved with a dose of 1mg of Fabrazyme per kilogram of patient body weight administered every other week - a dosing level chosen as a result of a prior Phase I/II trial comparing the effectiveness of three different doses (0.3mg/kg; 1.0mg/kg; 3.0mg/kg) over three months. In the earlier trial, a dose of 0.3mg/kg was shown to reduce GL-3 but not clear it consistently, resulting, for example, in a 75 percent reduction of GL-3 from baseline. The 1mg/kg dose cleared GL-3 from the plasma and from the blood vessels of the major organs.
Fabry disease is caused by a deficiency of the enzyme alpha-galactosidase. This deficiency results in the body's inability to break down certain glycolipids -- primarily GL-3 -- which then accumulate in the lining of the blood vessels within the kidney, heart, skin and other organs. Although some accumulation also occurs in other cells, it is the progressive accumulation of these lipids in the blood vessels that results in symptoms such as kidney failure, stroke, cardiovascular disease, severe pain and numbness. These organ complications lead to death on average around age 40 unless patients undergo dialysis or a renal transplant.
These phase III data, along with results from the earlier phase I/II study, were submitted to regulatory agencies last summer for marketing approval in the U.S. and Europe. Fabrazyme has been recommended for marketing approval in the European Union, and it has been sold in France since late last year. A biologics license application is under regulatory review in the United States.
SOURCE: Genzyme General
Related Links: New England Journal of Medicine and Genzyme General .
