Dr J C Pompe

Dr J C Pompe
Discoverer of Pompe disease

About this blog

What you can read here is the story of the development of enzyme replacement therapy (ERT), the first effective treatment for Pompe disease. It is an incredible story, rich with events, characters and science. Above all, it is the story of an international community of scientists, doctors, patients and companies, working together towards a common goal.

It is not a story that features in Geeta Anand's book, The Cure , or the film based on it, Extraordinary Measures despite the fact that they are ostensibly about the development of ERT for Pompe ( you can link straight to the relevant articles covering the events described in the book and film here, here and here).

This blog represents my small attempt to set the record straight and to give the story back to its rightful owners - the international Pompe community. It is written here in roughly chronological order i.e. you'll need to start at the bottom of the April 2009 archive page and work your way up.

It is also a personal account and, although I've tried to make it as objective as possible, there is an inevitable degree of subjectivity. For that reason I have included contributions from other members of the worldwide Pompe community and would be delighted to receive more. Feedback is also welcome.

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Sunday, 27 December 2009

The rest of 1999

1999 was a waiting game. We were all waiting for the results of the ERT clinical trials. From the accounts of the various patient conferences held by national groups, we knew that things were going fairly well. But we wanted to know more. We wanted the hard data and to know what the next stage would be.

In the meantime, the patient community continued to expand. The IPA held telephone conferences of its executive (facilitated by the VSN) and soon these would be expanded to include industry representatives.

People were busy - but all eyes were towards 2000.

IPA Founding Conference part 5

Last on the IPA conference for now - though I may come back to it.

A couple of take-home messages.

Firstly, we now knew that the trials were progressing fairly well. Ans van der Ploeg's comment that they they would be celebrating 2 birthdays in the next week was a broad hint that things were going quite well but also that we should not expect any preliminary accounts of results. An optimum balance between compassion and professionalism.

Secondly, the patient representatives went away with specific goals to broaden and strengthen the international patient community. The IPA itself was to prove a durable framework for future work, particularly as a focus for dealing with industry. Special mention here must go to Helmut Erny who did the hard work of writing up a proper legal constitution.

Lastly, some archive photos courtesy of the VSN:

 (L to R: John Hopwood, Kevin O'Donnell, Ysbrand Poortman)

 (L to R Marylyn House, Gezinus Wolters, Kevin O'Donnell

Arnold Reuser and John Hopwood

John Hopwood is a good guy and a stalwart supporter of the Aussie patient group. His contributions to Pompe research are many and varied, from the first cell line producing enzyme to new approaches to neonatal diagnosis. However, I have to confess that I felt his talk at this conference - which was excellent - was somewhat over-shadowed by his enthralling account of how he resuscitated his son's goldfish.

IPA Founding Conference part 4

Here is my own contemporary account (posted on GSDNet on 7 July 1999):

There's not much that I can add to Gezinus's very good report but I'll give some of my own impressions.

It was a very intense few days, to the extent that I feel a little drained and flat right now. But it was very good - I got the feeling that there really was a Pompe's community, the different parts of which were represented at the meeting.

I should say right at the start that the VSN (Miriam and Haske) did a good job of organising the meeting - the arrangements and venue were very good.

The scientific talks were all good. I have to make a small complaint because I had to follow Maryze's talk which had made a deep impression on the audience. You could have heard a pin drop while she spoke. As she spoke for a while, I'm sure the audience must have been breathing but I didn't see or hear anyone do it. She did a first class job of impressing on the audience just why this research was so important.

Ans van der Ploeg's talk was quite positive but didn't give the definitive results. She was obviously bursting to say what she thought the trial was showing but, quite properly, only wanted to give facts not her impressions. The facts that she gave were: All 4 babies who started
the trial 5 months ago are still alive. There will be 2 birthday celebrations this week. That is obviously encouraging but while it is unusual for children to live so long after diagnosis, it is by no means unknown. Some Pompe's babies do live well past their first birthday and, in addition, these particular babies are receiving a high level of care. So, cautious optimism is the order of the day.

There was no word on extension of the trial other than 'later this year'.

Synpac are very much in the business of developing enzyme replacement therapy for Pompe's and have enormous resources to put behind this aim.  Ed Tang of Synpac made a short statement which seemed to me to be full of restrained passion (my subjective impression of course) and which left me in no doubt of  his and Synpac's commitment.  Also on the company front, Genzyme will be the company patients' groups deal with, rather than Pharming.

I don't know which of these two companies will win the race. Normally, I have an inclination to support the underdog - but in this case I don't know who the underdog is!

As regards the IPA itself, it seems to have a head of steam behind it. I wasn't 100% sure of this before the conference but I am now. We will meet again next year, and a working group was set up to  co-ordinate this and to make the IPA into a formal, legal entity. The website at
http://www.worldpompe.org will contain the text of decisions and also of the presentations given. It might take a few weeks though...

And that's it really. I've probably forgotten all sorts of important stuff so others can correct me. However, I don't think it is going too far to call it a historical occasion and I was glad to be part of it. I met old friends and new friends and even some old friends that I hadn't actually met yet, like Thomas Schaller.

Onwards and upwards..


IPA Founding Conference part 3

The conference was reported to the worldwide GSDNet audience by Gezinus Wolters. Here are his contemporary accounts (reprinted with permission):

Part 1 (posted Saturday 3 July, 1999)

As announced earlier I attended yesterday the first day of the IPA (International Pompe Association) in Naarden, Netherlands.

The conference is in a small hotel outside Naarden with conference facilities. Today the talks are mainly about the founding of the IPA itself and tomorrow (Sunday) Dr Ans van der Ploeg will report on the ongoing trials, which she leads. I will try to tell you about that too, later.

First, the atmosphere at the conference was very good, it had an exciting feeling.  No wonder, something is really happening.

A lot of faces of the names you only know from the GSDNET, all the icons of the Pompe-history (Dr. Loonen, Dr. Reuser, Kevin, the Houses, etc.). About 60 or 70 participants from all over the world (USA, UK, Netherlands, Belgium, France, Germany, Spain, Italy, India, Australia, Phillippines) and from all sectors: Industry, Universities, and Patient Organisations.

All in all there were ten presentations yesterday with a good overview of what is going on at the moment. I will not try to report on each introduction, but I will try to select the most interesting things.

There were three kinds of presentations: historical (Dr. Loonen and Dr. Reuser);reports on ongoing research (Prof Hopwood, Dr. Ausems, the Pharming people, Dr. Devlin (Synpac) and Dr. Amalfitano) and presentions from the patient (organisation) (Maryze, Kevin).

I'll skip the historic presentations, although they were both very interesting and inspiring. What is really amazing is, that this whole thing is still relatively new. Thirty years ago almost nobody knew anything about Pompe. And there is still a lot to be explained and investigated. Dr. Reuser and Dr. Looonen concluded with these things. What is really the differnce between infantile and adult forms? Why are different organisms affected? What exactly is the role of the missing enzyme (acid maltase)? We don't know.

Dr. Reuser emphasised the good relations between all Pompe researchers all over the world. Of course ther are different interests by the companies, but the academic researchers are cooperating and exchanging information very well. The presentaion of prof. Hopwood (Australia) was mainly about diagnosing. How to screen and diagnose Pompe early. Especially very, very important for the babies. For now a good indication can be gotten from a blood test (the standard Guthrie blood spots), which can be followed by a further diagnosis. So there is no viable blood test yet (but ther will be in the near future) but there are good indicative screening tests.

The presentation of Dr. Ausems (somebody called her Dr Awesome) had equally interesting conclusions. She investigated by several methods (genetic and from diagnoses) how much Pompe-patients there are. She concluded convincingly that there are a lot more Pompe patients than everybody thought earlier. Earlier number were that 1 in 100.000 (at least) people have Pompe.

Ausems concludes that here are 1 in 40.000 Pompe patients ! (about 1 in 100.000 infantile/juvenile and 1 in 57.000 adult).

So what does this mean? Is that good or bad? (I'm speaking for myself now, GW). Of course it is not good that there are much more Pompe-patients than we thought. And there is a higher chance that our children are effected. Maybe even there is a chance as high as 0,25 % (1 in 400) that a child of a Pompe-patient is effected.

But there is also a very beneficial positive effect. It may sound very cynical, but it means that there is a very much bigger market for the Pompe treatment than was estimated before and that it is much more interesting for companies to invest.  But these are all my conclusions, nothing to do with or said by Dr. Ausems, who just did a terrific job.

I come to the main dish now: the report on the ongoing research for the Pompe treatment.

Maybe you did not realise (I did not) but there is a three horse race going on to reach a admitted Pompe drug first. Or rather it is a two horse race with a third black horse as a very promising outsider.

Of course we know the first horse (leading by a length at the moment). A Dutch horse partly American-owned: the Therapy developed by Pharming and Genzyme.Pharming is producing the medicine, the enzyme alpha glucosidase (acid maltase), in the milk of transgenic rabbits. We passed animal tests (very positive results), phase 1 (safety tests on healthy people) and we are now in the middle of phase 2 (trials on 4 infantile and 2 juvenile patients). Dr. van der Ploeg will hopefully say more on Sunday, but according to reports now everything is going as well as can be expected. But it is too early for solid conclusions as yet. Pharming is expanding facilities at the moment, which means that they are building facilities for more rabbits and purification etc. All Pharming people reported that everything on the technical side is going well and that maybe (depending on the admission, the licensing, the approval) the medicine could be available mid-
or late 2000.

The second horse has good qualities too. And keeps the first horse very alert, of course. It is the company Synpac, represented by Dr. Blythe Devlin. Synpac is supported by Dr. Y.T.Chen from Duke University.

Synpac produces in fact the very same medicine but in a totally different way. It is a small company but backed up financially by a very heavy pharmaceutical company. So they do not perform the research themselves but do this by contract research. Which has advantages (little investment) but also disadvantages (contracts and lawyers I imagine). Also the way of manufacturing is very different. Synpac uses no animals, but fermentation. The medicine is brewed in a jacuzzi-like soup. I have no opinion on the relative qualities of both manufacturing processes, but Pharming/Genzyme is undoubtedly ahead at the moment.  Synpac however will also try to perform a trial with infants this year and juvenile/ adult trials next year. Problems with formulation (which means stable storage as I understood) are overcome, said Dr. Devlin, but she did not tell a lot more.

A disadvantage of the fermentation process seems to be (somebody told me) the low concentration of the difficult purification therefore. But there will be advantages too, no doubt.

And then, finally the last, black horse.Introduced expertly by Dr. Amalfitano from Duke University, NC, USA. Also cooperating with Dr. Y.T.Chen. This horse follows a different route, so it is not really the same race.

Pharming/Genzyme uses genetic modification in animals to produce the medicine (enzyme) but does not change any genes in the patient. Dr. Amalfitano and his people are working on a real gene therapy for the patient. The idea is there for years, but maybe there is a breakthrough coming soon! The point is not, how can you change genetic material, but how can you get the changed material in the muscle cells. Dr. Amalfitano explained a few tricks to do this. First the
genetic material need some transportation (vectors). This is found in viruses. You bring the material in relatively harmless viruses and infect the patient. The viruses are then mostly stored in the liver and afterward they produce a lot of the enzyme which is secreted in the blood.

So the viruses are not needed to go to every muscle cell,;the enzyme does, just like in the other two therapies. So there are some similarities between these therapies. There are still a lot of problems to overcome. For instance, the virus infection must, to be effective, last as long as possible. And afterward, once the infection is over, you can not use the same virus again, because the patient has produced antibodies.

Dr. Amalfitano was very convincing in the potential strength of this therapy. So probably this black horse will not win this race, but on the long run they may have a potentially very effective therapy. We will see and follow this with great interest, regardless which one of the other two wins the race.

In the end of the afternoon (our) Maryze and (our) Kevin gave their presentation.Impressive both and that is not just my opinion.

Maryze emphasized the importance of initiatives of patients and patient organisations. They played a very, very important role in organising and stimulating research and bringing parties together.

There are three main parties: patients/patient organisations ; research (universities/ hospitals) and industry. And these parties are surrounded by  social, political and economic forces. We have to be alert always and produce publicity and counter forces with the media if needed.We must also be critical towards the power of the industry. The medication must not only be become available, it must also be affordable. (By the way, nobody was willing tospeculate about the price of the Pompe drug). Maryze concluded with a moving story about her personal emotions during the turbulent events in the last years. How can you cope with all the new expectations? What if the hope is false? What if the drug is not regenerating, but only stabilises the disease? You have to be a very emotionally stable person to handle all this possibilities and expectations.

Kevin put his personal experiences (the diagnosis and death of his son) at the begin of his presentation. He emphasised the importance of knowledge by the patients. It is really of the greatest importance that Pompe patients and a lot of physicians will be much more aware. Kevin has a lot of humor but there are two things he hates: ignorance and bigotry. Good choice, but not easy ones to correct.

I forgot a lot. One interesting thing I like to mention. Mr Andrew Curtis from Genzyme proposed to initiate to establish in different countries Genetic Centres of Excellence. These institutes (maybe connected to a hospital) could support diagnosis, treatment, education and support for Pompe patients and other comparable diseases. A bit like the existing Centers for Respiratory Support we have in the Netherlands. A splendid idea. I hope they will discuss this further to

That is it for now. Confused? Never mind, that is a good state of mind. I hope I can give you part 2 tomorrow. Kevin and Maryze and others can fill you in about the discussions today an tomorrow later.

Bye, Gezinus

Part 2 (posted Sunday 4 July, 1999)


My second report from the IPA conference could be very brief: no real news. As you know, today the only and final speaker was Dr. Ans van der Ploeg, who leads the clinical trials for the Pharming/Genzyme treatment in the Sophia Hospital.

They started the phase 2 trials with 4 babies and 2 juveniles in january/february. The patients get the medicine (the enzyme alpha glucosidase) once a week intravenously. All trials subjects are still alive and tolerating the drug well.

As could be expected Dr van der Ploeg could not give us some prelimonary conclusions other than all seems to be going well, There are no indications that the treatment is  not working. Dr. van der Ploeg is a scientist, so she refused to draw any conclusions before it is really possible. The conclusions must be made according to objective criteria, on measurements of muscle strength or pulmonary function, not on the basis of impressions etc. The first real conclusions can not be expected before the fourth quarter of this year.

It was really pitiful to watch her trying very hard not to give answers to all the questions. You could feel that she really wanted to tell us all about what was going on at the trials but she just could not. But while she was telling us again and again that she could not give us any conclusions she was always smiling !! You should have seen her, trying very very hard not to tell us a lot of things she wanted badly to tell us.Which gave us in the audience the feeling that everything is really going very very well.

There is another indication to confirm this. Two of the babies are having their first anniversary. And as you know the majority of the Pompe babies do not reach this age unfortunately.

There were a lot of questions and very few answers. Some of us were a little disappointed I noticed afterwards. I was not in the least, because I knew before that there would be no hard conclusions, and what I heard gave me confirmation and confidence that all is going (very) well. Nothing more or better can be expected at this moment.

One important question and answer was: when will adult trials start. Answer: it is not sure that adult trials will be executed. The objective is to have the drug on the market as soon as possible. If this can be done without adult trials, then these will be omitted. As Dr. Reuser said strongly: in fact the adult trials have already been started, because there is no real difference between the infantile/juvenile form and the adult form of Pompe. So way have adult trials if this would just delay the introduction of the drug.

Other people (Kevin maybe) will tell you how the founding of the IPA has come along. I got the impression that evrything in that department also went all right. During and after the lunch today we said till next time, au revoir, auf wiedersehen, arriverdecci and tot de volgende keer to a lot of nice people. Hard to believe that we did not know them personnaly three days earlier. I am convinced that the conference will later show to have been very succesfull in particular because there have been a lot of personal contacts. Just to give an example, the people from Genzyme told me that they were really inspired by a conference like this. Meeting patients and patient organisations and academic people from another line of research.

So I was not disappointed because of the lack of hard news. On the contrary. Next year there will be news. I'm sure.


IPA Founding Conference part 2

As Trotsky once said "While we fight to change life, let us not forget the reasons for living."*

A few facts, first of all. The attendance list shows 66 people, drawn from patient representatives, scientists, doctors and industry. Patient represntatives came from Spain, Belgium, The Netherlands, India, USA, UK, Germany, France, Australia, Italy, The Phillipinnes, Japan and Australia, with scientists and doctors covering much the same spread. There were industry representatives there from Pharming, Synpac and Genzyme.

Those are the ingredients. The recipe involves people with a common goal, in touch via email and telephone, finally meeting for the first time.  Bring together in a Dutch hotel and let simmer for 3 days of intense discussion.

The end result was an occasion that none of the participants will ever forget. Both personal and organisational bonds were formed that have stood the test of time. The formal programme was, as can be seen from the link in the previous post, a comprehensive review of the 'state of the art'. Perhaps even more important though were the many discussions that took place 'in the margins'. That is one of the reasons I've kept the wine bottle shown above - to remind me that the social side was as important as the scientific.

It was a remarkable, unique occasion and one which hardly seemed possible just a few years before. It's fair to say, I think, that the internet helped make it possible. However it was people actually meeting together that provided the alchemy.  Everyone present went away enthused, and energised.

There was a real feeling that, at long last, progress was being made and that, even more importantly, here was a group of people who were joining together to take charge of their own destiny.

From now on the IPA would be the voice of patients worldwide.

*Yes, that quote is tongue in cheek. This commemorative wine given to participants by the VSN. While I've kept the bottle, the wine itself was drunk on 29 July, 2000.

Tuesday, 22 December 2009

Towards a Therapy for Pompe Disease: founding IPA conference

The founding conference was held on 2-4 July, in Naarden, a town in The Netherlands, entitled Towards a Therapy for Pompe Disease. It was the result of much organisation, of course. And the credit for it being the well-organised event it was rests with the VSN, who provided (and provide) the IPA secretariat. Credits coming shortly. Meantime, at the risk of jumping to the end, here's the 'team photo' taken for posterity. I have a list of names of attendees and will have a stab at a full 'who's who' when I get the chance. All help gratefully received!

OK, here's my off the top of my head indentifications. Far left is Christelle Faure (that's her dad behind her, I think), then front row (L to R) Commander Prasad, Randall House, Marylyn House, Nina Raben, Ria possibly?, Ans van der Ploeg, Thomas Schaller (John Hopwood over his shoulder on the right), not sure, I C Verma, Maryze seated, Haske  van Veenendaal on the left, with Anton behind her (Andy Amalfitano behind Anton, in the green shirt), Victor Magdaraog,Ysbrand Poortman .

A full report of the conference, with abstracts, is available online at the IPA website. So I'll add the things that can't be found in the dry factual accounts here.  I would also welcome contributions from other participants in this little piece of history.

Monday, 21 December 2009

The dark horse enters the race

On 25 May, a press release from Duke University announced the start of a new set of clinical trials. Again, this would involve a small number of patients, this time using an enzyme produced using cell culture methods. Another primary source(edit: have moved to the comments section). As previously noted, this meant that there was now real competition, with a race to be first to announce results and to commercialise the product.

At the time I thought this competition was a good thing. With hindsight...not so sure.

Pharming Press release of 3 May 1999

Another bit of primary source - a Pharming Press release (edit: since added as a comment, rather than as a blog entry. That's where I'll put such material from now on. Like a footnote.)

Some interesting undercurrents here. Firstly, the competition with Synpac (see next entry) seemed to drive Pharming towards 'talking up' the trials to investors. No wild claims, of course,  but perhaps making sure that investors in their stock hung on. Interesting to note that the Belgian government put a large sum towards the building of the plant in Geel. That PR investment obviously paid off!

We began to see though that there was some tension between the needs of Pharming as a business, the principles of the scientists involved and the thirst for knowledge amongst the patient community. There was a substantial overlap between all three, of course - however those tensions would also grow and would need careful management in the years ahead.

There were changes in the Genzyme/Pharming relationship too. We were told that communication would in future be through the local Genzyme representative, rather than through Gerben Moolhuizen at Pharming. This made some sense - it freed up Gerben for the work he was supposed to be doing - but also raised the potential for divide and rule. Plus, as rapidly became clear, our connections with scientists, doctors and indeed within the various companies, meant that the patient representatives were usually better informed about the Pompe project than the local country reps, who had a wide range of responsibilities.  We would soon evolve a system where local reps dealt with individual patients and Genzyme HQ dealt with the representative organisations.

For entirely unconnected reasons, Gerben Moolhuizen left to pursue his career elsewhere at the end of May 1999. I, like many others, was sorry to see him go.

Tellingly, his place as a patient representative contact was taken by someone from Genzyme - Andrew Curtis. Another good guy, by the way.

1999 - The Year of the Rabbit!

In one of life's pleasing coincidences, 1999 was the Year of the Rabbit in the Chinese calendar. There was, of course, continued strong interest in the ERT trials and eventually the Genzyme/Pharming partnership agreed to answer patients' questions with a Q & A, released to the AMDA, AGSD-UK and VSN and posted to GSDNet (22 February):

Questions and Answers

1. Have the clinical trials started?

Approval for a small pilot study on 4 infants and 3 juvenile patients was
recently received in the Netherlands. The study has begun at the Sophia
Children's Hospital in Rotterdam and inclusion of patients has started. Dr.
Ans van der Ploeg is the principal investigator. This study is designed to
assess safety and give indications of efficacy of recombinant human
alpha-glucosidase in this population.

If successful, data obtained while the pilot trial is in progress will be
used to design two larger Phase II/III trials in the US and Europe.
Detailed design of these trials can only be done when data from the pilot
trial are available. Our goal is to initiate the first of these 2 studies
in mid-1999.

2. How can I participate in upcoming additional clinical trials?

Once the protocol and sites have been established, your physician should
contact the principal investigator at the participating center to determine
whether a patient can participate. Your physician should also inform you
about the consequences of trial participation, such as potential side
effects, additional examinations, prolonged hospital stay and costs.

3. How are patients selected for these clinical trials?

Before starting clinical trials, the principal investigators and
participating institutions will be identified. The investigators will
follow a predefined protocol with patient inclusion and exclusion criteria
that define patient eligibility for trial participation, as well as the
number of patients that can be enrolled. Inclusion or exclusion is
determined by a selection committee consisting of several physicians
including the primary investigator(s) based on the protocol.

4. What are the inclusion/exclusion criteria for the trials?

The protocols for the Phase II/III clinical trials have not been determined
to date as they will be dependent on the results of the Phase II pilot
trial in the Netherlands.

5. Who are the principal investigators and institutions in the next trials?

The participating physicians and institutions have not been determined yet.
Your local patient organization (AMDA in the U.S., AGSD in UK, VSN in
the Netherlands) will be informed on all progress toward trial preparation.

6. How will patients from other countries be able to participate in
clinical trials performed in the US and/or Europe?

Your physician should contact the principal investigator(s) at the
participating center(s) to understand the inclusion and exclusion criteria
for the protocol, and to determine whether a patient might be eligible for

7. What are the starting dates for the trials?

The initial, small pilot study taking place in Rotterdam has begun. Our
goal is to implement the next trial in mid-to-late 1999.
8. Will therapy be continued for trial patients after completion?

If the product proves efficacious in the trial, our plan is to continue
patient treatment under the Pharming/Genzyme LLC until regulatory approval
has been obtained.

9. Is it possible to start treatment for patients concurrently with or
after completion of the clinical trial?

Construction of a large scale production plant is underway in Belgium.
Until that time, product supply is available from a small pilot plant to
support the limited patients that are enrolled in the Phase II/III clinical
trials. The large scale production plant is scheduled to be operational
around mid-2000. Within the framework set by international legislation and
the limits to product supply, the Pharming/Genzyme LLC joint venture will
evaluate the possibilities for patient treatment concurrently or after
completion of the clinical trial.

10. Has the FDA already given the go-ahead in start clinical trials in the

Not at this time. Pharming/Genzyme LLC is working to complete the
application to perform the clinical trials in the US (i.e.. the IND,
Investigational New Drug Application). The FDA will allow us to start
clinical trials only after we have finalized the clinical protocol and
submitted it to them for review. In Europe, the required approvals to
perform clinical trials must also be obtained.

11. When will the product be approved?

The Pharming/Genzyme LLC is committed to working diligently and thoroughly
to develop a safe, efficacious product as quickly as possible. As always,
timelines may shift depending upon the outcome of the trials, review time
by the FDA in the 'US and the EMEA in Europe, and production capacity at
our manufacturing facilities.

After successful completion of the Phase II/III clinical trials in infants,
the Pharming/Genzyme joint venture will apply for product approval for this
population. Completion of this clinical trial, assessment of results,
filing of the application and review by the FDA may take as long as 12-24
months. In Europe, we must complete a Market Authorization Application with
the EMEA, the central European regulatory body, to obtain approval in the
member states of the European Union.

A second trial in juvenile patients is planned to start later, and the
trial will most likely take longer to complete. Thus, the process until
approval for treatment of juvenile patients may take until mid-to-late

This document contains forward-looking statements about the anticipated
initiation of clinical trials, the expected continuation of patient
treatments, the adequacy of the capacity of the small pilot scale plant for
clinical trials and of the large scale production plant, the expected time
the large scale production plant will become operational, the estimated
time required for conducting development and regulatory approval
activities, and the estimated size of the Pompe disease patient population.
Actual results may differ materially depending on the actual timing and
results of clinical trials, the timing of regulatory submissions, the
content and timing of decisions of the FDA and other regulatory agencies
concerning products and manufacturing facilities, actual amounts of product
needed for clinical trials and commercialization activities, the rate of
enrollment of patients in clinical trials, the continued funding of the
joint venture, and the adequacy of the companies' information about the
Pompe disease patient population. (Pharming/Genzyme LLC--February 1999)
Apologies for this cut and paste job, however it is not (just) laziness on my part. This is an important historical document and therefore worth quoting in its entirety.

A few things to note.

1) This confirmed for the first time that the trials were actually underway i.e. that actual Pompe patients were receiving the enzyme (and had been for a while).

2) While this was exciting, it was also a disappointment to many - there was no mention of a trial for adults, for example. 

A short statement from Synpac  indicated that they too expected to start clinical trials, in conjunction with Y T Chen, by the middle of 1999.

So, we now knew that trials had started and what the plan was for future development. We had to  hold our breaths and hope that it worked.  In the meantime, the nascent International Pompe Association began to grow and the date of the first conference was fixed for 2-3 July, 1999, in Naarden, the Netherlands.

Sunday, 20 December 2009

December conference postscript

A few loose threads crystallised for me at the Bethesda conference. Firstly, Alf Slonim gave a talk where he descrined a new sub-type of patient - onset of the disease in early infancy but without heart involvement.  I remembered Rick Garrett telling me something about this at the Oxford conference he and his wife mary's son, Luke, was one of that sub-type. Rick had told me about someone called John Crowley who also had two children in that position. I remembered that when I was introduced to John at the Bethesda conference by, I think, Alf Slonim.

My heart went out to him. I thought he looked punch drunk, understandably enough.  I remember him saying that he had been to a good school and had influential friends and would do his best to get them to help. Normally, this is the sort of talk that makes me want to slap someone about the head with a wet fish. However, I recognised John as a fellow member of a different sort of exclusive club - the Pompe parent club that no-one wanted to join but that we had been forced to. That counts for a lot with me.

I knew he had started up a new group called the Children's Pompe Foundation. My first reaction had been that this was a People's Front of Judea (warning: some swearing in that linked video)

 In other words, an unnecessary diversion from the goal of ERT and a united patient community (the US seems prone to this kind of thing, for some reason). I was conscious though that the children in this  newly described non-classical infantile 'sub-type' were not part of the initial clinical trial. Although it was absolutely logical (necessary, in fact) that this was the case, I knew that it was easier for me to accept. My child was gone; theirs needed help now.

I felt less forgiving though, when I read The Cure and found out that the Children's Pompe Foundation was actually a Potemkin village - a fake. John had realised that patient groups carried some weight, so he had simply invented one on the spur if the moment.

The reason patient groups carry weight is because they are the sum total of the collective hard work of the people who belong to them. Inventing one in an attempt to change the clinical trial criteria to help your own children might be, on a human level, understandable but is undoubtedly wrong. This is not just an instinctive British aversion to queue-jumpers on my part. Had the first clinical trials been changed to include a subset of children who would not have given clear results, the whole future of ERT might have been in jeopardy. It would not have been a victimless crime. 

The Children's Pompe Foundation played no part whatsoever in the international patient community and soon disappeared as quickly as it had arrived. John Crowley however was to reappear in another guise.

The 3rd AMDA conference - December 1998

As the IPA had been formed, albeit with an interim committee, the patient community was on a more solid footing. Therefore  Ysbrand Poortman and I were invited to attend the 3rd AMDA conference with took place in Bethesda, Maryland on December 3-5 1998. This was at the HQ of the US National Institutes of Health and Paul Plotz of the NIH had a hand in putting the programme together, along with Arnold Reuser, Gerben Moolhuizen and Randall House.

When I was invited in July, I was naturally thrilled at the thought of a front row seat at such a gathering. People who I had corresponded with by email, or who only knew as names from scientific papers - fantastic! However, as December approached, it became clear that I was also going to have to give a talk. What on earth would I say to such an audience and would they even be interested?

The programme was everything I had hoped for. There was a session on animal models, which included not only a reprise of the quail work but also reports of the development of different strains of 'knockout' mice (mice genetically engineered to have the alpha-glucosidase gene removed, so that they showed Pompe symptoms) by Arnold Reuser and Nina Raben.

Rochelle Hisrchhorn, a Pompe research veteran, chaired a  session on 'molecular and metabolic aspects' which included a talk by someone I had not previously heard of, called William Canfield. He had a unique take on ERT. I've previously described how the Dutch team showed that previous ERT attempts had failed because the enzyme used lacked mannose-6-phosphate residues, which would have allowed them to be targeted on the lysosomes. Consequently, the forthcoming ERT trials would use enzyme with those residues on them. However Dr Canfield reckoned that these would fail because they didn't have enough residues. The greater the number of residues, the more enzyme would end up in the lysosomes.

I wasn't convinced by this. The Dutch work had shown that enzyme levels could be increased beyond the point where clinical symptoms occurred. Wouldn't that be enough? And enzymes are, after all, a catalyst; adding them in excess doesn't necessarily mean that you have more reactions taking place (in this case, more glycogen breaking down). It didn't make sense to me and talking with the scientists there afterwards, it didn't wash its face with them either. So I soon forgot about it. Like did I realise what a spectacular and costly waste of time that presentation would turn out to be.

The other sessions were of more immediate interest. two sessions on gene therapy, which looked very much like the long-term solution. Gene therapy would entail replacing the faulty gene in patients so that they could make their own enzyme, rather than need ERT.  There were good talks from such luminaries as Barry Byrne, Paul Kessler and Andy Amalfitano.

However, the main event was the human trials session chaired by Arnold Reuser. This featured a real guest star turn, Roscoe Brady, the pioneer of ERT for Gaucher disease, as well as Ans van der Ploeg, who described the Phase II clinical trial for Pompe disease.

This would consist of two groups. Firstly, a small group of infants. The reasoning was obvious - these were the most severely affected and the clinical outcome was well characterised and devastating. Any effect of ERT would therefore be obvious. There would also be a second group with the 'juvenile' type. These would be older children who would be able to respond to a wider range of tests and also answer the questions put to them during the trial. It seemed obvious that this was the best way forward to ensure as rapid a demonstration of the effectiveness of ERT as possible.

On the final day, Nina Raben and Rochelle Hirschhorn spoke about mutations and population incidences. Hannerieke van der Hout spoke on the need for a formal patient database. Ansd then it was my turn to speak.

I'd given my paper the snappy title Translating science into English: the role of patient organisations and the internet in helping patients to become intelligent customers. I gave some of my own back ground and then what was essentially an argument in favour of scientists engaging with patients, through the medium of patient organisations. I had been looking for something to finish with and it had finally come to me. I recalled a quote from rabbi Hugo Gryn, a UK Jewish leader whose distinctive gravelly voice was a regular feature of radio discussion programmes. He had a saying which I related: "You can live for 3 weeks without food and 3 days without water - but you cannot live for 3 minutes without hope."  Then I ended my talk with: "We look forward to ERT becoming a reality. However, all of you in this room, every one of you who has worked on Pompe's for all of those years,  brought us something very important: hope. On behalf of the patient community, I thank you all from the bottom of my heart for what you have done."

I meant it then and I mean it now.

The finale was an impressive presentation by Randall and Marylyn on the work of the AMDA.- an organisation which many of those present had, of course, directly benefited from.  In my view, this conference, exciting enough in itself, marked a further evolution of the relationship between scientists and patients. From now on, we were all on the same team.

The full programme, list of participants and summary is available online.

The 1998 AGSD-UK Conference

The 1998 AGSD-UK conference was held on 3rd October, in Oxford. I should say that I've only mentioned the Pompe parts of these conferences, however the covered all the different types of GSD.

As was now becoming customary, there were a number of international visitors. Randall House from the USA, also Rick Garrett, whom I knew from GSDNet, and from France, a charming girl called Christelle Faure.  Christelle was the French leader of the Pompe patients right up until her untimely death. While researching this project, reading over the many email exchanges we had has made me realise what an impact she had and how much she is missed. More of Christelle later.

There were two important talks in the Pompe session. One was from Gerben Moolhuisen, who was pretty sporting about his Synpac rival sitting in the audience. Gerben talked people through the Pharming process and - I think - confirmed that the Phase I trials (in healthy individuals) had been successful. The Phase II trials would not start until December at the earliest. The participants and locations had not yet been finalised, however he emphasised that the numbers would be small.

Needless to say, this was all spell-binding news. However he also said something else which sent the spirits soaring. Gerben pointed out that what Pharming had at present was essentially a pilot production facility and a full scale production plant would take two years to build. However, Pharming were so confident/commited to the Pompe project that they were already one year into the building of this facility, in Geel, Belgium. This went down very well with the audience. Of course, the international patient network was now such that we had received regular accounts from Belgium of progress on the Geel site, from planning permission meetings onwards!

That was a difficult act to follow. However the next speaker had, if anything, an even more profound effect upon the audience. I have already mentioned that Genzyme's lead product was Ceredase/Cerezyme, the ERT for Gaucher disease. As the UK Gaucher patients were already receiving ERT under the NHS (it was, at that point, the most expensive treatment available via the NHS) I thought that it would be interesting to hear what they had to say. As I had made contact with the Gaucher Society's secretary, Susan Lewis, via Wayne Rosenfield's mailing list, I invited her along.

Susan was absolutely spell-binding. She spoke about the difference ERT had made to her and other Gaucher patients and went on to demonstrate the equipment used to deliver enzyme infusions and described how easy and routine it could be. The effect on her audience was electrifying; she had made ERT real.  For the first time, the UK patients knew that ERT was actually something real and attainable. I think the same went for Randall House too.

Susan Lewis continued to be a good friend to the Pompe community and supplied the AGSD-UK with frank and open advice about dealing with the NHS, politicians and pharmaceutical companies. Sadly, Susan died on 8 May 2007. Her obituary gives more details of her remarkable life.

Tuesday, 15 December 2009

The first clinical trials

Pharming got off to a quick start, announcing the start of Phase I clinical trials on 15 April 1998. This stage of clinical trials involves dosing healthy human volunteers to check of toxic effects. Even so, the effect was electrifying - wow these guys really do mean business!

Of course it was difficult for so many people to be so close and yet so far. Many adults were suffering terribly from the effects of the disease. Yet it was understood by all that the best way forward was for trials to be carried out on infants, as that was the quickest way to demonstrate the efficacy of the product - if, of course, there was any.

This was followed in July by the news that Pharming had entered into a partnership with Genzyme to produce the Pompe ERT. This immediately seemed like good news. After all, Genzyme already produced the successful ERT for Gaucher disease. I was surprised, given Genzyme's apparent past lack of interest in Pompe, however I assumed that the prospect of another company moving into 'their' market (the Gaucher product was very profitable) had galvanised them into action.

And we were aware of the Synpac/YT Chen connection, although lines of communication were more difficult to open with then. That said, someone from their UK office, Ian Hodgson, did come to the AGSD-UK's 1998 conference in Oxford. I found Ian to be genuinely enthused about the project, though I suspect that Synpac weren't more forthcoming with him than they were with us! However Ian did manage to secure us some Synpac sponsorship for the conference, so good on him.

Of course, the intense interest in the clinical trials made the role of patient groups even more important. The pharmaeutical companies quickly realised that we were an essential gateway to their customer base. We allowed them to manage communications in a structured way, rather than trying to deal with hundreds of individual letters, emails and phone calls from individual patients.

The relationship with Pharming in particular was a very good one, with a degree of openness and trust. That developed over time, of course, however there was a real sense that we were all on the same side, working towards a common goal. And I'm sure that the same would have been true of Synpac, had they spoken to us.

Monday, 14 December 2009

The 1998 scene

I've been looking back through my archive of 1998. It's difficult to convey in words the sense of momentum, of excitement, of a community waking up. I have hundreds and hundreds of pages of Pompe emails from this time (they were all bundled into a Word document at some point) - and that is only the archive from my work email address. Along with the hard copy archive, they build up a picture of almost feverish activity. Patients, scientists and industry all communicating, sharing information, building relationships - motivated by a common goal.  Something truly wonderful happened in those few years, starting in 1998.  Although I wish I had never heard of Pompe disease, I also that feel, strongly, that it was a privilege to be part of that time. 

Once again, I must make special mention of Randall and Marylyn House. Their prime motivation, understandably, was to find a treatment for Tiffany. But they did not stop there. They could have developed their connection with Pharming, went home and not bothered to return anyone else's calls. But they didn't.  Randall spent a great deal of time and resources travelling the world attending conferences and encouraging people to start their own Pompe patient groups.  Marylyn continued to run the AMDA, grouping together the US patient community, putting out newsletters and organising conferences. They didn't have to do any of those things. But they did. And they made a difference - not just for Tiffany but for everyone.

I was soon to get the opportunity to see the work of the AMDA at first hand, when I was invited to speak at their third conference, organised in Bethesda, Maryland USA in December 1998.

Sunday, 13 December 2009

The birth of the International Pompe Association

The birth of the IPA was an important event in the Pompe story. In fact, I think it was almost - but not quite - as important a development as ERT itself. Certainly the two stories are very intertwined. It represented the maturing of an international patient community into a representative organisation that could talk on something like equal terms with industry and scientists.

The roots of the IPA are as follows. I should say that my picture here is incomplete, for reasons that will become clear. Where I have gaps, I will follow my usual course of guessing (i.e. making stuff up) to fill them in. I will point out when I am doing that though.

I knew that Pompe groups were beginning to coalesce in different parts of the world. Helen Walker, Bet Cook and Bob Morrison were organising up a storm in Australia; Thomas Schaller and Gerd Hassler were bringing together the German patients within the glycogen storage disease group there. The UK and US have been mentioned. However there is a gaping hole in the canvass that I will now try to fill - The Netherlands.

The Dutch patients were the largest group of all and were organised within the neuro-muscular diseases charity, the VSN (Vereniging Spierziekten Nederland).  This was a very different group from the others. The VSN was a professional organisation, well-funded, with a critical mass that allowed it to sustain full time employees and a national head-quarters. They would bring those resources to bear on helping to organise the international Pompe community. This was, I think, a strategy formulated by the VSN head, Ysbrand Poortman, who had the far-sighted idea that the interaction of the Pompe patient community with scientists/doctors and industry could be a model for the development of treatments for other diseases.

The VSN were obviously closely involved with Pharming. This, in turn, brought them into contact with Randall and Marylyn House. The Houses took a close interest in Pharming, for obvious reasons, and may (I don't know; none of my business) have invested in the company. Randall, I think, viewed this fledgling company with a businessman's eye.

Ysbrand therefore suggested that, with the prospect of clinical trials, now was the time for an international patient organisation. I remember that Randall called me about this is obviously had some doubts. I think he had a concern that this would be a distraction and would there actually be a benefit? I was immediately struck by the thought that this was an idea whose time had come and hopefully my enthusiasm went some way to bringing the AMDA on board. The IPA would not have been the success it became without them; together we were all stronger.

The upshot of that was a letter from Ysbrand Poortman, inviting me to a meeting on 21 March, to discuss the organisation of an international Pompe conference.  The meeting was to be held after a meeting of the Dutch Pompe group, which I also attended. The international conference was original planned for October 1998 but was held over until 1999, both to accommodate some clinical trial results and to avoid a clash with a US conference being held at the National Institutes of Health, Bethesda, Maryland (of which more later).

I went along to the Dutch patient meeting.  I remember being impressed at the size of the meeting (though, of course, the actual proceedings were in Dutch). I met, for the first time, Maryze Schoneveld van der Linde, who also took part in the organising meeting and this was also the first time that I met Marylyn House. As you can imagine, both of them made a strong impression on me.  But more of that later.

The Rotterdam team were present, as were Pharming and their PR company. Actually, I've just remembered an amusing side track. Before we left for the IPA meeting, there was discussion where the Pharming PR man (Rob Meines?) invited the Houses to a lunch meeting the next day, with some politicians and Pharming senior staff. I was clearly not part of the plan, however Arnold Reuser interjected with "And of course, Kevin will be there too, yes?". They could hardly say no, so I ended up sitting in on a lunch at a rather grand hotel in The Hague (the Indies perhaps?), where I was the only person in the building without a tie. Arnold was making sure the AGSD-UK was in the loop and was at the same time entertained by 'the game'.

Anyways, back to the  founding IPA meeting. It took place at the Tulip Inn in Naarden. Present were Randall and Marylyn, Ysbrand Poortman, Helmut Erny, Maryze (and Anton), Miriam Bonink and Nelleke van den Berg (both VSN) and myself.  We agreed to some important actions:

  • To contact individuals in different countries and encourage them to form their own Pompe groups
  • To found an International Pompe Association at an international conference, meantime to be run by an Interim Executive Committee consisting of the above people (but with Ria Broekgaarden representing the VSN)
  • To organise an international Pompe conference for October 1998 (later changed as above)
  • To continue to meet via telephone conferences
And we were off. From now on the Pompe community was a force to be reckoned with.

Saturday, 12 December 2009

A two-horse race

In September 1997 one of those twists took place. Duke University announced that YT Chen's group would also be conducting clinical trials of ERT, in collaboration with a company called Synpac Pharmaceuticals. They would be using the more 'traditional' method of producing the enzyme in Chinese hamster ovary (CHO) cells engineered to produce the human enzyme.

This just seemed incredible - not one but two pharmaceutical companies, competing to conduct a clinical trial and bring a product to market.

In a pretty strange and complicated saga, Synpac were one of the more mysterious participants. They were (probably still are) a Taiwanese company, very private, whose main line of business was the bulk production of generic pharmaceuticals like penicillin.  How they became involved with Pompe disease is a story that I suspect only YT Chen knows.

Anyhow, by the end of 1997 we had two teams racing to stage a clinical trial of ERT, something which seemed impossible just a few years before.

However, this was just a taste of what was to come...

The 1997 AGSD-UK conference: an international gathering

The 1997 AGSD-UK conference took place on 25 May, in Slough, near London. Coincidentally, I used to live in Slough and managed to get the Mayor, Lakhbir Minhas, to come an open the conference, which ensured some local news coverage and also gave a suitable sense of occasion. I also managed to blag a few boxes of chocolate bars from my old employer. Let's just say that we were well prepared for work, rest and playing. And just as well, for this was to be a remarkable conference, for all sorts of reasons.

A report from the Slough Observer! Photo shows Mayor Minhas, Me, Elaine & Euan, Arnold Reuser and Ann Philips. It also contains my embryonic daughter, Catriona who was born in December. We got the CVS all-clear on the drive down.

 And the rival Sough Express was not to be outdone! 

Firstly, there were a number of international attendees, mainly from the Pompe field. From memory, Gerd Hassler from Germany, Bob Morrison from Australia, Ross Harvey (jr's brother),Randall House and YT Chen from the USA and Gerben Moolhuizen and  Arnold Reuser from the Netherlands. Many of us had 'met' online, so in a way it was a GSDNet conference too! In retrospect, this really helped to cement the development of a Pompe community.

There were a series of remarkable presentations too. Arnold Reuser gave a talk on the latest developments in ERT and was helped in the following Q & A session by Gerben Moolhuizen.

That was obviously exciting. However, the following presentation by YT Chen was a real show-stopper. Yt presented his work involving Japanese quails, an unusual choice of experimental animal, explained by the fact that they have the bird equivalent of Pompe disease.

The affected birds were unable to move their wings, or to right themselves after being turned over. After 3 weeks treatment with enzyme produced in YT's lab (at Duke University USA) one of the birds was able to fly - and was only stopped after it hit a light stand! Analysis showed that their heart and liver had returned to normal and that their skeletal muscle, while still containing some glycogen, showed obvious signs of improvement - and, more to the point, fairly spectacular evidence of recovered function!

It was a remarkable double-whammy for everyone in that room. ERT was being developed - and there were the people developing it, right in front of us, answering questions. Not only that but a researcher had come from the US with dramatic evidence that it would actually work. This work was published in 1998 and the paper - well worth reading - is online. To my continued astonishment it manages to avoid all mention of the pioneering series of papers published by the Rotterdam group that demonstrated that ERT was a runner. I guess this was a sign that things were about to become competitive (the paper acknowledges funding by Synpac). Aside from the fact that the reviewers should have picked the omission up, it was just plain bad form.

However, just like a TV drama, there were twists and turns ahead that we could not conceive of. And speaking of TV, do I get a prize for an article involving Slough that does not mention The Office?


Pharming were - and are - a fantastic company. They were pioneers in the field of transgenic animals. Relatively small, young and adventurous. That's why they were willing to take a risk on a product for a disease that no-one had heard of. I am of the belief that without Pharming the development of ERT for Pompe disease would have been much delayed. Certainly, Genzyme had not shown any interest when I had written to them regarding the Rotterdam work.

Over the years they were involved with the Pompe project, I always got the impression that this was more than just a job - they believed in this project. That high level of motivation made for good relations with the patient community and undoubtedly helped progress. They were the right company, with the right product at the right time. And the fact that they were nearly destroyed by later corporate chicanery does not detract from that one bit. I hope that all those from Pharming look back on their involvement with the patient community with pride. We owe them our thanks.

No-one exemplified the Pharming commitment to the Pompe project better than Gerben Moolhuizen, the Project Director. Gerben got in touch in early 1997, to bring me up to date with the project. That established a relationship between the AGSD-UK and Pharming based on openess and trust. They knew that confidential and commercially sensitive information could be shared without it going any further.

Pharming were taking a novel and potentially controversial approach. They had genetically engineered animals by adding the human alpha-glucosidase gene to them, along with a marker that meant that the resulting human enzyme was expressed in the animals' milk. This cleverly did away with the need for complex bioreactors, with all their special growth mediums, difficulties in keeping sterile. Just feed grass in and get alpha-glucosidase-rich milk out.

One problem though was that the animal Pharming were not producing the milk in cows, or even sheep or goats - but rabbits.  At first this seems odd, not to say bizarre. However the reasoning was solid - the rapid generation time allowed production to be increased quickly due to the relatively short time taken for the animals to reach breeding (and milk producing) maturity. The downside was that it was going to take an awful lot of rabbits to produce the required volume of milk.

One question I often used to get asked was "But how do you milk a rabbit?" To which the obvious answer was "You sit on a very small stool." However the true - and only slightly less amusing answer - is that you buy a rabbit-milking machine. Apparently cheese made from rabbit milk is considered to be a delicacy in some quarters. Who knew?

As a postscript to the above, I once asked Gerben Moolhuizen what precautions were taken to preserve these very valuable rabbits, in the case of some catastrophic accident. he replied that I shouldn't worry because samples of semen from the genetically engineered rabbits were deep frozen so that, in such an event, the breeding line could be quickly restored. I mention that simply to point out that there are worse jobs than milking rabbits.

Thursday, 3 December 2009

1997: Lift off!

Looking back, 1997 was an absolutely pivotal year.

Browsing the email archive, I see that this was when many leading lights of today's patient community first made contact with each other - for example, Thomas Schaller, Helmut Erny, Juan Magdaraog, Bet Cook, Helen Walker and Bob Morrison.  The international network was growing and starting to become a community.  Increasingly, this included scientific and medical professionals from around the world too.

I have to make a small confession here. Researchers and doctors are often, for entirely understandable reasons, uncomfortable about talking with individual patients or parents. That's one reason why patient groups are such a good idea. However it did occur to me that my own scientific background would be of use in making initial contacts. Seldom has a PhD been so shamelessly exploited - and to such good end.

I was kept also busy by a whole range of people getting in touch from all over the world. This could be quite difficult at times, such as speaking with someone who had just been told their child had a terminal illness. No matter how many people I spoke with, that never got easier. I guess some things should never be easy.

However towards the end of 1996, came some news that was like a dream come true. A Dutch pharmaceutical company, Pharming, announced a £14 million collaboration with the Rotterdam group to run a clinical trial of ERT for Pompe's. Fantastic! They also announced that were going to produce it in the milk of genetically engineered animals - a novel method. More on that, and on Pharming, later.

Arnold Reuser and Ans van der Ploeg kept us well informed of developments, of course. The March 1997 edition of the Pompe's Bulletin included this article by them (note that the fruits of the conference organised by the Houses are already obvious):

Enzyme Therapy for Glycogen Storage Disease Type II: Dream or Reality?
by Arnold JJ Reuser, Biochemist, Clinical Genetics Erasmus University, Rotterdam and Ans T van der Ploeg, Paediatrician, Sophia Children's Hospital, Rotterdam
A number of recent events have brought the answer to this question near. When Dr. Kevin O'Donnell asked us for the latest news, we thought it would be nice to put these recent events in a historic perspective.

At the basis of enzyme therapy for lysosomal storage diseases, such as GSDII, is the discovery of lysosomes in the mid fifties by the later Nobel price winner Dr. Christian De Duve. Lysosomes form a compartment inside the cell in which large sized biological substances from inside and outside the cell are degraded by over 40 different enzymes.

In the early sixties a deficiency of one of these enzymes, namely acid a-glucosidase, also known as acid maltase, was discovered by Dr. H.G. Hers as the cause of glycogen storage disease type II. Together, these discoveries have led to the concept of lysosomal storage diseases and given rise to the idea that patients could possibly benefit from administration of the lysosomal enzyme they are deficient in. Why did it take more than 30 years before enzyme therapy was successfully put into practice, and only so far for a single disease, Gaucher disease?

One major cause of delay was the technical inability to produce lysosomal enzymes pure and in sufficient amounts for clinical application. The second was the initial unawareness that cell type specific receptors can be used to target the administered enzyme to the affected cell and promote uptake by lysosomes.

In late onset (juvenile and adult) GSDII the target tissue is skeletal muscle. In infantile GSDII skeletal muscle and heart has to be reached, and it is possible that other tissues are also in need of therapeutic enzyme. Both heart and skeletal muscle have cell surface receptors that can be utilised for enzyme targeting, and a-glucosidase can be made to fit these receptors. Thus, it was demonstrated in an artificial system with cultured muscle cells, that glycogen stored in cells of patients was degraded by the a-glucosidase added to the culture media. Mice receiving a-glucosidase intravenously, showed an increase of a-glucosidase activity in muscle and heart tissue. But, these mice were healthy so that the therapeutic effect of enzyme therapy could not be tested.

In parallel to these studies, there has been a search for natural sources of a-glucosidase and biotechnological production methods. The latter activity has been successful, as many of you will know. Chinese hamster ovary cell lines suitable for human a-glucosidase production were developed by Dr. J.J. Hopwood and colleagues from Adelaide, Australia, and by Dr. Y-T. Chen and colleagues from Durham, North Carolina, in collaboration with our research group in Rotterdam. The production capacity of the "Hopwood" cell line was tested in a bioreactor, designed and built by BioCell Technology with financial support from the AGSD (UK).

With this reactor we have now produced enough human recombinant a-glucosidase to perform the necessary preclinical tests, but we have learnt that the production capacity of the cell line in this reactor is too low to enter safely into a clinical test in humans. Does this mean that the project is bound to fail? On the contrary, the activities developed in conjunction with the CHO production line and the promising results obtained have stimulated other parties to join and support the project. Very importantly, the Dutch based biotechnology company Pharming B.V. has now set its goal on the production of human recombinant a-glucosidase in the milk of transgenic rabbits and has entered into a collaboration with our research group at the Erasmus University and the Academic Hospital Rotterdam to realize a clinical test within two years.

This news was made public by Pharming B.V. at a press conference held in November last year in Geel, Belgium, where a production facility will be built. The collaboration program foresees in development of a complete production process. With financial support of the Prinses Beatrix Fonds (a Dutch charity fund for neuro-muscular diseases) we have already demonstrated that human recombinant a-glucosidase produced in milk of transgenic mice has all the required characteristics, including a targeting signal. Importantly, the concentration of human recombinant acid a-glucosidase in the mouse milk is far higher than in the CHO cell culture medium.

Production in rabbit milk will solve the problem of production capacity. In the research program it is further planned to generate a mouse model of GSDII. To our knowledge at least three laboratories world wide are pursuing this goal, and the first mouse models may become available this year. The therapeutic effects of human recombinant a-glucosidase produced in CHO cells and in rabbit milk can then be tested. If the test results are positive, the clinical trial in humans can start as soon as the a-glucosidase production process is ready.

Although the final results of this technical, costly and emotional adventure are still uncertain we should feel encouraged that after so many years of waiting a realistic and promising attempt at enzyme therapy for GSDII will be taken.
I can hardly describe the sense of excitement at this time. It really seemed that the fledgling Pompe community could, at last, dare to hope.

Wednesday, 2 December 2009


As well as ever-expanding email contacts, I was also involved with the flesh and blood GSD community in the form of the AGSD-UK.

I was a member of the AGSD-UK Executive and I'll try and give some small flavour of that here.  When I joined in 1993, the AGSD-UK was already an organisation in transition. From meeting in scout huts, it was growing in size and professionalism, with all the accompanying strains. The 1994 conference, organised by Henry and Janet Thomson, was the first which had gathered people in the same hotel overnight, with the conference proper in a nearby hospital. My wife and I took that to its logical conclusion in 1996, by organising the conference in Edinburgh and making it entirely hotel based - and so it has been ever since.

The AGSD-UK Executive used to meet in London, at the rather grand offices of a firm of solicitors, Winckworth and Pemberton, just round the corner from the Houses of Parliament. This was courtesy of the late Nick Owston who was a partner in the firm. Nick had Mcardles disease (GSD type 5) and represented those patients on the Executive. Nick was a real gentleman. He could have bought and sold the lot of us but you'd never have guessed - he was entirely unassuming. He was happy to host the AGSD-UK meetings and, on occasion, to provide top notch legal advice, all the while quietly encouraging things along from the sidelines. He also organised a robust international survey of Mcardles patients which remains the gold standard for information about that disease. It's a cliche, I know, but he really is much missed by everyone who knew him.

In my time, the husband and wife team of John and Sue Del Mar were chairman and treasurer respectively. Sue is charm personified and absolutely unflappable. She has always reminded me, as she will now be surprised to read, of Lady Penelope from Thunderbirds. I suspect that Sue will not find the comparison with a puppet to be a very flattering one. However, I can assure her that it is, as all men of a certain age will agree. John will be relieved to hear that he bears no resemblance to Lady Penelope's side-kick, Parker. John brought a business-like approach to the chairing of meetings and helped smooth things along, when they got sticky. As they did. Again, a successful businessman who cheerfully gave his free time to helping a small charity. John and Sue were two of the original founders of the AGSD-UK and have a son, Hugo, who has type 1.

Another regular presence was Phil Lee, a doctor specialising in metabolic diseases at the Institute of Child Health in London. Phil gave a lot of his time to help the GSD, coming to conferences as well as exec meetings  and providing some essential medical backbone and advice. He had enormous enthusiasm and, as well as research, was something of a pioneer in establishing clincis for adults with metabolic diseases. Again, a remarkable talent attracted to this small charity, helping it punch above its weight and a good friend to the GSD community. I was sorry to hear that he has recently retired through ill-health and I wish him well.

Which brings me to Ann Phillips, El Presidente. I love Ann dearly, and the fact that the range of talented people described above gave up so much time to such a small charity is a testament to her energy and commitment. She was (still is) a force of nature that the AGSD-UK just gravitated around. All that talent was just drawn in by centrifugal force. But, goodness me, it could be hard work.  Ann could be very single-minded and also had an understandable attachment to the organisation she had co-founded. This made for interesting meetings, which could ocasionally get heated. Sometimes she and I argued - she would occasionally try to spend the Pompe fund on other things, for example. However, Ann has a heart as big as the Atlantic that separates her US birthplace from the UK. You could have a stand-up row with her one minute and it was done and forgotten the next. The bottom line is that AGSD-UK simply wouldn't have existed without her and GSD patients in the UK and beyond will always be in her debt.

Ann co-founded the AGSD-UK because her youngest son Peter had GSD type 1. It is a real tragedy that Peter died in 2008, after 3 failed liver transplants. He was a fine young man, who, as well as contributing to the AGSD-UK in his own right, was a paediatric nurse, dedicated to helping others. The apple doesn't fall too far from the tree.


The Pompe report stuck out like a sore thumb from the rest of the AGSD-UK business, simply because there was so much going on - research, clinical trials, conferences, meetings with companies and so on. I would give some rather breathless account of what was happening and one of Ann's foibles was to listen and then say "Kevin, that's great but, you know, you should always say 'AGSD-UK' and not 'AGSD'  because that will confuse people."  Which always seemed like a bit of a non-sequitur and classic Ann. Imagine my huge amusement then, when I'd started writing this blog, to receive an email from Allan Muir, my Pompe group successor, saying "Good blog Kevin - but please remember to say 'AGSD-UK' and not 'AGSD'" Well it amused me anyway. You had to be there, I guess.

I do miss those AGSD-UK Executive meetings. They were a good supportive bunch of people (apologies to those I haven't mentioned - I stuck to the core people who were there all the way through my time on it.) and I always came away from them with a spring in my step.

Tuesday, 1 December 2009


I have a huge file of emails, dating from 1995 or so onwards. Looking through 1996, I'm struck by the number of contacts from around the world, many of them nothing directly to do with Pompe disease but with genetic diseases in general. The internet was a much smaller place in those days!

Through hosting the AGSD-UK website, I was gradually amassing a number of glycogen storage disease contacts and I wanted to do something with them, to enable all these people to speak to each other. But what?

For some time the only place where patients could communicate on genetic diseases was an email mailing list called gendisease-j, run by a chap called Wayne Rosenfield. Gendisease-j (now called gaucherdisease) was ostensibly for diseases that have a greater predominance in the Jewish community, which included a number of lysosomal storage diseases. Importantly, this included Gaucher disease, which already had an enzyme replacement therapy. Although I am not Jewish and Pompe wasn't really within gendisease-j's remit, I was welcomed and made to feel right at home in that community. A small but characteristic kindness on Wayne's part. That in turn led to contacts with the Gaucher Society in the UK, which proved important. But I digress.

Having seen at first hand the community that Wayne had created, I thought it would be good to try and create something similar for the glycogen storage diseases. And welcoming as the gendisease-j community were, it's one thing to be a guest and another to invite all your friends and family to stay too.  So I asked Wayne how to go about setting up a mailing list and he kindly took the time to put me in contact with someone who could help at St Johns University (which at that time hosted a number of medical lists) and then talked me through the business of setting up and running a mailing list. Wayne has been a source of help and advice over the years since - indeed, I have shamelessly plagiarised many of his ideas. So can I just take this opportunity to say - Wayne, thanks for everything.

I had an accomplice in setting up the new mailing list - John Bird of the AGSD-US. John - inexplicably - didn't think my initial title of Gendisease-gsd was a good one and so a return to the drawing board came up with GSDNet - which was duly launched in June 1996. I thought at the time that it would be great if we could get 50 people to join and hoped that we would have enough to talk to each other about. I needn't have worried. GSDNet quickly grew in size and also, I think, in depth.  People from all over the world found that they were no longer isolated but part of a community. A community that has shared successes and supported each other through life's ebbs. It has also provided those affected by GSD with a voice at crucial junctures. I can't better the description from the Australian Pompe Association website:

GSDNet is an Internet Mailing List for patients, their families and friends, and professionals.
It is a mailing list for all Glycogen Storage Diseases, including Pompe’s Disease, and here you will meet a great bunch of people.
You can email with other Pompe’s patients world-wide. And if you feel alone and isolated with this disease, or if you want to talk with someone  who will understand just what you are going through, if you want to ask questions or you just want to receive the latest news, then this is the right place for you.
You can receive email for all Glycogen Storage Diseases or you can set your particulars so that you will only receive mail pertaining to Pompe’s Disease.
And the good thing is - It’s Free!!

Along the way, we added Ruth Speary and then Bet Cook as co-owners. Truth be told, it's Bet who does most of the actual work these days. Take a bow, Bet.

Today GSDNet has over 500 members, from all parts of the world and is the leading online resource for glycogen storage diseases. It works so well because it is more than the sum of its parts - and that is down to every one of its members. Well done all.