Substrate Balance Therapy


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Irene Gow Clinical Operations Manager of Oxford GlycoSciences (OGS) gave a talk on substrate balance (deprivation) therapy, a potential new way to treat Gauchers disease, at the Neuronopathic Gaucher's Disease Family Conference. OGS currently has a drug called OGT 918 in clinical trials involving patients with Type 1 Gaucher disease. Based in Abingdon, Oxfordshire, OGS employs approximately 135 staff and is a drug discovery and development company.


Ms Gow's talk on substrate balance (deprivation) therapy concentrated on three main areas. What is substrate balance? What is OGT 918? And finally, how are the clinical trials of OGT 918 progressing?

The talk started with an explanation of Gaucher disease, showing how the waste material (glucocerebroside) stores in the macrophage (a certain white blood cell found in the body eg in the spleen, liver and bone marrow) and how a lack of the enzyme, glucocerebrosidase, which normally degrades the stored material, results in the problems associated with Gauchers disease.

In the case of enzyme replacement therapy, this stored material is degraded directly. However with substrate balance therapy, OGT 918 partially inhibits the formation of glucocerebroside in the first place, resulting in less storage in the macrophage. This allows the reduced levels of residual enzyme present in the macrophages to degrade the lower levels of stored material.

Ms Gow went on to explain that in theory this mode of action would take longer to act on the symptoms of Gaucher disease than enzyme replacement therapy, as it will take time for the residual enzyme to act on existing storage material.

OGT 918 is an oral therapy and was previously developed as an anti-HIV drug by Searle.

Ms Gow described how Dr Fran Platt and Dr Terry Butters at the Glycobiology Institute in Oxford had researched the compound as a potential treatment for glycosphingo-lipid storage disorders such as Gaucher disease.

It was of particular interest to the neuronopathic Gaucher disease community that the two scientists' work had shown OGT 918 to reduce storage in the brain in the mouse model of Tay-Sachs disease.

Clinical Trials

The first clinical trial of OGT 918 in Type 1 Gauchers disease enrolled 28 adults with the disease who are not on enzyme replacement therapy. The trial started in March 1998 at the Gaucher Clinic at Addenbrooke's Hospital in Cambridge.

The trial programme has now expanded to study centres in the Netherlands, Czech Republic, Israel and South Africa. The first trial was completed at the beginning of this year, 2000.

Each patient on the trial has monthly assessments to monitor their progress. Key parameters include spleen and liver organ volumes, haemoglobin and platelets, bones and the levels of OGT 918 achieved in the blood.

OGT 918 is formulated as 50mg or 100mg capsules to be taken three times a day every day.

Main Questions to be Answered

The trial programme sets out to address some very important questions. Is OGT 918 well tolerated? Is OGT 918 effective as a treatment on its own? Is OGT 918 effective when given with Cerezyme?

Some of these questions will start to be answered after the first trial is complete and the data is analysed. It is anticipated that the results of the first clinical trial will be available in early 2000.

A number of families attending the conference asked if Oxford GlycoSciences were planning to extent their clinical trials to children and to neuronopathic Gauchers disease.

Ms Gow said that there are still many unknown factors to be addressed before trials in children could take place. However this is an area that OGS are interested to explore.


First Clinical Trial Results for OGT 918
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Source: Gaucher's News February 2000. © Copyright Gauchers Association 2000