Current treatment for Gaucher's disease involves administration of intravenous glucocerebrosidase
to degrade glucocerebroside stored in lysosomes. Lowering the rate of biosynthesis
of glucocerebroside should decrease accumulation 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.
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 and spleen volume by computed tomography or magnetic
resonance imaging at baseline 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 times daily.
Baseline liver volumes were 1.1-2.7 times normal and spleen volumes 5.1-24.8 times
normal. At 12 months, mean liver and spleen volumes were significantly lowered by
12% (95% CI 7.8-16.4) and 19% (14.3-23.7), respectively (each p<0.001). 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 months (p<.0001). Six patients withdrew because of gastrointestinal
complaints (two), personal reasons (two), or severe pre-existing disease (two). The
most frequent adverse effect was diarrhoea, which occurred in 79% of patients shortly
after the start of treatment.
Decrease of substrate formation by OGT 918 improves key clinical features of non-neuronopathic
Gaucher's disease. The strategy justifies further trials in this and other glycosphingolipid
storage disorders.