Substrate reduction therapy is an investigational treatment method for Fabry disease and other lysosomal storage disorders.

Fabry is a rare genetic disorder caused by the deficiency of an enzyme called alpha-galactosidase A. In the absence of this enzyme, excessive buildup of a fatty substance called globotriaosylceramide (Gb3 or GL-3) in the cells results in severe and irreversible organ damage.

How substrate reduction therapy works

Enzymes are proteins that can modify specific molecules, called substrates. Cells constantly degrade and generate molecules in cascades of biochemical reactions. Enzymes turn their substrates into different molecules in each step of a cascade.

The enzyme glucosylceramide synthase (GCS) makes glucosylceramide (GL-1) from its substrate, ceramide. Other enzymes modify GL-1 further to make globosides, a subclass of lipids to which Gb3 belongs.

Substrate reduction therapy takes its name from the fact that it reduces the amounts of the substrate of a certain enzyme. In the case of Fabry, the activity of the GCS enzyme is inhibited, blocking the formation of GL-1, which then prevents the production of Gb3, the substrate of alpha-galactosidase A. In this way, the therapy ensures that lack of this enzyme in Fabry disease is no longer a problem.

Substrate reduction therapies in clinical development

Lucerastat, developed by Idorsia, has been reported in a Phase 1 clinical study (NCT02930655) to significantly decrease the amounts of three substrates: GL-1, lactosylceramide, and Gb3. It received orphan drug designation from the U.S. Food and Drug Administration and the European Medicines Agency. A randomized Phase 3 clinical trial (NCT03425539) testing Lucerastat in approximately 100 Fabry patients will start soon and is expected to be completed in September 2019.

Another substrate reduction therapy, Venglustat, being developed by Sanofi Genzyme, is currently in a long-term Phase 2 clinical trial (NCT02489344) to evaluate its effectiveness in men with Fabry disease who previously completed another Phase 2 trial (NCT02228460). Venglustat was granted fast-track designation from the FDA in 2015.

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