Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis

Background Current treatment for Gaucher's disease involves administration of intravenous glucocerebrosidase to degrade glucocerebroside stored in lys osomes. Lowering the rate of biosynthesis of glucocerebroside should decrea se accummulation of this substrate. We investigated the safety and efficacy of OGT 918 (N-butyldeoxynojirimycin), an inhibitor of glucosyltransferase, as a novel oral treatment for non-neuronopathic Gaucher's disease. Methods We recruited, into a 1-year open-label study, 28 adults (seven with previous splenectomies) from four national Gaucher's referral clinics, who were unable or unwilling to receive enzyme treatment. We measured liver an d spleen volume by computed tomography or magnetic resonance imaging at bas eline and at months 6 and 12, and biochemical and haematological variables monthly, including chitotriosidase activity (a sensitive marker of Gaucher' s disease activity). Patients were started on 100 mg oral OGT 918 three tim es daily, Findings Baseline liver volumes were 1.1-2.7 times normal and spleen volume s 5.1-24.8 times normal. At 12 months, mean liver and spleen Volumes were s ignificantly lowered by 12% (95% CI 7.8-16.4) and 19% (14.3-23.7), respecti vely (each p<0001). Haematological variables improved slightly, Mean organ volume and blood counts improved continually between 6 months and 12 months of treatment. Mean chitotriosidase concentrations fell by 16.4% over 12 mo nths (p<0.001). Six patients withdrew because of gastrointestinal complaint s (two), personal reasons (two), or severe preexisting disease (two). The m ost frequent adverse effect was diarrhoea, which occurred in 79% of patient s shortly after the start of treatment. Interpretation Decrease of substrate formation by OGT 918 improves key clin ical features of non-neuronopathic Gaucher's disease. The strategy justifie s further trials in this and other glycosphingolipid storage disorders.