Fabry disease (FD) 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 50% chance of inheriting the disorder, and daughters have a 50% 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:
- 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
- Fever
- Gastrointestinal difficulties, particularly after eating
Although FD 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 FD was initially limited to some oral medications (e.g., carbamazepine [Tegretol®], phenytoin [Dilantin®], and metoclopramide [Reglan®]) that were prescribed for an individual's 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 (FDA), on April 24, 2003, as an orphan drug (a drug used to treat, prevent, or diagnose a rare disease) for treatment in individuals with FD. 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.
CLINICAL STUDIES
The FDA approval of agalsidase beta (Fabrazyme) was based on the results of five clinical studies in individuals with FD. Study 1 was a randomized, double-blind, placebo-controlled, multinational, multicenter study of 58 individuals, ages between 16 and 61 years, who have a diagnosis of FD and are naive to enzyme-replacement therapy (ERT). For 5 months, individuals received either agalsidase beta (Fabrazyme) or placebo every 2 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 FD and are naive to enzyme replacement therapy (ERT). 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 agalsidase beta (Fabrazyme) group compared to the placebo group was statistically significant at 1 year and at 2 years.
Study 3 was an open-label, uncontrolled, multinational, multicenter study evaluating safety, pharmacokinetics, and pharmacodynamics of agalsidase beta (Fabrazyme) in 16 pediatric individuals with FD, ages between 8 and 16 years at first treatment. All individuals received agalsidase beta (Fabrazyme) every 2 weeks for up to 48 weeks. At baseline all the male individuals had elevated plasma GL-3 levels. Twelve of the 12 male individuals had observed GL-3 inclusions in the capillary endothelium on skin biopsies. At week 24 and 48, the 12 male individuals 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 male individuals, who had experienced multiple or recurrent infusion reactions during 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.
Study 5 was an observational study that analyzed 24 agalsidase beta (Fabrazyme)–treated pediatric individuals with FD aged between 2 to less than 8 years at agalsidase beta (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.
The long-term safety and efficacy of pegunigalsidase alfa-iwxj (Elfabrio), a novel PEGylated α-Gal-A enzyme replacement therapy (ERT), was evaluated in a phase-1/2 dose-ranging study (NCT02795676). Fifteen ERT-naive adult individuals with FD completed 12 months of pegunigalsidase alfa-iwxj (Elfabrio) and enrolled in this 60-month open-label extension of 1 mg/kg pegunigalsidase alfa-iwxj (Elfabrio) infusions every 2 weeks. Fifteen individuals were enrolled (eight males; seven females); 10 completed 48 months or longer (60 months total treatment), and two completed 60 months (72 months total treatment). Most treatment-emergent adverse events were mild to moderate in severity and all infusion-related reactions were mild to moderate in severity. Four individuals were transiently positive for antipegunigalsidase alfa IgG. Participating individuals showed continuous reduction in plasma lyso-Gb3 concentrations with mean (standard error) reduction of 76.1 ng/mL from baseline to month 24. At 60 months, the estimated glomerular filtration rate slope was comparable to that observed in individuals treated with other ERTs. Cardiac function assessments revealed stability; no cardiac fibrosis was observed. In this first long-term assessment of pegunigalsidase alfa-iwxj (Elfabrio) administration in individuals with FD, pegunigalsidase alfa-iwxj (Elfabrio) had favorable safety/efficacy.
Trial NCT01678898 was a noninferiority randomized, double-blind, and active-controlled trial in ERT-experienced adult individuals diagnosed with FD. Participating individuals were treated with agalsidase beta (Fabrazyme) for at least 1 year prior to trial entry (the mean duration of agalsidase beta [Fabrazyme] treatment prior to enrollment was 5.7 years). Individuals were randomly assigned 2:1 to receive pegunigalsidase alfa-iwxj (Elfabrio) (1 mg/kg intravenous infusion) or agalsidase beta (Fabrazyme) (1 mg/kg intravenous infusion) every 2 weeks for 104 weeks. A total of 77 individuals were randomly assigned and received at least one dose of pegunigalsidase alfa-iwxj (Elfabrio) (N=52; 68%) or agalsidase beta (Fabrazyme) (N=25; 32%). Individuals were between 18 and 60 years of age with a median age of 46 years at baseline; 72 (94%) were White, three (4%) were Black or African-American, and two (3%) were Asian. Two individuals were Hispanic/Latino and 75 individuals were not Hispanic/Latino. Forty-one (53%) individuals had the classic phenotype. The median baseline eGFR and proteinuria was 75 mL/min/1.73 m2 and 0.11 g/g, respectively. The primary efficacy endpoint was the annualized rate of change in eGFR (eGFR slope) assessed over 104 weeks. The estimated mean eGFR slope was −2.4 and −2.3 mL/min/1.73 m2/year on pegunigalsidase alfa-iwxj (Elfabrio) and agalsidase beta (Fabrazyme), respectively. The estimated treatment difference was −0.1 (95% CI, −2.3–2.1) mL/min/1.73 m2/year. Proportions of individuals experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups. At the end of the study, neutralizing antibodies were detected in seven of 47 (15%) pegunigalsidase alfa-iwxj (Elfabrio)–treated individuals and six of 23 (26%) agalsidase beta (Fabrazyme)–treated individuals.
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 FD aged 8 to 16 years, and additional data in 24 individuals with FD aged between 2 and 7 years.
ERT has been approved by the US Food and Drug Administration for the treatment of FD. 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 FD.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.