Different Aspects of Enzyme Replacement Therapy

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Dr Ari Zimran travelled from the Gaucher Clinic at the Shaare Zedek Medical Centre in Israel last September 1995 to participate in the European Lysosomal Diseases Workshop held in Cambridge. He also gave a talk to 30 members of the Gauchers Association in London. This is a summary of this talk:

'It is my intention to discuss several aspects of enzyme replacement therapy for Gauchers disease,' said Dr Zimran, 'particularly since many sufferers in the UK receive low dose therapy as they do in Israel, which protocol was initially originated by Dr Ernest Beutler of the Scripps Clinic in California.

'Today there are more than 300 patients in my Jerusalem Clinic, of whom about 85 are being treated with either Ceredase or Cerezyme. Overall in Israel there are currently about 110 patients on therapy.'

Dr Zimran said that there were five main aspects to his talk:

Bones and Low-dose Therapy

'Gauchers patients with documented skeletal involvement have shown subjective and objective improvement after receiving low-dose Ceredase,' stated Dr Zimran. 'In our experience of 13 patients with severe skeletal involvement receiving low-dose Ceredase for 24 months, seven patients described considerable reduction or complete disappearance of pain, and most showed a significant increase in cortical bone thickness, a measure we use to demonstrate an increase in net cortical bone mass with therapy. Only one patient developed new avascular necrosis (bone damage) after 2 years of therapy yet she also demonstrated increased cortical bone thickness and improvement in bone densitometry. Thus, the clinical (subjective) situation may conflict with objective findings, which is true in all dosing regimens (routines).

'Bone response lags behind haemoglobin, platelets, spleen and liver, but just as these latter parameters respond to low-dose Ceredase along the same continuum (lines) as the high-dose, bone improvement may also be demonstrated with low-dose treatment within the same time-frame as high-dose. Therefore the results of other researchers using high-dose therapy cannot argue against the use of low-dose therapy for Gauchers patients with skeletal involvement.

'Clinical evaluation of bone disease in Gauchers disease remains difficult. Unfortunately, quantitative chemical shift imaging (the sophisticated equipment needed to assess it) is not available in most medical centres world-wide and further studies are required to confirm its clinical relevance.


'Early presentation of signs and symptoms of Gauchers disease is a hallmark of more severe disease. Hence, children were among the first to be put on therapy in Israel,' said Dr Zimran.

'We have assessed 18 children who have been treated with Ceredase for 9 months to 4.5 years. Their average age was 6.5 years at the start of therapy. Three of the children are Arab with Type 3 disease; whilst two Arab and 13 Jewish children have Type 1 disease. None is splenectomised.

'All began with the low-dose therapy, 2.3units/kg of bodyweight/3 times a week. Five required increased doses for variable periods. Today most are on home therapy with improved haemoglobin and platelet counts and with variable reduction in spleen and liver volumes as assessed by ultrasound evaluation.

'Seventeen showed evidence of growth retardation when first assessed but 8 have shown growth spurts since the onset of therapy. Oculomotor apraxia (abnormal eye movements) was unchanged in the Type 3 patients. There were no adverse effects although two children developed antibodies. Psychological function and school performance were high and there was no deterioration even in Type 3 children. Intelligence score of Type 1 children was in the high normal range.

Home Therapy

'Forty out of 73 of my patients are receiving home therapy. Aged between 2 and 49, 31 are infused through a portacath and nine through a vein. A portacath is a device permanently inserted under the skin on a patients chest with a tube which goes into a peripheral (surface) vein. Ten patients infuse themselves, eight are infused by a parent, seven by a spouse and 15 by others,' said Dr Zimran.

Although a few patients had experienced problems with their portacath, through infection, obstruction or poor surgical technique, he considered them worthwhile. He stressed home infusions were safe, feasible and convenient. No serious complications had arisen and there was a substantial reduction in hospital costs.

Clinical Trial with Cerezyme

'In May 1994 the Food and Drug Administration of the US government approved Cerezyme based on initial trials at the National Institutes of Health in Bethesda and the Mount Sinai Medical Centre in New York, comparing the safety and efficacy of the recombinant enzyme (Cerezyme) with the placental enzyme (Ceredase), both at the high-dose schedule of 60 units/kilogram body weight/every two weeks.

'There were no significant differences between the two groups other than formation of antibodies, which in the Ceredase group was twice that of the Cerezyme group, but nonetheless did not interfere with the therapeutic response.

'At the Shaare Zedek Medical Centre in Jerusalem, the low-dose trial of Cerezyme, 30 units/kilogram body weight, was compared at two frequency schedules: once every 2 weeks and 3 times a week. There were no significant differences between the groups except for liver reduction which was greater in the first six months in the group with more frequent administrations.


'We are fortunate that in 1995 a New Health Bill was passed in Israel giving special funding for four chronic diseases including Gauchers disease.

We also have new criteria to decide who should begin treatment. However just one of these reasons is sufficient:

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Source: Gauchers News March 1996.

© Copyright Gauchers Association 1996.