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Dec 13, 2012
 |  BC Innovations  |  Targets & Mechanisms

Muscling up on Myozyme

Oxyrane U.K. Ltd. and BioMarin Pharmaceutical Inc. have separately reported on their next-generation enzyme replacement therapies for Pompe's disease. Both molecules cleared glycogen from mouse muscle better than the marketed drug Myozyme from Sanofi.1,2 BioMarin has moved its therapy into a Phase I/II trial, whereas Oxyrane is carrying out IND-enabling animal toxicology studies.

Pompe's disease is an inherited disorder of glycogen metabolism caused by an absence of or deficiency in the lysosomal enzyme acid α-glucosidase (GAA). The resulting accumulation of glycogen in cardiac and skeletal muscle leads to severe and progressive muscle weakness, cardiomyopathy and respiratory failure.

Sanofi's Genzyme Corp. unit markets the enzyme replacement therapy Myozyme and Lumizyme to treat the disease.

The problem is that skeletal muscle cells are less accessible to systemic enzyme replacement therapy than cells targeted in other lysosomal storage diseases. Indeed, the drugs are typically delivered at doses 20-30 times higher than other enzyme replacement therapies.3 These high doses can lead to long infusion times and adverse reactions, including fever, tachycardia, cyanosis and hypotension.4

Thus, Oxyrane and BioMarin have been modifying GAA to improve its uptake into skeletal muscle and make possible the use of lower doses.

Both companies focused on modifying GAA to increase its affinity for the insulin-like growth factor 2 receptor (IGF2R; M6PR), which mediates uptake of GAA and other lysosomal enzymes into the muscle cell. The Oxyrane group used carbohydrate modifications,...

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