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Pompe disease is an inherited lysosomal storage disorder
caused by deficiency of an enzyme called acid α-glucosidase (GAA). Reduced or absent
levels of GAA lead to the accumulation of the substrate glycogen in the lysosomes
of muscles and other tissues. Progressive accumulation of glycogen is believed to
lead to the symptoms of Pompe disease, including muscle weakness and respiratory
insufficiency. ERT with recombinant human GAA (rhGAA, Myzoyme®/Lumizyme®) are the
first and only treatments approved for Pompe disease. However, ERT is not a cure
and has several potential limitations,
including the occurrence of immune responses
in a majority of Pompe patients receiving rhGAA infusions.1 For more information
about Pompe disease, please click here.
Amicus is leveraging its Chaperone-Advanced
Replacement Therapy (CHART™) platform in combination with a uniquely-engineered,
proprietary rhGAA (designated AT-B200) to develop a next-generation ERT for Pompe
disease. AT-B200 has significantly higher amounts of mannose 6-phosphate (M6P) carbohydrates
which may enable better drug targeting than existing Pompe ERTs. In preclinical studies,
AT-B200 was shown to have superior uptake and activity in disease-relevant tissues
that correlated with clearance of accumulated glycogen substrate when compared to
current standard of care. AT-B200 may be further improved through the application
of the Company’s proprietary conjugation technology to attach vIGF2 (a variant of
the insulin growth factor 2 receptor) to further enhance drug targeting. The vIGF2
peptide binds the intended IGF2 receptor, but does not bind to insulin or the IGF1
Co-formulating AT-B200 with the pharmacological chaperone AT2220 (duvoglustat
HCl) may also deliver benefits. In preclinical studies of AT2220
and co-formulated4 with Myozyme/Lumizyme, greater enzyme uptake in disease-relevant
tissues led to greater glycogen reduction compared to either of these ERTs alone.
Taken together these results support the further investigation of a next-generation
ERT that combines AT-B200 with a pharmacological chaperone for Pompe disease.
Amicus is currently conducting preclinical studies to assess AT-B200 in combination
with AT2220. Initial human proof-of-concept for the chaperone-ERT combination approach
in Pompe disease was established in a Phase 2 study (Study 010).
The results from
this study demonstrated that co-administration of oral AT2220 just prior to infusing
Myozyme/Lumizyme increased GAA enzyme activity in muscle tissue compared to these
Pompe disease is an inherited lysosomal storage disorder caused by deficiency of an enzyme called acid α-glucosidase (GAA) that leads to progressive muscle weakness and respiratory insufficiency.
To learn more about Pompe disease, click here.