Two new oral treatments for Gaucher disease, the most common of the Jewish genetic diseases, have reached Phase II clinical trials and could be on the market within the next few years. Two pharmaceutical companies, Genzyme and Amicus Therapeutics, are each developing their own oral drugs and have taken very different approaches to tackling the enzyme deficiency that is at the root of the disease.
Gaucher (pronounced go-SHAY) affects 1 in 450 Ashkenazic Jews and, like Tay-Sachs and Niemann-Pick, is a lysosomal storage disease. The disorder results from a deficiency in the enzyme designed to break down the fatty substance glucocerebroside. Because of the shortage of usable enzyme, glucocerebroside accumulates in the body and can cause anemia, poor blood clotting, an enlarged liver and spleen, bone damage and, occasionally, neurological problems.
Gaucher is often treated with enzyme replacement therapy, which provides the necessary enzyme and can decrease symptoms dramatically. But a person must have frequent intravenous treatment with the enzyme replacement drug Cerezyme, which can cost anywhere from $100,000 to $750,000 per patient per year. The high cost and inconvenience of the treatment have led many researchers to try to develop a less costly orally administered alternative.
Scientists at Genzyme, the maker of Cerezyme, are working on a potential new oral drug known as a substrate inhibitor. Rather than providing additional enzyme, like Cerezyme, a substrate inhibitor could help prevent glucocerebroside from initially building up by targeting the areas of the cell that produce the substance. A similar medicine, called miglustat and marketed under the brand name Zavesca, has been available for several years, but is prescribed only to patients who cannot be treated with Cerezyme. According to Dan Quinn, Genzyme’s director of corporate communications, the new drug would be more efficient than Zavesca. “It’s much more potent than Zavesca; it acts in a much more specific way,” he said. “It could potentially work as a replacement or a complementary therapy.”
Amicus Therapeutics, a relatively new pharmaceutical company, is taking a different approach. According to Jayne Gershkowitz, the company’s director of patient advocacy and DEL public policy, Amicus has been focusing on developing a pharmacological chaperone drug that has the potential to repair damaged enzymes in a cell rather than reducing the amount of glucocerebroside there to begin with. According to Gershkowitz, the mutation that causes Gaucher disease prevents the enzyme from being properly shaped and thus from being trafficked to the part of the cell where glucocerebroside is stored. A pharmacological chaperone drug has the potential to reshape the pre-existing damaged enzyme, allowing it to work properly. “In the case of pharmacological chaperones, you’re working with the body’s natural production of enzyme,” she said. “You’re working with what’s there and stabilizing it into the correct shape so it can do what it’s supposed to do.”