Gauchers News Contents
Prof Ari Zimran has observed 500 patients at the Gauchers Clinic in Jerusalem, Israel and spoke at the 5th Conference in November 2002 about the changing pattern in the symptoms of Gauchers disease and the new substrate balance therapy (OGT 918) which is currently on trial.
'The success of Ceredase and then Cerezyme enzyme replacement therapy has stimulated research into new treatments and created a changing pattern of symptomatic disease,' said Prof Zimran.
He described a boy who he first saw eleven years ago. He was then two years old and had Type 3 Gauchers disease but his only neurological symptom was the characteristic abnormal eye movement.
'This boy has just celebrated his 13th birthday and barmitzvah for which he had to prepare much work. He also attends normal school. This would not have been possible without enzyme replacement therapy.
'Children with Gauchers disease who start treatment now will not have such severe symptoms as those who started treatment ten years ago when irreversible skeletal complications had already occurred.
'The disease is now diagnosed and treated earlier when the symptoms have not developed so far. If patients are treated earlier when they have a lesser degree of abnormality, their improvement will be seen as less pronounced when expressed as a percentage change from baseline (when the patient was first assessed). This point must be remembered when comparing the results with new drugs to those originally reported with Ceredase and Cerezyme.
'OGT 918 is a small molecule which prevents some of the glucocerebroside (fatty substance) forming in the first place. This enables the patient's own enzyme to get rid of the rest thus creating a balance.
'The drug was originally developed to treat HIV and 120 patients received OGT 918 at ten times the dose given to patients with Gauchers disease. Although, unfortunately the drug was not effective for HIV patients, the clinical trial provided huge safety data that, along with the biological rational and results in animal models of similar storage diseases, convinced us to join the clinical trial for Gaucher disease.
'Twenty eight patients with Gaucher disease were enrolled in the first clinical trial between March and December 1998 in four centres in the UK, Holland, Czech Republic and Israel. Patients were aged 18 or over and their ages ranged from 22-69. The drug has been taken as a pill three times a day.
'During this trial, which was a 12 months study, the patients' spleens decreased in size by an average of 19% and their livers by 12%. Although their chitotriosidase activity (a specific and sensitive marker for Gauchers disease) progressively decreased, their haemoglobin and platelet counts did not increase significantly.
'Eleven (39%) of the 28 patients who took the drug suffered from weight loss (defined by a greater than 5% reduction in body weight) and most of them (79%) had diarrhoea which improved spontaneously within several weeks or responded to over the counter treatment.
'The results of this trial, which were published in the Lancet in April 2000, provided the proof of concept and led to the design of an additional two clinical trials.
'After 12 months, 22 patients remained on the trial and it was decided to extend the trial for another 12 months. 18 of the 22 patients agreed to do this and after 24 months 14 patients remained on the trial (the same 14 patients have also finished 36 months using the drug but the three year data have not yet been analysed). In these 14 patients, there was a further reduction in spleen and liver volume by an average of 26% and 14% respectively.
'The haematological parameters showed a statistical improvement after 18 months with significant increase at 24 months but still the platelets improvement was shown to be inferior to the results achieved by enzyme replacement therapy.'
Prof Zimran surmised that perhaps the way forward in patients with severe thrombocytopenia (very low platelets counts) would be to receive enzyme replacement first before going onto substrate balance therapy.
'Of four patients who stopped during the second year, two suffered from peripheral neuropathy (burning, numb sensations in the hands with characteristic abnormalities in neuro-physiological tests) and there was con-cern by the principal investigator that led to the withdrawal of the other two.
'After 24 months, there was reduction in the report of diarrhoea with only two of 14 patients reporting this side effect (14%) and the weight loss improved in the majority of the patients with only three (21%) still having more that 5% reduced body weight). There were no additional cases of peripheral neurology.'
Prof Zimran described the second clinical trial carried out in South Africa and Israel by Dr Rene Heitner and by Dr Debby Elstein and himself, respectively, in which 18 patients (10 in Johannesburg and 8 in Jerusalem) took a reduced dose of the drug: 50 mg given three times a day.
Seventeen patients completed the 6 months trial. The results showed half the improvement of patients taking the full dose (100mg three times a day); the hematological parameters were not boosted but the patients showed no reduction in the amount of side effects.
It is therefore recommended that 100mg should be the preferred regimen of treatment with OGT 918.
A third trial has been carried out comparing OGT 918 to enzyme replacement as maintenance therapy. This study enrolled 36 patients with Type 1 Gaucher disease who have been on enzyme replacement therapy for a minimum of two years: These patients were randomised into three groups: 12 patients took OGT 918, 12 took both and 12 took enzyme replacement therapy alone.
After six months, 29 out of the 36 patients (80%) elected to continue with OGT 918 alone. The results of this study will be released later this year.
The results of all three clinical trials have been included in the submission of the drug OGT 918 to the relevant regulatory bodies for approval in the USA and Europe.
Prof Zimran posed the question: Assuming OGT 918 gets approval, who would benefit from which treatment: enzyme replacement therapy or substrate balance therapy? He suggested the following scenarios:
Enzyme Replacement Therapy
However the disadvantages of enzyme therapy are:
OGT 918 as Oral Substrate Balance Therapy
The disadvantages of substrate balance therapy are:
Prof Zimran said that ten and even five years ago, gene therapy was predicted to be available in five years' time. Unfortunately the view is that effective gene therapy still remains at least five years into the future.
'Exciting times lay ahead. Competition amongst drug companies is good and the next 10 years should see more advances.'
Gauchers News Contents
Source: Gauchers News March 2002.
© Copyright Gauchers Association 2002