Lysosomes are small cellular compartments that collect, digest, and dispose of the waste in the cell. In Fabry disease, the lack of the alpha-galactosidase A enzyme in the lysosomes causes incomplete digestion of some lipids (fatty substances) and leads to the accumulation of an intermediate molecule called globotriaosylceramide (Gb3 or Gl-3).
How venglustat works
Venglustat is an oral inhibitor of an enzyme called glucosylceramide synthase (GCS). Enzymes modify specific molecules called substrates. GCS turns its substrate, ceramide, into glucosylceramide (GL-1) during lipid metabolism, a series of biochemical reactions that degrade and generate lipids. GL-1 acts as a substrate to other enzymes and is turned into globosides, a subclass of lipids where Gb3 belongs.
When venglustat inhibits GCS, it prevents the synthesis of GL-1, thereby reducing the substrate of the following reactions that lead to the formation of Gb3 and its accumulation in the absence of α-galactosidase A. That’s why venglustat is called a substrate reduction therapy.
Venglustat in clinical trials
The first Phase 2 clinical trial (NCT02228460) of venglustat was conducted to assess the short-term safety and effects of the treatment in adult men with Fabry disease. It involved 11 patients treated with daily venglustat given by mouth for 26 weeks.
An extension study of the first trial (NCT02489344) is investigating the long-term effects of venglustat, where eight patients receive venglustat for 30 months. The aim of the study is to see whether venglustat decreases Gb3 levels in the blood vessel cells of the skin.
The U.S. Food and Drug Administration granted venglustat fast-track designation in 2015 for the treatment of Fabry disease. With this designation from the FDA, venglustat’s clinical development is expected to speed up. Researchers hope that once-daily oral administration of this inhibitor will help prevent the extensive organ damage caused by Fabry disease.
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