Eliglustat tartrate for the treatment of adults with type 1 Gaucher disease

Abstract

The purpose of this article is to review eliglustat tartrate, a substrate reduction therapy, for the treatment of Gaucher disease type 1 (GD1). GD is an rare inborn error of metabolism caused by accumulation of lipid substrates such as glucosylceramide within the monocyte-macrophage system that affects the body by causing enlargement of the spleen and liver, destruction of bone, and abnormalities of the lungs and blood, such as anemia, thrombocytopenia, and leukopenia. GD is classified into three types: GD1, a chronic and non-neuronopathic disease accounting for 95% of GD cases; and types 2 and 3 (GD2 GD3) which are more progressive diseases with no approved drugs available at this time. Treatment options for GD1 include enzyme replacement therapy and substrate reduction therapy. Eliglustat works by inhibiting UDP-glucosylceramide synthase, the first enzyme that catalyzes the biosynthesis of glycosphingolipids, thus reducing the load of glucosylceramide influx into the lysosome. Eliglustat was approved by the US Food and Drug Administration after three Phase I, two Phase II, and two Phase III clinical trials. The dose of eliglustat is 84 mg twice a day or once daily depending on the cytochrome P450 2D6 genotype of the patient.

Keywords: Gaucher disease; eliglustat tartrate; glucocerebrosidase; glucosylceramide synthase; substrate reduction therapy.

Figure 1

Synthesis of glycosphingolipids. In Gaucher disease, glucosylceramide accumulates due to a decrease or loss of activity of β-glucocerebrosidase. Eliglustat tartrate blocks the enzyme glucosylceramide synthase. Glucosylceramide synthase is localized in the cis/medial Golgi membrane which plays an important role in catalyzing the formation of glucosylceramide from ceramide and UDP-glucose. Glucosylceramide is further metabolized to other glycosphingolipids (not shown).