Background: Gaucher disease is an autosomal recessive lysosomal glycolipid storage disease that results from a deficiency of acid â-glucosidase. The major natural substrate for this enzyme is glucosylceramide (GL-1), an intermediate metabolite in the synthesis and catabolism of more complex glycosphingolipids. Gaucher disease is characterized by lysosomal accumulation of GL-1 due to impaired GL-1 hydrolysis secondary to the deficiency of the enzyme acid â-glucosidase. In patients with Gaucher disease, different tissues show increases in GL-1 concentration, leading to the main manifestations of the disease: Anemia, thrombocytopenia, hepatosplenomegaly, skeletal disease, and neurological disease. The hallmark of Gaucher disease is the presence of lipid-engorged cells derived from the monocyte/macrophage system (Gaucher cell), which show a characteristic histological appearance and are distributed in tissues where macrophages reside (i.e., liver, spleen, lung, and bone marrow). It is believed that the storage material within these Gaucher cells of visceral tissues originates from phagocytosis of the blood cells, while in neurons of the brain, the storage material is believed to originate from endogenous synthesis.

The approach under development is the use of substrate reduction using Genz-112638, which acts by partially inhibiting the enzyme GL-1 synthase. The goal of this approach is to reduce the synthesis of the accumulated GL-1 (substrate reduction therapy) to a level where the residual enzyme activity of the mutant acid â-glucosidase, the enzyme deficient in Gaucher disease, can degrade GL-1, thus preventing storage of GL-1.

Study Design: This is a Phase 3, randomized, multi-center, multi-national, double-blind study to evaluate the efficacy, safety, and PK of QD versus BID Genz-112638 in male and female patients with Gaucher disease type 1 who have demonstrated clinical stability on BID dosing of Genz-112638.