About Migalastat HCl for Fabry Disease

Migalastat HCl is an investigational pharmacological chaperone migalastat in development as a monotherapy and in combination with enzyme replacement therapy (ERT) for the treatment of Fabry disease. As a monotherapy, migalastat HCl is designed to bind to and stabilize, or "chaperone" a patient's own alpha-galactosidase A (alpha-Gal A) enzyme in those with genetic mutations that are amenable to this chaperone in a cell-based assay. For patients currently receiving ERT for Fabry disease, migalastat HCl in combination with ERT may improve ERT outcomes by keeping the infused alpha-Gal A enzyme in its properly folded and active form.

Fabry disease is an inherited lysosomal storage disorder caused by deficiency of the alpha-Gal A enzyme. The role of alpha-Gal A within the body is to break down specific lipids in lysosomes, including globotriaosylceramide (GL-3, also known as Gb3). Lipids that can be degraded by the action of alpha-Gal A are called "substrates" of the enzyme. Reduced or absent levels of alpha-Gal A activity leads to the accumulation of GL-3 in the affected tissues, including the kidneys, heart, central nervous system, and skin. This accumulation of GL-3 is believed to cause the various manifestations of Fabry disease, including pain, kidney failure, and increased risk of heart attack and stroke. It is currently estimated that Fabry disease affects approximately 5,000 to 10,000 people worldwide. However, several literature reports suggest that Fabry disease may be significantly under diagnosed, and the prevalence of the disease may be much higher.

About CHART for Pompe Disease

In chaperone-advanced replacement therapy programs for Pompe disease, the small molecule pharmacological chaperone AT2220 is designed to bind to and stabilize human recombinant GAA (rhGAA) enzyme. Amicus is developing AT2220 co-administered with currently marketed ERTs (rhGAA enzymes, Myozyme/Lumizyme) in parallel with the development of a next-generation ERT (AT2220 co-formulated with a proprietary rhGAA enzyme). Positive results from a Phase 2 study ( Study 010) established human proof-of-concept that oral administration of AT2220 just prior to infusing Myozyme/Lumizyme increases enzyme activity in muscle compared to ERT alone. In preclinical studies of AT2220 co-administered and co-formulated with Myozyme/Lumizyme, greater enzyme uptake in disease-relevant tissues led to greater glycogen reduction compared to Myozyme/Lumizyme alone. These chaperone-advanced replacement therapies also have the potential to mitigate Pompe ERT-related immunogenicity because properly folded proteins are generally less prone to aggregation and less immunogenic.

Pompe disease is a lysosomal storage disease characterized by progressive skeletal muscle weakness and respiratory insufficiency. It is caused by a deficiency in GAA activity, which leads to accumulation of glycogen in tissues affected by the disease (primarily muscle). Pompe disease affects an estimated 5,000 to 10,000 individuals worldwide and is clinically heterogeneous in the age of onset, the extent of organ involvement, and the rate of progression.

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