Eliglustat tartrate, a prototypic glucosylceramide synthase inhibitor

Abstract

Eliglustat tartrate is a highly specific inhibitor of glucosylceramide synthase, developed for the treatment glucosylceramide-based glycosphingolipidoses. Eliglustat is in late clinical development for Gaucher disease type 1. Phase II and III clinical trials have demonstrated clinical efficacy for eliglustat as a stand-alone agent for newly diagnosed patients that are naïve to prior therapy and for patients who have been previously treated with enzyme replacement therapy. Importantly, the reported toxicity of eliglustat has been limited. Eliglustat will be submitted for the US FDA and EMA review in late 2013. Several structurally unrelated glucosylceramide synthase inhibitors have been identified and are in various stages of development, some of which cross the blood–brain barrier. Targeting glucosylceramide synthesis is also a promising approach for the treatment of type 2 diabetes mellitus, autosomal dominant polycystic kidney disease and certain cancers.

Keywords::

• Fabry disease
• Gaucher disease
• glucosylceramide
• glycosphingolipid
• polycystic kidney disease
• type 2 diabetes mellitus

Financial & competing interest disclosure

JA Shayman is an employee of the University of Michigan and is a co-inventor of eliglustat tartrate. All of the relevant patents on glucosyl-ceramide synthase inhibition concerning eliglustat tartrate, including composition of matter, synthesis and use on which Shayman is a coinventor are held by the University of Michigan. The University of Michigan holds a license agreement with Genzyme Corp. and has received licensing fees and royalty payments. Shayman is neither an employee nor a consultant for Genzyme or its parent company Sanofi. He has recused himself from any direct participation in the clinical studies of eliglustat tartrate. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Synthesis inhibition for the treatment of glycosphingolipidoses is a strategy first proposed over 40 years ago.

• • Primary efforts in synthesis inhibition have targeted glucosylceramide synthase, the first step in glucosylceramide glycosphingolipid synthesis.

• • Two classes of glucosylceramide synthase inhibitors have been developed clinically for synthesis inhibition therapy, the imino sugars (miglustat) and d-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol (PDMP)-based inhibitors (eliglustat tartrate).

• • Miglustat has been approved for the treatment of Gaucher disease, but is limited in its use due to its relatively low activity and lack of specificity against glucosylceramide synthase, and significant toxicity.

• • Eliglustat tartrate has low nanomolar inhibitory activity and high specificity. It is scheduled to be submitted for registration in the USA and Europe in late 2013.

• • Several potential extended use applications for eliglustat have been proposed but are not yet the subject of active clinical trials. The potential clinical uses of glucosylceramide synthase inhibition for type 2 diabetes and polycystic kidney disease are particularly promising.

• • Future challenges include the identification and development of compounds that cross the blood–brain barrier and that have superior ADME profiles, determination of the long-term effects of glucosylceramide synthase inhibition and the clinical development of these inhibitors as anti-neoplastic and insulin–sensitizing agents.