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Fabry Disease

Fabry disease is an inherited lysosomal storage disorder caused by deficiency of an enzyme called α-galactosidase A (α-Gal A, referred to here as α-Gal). The primary biological function of α-Gal is to degrade specific lipids in lysosomes, including globotriaosylceramide (GL-3, also known as Gb3). Progressive accumulation of GL-3 is believed to lead to the symptoms of Fabry disease, including pain, kidney failure, and increased risk of heart disorders and stroke. Enzyme replacement therapy (ERT) with recombinant human α-Gal (Fabrazyme®) or gene-activated α-Gal (Replagal®) is the current standard of care for Fabry disease. However, ERT is not a cure and has several potential limitations. For more information about Fabry disease please click here.

Migalastat HCI (AT1001) is an investigational pharmacological chaperone for the treatment of Fabry disease. Amicus is developing oral migalastat HCl for Fabry patients with α-Gal mutations that are amenable to this chaperone as a monotherapy. For all other Fabry patients, the Company is leveraging is Chaperone-Advanced Replacement Therapy (CHART™) platform to develop migalastat HCl co-formulated with ERT as next-generation therapy.

Migalastat HCl Monotherapy
Many individuals with Fabry disease make some α-Gal enzyme in their cells that may be capable of degrading GL-3 if the mutant enzyme was effectively delivered to lysosomes in sufficient quantities. As a monotherapy, migalastat HCl is designed to bind to and stabilize the endogenous α-Gal that is made in the patient’s own body, thereby increasing its trafficking to lysosomes (that is, migalastat HCl acts as a “chaperone”). Once delivered to lysosomes, the α-Gal enzyme degrades GL-3. Individuals with Fabry disease who have certain genetic mutations may be suitable for oral migalastat HCl monotherapy instead of ERT.

If approved, Amicus estimates that approximately one-third to one-half of the Fabry population may be eligible to receive migalastat HCl monotherapy based on extensive preclinical and clinical work that characterized the properties of nearly 600 known Fabry disease-associated mutations1.

Development Status
Amicus is conducting two Phase 3 global studies (The FACETS Study, Study 011 and The ATTRACT Study, Study 012) of migalastat HCl monotherapy in males and females with Fabry disease who have α-Gal mutations that are considered amenable to chaperone monotherapy based on a proprietary cell-based assay. For more information about these studies please click here.

Regulatory authorities in the United States, the European Union and Japan have granted orphan drug designation for the active ingredient in migalastat HCl.

Next-Generation Fabry ERT (Migalastat HCl Co-Formulated with ERT)
Amicus is leveraging its CHART platform to develop AT-B100 (also known as JR-051), a proprietary investigational recombinant human α-Gal enzyme, co-formulated with migalastat HCl. In combination with ERT, migalastat HCl binds to infused α-Gal in the circulation and stabilizes the active form of the enzyme. Any individual diagnosed with Fabry disease is potentially suitable for this next-generation ERT.

In published preclinical studies2 migalastat HCl in combination with currently approved Fabry ERTs led to stabilization of the enzyme in the circulation, and increased uptake of the active enzyme into key organs of disease compared to ERT alone. This increased uptake of active enzyme also led to further reductions in GL-3. These preclinical studies as well as initial human proof-of-concept data from a Phase 2 study of migalastat HCl co-administered with ERT (Study 013) have served as the foundation for further development of AT-B100 co-formulated with migalastat HCl as a next-generation ERT for Fabry disease.

Development Status
Based upon positive initial human proof-of-concept from a Phase 2 study evaluating a single administration of migalastat HCl co-administered with ERT (Study 013), Amicus plans to advance AT-B100 co-formulated with migalastat into clinical studies in 2014. The results from Study 013 have built confidence around the concept that migalastat HCl in combination with ERT can increase levels of active enzyme in plasma and tissues and support the rationale for the first repeat-dose clinical study with the next-generation ERT.

1. Wu X, et al., Human Mutation: July 2011, Vol. 32, No. 8, pp. 965–977

2. Benjamin E, et al., Molecular Therapy: April 2012, Vol. 20, No. 4, pp. 717–726

3. Bichet D, et al., LDN WORLD 2013
Fabry disease is an inherited lysosomal storage disorder caused by deficiency of an enzyme called α-galactosidase A. Symptoms include pain, kidney failure, and increased risk of heart attack and stroke.

To learn more about Fabry disease, click here.

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