Afegostat

Mechanism of action

β-Glucocerebrosidase, an enzyme needed for the metabolisation of glucocerebroside, is misfolded in individuals with Gaucher's disease due to various mutations, one of which is called N370S. Afegostat, an iminosugar, binds selectively to N370S glucocerebrosidase and restores its correct conformation and, consequently, enhances its activity about threefold.

Invention and development

Afegostat was invented by Mikael Bols and Troels Skrydstrup and was first prepared by Jespersen and Bols.

Amicus Therapeutics licensed patents related to afegostat from Mt. Sinai School of Medicine, University of Maryland, and Novo Nordisk A/S. They also signed a collaboration agreement with Shire plc related to this drug and others.

It was granted orphan drug status by the European Medicines Agency (EMA) and by the US FDA.

When afegostat failed a Phase II clinical trial in 2009, Shire terminated the collaboration agreement and Amicus determined it would no longer develop the afegostat. The first patents in Amicus' patent portfolio on afegostat expired in 2015.

References

References

1. (2009). "Isofagomine tartrate". Drugs of the Future.
2. (September 2006). "The iminosugar isofagomine increases the activity of N370S mutant acid beta-glucosidase in Gaucher fibroblasts by several mechanisms". Proceedings of the National Academy of Sciences of the United States of America.
3. (1994). "Isofagomine, a Potent New Glycosidase Inhibitor". Angewandte Chemie International Edition in English.
4. Amicus Therapeutics, Inc.. (10 March 2010). "Amicus 10-K Annual Report".
5. (10 March 2010). "Public summary of positive opinion for orphan designation of isofagomine tartrate for the treatment of Gaucher disease". European Medicines Agency.