Amicus Therapeutics Presents Preclinical Studies of Chaperone AT3375 for Gaucher Disease

Amicus Therapeutics

presented preclinical studies of AT3375 as a monotherapy and in combination with enzyme replacement therapy for Gaucher disease during the 8th Annual Lysosomal Disease Network WORLD Symposium (LDN WORLD). AT3375 is a next-generation, small molecule pharmacological chaperone that targets the glucocerebrosidase (GCase) enzyme deficient in Gaucher disease, a mechanism with the potential to address Gaucher and Parkinson's. AT3375 was the lead compound selected from a series of chaperones designed by Amicus to improve upon the properties of AT2101 (isofagomine tartrate), a first-generation chaperone that Amicus was originally developing for Gaucher disease. The oral presentation at LDN WORLD was titled, "Preclinical Results Exploring the Use of Pharmacological Chaperone AT3375 Alone and in Combination with Recombinant Human Beta-Glucosidase for Gaucher Disease." Key highlights were as follows: In combination with ERT, AT3375 binds to and stabilizes the recombinant enzyme, minimizing its thermal denaturation and loss of activity in vitro. AT3375 co-administered with ERT increased active enzyme in plasma and Gaucher-disease relevant tissues (liver, spleen and lung) compared to AT2101 co-administered with ERT. In addition, ERT co-administered with either chaperone increased enzyme activity compared to ERT alone. When used as a monotherapy, AT3375 increased GCase activity in patient-derived cells with greater potency compared to AT2101. In mouse models, higher levels of AT3375, orally administered as a monotherapy, were present in the brain and the compound was cleared more rapidly than AT2101. AT3375 increased brain GCase levels with greater potency compared to AT2101.