Rare Disease Spotlight - Fabry Disease Treatments

Christina T. Loguidice

Fabry disease is a lysosomal storage disease caused by a mutation of the GLA gene on the X chromosome, which leads to deficient lysosomal alpha-galactosidase A activity and subsequent accumulation of globotriaosylceramide (GL-3) in cells throughout the body.1 This accumulation causes signs and symptoms that often manifest in childhood and affect many body systems, potentially progressing to kidney failure, myocardial infarction, and stroke if left untreated. The severity of the mutation affects the level of accumulation. Mutations that decrease but do not eliminate activity result in milder, late-onset forms of Fabry disease that affect only the heart or kidneys.  
Fabry disease is estimated to affect 1 in 40,000 to 60,000 males, but can also affect females. Although the disease has been thought to be asymptomatic or less severe in female patients because the second X chromosome can compensate for the deficiencies of the mutated X chromosome,1 this thinking is changing. Questionnaire-based studies of patients with Fabry disease have indicated that female patients can experience a range of symptoms similar to that of their male counterparts.2 Therefore, it has been suggested that females should be regarded as potential patients and not simply as carriers.2

Treatments - Approved

Enzyme replacement therapy (ERT) with agalsidase beta (Fabrazyme), which is administered by an infusion every 2 weeks, is standard treatment for Fabry disease. Agalsidase beta lowers the amount of GL-3, which is thought to reduce the signs and symptoms of the disease, but this relationship has yet to be proven.3 In clinical trials, the most common side effects were infusion-related reactions, some of which were severe.3

Treatments –In Development

Several other treatments are in development. This includes migalastat HCl (Galafold), a pharmacological chaperone for the treatment of patients with alpha-galactosidase A mutations that are amenable to chaperone therapy. Migalastat binds to and stabilizes endogenous alpha-galactosidase enzyme molecules so that they are delivered to the lysosomes, where they begin breaking down globotriaosylceramide.4 Amicus Therapeutics, which is developing migalastat, estimates that up to 50% of patients with Fabry disease may be suitable for migalastat monotherapy. On June 3, 2015, Amicus submitted a Marketing Authorization Application to the European Medicines Agency seeking approval of migalastat HCl for the treatment of patients with amenable mutations. The company plans to conduct a pre-New Drug Application (NDA) meeting with the US Food and Drug Administration to submit an NDA for migalastat HCI in the United States in the second half of 2015.4
Amicus is also investigating migalastat in combination with ERT for patients without amenable mutations, and any patient with Fabry disease can be a candidate for this therapeutic approach. In combination with ERT, migalastat binds to infused alpha-galactosidase A in the circulation and stabilizes the active form of the enzyme.5 Preclinical studies showed the combination approach to increase uptake of the active enzyme into key organs of disease compared with ERT alone, and there were also greater reductions in GL-3 than observed with ERT monotherapy.5
Genzyme, the manufacturer of Fabrazyme, is working on developing a new oral substrate reduction therapy for the treatment of Fabry disease: GZ/SAR402671. The compound is currently being investigated in a phase 2a, open-label, single-arm, 26-week clinical trial where patients will receive the oral medication once daily.6 The primary endpoint is the ability of GZ/SAR402671 to reduce accumulated GL-3 from the skin capillary endothelium. Upon completion of the study, patients will have the option to enroll into an extension study.          


1. National Institutes of Health. Genetics home reference: Fabry disease. Published June 15, 2015. Accessed June 17, 2015.
2. Deegan PB, Bähner F, Barba M, Hughes DA, Beck M. Chapter 30: Fabry disease in females: clinical characteristics and effects of enzyme replacement therapy. In: Fabry Disease: Perspectives from 5 Years of FOS. Accessed June 17, 2015.
3. Fabrazyme (agalsidase beta). Accessed June 17, 2015.
4. Amicus Therapeutics Submits Marketing Authorization Application (MAA) for Full Approval of Fabry Monotherapy Galafold(TM) (Migalastat) in European Union [press release]. Cranbury, NJ; Amicus Therapeutics. Dated June 3, 2015. Accessed June 17, 2015.
5. Americus Therapeutics. Fabry disease. Accessed June 17, 2015.
6. Genzyme Initiates Phase 2a Clinical Trial to Evaluate Oral Therapy for Fabry Disease [press release]. Cambridge, MA; Genzyme. Dated April 21, 2015. Accessed June 17, 2015.
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