Fabry disease is a rare gene mutation disorder that is inherited in an X-linked recessive pattern. Because the altered gene is carried on a mother’s X chromosome, sons have a fifty percent chance of inheriting the disorder, and daughters have a fifty percent chance of being a carrier. Some female carriers may also exhibit symptoms, especially cloudiness of the cornea.
This mutation causes a deficiency of the lysosomal enzyme known as alpha-galactosidase A. The lack of this enzyme causes an insufficient breakdown of lipids (fats), which then build up to harmful levels in the eyes, kidneys, autonomic nervous system, and cardiovascular system. Symptoms, which usually begin during childhood or adolescence, include the following:
Although Fabry disease usually presents in childhood, a diagnosis may not be confirmed until considerable organ damage has occurred. The average age of diagnosis is about 30. Diagnosis is confirmed by low or absent alpha-galactosidase A activity in plasma or serum, leukocytes, tears, biopsied tissues, or cultured skin fibroblasts. Because of the delay in diagnosis, the increased lipid storage may lead to impaired arterial circulation and an increased risk of heart attack or stroke. The heart may also become enlarged, and the kidneys may become progressively damaged.
Treatment of Fabry disease was initially limited to some oral medications (e.g., carbamazepine [Tegretol®], phenytoin [Dilantin®], and metoclopramide [Reglan®]) that were prescribed for an individuals' specific symptoms. In the past few years, agalsidase beta (Fabrazyme®) was developed through recombinant DNA technology and was approved by the US Food and Drug Administration, on April 24, 2003, as an orphan drug (a drug used to treat, prevent, or diagnose a rare disease) for treatment in individuals with Fabry disease. Agalsidase beta (Fabrazyme®) is almost identical to alpha-galactosidase A. The replacement of the missing lysosomal enzyme reduces globotriaosylceramide (GL-3), a type of lipid that accumulates in many types of cells, including blood vessels in the kidneys and other organs. With the reduction of fat deposition, it is believed that life-threatening organ damage will be prevented.
The FDA approval of agalsidase beta (Fabrazyme®) was based on the results of five clinical studies in individuals with Fabry disease. Study 1 was a randomized, double-blind, placebo-controlled, multi-national, multi-center study of 58 individuals, ages 16-61 years, who have a diagnosis of Fabry disease and are naive to enzyme replacement therapy. For five months, individuals received either agalsidase beta (Fabrazyme®) or placebo every two weeks. The primary efficacy endpoint was assessing GL-3 inclusion in renal interstitial capillary endothelial cells by light microscopy and grading on an inclusion severity scale ranging from 0 (normal or near normal) to 3 (severe inclusions). There was a statistically significant reduction in the inclusion of GL-3 in the Fabrazyme-treated group compared to the placebo-treated group; 69% of the Fabrazyme group achieved a score of 0 compared to the placebo group with none of the individuals reaching a score of 0. These similar reductions were also observed in the capillary endothelium of the heart and the skin.
Study 2 was a randomized, double-blind, placebo-controlled, multinational, multicenter study of 82 individuals, ages 20 to 72 years, who have a diagnosis of Fabry disease and are naive to enzyme replacement therapy. Individuals received either agalsidase beta (Fabrazyme®) or placebo every two weeks up to a maximum of 35 months. The reduction in plasma GL-3 levels in the Fabrazyme group compared to the placebo group was statistically significant at one year and at two years.
Study 3 was an open-label, uncontrolled, multi-national, multi-center study evaluating safety, pharmacokinetics, and pharmacodynamics of agalsidase beta (Fabrazyme®) in 16 pediatric individuals with Fabry disease, ages 8 to 16 years at first treatment. All individuals received agalsidase beta (Fabrazyme®) every two weeks for up to 48 weeks. At baseline all the males had elevated plasma GL-3 levels. Twelve of the 12 males had observed GL-3 inclusions in the the capillary endothelium on skin biopsies. At week 24 and 48 the 12 males with GL-3 inclusions in capillary endothelium at baseline achieved a GL-3 inclusion score of 0.
Study 4 was an open-label, re-challenge study to evaluate the safety of agalsidase beta (Fabrazyme®) in individuals who had a positive skin test to agalsidase beta (Fabrazyme®) or who had tested positive for agalsidase beta (Fabrazyme®) specific IgE antibodies. Six adult males, who had experienced multiple or recurrent infusion reactions during a previous clinical trials with agalsidase beta (Fabrazyme®), were re-challenged with agalsidase beta (Fabrazyme®) administered as a graded infusion for up to 52 weeks of treatment. Four of the six individuals treated received at least 26 weeks of agalsidase beta (Fabrazyme®). Two individuals discontinued prematurely due to recurrent infusion reactions.
- Generalized fatigue and weakness
- Burning sensation in the hands that worsens with exercise and hot weather
- Small, raised, red-purple blemishes on the skin
- Decreased sweating
- Gastrointestinal difficulties, particularly after eating
Study 5 was an observational study that analyzed 24 Fabrazyme-treated pediatric individuals with Fabry disease aged 2 to <8 years at Fabrazyme initiation and with elevated plasma GL-3 levels (i.e., >7.03 μg/mL) at baseline, plasma GL-3 levels fell within the normal range (i.e., ≤7.03 μg/mL) in 91% (20/22), 95% (18/19), and 92% (12/13) of individuals at 6, 12, and 24 months, respectively. Common adverse reactions reported were upper respiratory tract infection, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness, and rash.
Enzyme replacement therapy has been approved by the United States Food and Drug Administration for the treatment of Fabry disease. This therapy can ease pain, improve organ function, and reduce lipid storage. The National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), continues to support research to find ways to treat and prevent lipid storage diseases such as Fabry disease.
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
The safety and effectiveness of Fabrazyme have been established in pediatric individuals based on adequate and well-controlled studies in adults, a single-arm, open-label study in 16 pediatric individuals with Fabry disease aged 8 to 16 years, and additional data in 24 individuals with Fabry disease aged 2 to 7 years.