Genzyme Medical Director Answers Questions on Ceredase


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Dr Richard Moscicki has been Medical Director of Genzyme Biotherapeutics, the makers of Ceredase enzyme replacement therapy, for the past year. He came to London from his base in Boston, USA, at the end of April 1993 and agreed to be interviewed for the Newsletter. Dr Moscicki previously taught Clinical Immunology at Harvard Medical School and practised at the Massachusetts General Hospital for 13 years.

How many people are now receiving Ceredase?

About 800 patients are currently on Ceredase, about 600 in the US. The first, a little boy in Washington DC, started treatment seven years ago. Twelve patients from the original trial which started in 1990 have now been on treatment for three years. When Ceredase received FDA (Food and Drug Administration) approval in the US in April 1991, about 70 patients were already on treatment.

What are Genzyme's views on the high dose, low frequency regime compared to the low dose, high frequency regime which most UK patients are on ? Genzyme, of course, earns more money by selling Ceredase on the high dose regime.

Genzyme does not advocate any one treatment regime. I believe it is more important that patients who are symptomatic from Gaucher disease receive treatment. Ceredase has been shown to have a beneficial effect with almost all doses and schedules that have been examined. Our greatest experience so far has come from patients being treated on the high dose 60 u/kg/bw (units per kilogram of body weight) regime administered every two weeks. We have data on 250 patients treated on this regime and it works well. Once a satisfactory response is achieved, patients have undergone progressive decreases in dose to 30 u/kg/bw and many to 10 or 15 u/kg/bw for maintenance of the response achieved.

We also know that patients have improved on lower doses. Dr Beutler has used a regime of 2.3 u/kg/bw administered three times a week. This regime has also been used in the UK and Israel and patients have improved.

In addition Dr Grabowski has shown improvement in patients treated with 30 u/kg/bw every two weeks.

The rate, extent and frequency of improvement may differ among these regimes as it has been very difficult to make meaningful comparisons due to the heterogeneity of the patients.

Whether administering the enzyme with high frequency, that is three to four times per week, truly increases the efficiency or 'activity' of the enzyme is still in question and not adequately proven. It is difficult to say whether or not a patient might not do as well on the same total dose given less frequently. Of note, patients who begin with higher doses, after a period of time, will come down to a similar total dose.

The primary evidence of bone improvement has been gathered in patients on the higher doses; it may occur at lower doses but that remains to be demonstrated. I believe that care of patients must best be individualised and that, ultimately, the physician needs to evaluate each patient and their problems and choose the best dose or schedule for that patient.

I understand that proteins (and Ceredase is a protein) are 'sticky' and adhere to glass and plastic. Is there a danger that low doses will get 'lost' in 100ml saline bags and long infusion sets? Have you tested to see how much Ceredase is lost in this process?

Proteins, to a small degree, are absorbed by plastic and glass. A small amount can stick to the sides of the bag and infusion sets and this amount will be the same whether the total amount of units is large or small. Thus a larger percentage of a small dose will stick in comparison to a bigger dose. The presence of albumin in Ceredase reduces this problem. This problem has been evaluated and is believed to be minimal.

ADVERSE REACTIONS

How many adverse reactions have been reported and what were they?

Genzyme learns about adverse reactions in two separate ways: through spontaneous reporting by doctors or patients if something occurs, or through the ICGG (International Collaborative Gaucher Group) programme. All physicians who prescribe Ceredase are asked to join the ICGG and they are asked to send results on the patients' progress and any adverse effects. We also look through medical literature for any side effects. Genzyme reports any adverse effects to the FDA every quarter.

The number of adverse reactions reported have been small and most have been mild, self-limiting and easy to manage. We only know about two patients who have interrupted treatment because of side effects.

To date, adverse effects have been reported in 91 patients although probably only 42 had reactions related to Ceredase, 18 were possibly related and 31 were not related. Many adverse reactions not related to the treatment appeared to be caused by Gaucher disease itself.

Some reactions were related to the route of administration including discomfort, itching, bruising and swelling or sterile abscess at the site of the vein puncture.

Symptoms suggestive of allergic reactions have occured shortly after or during infusion and included itching, flushing, hives, chest discomfort and/or breathing symptoms, swelling of the lips or tongue and possibly the throat (although not bad enough to interfere with breathing), stomach cramps and nausea. Two patients had momentary loss of consciousness. All the patients with allergic reactions recovered quickly.

Treating these patients with antihistamines and using a slower rate of infusion has allowed continued use of Ceredase in most patients without further significant reactions.

Other non-allergic reactions have included fever, chills, abdominal discomfort, nausea, vomiting or diarrhoea. Additional reactions reported only once or twice have included fatigue, weakness, headache, lightheadedness, mouth ulcers, unusual smells, backache and swelling of the feet. The exact relationship to Ceredase of these symptoms has not been established. Most of these reactions did not require medicine or a change in treatment.

Do you test for antibodies and do these antibodies cause reactions?

Ceredase is a protein. It is common for a proportion of patients receiving protein treatments to develop anti-bodies to the protein. We recommend assessment for antibody to Ceredase be examined every three months for the first year of treatment with a base-line examination performed before treatment begins. Genzyme has received samples from over 700 patients for antibodies. Approxim-ately 13% of 509 patients treated clinically over time and tested have developed antibodies to Ceredase during the first year of therapy. The average time to developing the antibody was about 5 months.

Of those who developed antibodies, 90% developed them within 9 months of starting Ceredase. To date, no patients have been shown to develop antibodies if they had not done so within the first year of treatment.

The majority of patients with antibody showed decreasing amounts as treatment continued and 35% at present returned to normal test levels.

Having antibodies does not necessarily mean having side effects. Of the patients with antibodies, only about 25% had allergic symptoms. In addition, only about half the patients with an allergic reaction had detectable antibodies.

Genzyme has also checked whether antibodies interfere with the Ceredase enzyme activity in patients. We compared patients with and without antibodies and found there was no difference on the response to improvement in haemoglobin, platelets and other markers.

RESEARCH TRIALS

What trials and research projects are being carried out worldwide?

Several independent studies are taking place in universities. I can list:

RECOMBINANT ENZYME

You mention the recombinant enzyme. When will it become available for general patient use?

Genzyme hopes to receive FDA approval over the next year. We hope to receive approval of our new manufacturing facility in 1994/95 so that recombinant enzyme will be available in 1995.

Will the production of the recombinant enzyme bring the cost of Ceredase down?

We don't know yet what the price will be. It is too early to accurately predict the cost of manufacturing.

RISKS

How safe is Ceredase using human placentas? Do you have a regular update process to test for newly discovered viruses?

The manufacturing process includes several steps validated to inactivate panels of test viruses. In addition before release we test every lot for HIV-1 and Hepatitis B. Our one concern is of slow growing viruses but we feel that there is an incredibly low chance of such a virus occuring.

PREGNANCY

Does your data include information on women who have been on Ceredase and then go on to become pregnant and have babies?

We know of one woman who was receiving Ceredase and then discovered she was pregnant. Ceredase was stopped but restarted at about 6 months of her pregnancy. She has had a healthy baby boy.

Several other women have become pregnant and have stopped Ceredase, one of these has also had a healthy baby (we have no data on the others).

We also do not have any data on women who have stopped Ceredase in order to become pregnant.

It is not known whether Ceredase can cause foetal harm to a pregnant woman or can affect reproductive capacity. It is also not known whether the enzyme is excreted in human milk so caution should be exercised if Ceredase is given to a nursing woman.


Source: Gauchers News September 1993

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