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The results of a multinational clinical trial of a new drug OGT 918 (also known as substrate balance therapy) which could possibly be used instead of or together with enzyme replacement therapy were published in the medical journal, The Lancet on 29 April 2000. David Lewis reports.
Twenty eight adults in four countries (The UK, Netherlands, Czech Republic and Israel) were enrolled in the trial which started in December 1998. Six (21%) patients had previously received enzyme replacement therapy but none had any while on the trial. Seven patients (25%) did not have spleens - the rest did. The results refer to a 12 month period although some patients have been on treatment with OGT 918 for nearly 18 months.
OGT 918 is given as a tablet. Patients were started on 100 mg oral OGT 918 three times daily.
The trial measured spleen and liver volume by computed tomography and MRI at the outset and after 6 and 12 months. Biochemical and haematological blood tests were taken monthly, including chitotriosidase activity (a sensitive marker of Gaucher's disease activity).
Patients' liver volumes at the beginning of the trial were 1·1 to 2·7 times normal. Spleen volumes were 5·1 to 24·8 times normal.
After 12 months mean liver volumes were lowered by 12%. Mean spleen volumes were lowered by 19%. Mean chitotriosidase concentrations fell by 16·4%.
"Despite the clear improvement in spleen and liver volumes, as well as the progressive decline in chitotriosidase activity, haemoglobin concentrations and platelet counts did not increase significantly in all patients," the article explains. It is not known why OGT918 gave significant spleen and liver reduction but only showed a slight effect on these blood parameters.
Eighteen patients have continued to take the drug after the end of the 12 month period. "They continue to show improvement in organ volume and haematological variables," the article states, although no details are given.
"The most frequent adverse side effect was diarrhoea, which was reported in 79% of patients shortly after OGT 918 treatment was started. This effect improved spontaneously within several weeks or responded to treatment with loperamide or codeine phosphate."
"Six patients withdrew from the study - two because of gastrointestinal complaints, one because of concern about pre-existing pulmonary hypertension, one for religious reasons, one to have a child, and one because of an unrelated serious adverse event, hepatic venous thrombosis, 3 days after starting OGT 918."
Two other patients have had to leave the study after the initial 12 months because of tingling and numbness in their hands and feet (paraesthesiae). One of the two patients improved during follow up.
The safety of the drug has been assessed in earlier trials on HIV positive patients in 1994 and 1995 who were given up to 3g daily. However the drug was not successful in treating them.
Dr Chris Moyses, Clinical and Development Director, Oxford Glycosciences, the company which has the rights to this compound, said "Further trials are underway and fully recruited to define how OGT 918 can be used by physicians to treat patients with this disease. These include a study where patients currently receiving enzyme are randomised to continue on enzyme, switch to OGT 918 or receive both in combination." This trial is taking place in Israel.
Another trial is taking place in South Africa where a lower dose of 50mg oral OGT918 three times daily is being given. No results have yet been published on this trial.
The Lancet article concludes: "Further exploration of OGT918 is warranted in patients with glycospingolipid diseases. This compound could be used as monotherapy and has additional potential as a treatment combined with enzyme replacement.
"Combination therapy could lead to significantly lower doses of each drug being required to benefit patients with Gaucher's disease.
"Our data show that OGT 918 reverses many of the clinical signs and laboratory hallmarks of Gaucher's Disease and may broaden the options for treating this family of metabolic diseases, including those with involvement of the nervous system."
Link to Lancet
Correspondence in a subsequent issue of the Lancet regarding the paper
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