Plicera™ (AT2101) for Gaucher Disease
AT2101 is an experimental, oral therapy for the treatment of Gaucher disease and belongs to a class of molecules known as pharmacological chaperones.
Gaucher Disease
Gaucher disease is a lysosomal storage disorder resulting from a deficiency in the key enzyme b-glucocerebrosidase (GCase). This enzyme is responsible for breaking down a specialized type of fat molecule, known as glucocerebroside, in the lysosome. The enzyme deficiency is caused by genetic mutations, which result in the production of misfolded GCase protein. The absent or defective GCase enzyme activity leads to build-up of glucocerebroside inside certain cells. Over time, these Gaucher cells can accumulate and may cause inflammation or damage to specific areas within the body, including the liver, spleen, bone marrow, lung, and the central nervous system. For more information on Gaucher disease, please click here.
AT2101 for Gaucher Disease
AT2101 is designed to act as a pharmacological chaperone by selectively binding to the misfolded enzyme responsible for Gaucher disease, GCase. After binding to the enzyme, it is thought that AT2101 promotes the proper folding, processing, and trafficking of the enzyme from the endoplasmic reticulum to its final destination, the lysosome, the area of the cell where the enzyme does its work. Once it reaches the lysosome, the pharmacological chaperone is displaced and the enzyme can perform its normal function, which is the breakdown of its natural substrate, glucocerebroside.
Clinical Progress
Several in vitro and in vivo preclinical studies have been conducted. In these studies AT2101 increased GCase enzyme level in cells derived from Gaucher disease patients with different genetic mutations, including cells with a genetic mutation associated with the neurologic form of Gaucher disease. In normal mice, oral administration of AT2101 resulted in a dose-dependent increase in GCase level in the liver, spleen, brain, and lung.
Amicus filed an IND for AT2101 for the treatment of Gaucher disease and has completed Phase 1 clinical trials. Phase 2 clinical trials began in March 2007. In January 2006, the FDA granted AT2101 orphan drug designation, which provides extended marketing rights and other incentives to support and encourage development of therapies for rare diseases and disorders.