Therapy (2007)

Allan Muir
Category: Archive
September 5, 2007

Enzyme Replacement Therapy for Pompe Disease: Expert Opinion from a Leading Pediatrician

An interview with Dr Ans van der Ploeg, MD, PhD, Erasmus Medical Centre, Rotterdam
By Allan Muir, Chairman, International Pompe Association


It is now over ten years since the research team in Rotterdam, led by Dr. Arnold Reuser and Dr. Ans Van der Ploeg, proved the principle of Enzyme Replacement Therapy for Pompe Disease in their laboratories at the Erasmus Medical Centre, Rotterdam, the Netherlands. Since that time the Pompe community has watched as industry attempted to apply that research to create a marketable therapy. It was very much like a very slow running movie that had us teetering at the edge of our seats, chewing fingernails and hiding behind the sofa. But, as with most blockbuster thrillers, we were finally presented with a fantastic conclusion as both the FDA and its European equivalent, EMEA, gave market approval to Myozyme; Genzyme’s enzyme replacement therapy for Pompe Disease. Approval in Europe was given in March 2006 for infants, children and adults to be prescribed the therapy, despite the fact that convincing results were only available from the infantile trials.

Enzyme for the earliest trials was extracted from the milk of transgenic rabbits, manufactured by Pharming in Belgium. Subsequently Genzyme used a biologic process (recombinant DNA technology) to derive human enzyme from cells of Chinese Hamster Ovaries (CHO). For a time the manufacturing was licensed to Synpac but, after a disastrous period of wasted batches of unusable enzyme, Genzyme developed an in-house manufacturing facility to produce the enzyme to their exacting standards. The manufacturing process started in small batches and as the project evolved, it was scaled up from 90 litre, through 160 litre to eventually 2000 litre bioreactors. This final stage was intended as the commercial product although the FDA has thus far only approved the 160 litre process for patients in the US. The rest of the world is using enzyme from the largest bioreactors currently approved for use in 33 countries.

Dr van der Ploeg has treated Pompe patients of all ages, from the earliest transgenic trials to the present day, and has gained a phenomenal wealth of experience; she is indeed a world leader in the treatment of the disease. Over the years she has treated patients with most if not all of the ERT variants but most recently has been treating her patients with the commercial (2000l) product in Europe. For over two years that enzyme has been the subject of two major clinical trials; the Late Onset Treatment Study (LOTS) and a small trial of 5 juvenile patients, the Mini-LOTS.

Given her vast experience and the fact that commercial Myozyme has been available to patients now for up to 18 months, I thought that it would be a good idea to interview Dr van der Ploeg to try to find answers to a few simple questions about how the commercial therapy is being received.

Questions and Answers

Q1 I first heard of your work at a UK conference in 1993, but when did you first start research into this disease and how many Pompe patients were you seeing at that time?

A1 I have been involved in research on Pompe disease since 1985. Development of enzyme therapy as you have indicated has always been one of our main interests. Since 1999 we have treated patients with Pompe patients with enzyme therapy. We started with 7 patients who were initially treated with recombinant human alpha-glucosidase form rabbit milk. Later we have treated patients with various species of the CHO enzyme that were produced during the developmental process in varying doses. During this developmental process we have also treated patients with the 160 litre product, currently approved by the FDA as the commercial therapy in the US.

Q2 And how many Pompe patients do you treat now, at the present time?

A2 At present 50-60 patients including infants, older children and adults receive this drug in our hospital.

Q3 Of those patients, how many of them will have been treated with Myozyme produced from the larger scale, 2000L bioreactor process in Allston, Massachusetts?

A3 Currently all our patients receive Myozyme from the large-scale reactor, because this is the product that is supplied commercially to Europe, including The Netherlands.

Q4 Of all the ERT variants that you have experienced, would you say that any of them noticeably outperformed or underperformed the others (in terms of safety or efficacy)?

A4 For me it very difficult to compare the efficacy of different enzyme species we have used, because there were no comparative clinical studies performed.

Q5 Concentrating on the European commercial product prescribed to your patients (I realize that you cannot make observations of the LOTS trial), what is your overall impression of the safety and efficacy of the therapy?

A5 The longest experience we have with the 2000 litre material is that from an open label study we have conducted together with Genzyme in 5 children ranging from 5 to 15 years of age. This study started in the beginning of 2005 and these patients have received the 2000 l material from start. We have recently analyzed the 2 year follow-up data of these patients. The drug was tolerated well by the patients. In fact there were no infusion associated reactions during the study period. The recent analysis shows significant benefit of the therapy and we are currently preparing to publish the results.

Q6 Is there anything you could add to that about the 50–60 patients that you are treating with Myozyme outside of a trial setting?

A6 What I can say about the patients receiving the 2000 litre product is that it is generally well tolerated.  It is difficult for me to speculate on the clinical effects of the 2000 litre product compared to the 160 litre product. For the 5 patients in the mini LOTS I am sure that there are clinical effects. For the other patients the period is too short to draw final conclusions.

Q7 I am aware that a small number of patients have experienced reactions to the therapy. Have you had to deal with any severe reactions to commercial Myozyme, and how have they been managed?

A7 Only a small minority of patients experience infusion associated reactions and these are generally well manageable. Two children had a more pronounced infusion associated reaction, but the symptoms subsided after adaptation of the infusion rates and administration of pre-medication.

Q8 Have any patients known to you stopped therapy completely because of an infusion reaction?

A8 No. But recently we had one adult patient who had some unspecified symptoms during his infusions. We decided together with the patient to stop the infusions after infusion 9, but this was more decided on base of lack of motivation of the patient since start of therapy (for example, he did not show up for his first infusion) than that we couldn’t manage the infusion associated symptoms. This was really an exception. Overall patients are very eager to receive the enzyme and rarely miss an infusion.


Ans, on behalf of the Pompe community I thank you very much for taking time out of your busy schedule to give such reassuring answers to my questions.  We will now look forward to forthcoming reports on mini-LOTS and also the results next year from the late-onset trial – LOTS.

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