The Development and Therapeutic Position of Substrate Reduction Therapy


Gauchers News Contents


Prof Timothy Cox described the development and therapeutic position of substrate reduction therapy and the first drug (Zavesca) of its type to receive marketing approval at the UK Conference held on 30 November 2003 and at the Dutch Conference held on 26 October 2003.


The deceptively simple concept of replacing the function of a missing component such as a hormone (insulin) and enzyme (eg glucocerebrosidase) has had spectacular success in medicine, said Prof Cox. Enzyme replacement therapy in Gaucher disease has attracted much attention and clearly merits great acclaim as a therapeutic success in modern medicine.

Substrate deprivation therapy has the potential to complement existing treatments for lysosomal storage diseases of which Gaucher disease is the most common. It provides an additional arm of therapy by reducing the formation of the storage material which is responsible for the disease.

Reducing the rate of production enables the residual activities of the patient's disabled lysosome system (the focus of the disease) to dispose of the toxic molecules that have already accumulated.

At present, several compounds which can interfere with the formation of the substrate that accumulates in Gaucher disease and a few related lysosomal diseases, are being evaluated. Some show promise to improve the outcome for patients with Gaucher disease and related disorders and to complement existing enzyme therapies. Again Gaucher disease has been a lead for clinical research in this fascinating field.

Zavesca (miglustat)

Hitherto, the greatest experience has been with Zavesca (miglustat, previously OGT 918), now licensed in the European Union for use by patients with mild to moderate Type 1 Gaucher disease for whom enzyme replacement therapy is not suitable. The drug is also approved in the USA.

Addressing some of the unwanted side effects of Zavesca, Prof Cox said that the diarrhoea experienced was in most cases easily overcome. Any tremor (shaking) was also transitory and he likened its character to that experienced after drinking too many cups of coffee. When the drug was stopped, the tremor went away and in any event resolved in nearly every case when the treatment continued.

A very few patients taking Zavesca in clinical trials had developed burning pain and tingling in their hands and feet associated with loss of conduction of nervous impulses in the nerves supplying these parts of the body. This condition is known as peripheral neuropathy.

Prof Cox felt such an occurrence would be extremely rare in Gaucher disease but he was personally con-vinced that the two established cases he knew were directly related to the drug. The neuropathy occurred late in the trials and in both instances was improving on withdrawing the drug.

Clearly it is necessary to look out for the occurrence of peripheral neuropathy in patients now taking Zavesca and rigorous protocols of surveillance have been insisted upon by the European authorities both in patients receiving the drug and to check on the occurrence of neuropathy in Gaucher patients generally.

Prof Cox said that there were instances of neuropathy in patients not taking Zavesca and a multi-site survey was being planned by Actelion Pharmaceuticals, which took over marketing responsibility from Oxford GlycoSciences, to determine the natural occurrence and features of neurological impairment in a large unselected group of Gaucher patients.

These studies would clearly be very important and were an excellent set of measures to resolve potential anxieties about the safety profile of Zavesca. Actelion has worked hard with doctors in the field on this area.

Prof Cox said that he considered the neuropathy to be a rare unwanted effect but one that required the monitoring outlined to ensure the safety of this licensed drug.


Gauchers News Contents

Source: Gauchers News March 2004.
© Copyright Gauchers Association 2004.