Introduction of Cerezyme


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Cerezyme is the recombinant, synthetic version of Ceredase, the enzyme replacement therapy for Gauchers disease produced by Genzyme Therapeutics. Martin Cortvriend Genzyme's UK General Manager, spoke about the new drug at the 1997 Conference. In introducing Mr Cortvriend, Jeremy Manuel said: 'It must not be forgotten that it was Genzyme, and in particular its Chief Executive Henri Termeer who made the commitment and investment to develop enzyme replacement therapy ten years ago. We are indeed grateful they had the conviction and foresight to produce the drug.'

Ceredase has been very successful in treating Gauchers disease and 2,000 patients are using it world-wide,' said Mr Cortvriend. 'It has a very good safety record. Genzyme has monitored all potential serious events and only a small proportion of patients have shown a hypersensitive reaction like flushing or rashes: in these cases, an anti-histamine has solved the problem.

Originally we thought we could not produce enough Ceredase to satisfy the demand. Fortunately recombinant DNA technology led to Genzyme developing Cerezyme over a relatively short period with the results of the first clinical trials published two years ago.

However introduction cannot occur world-wide overnight. Regulatory aspects have to be approved: by the MCA (Medicines Control Agency) in the UK and the FDA (Food & Drug Administration) in the USA.

The company needs to demonstrate it can make the product. Then it must show the drug is effective and com-parable to Ceredase. We have found the two products are alike and adverse events are similar. We also have to show that we can produce sufficient quantity and the production processes are properly validated and approved.

Commitment
Henri Termeer made a commitment to the Gauchers Association last Novem-ber that the new drug will be introduced to all patients by the end of 1997. We now feel confident we can honour that commitment by initially supplying a small number of patients and the rest by the end of the year.

We have permission from the MCA to import the drug on a named patient basis and we have applied to CPMP (Committee for Proprietary Medicinal Products) to get approval for market-ing the drug in the European Union. We hope to get this towards the end of the year. The drug is currently used in a few centres in Sweden, parts of the United States and Israel.

'The manufacturing process is complicated. Initially the drug was produced on a pilot scale in a bio-reactor which could be described as similar to a small brewery. This was then scaled up in two stages until a 2,000 litre bioreactor was built in Boston. This should provide enough drug for everybody. We have scaled up but are not at full speed. We shall continue to produce Ceredase on a limited scale to ensure no shortages .

Genzyme has discussed how the drug will be phased into the UK with Prof Cox, Dr Mistry and Dr Vellodi. Children will be our first priority. The drug prescribed in the UK will come from the 2,000 litre bioreactor.'

Mr Cortvriend was asked whether economy of scale in the new product would reduce the cost of the drug. He replied that the two drugs would be the same price.

Difference between Ceredase and Cerezyme
A fundamental difference between the two drugs is that Cerezyme is a powder whereas Ceredase is a liquid. This means there is one more step in making up the infusion. Sterile water will need to be added to the bottle to make the powder into a liquid. A re-constitution and administration guide on how to dilute the powder is available. However Cerezyme will still have to be kept in a fridge and treated with care.

Cerezyme is made in a sophisticated bio-pharmaceutical plant. At the heart of the process is cell-culture which harnesses the power of individual Chinese Hamster Ovary (CHO) cells that have been genetically modified to produce human glucocerebrosidase (GCR). The code that instructs a cell to produce human GCR is inserted into the CHO cells. As a result, each CHO cell is identical and is a mini factory producing tiny amounts of GCR.

The CHO cells start their lives in small culture dishes where they begin the process of doubling. When the population of CHO cells is large enough, they are transferred into 2,000 litre stainless steel vessels called bioreactors where eventually more than 20 trillion cells will spend their lives producing human GCR. Sophisticated systems maintain the cells. Special nutrients, growth factors, minerals and oxygen are constantly fed to the cells. The vessels are kept at a constant 98.6 degrees, monitored by a complex computer system.

More than 100,000 litres of nutrient rich liquid (media) is used to sustain the cells. As the media is fed into the bioreactor, excess media is harvested into stainless steel tanks. This old media is saved because it is from this that minute amounts of GCR that make up Cerezyme are collected.

Once enough of this bulk liquid is collected, a complex purification process begins during which the GCR is specially modified to correctly and efficiently target macrophages. Once completed, the GCR is formulated and the drug is freeze dried.


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Source: Gauchers News June 1997

© Copyright Gauchers Association 1997