"Enzyme replacement is the first therapy that may improve the prognosis of patients with Fabry disease," says Raphael Schiffmann, M.D., of the National Institute of Neurological Disorders and Stroke (NINDS), who led the study. The study was conducted at the National Institutes of Health (NIH) in Bethesda, Maryland, and will appear in the June 6, 2001, issue of the Journal of the American Medical Association (JAMA). 1
Fabry disease is a metabolic disorder that affects an estimated 2,000 to 4,000 people in the United States. It is caused by a deficiency of an enzyme called alpha-galactosidase-A that normally helps to break down a type of lipid, or fatty substance, called globotriaosylceramide (Gb3). Without enough alpha-galactosidase, Gb3 accumulates in many of the cells, tissues, and organs of affected patients. The earliest symptoms of the disease usually appear during childhood or adolescence and include episodes of severe neuropathic pain that causes burning sensations in the hands and feet. These symptoms tend to worsen with exercise and during hot weather. Patients also may have small, raised, reddish-purple blemishes on their skin. As they grow older, patients develop impaired arterial circulation, which can lead to early heart attacks, strokes, and many other medical problems. They frequently die in their 40s or 50s due to heart attack, stroke, or kidney failure. Fabry disease is an X-chromosome-linked genetic disorder that usually appears in males. However, some female carriers also have symptoms of the disorder.
In the JAMA study, the researchers enrolled 26 adult male patients with Fabry disease and severe pain. The patients were divided into two groups: 14 patients received the therapy and 12 received a placebo (one of the patients who received the placebo did not complete the trial). The patients received a total of 12 infusions of either the enzyme or the placebo: one dose every 2 weeks for 6 months. The researchers looked at the effect of the therapy on neuropathic pain as the primary outcome measure for this study. They found that patients' assessments of "pain at its worst" when they were not taking pain medication improved nearly two units on average on the Brief Pain Inventory (BPI) rating scale. One unit of change on the scale is considered clinically significant. Patients receiving the therapy also reported improvements in their quality of life related to pain. Four of the patients receiving the therapy were able to discontinue pain medications for the duration of the study, and others were able to significantly reduce the amount of medication they used. The patients who received therapy also had improvements in their kidney pathology and function, significant improvements in heart function, and more than a 50 percent decrease in their plasma levels of Gb3. The only side effects of treatment were mild infusion reactions that were readily controlled with low-dose corticosteroids. These reactions occurred less frequently after the infusion time was increased from 20 minutes to 40 minutes mid-way through the study.
After the initial 6-month period of the clinical trial, all the patients, including those who initially received placebo, began receiving the therapy as part of an open label study. This study confirmed the benefits of the initial trial: after they began receiving the therapy, the patients who had initially received the placebo had improvements similar to those of the initial treatment group.
The NIH researchers used an enzyme replacement product manufactured by Transkaryotic Therapies, Inc. (TKT). A similar product, produced by Genzyme Corporation, is in clinical trials at the Mt. Sinai School of Medicine in New York. The NINDS laboratory that tested this therapy the Developmental and Metabolic Neurology Branch, led by Roscoe O. Brady, M.D. also spearheaded the development of enzyme replacement for Gaucher's disease, another lipid storage disorder, a decade ago. That therapy, called alglucerase (Ceredase), was approved by the U.S. Food and Drug Administration (FDA) in 1991.
The researchers are now planning additional clinical trials to test the effects of the therapy in women and children affected by Fabry disease. With treatment, it may be possible to prevent many symptoms of the disease and allow people with Fabry disease to live normal lives, says Dr. Schiffmann.
Enzyme replacement therapy for Fabry disease has not been approved for marketing in the United States. However, both TKT and Genzyme have filed applications for marketing approval for their enzyme replacement products with the FDA, and final European market authorization for both products is expected soon.
The NINDS, part of the National Institutes of Health in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system. The NINDS is now celebrating its 50th anniversary.