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Fabry Disease (migalastat HCl)
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). Lipids that can be degraded by the action of α-Gal are called
“substrates” of the enzyme. 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. For more information about Fabry disease please
Migalastat HCI (AT1001) is an investigational, orally administered pharmacological
chaperone for the treatment of Fabry disease. In
collaboration with GlaxoSmithKline (GSK), Amicus is developing migalastat
HCl both as an oral monotherapy, and in combination with enzyme replacement therapy (ERT).
Migalastat HCl Monotherapy
Many individuals with Fabry disease make some α-Gal enzyme in their cells that might
be capable of degrading GL-3 if it were able to get into lysosomes in sufficient
quantity. As a monotherapy, migalastat HCl is designed to bind to and stabilize,
or “chaperone,” the endogenous α-Gal made in the patient’s own body, thereby increasing
trafficking to lysosomes where it functions to degrade 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 half of the Fabry population may
be eligible to receive migalastat HCl monotherapy based on extensive preclinical
and clinical work
characterizing the properties of nearly 600 known Fabry disease-associated mutations1.
Amicus and GSK are 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.
The safety and efficacy of a variety of doses and regimens of migalastat HCl have
been evaluated in four Phase 2 studies that have informed the design of the ongoing
Phase 3 registration studies. A separate open-label Phase 2 extension study (Study
205) is currently ongoing to evaluate the long-term safety and efficacy
of migalastat HCl.
Regulatory authorities in the United States, European Union and Japan have granted
orphan drug designation for the active ingredient in migalastat HCl.
Migalastat HCl in Combination with ERT
Preclinical studies indicate that migalastat HCl may also chaperone and improve
the function of α-Gal ERT. The action of migalastat HCl in combination with ERT
may address some of the current ERT limitations and improve treatment outcomes as
compared to the use of ERT alone.
When co-administered with ERT in preclinical studies, migalastat HCl binds to the
infused α-Gal enzyme in the circulation and stabilizes the active form of the enzyme. Therefore,
any individual diagnosed with Fabry disease who is currently receiving infused α-Gal
ERT is potentially suitable for chaperone-ERT co-administration therapy.
published preclinical studies2 migalastat HCl co-administered
with ERT in Fabry knock-out mice 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.
Amicus and GSK, in collaboration with Japan-based JCR, are also developing migalastat HCl co-formulated with a preclinical proprietary recombinant human alpha-Gal A enzyme (JR-051). This ERT was developed by JCR and licensed to GSK for all markets outside Japan. Preclinical studies conducted by Amicus, GSK and JCR suggest that this co-formulated chaperone-ERT product may provide greater alpha-Gal A enzyme uptake into tissue and markedly reduced levels of GL-3 in Fabry disease-relevant tissues compared to recombinant enzyme alone.
Amicus and GSK are currently conducting a Phase 2 drug-drug interaction study (Study
013) evaluating migalastat HCl co-administered with ERT for the treatment
of Fabry disease. For more information about this study,
please click here.
A repeat-dose global study of migalastat HCl co-administered with ERT is
also being designed by Amicus and GSK as the next step in U.S. and global development.
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
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.