Elsevier

The Lancet

Volume 355, Issue 9214, 29 April 2000, Pages 1481-1485
The Lancet

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

https://doi.org/10.1016/S0140-6736(00)02161-9Get rights and content

Summary

Background

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 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 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.

Findings

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% Cl 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<0·001). 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.

Interpretation

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.

Introduction

Gaucher's disease is the most common glycosphingolipid lysosomal storage disorder and the first to be treated by enzyme replacement. Inherited deficiency of the lysosomal enzyme, glucocerebrosidase, leads to the accumulation of glucocerebroside, mainly in the cells of the mononuclear phagocyte system.1 The clinical features of the disorder are dominated by progressive hepatosplenomegaly, hypersplenism, skeletal lesions, and, in the rare neuronopathic forms, neurological disease.2, 3 Macrophage-targeted human glucocerebrosidase is currently supplied to a few thousand patients, in whom it reduces organomegaly, improves hypersplenism, and frequently lessens bone pain.4, 5 Treatment is required for life and involves repeated intravenous infusions that are inconvenient for some patients; intravenous administration by indwelling catheters may be required, which carries a risk of infection, especially in patients who have undergone splenectomy.

There are estimated to be 20–30 000 cases worldwide,3 and, therefore, only a fraction of patients are receiving treatment. In practice, the costs of replacement enzymes for such rare disorders and concerns about the ability of the enzyme to penetrate the central nervous system restrict the usefulness of this approach. An oral treatment that uses a small molecule has the potential to improve access to treatment and lessen the burden of treating these disorders with parenteral agents.

Inhibition of substrate formation is a new approach to the glycosphingolipidoses6 and was first advocated by Radin and colleagues7 for the treatment of non-neuronopathic Gaucher's disease. The strategy seeks to lower the formation of glycosphingolipids to rates at which the residual enzyme activity in a given patient can catabolise stored and incoming lysosomal substrate.8 The iminosugar, N-butyldeoxynojirimycin (OGT 918) is an inhibitor of the ceramide-specific glucosyltransferase that initiates the glycosphingolipid biosynthetic pathway and catalyses the formation of glucocerebroside. Previous clinical trials have explored the use of OGT 918 at doses of up to 3 g daily as an α-glucosidase-1 inhibitor in an attempt to decrease viral burden in patients with HIV-1 infection, in whom it was well tolerated.9, 10 In an in-vitro model of Gaucher's disease, the compound prevented the lysosomal storage of glucocerebroside, and, therefore, it was a candidate for clinical use in glycosphingolipid disorders.6 Furthermore, oral administration of OGT 918 in gene-knockout mice that serve as a model of human GM2 gangliosidosis delays the onset of disease and prolongs the life of affected animals.11, 12 These and other studies of animals lacking key enzymes in the pathway of ganglioside biosynthesis generated by targeted gene disruption13 show that deficiency of glycolipids may be compatible with normal growth to maturity.

Decrease in formation of substrate therefore represents a potential approach for Gaucher's disease and other glycosphingolipid lysosomal disorders for which no specific treatment is available. We did a 1-year open-label study to investigate the efficacy and safety of OGT 918 for non-neuronopathic Gaucher's disease.

Section snippets

Patients and methods

The trial was approved by the local independent ethics committee of each participating centre and the appropriate national regulatory agencies.

Study population

Seven (25%) of the 28 patients had undergone previous splenectomy and six (21%) had previously received enzyme therapy (table 1). If we assumed that healthy livers and spleens comprise 2·14% and 0·2% of bodyweight, respectively,16 liver enlargement ranged from 1·1 to 2·7 times normal and splenic enlargement from 5·1 to 24·8 times normal at baseline.

Safety

Six patients withdrew during the study—two because of gastrointestinal complaints (patients 2 and 13 at weeks 4 and 5, respectively), one because of

Discussion

As well as assessing use of OGT 918 for Gaucher's disease, this study provided an opportunity to test the hypothesis that reducing the rate of the biosynthesis of substrate would improve the effects of an enzyme deficiency.7, 8 Our findings supported this principle, since glycolipid synthesis was decreased, organomegaly was significantly reduced, blood counts improved, and chitotriosidase activity was significantly lowered.15, 17

We chose non-neuronopathic Gaucher's disease for initial

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