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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). The primary biological function of α-Gal A is to degrade specific lipid substrates in lysosomes, including globotriaosylceramide (GL-3, also known as Gb3). Progressive accumulation of GL-3 is believed to lead to the morbidity and mortality of Fabry disease, including pain, kidney failure, heart disease and stroke. Enzyme replacement therapy (ERT) with recombinant human α-Gal A (agalsidase beta) or gene-activated α-Gal A (agalsidase alfa) is the current standard of care for Fabry disease. However, ERT is not a cure but instead is a chronic treatment that has several potential limitations. For more information about Fabry disease please click here.

Migalastat (AT1001) is an investigational pharmacological chaperone for the treatment of Fabry disease. Amicus is developing oral migalastat as a monotherapy for Fabry patients with α-Gal A mutations that are amenable to this chaperone therapy. For all other Fabry patients, the Company is leveraging is Chaperone-Advanced Replacement Therapy (CHART™) platform to develop migalastat in combination with ERT as a next-generation therapy. Amicus envisions establishing a Fabry franchise that may provide all patients with a regimen of migalastat to treat their disease.

Migalastat Monotherapy
Many individuals with Fabry disease make some α-Gal enzyme in their cells that is capable of degrading substrate. However, because of the genetic mutation the endogenously produced α-Gal A, the enzyme is not effectively delivered to lysosomes in sufficient quantities to reduce GL-3. As a monotherapy, migalastat is an oral drug designed to bind to and stabilize the endogenous α-Gal A that is made in the patient’s own cells, thereby increasing its trafficking to lysosomes (that is, migalastat acts as a “chaperone”). Once delivered to lysosomes, the α-Gal A enzyme degrades the accumulated GL-3. This precision medicine approach is designed for patients with “amenable mutations”, that is, specific mutations that are capable of responding to oral migalastat as a monotherapy treatment.

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

Development Status
Amicus is seeking global regulatory approval of migalastat monotherapy for Fabry patients who have amenable mutations. The Company conducted two Phase 3 global studies (the FACETS Study, Study 011 and the ATTRACT Study, Study 012) of migalastat monotherapy in males and females with Fabry disease who have α-Gal A mutations that are amenable to chaperone monotherapy. Amicus has reported positive Phase 3 data from studies in both treatment naïve and ERT switch patients. Results from these studies have shown that treatment with migalastat has resulted in reductions in disease substrate, stability of kidney function, reduction in cardiac mass, and a positive impact on patient-reported outcomes.

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

Migalastat in Combination with ERT
For Fabry patients who do not have amenable mutations, Amicus is leveraging its CHART platform to advance migalastat in combination with ERT. In combination with ERT, migalastat is designed to bind to infused α-Gal A in the circulation and stabilize the active form of the enzyme. Any individual diagnosed with Fabry disease is potentially suitable for this novel treatment approach.

In published preclinical studies2 migalastat 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 reductions in GL-3 that were greater than those seen with ERT alone.

Development Status
Positive initial human proof-of-concept data from a Phase 2 study of migalastat co-administered with ERT (Study 013)3 showed that the addition of the chaperone increased levels of active enzyme in blood and increased enzyme uptake into tissues. Based on these results, Amicus plans to conduct a longer-term Phase 2 study of migalastat co-administered with currently approved ERT. In parallel the Company is developing its own proprietary cell line to produce a next-generation Fabry ERT to be used in combination with migalastat.

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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