Avalglucosidase alfa

Pompe disease is a genetic glycogen metabolism disorder that is also referred to as acid maltase deficiency or glycogen storage disease type II (GSD II). It is caused by mutations in the GAA gene, which encodes the lysosomal hydrolase acid α-glucosidase (GAA), an enzyme that normally catalyzes hydrolysis of glycogen to release free glucose for absorption and use for cellular functions. GAA deficiency leads to accumulation of glycogen within lysosomes and progressive disruption of cellular function, especially in smooth, cardiac, and skeletal muscle cells.

Enzyme replacement therapy using avalglucosidase alfa aims to restore the missing GAA enzyme. Avalglucosidase alfa is a hydrolytic lysosomal glycogen-specific recombinant human GAA enzyme that is conjugated with multiple synthetic bis-mannose-6-phosphate (bis-M6P)­ tetra-mannose glycans for enhanced targeting to skeletal muscles. The M6P of avalglucosidase alfa binds to cation-independent mannose-6-phosphate receptor (CI-MPR) on the cell surface with high affinity, which allows drug uptake into cells. Avalglucosidase alfa is internalized and transported into lysosomes to undergo proteolytic cleavage. It then exerts GAA enzymatic activity to cleave glycogen.