ELIGLUSTAT TARTRATE: Glucosylceramide Synthase Inhibitor Treatment of Type 1 Gaucher Disease

Abstract

Eliglustat tartrate (Genz-112638) is a novel, orally administered agent currently in development for the treatment of lysosomal storage disorders, including type 1 Gaucher disease and Fabry disease. This glucosylceramide analogue acts as an inhibitor of glucosylceramide synthase, a Golgi complex enzyme that catalyzes the formation of glucosylceramide from ceramide and UDP-glucose and is the first step in the formation of glucocerebroside-based glycosphingolipids. Pre-clinical pharmacological studies demonstrate that the agent has a high therapeutic index, excellent oral bioavailability and limited toxicity. Phase I studies in healthy volunteers revealed limited toxicity with an excellent pharmacodynamic response, as measured by decreased plasma glucosylceramide concentrations. Phase II studies in patients with type 1 Gaucher disease have demonstrated promising clinical responses, as measured by decreases in spleen size, improvement in hemoglobin concentrations and increased platelet counts. Two randomized phase III trials testing the efficacy and safety of eliglustat tartrate are currently in progress.

Figure 1

Pathways for simple glycosphingolipid synthesis and degradation. In Gaucher disease glucosylceramide accumulates due to a decrease or loss of activity of β-glucocerebrosidase; in Fabry disease globotriaosylceramide accumulates due to a loss or decreased activity of β-galactosidase A. Conventional enzyme replacement therapy directly restores deficient enzyme through i.v. infusion of the respective glycosidase. Eliglustat tartrate blocks the first step in glycosphingolipid synthesis, glucosylceramide synthase. In the presence of eliglustat tartrate, all glucosylceramide-based glycosphingolipids are inhibited, including globotriaosylceramide.

Scheme 1

Synthesis of Eliglustat