OGT-918 is a generic name for the drug N-Butyldeoxynorjirimycin. Oxford Glycosciences (OGS), which is developing practical uses for the drug, initially trademarked Vevesca as the brand name and later changed to Zavesca. It is also now referred to by the generic name, miglustat. Depending upon the source of information, you will see the drug referred to by any of these names.
OGT-918 acts as an inhibitor of glycolipid synthesis. Glycolipids are combined sugar-fat compounds. One group of glycolipids, known as gangliosides, accumulates abnormally in the brains of Niemann-Pick type C patients. Gangliosides are abundantly present even in normal brain, but unfortunately their function remains poorly understood. Some studies suggest that they are important in cell to cell communication but why their accumulation is associated with brain dysfunction in Niemann-Pick and other storage diseases is unknown. Cholesterol is also known to co-accumulate with gangliosides in these diseases.
OGT-918 and Niemann-Pick In individuals with Niemann-Pick type C disease, an excess of gangliosides and other glycolipids (and cholesterol) builds up in the brain. This excess eventually disrupts normal brain function but the mechanisms are not well understood. It is also unclear whether the excess of gangliosides is directly caused by the NPC1 or NPC2 gene defects or if it is due to the failure of some other process.
Dr. Steven Walkley, a professor in the Department of Neuroscience at the Albert Einstein School of Medicine in New York, has done extensive work with OGT-918 in animal models of NPC disease. He found that the onset of NPC was significantly delayed and that the progression of the disease was slower when OGT-918 was administered daily to mice that had genetic defects in NPC1. Dr. Walkley's results are the basis for the current clinical trial of OGT-918 in humans.
While Dr. Walkley's results are encouraging, mouse brains and human brains do not work in exactly the same way. The delay in disease progression found with the mice might not occur in humans. The clinical trial is the only way to determine if OGT-918 will work in people and strict guidelines must be followed so that the results are accurate. In addition, researchers know that NPC affects the brain in ways in addition to causing ganglioside storage (for example, cholesterol storage), and the drug may not be beneficial for these features of the disease.
In Spring and Summer 2002, human clinical trials began using OGT-918 for Niemann-Pick Type C. Enrollment in the trials is now closed and preliminary results are expected in Fall 2005.
Other OGT-918 Trials OGT-918 has been tested in clinical trials for other diseases, including HIV, Gaucher's Type I disease, and Fabry's disease. In each case, the trial was limited to adults. Few side effects were noted from taking the drug but the results of the trials are mixed. The HIV trial showed no improvement; the Gaucher's trial showed improvement in the liver and spleen; and the Fabray's trial is still underway (as of early 2002). Gaucher's and Fabray's are both lipid storage diseases, somewhat similar to Niemann-Pick Type C. However, there is little or no neurological involvement with Gaucher's Type I.
Zavesca has been approved for sale in Europe and the United States for Gaucher's Type I when patients are unable to take enzyme replacement therapy.
Oxford Glycosciences (OGS), Celltech, UCB, and Actelion The company Oxford Glycosciences was created by Oxford University to develop and market discoveries made by Oxford's faculty. Oxford Glycosciences performed the initial research and clinical tests necessary to obtain approval for the commercial sale of a drug. In 2003, Oxford Glycosciences was sold to Celltech (which was later bought by UCB). OGS/Celltech licensed the rights to manufacture and sell the compound to a major pharmaceutical company.
Rights to sell Zavesca have been licensed to Actelion. Zavesca is currently sold in the United States, Canada, and much of the European Union (as of May 2005) for treatment of Gaucher's Type I. Actelion is also managing the OGT-918 Niemann-Pick clinical trial.
