Pompe disease - the real story

2003 - onwards and upwards

2010-02-06T18:28:00.003Z

2003 signaled the end of one era and the beginning of another. From now on, news of friends receiving ERT would begin to come thick and fast - every one of them a cause for rejoicing.

It would take until 29 March 2006 (Europe) and 28 April 2006 (USA) before the formal approval of Myozyme as a treatment. However even that was not the end of the road - there are still issues around funding and, above all, ERT is a treatment, not a cure.

The fight goes on, carried out by an international community of patients, scientists, doctors and companies. I hope that others will contribute the rest of the story here.

I myself 'retired' from the Pompe scene at the end of 2003. It had been 10 years since Calum died and my dream of seeing an effective treatment for Pompe disease had come true. We wanted to remember our son for his short, but wonderful, time with us and not for his disease. There were other people better suited than I to do my remaining jobs. It was time to move on.

Heidelberg

2010-02-06T18:20:00.001Z

I go to many conferences as part of my work as well as personal activities and I can honestly say that the 2003 IPA conference remains the best I have ever been to. It was held on 31 October- 2 November, in Heidelberg, Germany. Everything was superb: the location, the presentations, the cameradie, the beer...

The conference website and follow-up (including proceedings) are still available to read for yourself.

There was also a Q and A session released on the website and GSDNet.

That the conference was such a roaring success is in large part down to the organisers, Thomas Schaller, Birgit Wolf, Rita & Helmut Erny from the German patient group.

Conference participants

However one other reason is that, here, for the first time, much of the talk was about success. Successful trials, successful enzyme production and the prospect of many more people being treated in the coming year. We had come a long way.

There was still a long way to go, of course, but as Marilyn House put it at the time " everyone came away with new sense of enthusiasm and cooperation for the treatment of Pompe's disease."

2003

2010-02-06T17:16:00.001Z

Before we get into the 2003 big picture, can I just step aside for a moment and mention something of huge significance for me. This was the year that, for the very first time, there was a UK clinical trial of ERT. This was at The Willink Centre in Manchester, under Dr Ed Wraith and co-workers. This was a dream come true and added to a growing feeling that my own part in the story, such as it was, was coming to a logical end.

2003 was again a year of solid progress. In retrospect, we had moved pretty clearly to a situation where we knew that ERT would be available. For many people, this was even more difficult than wondering if it would be available. It was now a waiting game, not a hoping game. In particular, many adult patients were wondering when it would be their turn to feature in a trial.

This led to occasional tensions. The IPA were in regular contact with Genzyme, yet much of this was under strict terms of confidentiality. This meant that information could not be passed on to the patients, who were - understandably - restive.

Nevertheless, a series of regular updates held things together.

Issue 10 of the Pompe's Bulletin came out in February, bringing people up to date on a whole range of things, including the Manchester trial.

There were regular Pompe Program updates (contents agreed between the IPA and Genzyme) of progress.

These were released on February 18, March 19 (Genzyme press release), September 10 (press release)

The latter brought the first news of adult onset trials and of 'Special Access' for patients who did not fit into clinical trials but who were in demonstrable need. This was a mark of Genzyme's success in ramping up production - they could not have made such promises without absolute confidence in supplies of enzyme. From now on, alpha-glucosidase would be much more widely available, in advance of formal commercialisation.

As you can imagine, having been aware of developments through regular contact with Genzyme, it was a great feeling of relief to have them out in the public domain. It was recognised though that something bigger and public was needed to signal progress to patients. That something was the biggest and best Pompe event so far - the 2003 IPA Conference at Heidelberg in Germany.

Maryze's story - Part 8

2010-01-31T20:35:00.006Z

On March the 29th Myozyme was officially approved in Europe. That special day for Pompe patients, I was at the funeral of a Pompe patient I knew very well. It was she who called me that day on November the 14th 1996, to ask if I had heard the news and what I thought of it. It was sad that she never could benefit from the treatment she too had been waiting for so long. Shortly after the FDA approved Myozyme as well. Slowly Pompe patients all over the world did start treatment. I know of one boy in Germany who was so affected that he didn’t meet the criteria for participation in the clinical trial in Rotterdam, but he was able to start commercial treatment with Myozyme just 2 weeks after the official approval.

A cake to celebrate the approval of Myozyme.

In spite of the approval the clinical trials on Myozyme in adults continued. The regulatory authorities had requested additional data that showed also efficacy of Myozyme in older Pompe patients. I personally admire these people who did continue going to Rotterdam and other trial sites in France and the USA to get their infusions not knowing if they received alpha-glucosidase or placebo, to do all the required tests and go through all the emotional feelings, even when they knew Myozyme was approved for the market already.

Over the years from 1996 till now, I collected a lot of documents, newspaper articles, publications etc on Pompe disease and related issues from all over the world. These 6 large files contain a lot of information on events and people not mentioned in the book ‘The Cure’. This book is a story of John Crowley and his family, but it's not the story of so many other Pompe patients in the world.

Maryze's story - Part 7

2010-01-31T20:33:00.002Z

In December 2005, Genzyme invited me to join them and Dr. Ans van der Ploeg to the official hearing at the European Medicine Agency (EMEA) in London. Genzyme had received permission from the EMEA to bring a patient to the official hearing to give her personal account. I immediately said ‘yes’, because it was important for all Pompe patients in Europe and beyond to get approval for the enzyme replacement therapy. At December 13 2005, it was the day of truth and it was one of the most exciting days in my life. We were all nervous, even after such a thorough preparation. Genzyme and Dr. Ans van der Ploeg gave an excellent and clear presentation on the effect of ERT. After their presentation it was my turn.

I had 5 minutes to tell about my personal experience with enzyme replacement therapy. For me these 5 minutes was worse than doing 3 school exams. I felt as if all the European patients were sitting on my shoulder, depending on my performance and ability to explain the impact of ERT on my life. All the experts in the room were silent and listened carefully. I was able to tell them the story behind the data Genzyme and my physician presented. This mixture of hard scientific data and a personal account was good and clear. After the official hearing we received a debriefing of the French and Belgium representatives who were leading this hearing. The French representative told us that apart from the data, my personal story was what they wanted to hear. Sometimes hard data can’t tell what one story can explain…the real impact of a treatment on a life.

On January the 27th 2006 we were told in a press release that Myozyme™ Receives Positive Opinion from European Regulatory Committee (London, 27 January 2006, Doc. Ref. EMEA/32796/2006). This meant that the regulatory committee would advise the European commission to approve Myozyme for Pompe disease. Just before this press release I was called by Genzyme by someone I know very well. He just asked me: ‘Do you have Champagne?’ Tears ran below my cheeks, as I felt so relieved that now all Pompe patients in Europe could start treatment and I knew other countries would follow Europe. We were both emotional and happy. It was as if we won a battle together and survived. One day after this press release, on January the 28th 2006, the VSN had organised a Pompe patient meeting. It couldn’t have be timed better and in a movie one wouldn’t belief it as it would be too good to be true. At that meeting Pompe patients from all over the Netherlands gathered and prepared to hear another delay in treatment as we had been hearing for so many years already. Someone of Genzyme did tell everyone about the press release, that most of the people didn’t know about yet as it was so fresh, but the message wasn’t understood. Then my mother decided to tell everyone this good news in a symbolic way.

She left the room and came back with a bottle of Champagne and some glasses. She entered the stage and called several people to get a glass of Champagne. Dr. Arnold Reuser, Dr. Ans van der Ploeg, Willem van Weperen (Genzyme), Gezinus Wolters, my father, and I. We all represented those who were so closely involved in the process of getting a treatment: scientists, physicians, industry, patient organisation, patients, parents and partners.

My mother, Tanneke van der Linde, and Dr Arnold Reuser opening a bottle of champagne.

When the Champagne was poured in the glasses, everyone started slowly to understand. It took a while as no one really could belief it. After all those years of waiting since 1996, there finally a treatment would be available. This was the moment everyone was waiting for so long. Some people got emotional and hardly could express their feelings. Later I received an email from a patient who thanked me as she couldn’t say it personally, because she was afraid to cry. In the afternoon of Monday the 30th of January 2006, our doorbell rang. I was surprised to see a fellow Pompe patient and his wife at my door. They live not very far from me and decided to give me a bouquet of flowers for the work that I had done. I was deeply touched, because it was for people like him that I hoped the treatment would help. From now on when a new Pompe patient would be diagnosed, they would be told: ‘I am sorry to tell you that you have Pompe disease, but there is a treatment available’.

Maryze's story - Part 6

2010-01-31T20:22:00.001Z

In April 2002, I met John Crowley, former CEO of Novazyme and at that time working for Genzyme at a meeting. I also knew he had two children with Pompe disease and both were severely affected. John and my mother sat next to eachother and talked about their children: Megan, Patrick and me. I saw two parents who were both very worried about their children. They cried together. This is how I remember John, crying with my mother as they both saw their children deteriorating and didn’t know if treatment would come in time.

Both his children, Megan and Patrick and I finally received our treatment on time. The opportunity to receive treatment was a gift of life. I told my physician, Dr. Ans van der Ploeg that I wanted to contribute to the knowledge of enzyme replacement therapy like the other patients were doing in the clinical trial. A muscle biopsy was taken and all neurological, lung and blood tests were done. These outcomes were also used in the data gathering to get approval for enzyme replacement therapy at the regulatory authorities. It was good to see that also other patients were able to start treatment. It was a time in which Anton and I regularly drank German Sekt to celebrate the start of treatment from a friend somewhere in the world.

Through the contacts with patients world wide, the IPA learned that it was important to inform Pompe patients about the issues involved in Pompe disease such as breathing problems, common health problems, exercises and physical therapy, pregnancy, genetics, medical developments etc. We felt that people should know how to stay in a as good physical condition as possible. Especially regarding the breathing problems that can occur we felt Pompe patients should know how to treat it and what to do and especially what not to do, like for example using oxygen or using a C-pap. To inform as many Pompe patients as possible, The Pompe Connections were written and reviewed by medical experts from several countries. Later it was translated in several languages such as Japanese, Turkish, German, Spanish, French and Dutch.

Later I heard that people around the world were very happy with this information, especially when it was in their own language. It was a tremendous task, but absolutely worth all the energy and effort.

In November 2003, the International Pompe Association organised an international conference in Heidelberg, Germany. Scientists, physicians, patients and industry were present and shared the latest information on research. It was at that conference a mystery was solved. The mystery of the ‘Holy Grail’, the treatment Novazyme had been working on, but that suddenly disappeared. This statement of ‘Holy Grail’ is not mine, but Novazyme used this terminology in one of their press releases.

In answer to a question, Dr. William Canfield told everyone at the conference that during a test with muscle cells stored with glycogen in a Petri dish where they added the ERT of Novazyme, a huge mistake was made. At first it was claimed that the Novazyme treatment was working so well that in just a couple of minutes the glycogen in these muscle cells was decreased to almost zero. Based partly on this result the Pharming ERT was wiped from the Pompe development program, as according to the results of that famous test it was the most inefficient treatment. Later it was admitted that the Pharming ERT should have been tested in vivo (experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment) as it would have been more fair and probably would have revealed that it was more effective in vivo than in vitro (experimentation done in live isolated cells). Genzyme was presented the great results of Novazyme and convinced that the treatment Novazyme was developing was indeed very promising.

Novazyme's mistake

Genzyme bought Novazyme in 2001, the company of John Crowley, for millions of dollars. John Crowley was offered the position of senior vice president at Genzyme Therapeutics after the sale. The take over from Novazyme by Genzyme was investigated thoroughly by the Federal Trade Commission. While this investigation was still going on, it became clear that the Novazyme treatment wasn’t promising at all, but that its results were based of a mistake. While doing the test, the in vitro muscle cells weren’t fixed, so when the Novazyme treatment was added, the glycogen simply was washed away. In such a situation even plain water would have been able to remove the glycogen from muscle cells.

Maryze's story - Part 5

2010-01-31T20:10:00.005Z

Meanwhile in 1999 the International Pompe Association was founded. One year before, in 1998 at the annual patient meeting of the VSN in the Netherlands, also some parents from other countries such as Germany, UK, USA and the Netherlands, were present. After the annual meeting we came together in a separate meeting and it was discussed how we could work together on behalf of all Pompe patients in the world. Also for those who didn’t have a strong patient organisation in their country. It was at that particular meeting the name International Pompe Association was mentioned. One year later the IPA was officially established and registered. The first board members of IPA were: Kevin O’ Donnell (UK), Ria Broekgaarden (the Netherlands), Bob Morrisson (Australia), Randall House (USA), Thomas Schaller (Germany) and Maryze Schoneveld van der Linde (the Netherlands).

In April 2000, at Easter, Anton and I went on holiday in Andalusia, Spain. I always wanted to see the beautiful Moorish architecture of the Alhambra near Granada and the Mesquita in Cordoba. When we returned home, my parents told us that Genzyme would stop the development of human alpha-glucosidasis in rabbits. For us this news was a complete shock as the Lancet had just published a convincing article that showed that enzyme replacement therapy was safe and effective in children with infantile onset Pompe disease (Van den Hout H, Reuser AJ, Vulto AG, Loonen MC, Cromme-Dijkhuis A, Van der Ploeg AT. Recombinant human α-glucosidase from rabbit milk in Pompe patients. Lancet 2000; 356:397-398). Many Dutch Pompe patients were emotional about this decision. The dutch company Pharming that we got to know so well from the beginning and that had proved to have a treatment that was effective, was now put aside without getting a real treatment in return. The treatment that would be further developed had still to be proven effective at that time

The decision to stop production of the rabbit enzyme received extensive coverage in the Dutch press

On September 28, 2001 Genzyme completed the take over of Oklahoma City-based Novazyme.

On October 30, 2001 Genzyme acquired the manufacturing facility in Geel, Belgium. In a pressrelease the following was said: ‘CAMBRIDGE, Mass.-Genzyme Corp. announced today that it has acquired certain assets of Pharming N.V., the Belgian subsidiary of the Pharming Group currently operating under a court-supervised receivership. These assets include a 70,000 square foot cGMP protein manufacturing facility currently under construction and a pilot plant that is currently used to produce transgenic human alpha-Glucosidase, both located in Geel, Belgium. The acquisition has been approved by the Commercial Court in Turnhout, the Province of Antwerp, and Genzyme's board of directors. In the near term, the acquisition of the Geel facility is intended to allow Genzyme to assume control over the production of the transgenic enzyme and secure its supply to nine patients with Pompe disease participating in the extension of a clinical trial. Genzyme has been solely funding the production of the enzyme since Pharming Group sought receivership’.

When we heard about the financial problems of Pharming. It was a shock to all of us. Who would have ever thought that the company that was developing and producing our treatment was not able to manage and continue the production? It was a real nightmare and it made clear that even when a treatment is successful, the race isn’t finalised. Patients always will be in a vulnerable position as they always will be dependent on markets, CEOs, politics, researchers, physicians, governments etc.

When Pharming had financial problems it became a difficult period for patients, physicians and the employees of Pharming. At a certain moment there wasn’t even money to pay salaries of those people who were producing the ERT in Geel, Belgium. Most of these people were young, just starting their carreer. I really was impressed with their persistence and loyalty to continue working for those 9 Pompe patients in the Netherlands and Germany who were depended on their ERT. They even continued working when they didn’t know if they would receive a salary for it. The problems of Pharming and especially the threads of the financial problems for the Pompe patients were discussed in the news.

When Genzyme finally took over the Pompe program from Pharming. The employees in Geel were taken over as well. Most of these employees stayed at Genzyme to continue producing the ERT with the genetically modified rabbits. Many of them still work there and are closely involved in the Myozyme production in the 4000 Liter bioreactors in Geel.

Maryze's story - Part 4

2010-01-31T20:00:00.002Z

In 1998, Pharming and Genzyme started to work together in a joint venture.

In 2000 Pharming started with the building of the factory in Geel, Belgium. This plant later was bought by Genzyme and now Myozyme in the 4000 Liter bioreactor is being produced. So in the end our treatment was being produced there after all.

However who would think that everyone was happy with these developments, is mistaken. The animal welfare organisations were criticizing the use of animals for medicines. For Pompe patients in the Netherlands it was quite shocking to hear this. For us the development of the production of ERT in rabbits was the only chance we got and then animal welfare organisations and animal right activists were opposed to it? Did they really prefer the life of rabbits over the life of human babies?

Greenpeace too was opposed to this development. I knew they were opposed to biotechnology anyway as their billboard posters showing their opposition of this technology had hung everyone in Leiden. Although at that time Pompe disease, wasn’t in the picture yet. At a debate on animals and biotechnology in the Dutch parliament, my father and I too were present. I just wanted to show everyone that I was serious and would fight to secure treatment for Pompe patients.

During the break of the debate, a lady came up to me and my father while we were having coffee. She introduced herself and said she was working for Greenpeace. I was honestly a bit shocked and thought by myself well here it is, now I need to use all my arguments to make clear why I am in favour of human babies instead of rabbits. Then however the lady of Greenpeace continued saying: ‘Greenpeace still is opposed to medical treatments produced in animals, but when it comes to treatments for diseases for which no other treatment yet exists and for which animals are the only solution, we will make an exception. Then we will not oppose it. I just want you to know about this’. I was relieved. I didn’t need to go into discussion with Greenpeace. They too cared for human babies who otherwise would die. The fight however wasn’t over yet.

On a normal day I was sitting behind my computer I suddenly heard a commercial on the radio. A voice was telling about a little boy who did love rabbits, but these rabbits were misused to get a treatment for Pompe disease, while another production method without animals also could be done. Listeners who also were opposed to this misuse of animals could donate money to the foundation against animal lab testing (Proefdiervrij). When I heard this I was shocked. What other production method was available? At that moment the transgenic rabbits were the only ones and 7 people were successfully treated with this. How could they say such a thing?

Animal rights lies. The Pompe community fights for the truth - and not for the last time.

I immediately called the VSN. They too heard the commercial that meanwhile had been repeated several times on several radio stations already. This foundation also had a big advertisement in one of the national newspapers in the Netherlands, giving the same statement. In that advertisement a boy of about 6 years old was shown among rabbits hopping around in his room. The advertisement text stated this boy too had Pompe disease, but was opposed to using rabbits. Even a non medical professional with knowledge on Pompe disease could see in a moment, this boy absolutely didn’t have Pompe disease. Pompe patients in the Netherlands were upset by this attack and the VSN decided to appeal at the regulatory authority to forbid this type of incorrect advertisement over the backs of Pompe patients. The director of the VSN, Marcel Timmen, and I went together and we won the case by far. The commercial and the advertisements were forbidden per direct.

Maryze's story - Part 3

2010-01-31T19:51:00.001Z

In February 1997 my brother, Onard, returned from his 6 month exchange program at Trinity
College in Dublin, Ireland. To hear the latest developments in Pompe disease,
he came with us to the patient meeting of VSN. At that meeting I introduced him
to Dr. Arnold Reuser. They talked and a little while later Onard applied for a
training opportunity at the Department of Clinical Genetics of the Erasmus
Medical Center in Rotterdam. He worked there from March 1997 till March 1998
and participated actively in the research in Pompe knock out mice and the
effect of enzyme replacement therapy derived from genetic modified rabbits.

He was not allowed to tell us anything, but my father always asked him if the sun
was shining in Rotterdam or if it was cloudy. Often the answer was that it was
shining. Later we heard from Dr. Arnold Reuser that it was sometimes tough, as
some mice got into an anaphylactic shock during the treatment with
alpha-glucosidase. This was a serious adverse effect, and then it is even more
serious when it concerns a disease your sister is suffering from. Luckily these
adverse effects could be managed well (Human Molecular Genetics, 1999, Vol. 8,
No. 12 2145-2153).

Thesis of Dr Anges Bijvoet, with a contribution from my brother, Onard Schoneveld.

Maryze's story - Part 2

2010-01-31T19:44:00.001Z

In the morning of the 14^th of November 1996 I was still in bed and felt not that well. My parents were at work and Anton too was busy with a project. I was thinking about what to do, while at the same time I couldn’t do much physical activity as my body had deteriorated. Walking was very difficult and also breathing became such an effort that I often just sat on my bed or desk using the ventilator.

That morning I turned on the radio while laying still in my bed. The news was on an I heard a male voice saying: ‘A dutch biotechnological company had announced to develop a treatment for a rare disease. It would be the first time ever in human history that genetically modified rabbits were used to produce a medicine’. I was somehow shocked and felt awake right away. I sat still in my bed awaiting for the next bulletin to be sure. Then again it was said, but this news reporter added one little important detail: He mentioned it was about Pompe disease. I somehow still couldn’t believe it and walked to the living room to turn on the television and to watch video text. There it was in black and white: Pompe disease, treatment, rabbits.

I called my father and Anton. They too heard this news and were like me excited, but also with a bit of restriction as this news was so overwhelming that we couldn’t fully understand it yet. This was what my brother told me about. Then the phone rang and a Pompe patient I knew very well, asked if I heard the news. We talked about it and she was like me very excited. We promised eachother to keep eachother informed. I dressed myself and kept listening to the radio that continued bringing the news out. Then I was called again. It was Ysbrand Poortman of the VSN who had attended the press conference in Geel, Belgium, where Pharming had a small pilot plant to produce the enzyme. Ysbrand Poortman too asked me if I was informed about the latest developments and I told him that I indeed was. He told me he was approached by the Dutch News Broadcasting Service (NOS) and they wanted to interview a Pompe patient. ‘Are you interested?’, he asked. I said yes, without understanding the impact of this answer.

Articles in the international media on Pompe diseaseand its upcoming treatment derived from genetically modified rabbits.

One and a half hour later the camera crew and reporter were at my home. Luckily my sister and a good friend of hers also were home from school already, so they had tidied up my room a bit. Three hours later the news item on Pompe disease, treatment with rabbit milk and Pharming was on prime time news in the Netherlands. This was my first television appearance and many more would follow on broadcastings in the Netherlands, Germany, Belgium, BBC world and of course interviews with magazines and newspapers in The Netherlands, Germany, Belgium, Norway and Finland. Pompe disease was brought into the world.

Maryze's story - Part 1

2010-01-31T19:26:00.010Z

Maryze at the IPA Founding Conference, 1999

This is my contribution to the Pompe disease blog that Kevin O’Donnell created. I will first introduce myself. I am Maryze Schoneveld van der Linde and I was diagnosed with Pompe disease in 1979 when I was 8 years old.

My parents immediately became member of the Dutch Association for Neuromuscular Diseases (VSN). Around 1985 diagnosis groups were established within the VSN, so that patients with a specific disease could meet and also learn about the latest developments in their disease. My mother became part of the Pompe group and remained active for many years. In 2008, she would finally receive a royal decoration for her voluntary work all those years.

During one of the meetings of the diagnosis group, Wil de Geus, a woman with Pompe disease told the group that it was good to talk about good care for Pompe patients, but she didn’t only want care, but also a cure…afterall no one wants to have Pompe disease and a treatment was much wanted. The group members agreed and they got in touch with the scientists and physicians with knowledge on Pompe disease. These scientists and physicians were Dr. Christa Loonen, Dr. Arnold Reuser and Ans van der Ploeg. They were invited at our annual patient meeting and it was during one of those meetings I met Ans van der Ploeg for the first time.

She was young and working on her PhD on Pompe disease. I must have been 16 years at that time. I really admired her for what she did. Doing research on my disease and trying to understand what exactly is going on. Dr. Loonen too always was present on those meetings and always was interested in the person behind the patient. She is still a regular guest at our meetings even years after her retirement. After all we were not only patients, but also people with a life. One year later, in 1987, at another annual patient meeting Dr. Reuser asked me if I was interested to write with a woman with Pompe disease in Australia. This lady has asked him about the latest developments in his laboratory and also asked him if he knew some other Pompe patient to exchange experience and knowledge. I agreed to write to her, though I wasn’t that skilled in English at that time. Though so I thought, it is a good way to learn English.

From that moment on Linda Zaidan and I exchanged letters for over a couple of years, until internet made email and chatting possible. Linda was a couple of years older than me and at the moment of writing less affected than I. Unfortunately that changed…she soon became also dependent on a ventilator and she deteriorated quickly. From her I learned that an enlarged tongue and the inability to speak well or even to smile was not only a symptom in children with the infantile onset form, but also in adults with a very severe progressive form of Pompe disease. In 1987 Anton and I met at a youth club and one year later when I was 18 we started our relationship. He knew about my disease, but decided that we could do it together. When we met I was still able to ride a bike and able to walk, but I too deteriorated.

In 1990, at the 2nd year of my study cultural anthropology at the University in Leiden, I was admitted to the ICU at the Utrecht Medical Centre to be put on ventilation. I was there for 5 days to get all the settings right and to receive optimal ventilation. After the weekend I went to my classes again, as I did have to prepare for some examinations. 3 years later my first wheelchair entered my life.

In 1993 my brother started his study Molecular Biology at the same University of Leiden. In 1995 I remember that he once came home and told my parents and me about exciting news he heard during class. He said that a teacher had told about this rare neuromuscular disease, that no one ever heard about, Pompe disease and that they were working on a very new biotechnological method to get a treatment for that disease. He told the students about their creation of transgenic rabbit that were genetically modified in such a way that the females produced the enzyme human alpha-glucosidase in their milk. The theory was that this enzyme, when purified, could be given to humans with Pompe disease.

My brother of course was excited and went to this teacher after class. He said: ‘Well you said that no one knows about Pompe disease, but I do. My sister does have this disease’. The teacher, Martin Verbeet, was very surprised that one of his students had a sister with this rare disease they were doing research for with the newest technologies available. He told my brother everything he knew. From that moment I had hope, though I also continued with my life knowing that people were at least working on my disease and that only 100 meters from where I lived in my students house in Leiden. Who could ever thought about that? If it was pictured in a movie, you wouldn’t believe it.

Receiving my Masters degree in Cultural Anthropology at the University of Leiden, June 19 1995

In 1995 I graduated with a masters degree in cultural anthropology and went back to live with my parents in Varsseveld. My body had deteriorated so that I knew I couldn’t live alone. In spite of my physical problems I decided that my life would be as normal as possible, so I did apply for a job at several companies. Not long after I was invited for a job of 4 hours per week to work as a community worker with Turkish women close to where I live. It was exactly what I liked and was able to handle.

The Fate of the Transgenic Patients - Tiffany House

2010-01-21T22:04:00.001Z

The Fate of the Transgenic Patients . . .

After Novazyme and Genzyme merged and Pharming went into receivership there was one looming question on the minds of those of us involved in the transgenic trials: what was going to happen to the patients?

As Kevin has already mentioned, when the decision was made to pursue the CHO method in lieu of the transgenic, the patients and the patient organizations were assured that treatment for the transgenic patients would continue until they could be transitioned to the CHO product–or indefinitely if transition was impossible.

However, shortly after Pharming went into receivership in August 2001 this tune changed. Instead, we were told that the transgenic patients were Pharming’s responsibility—NOT Genzyme’s. As you can imagine, this declaration was met with opposition from the international patient community and from the “team” in the Netherlands.**

The international Pompe community banded together and stood up to Genzyme. We said that this was not acceptable, and we held them accountable. At the end of the day (and after many “conversations”), Genzyme stepped up to the plate and accepted that the transgenic patients were their responsibility. BUT, there were still more “battles” to come.

While Genzyme agreed to continue treating the transgenic patients by transitioning them to CHO (the offer of indefinite treatment if transition from the transgenic enzyme was impossible was now off the table), they declared that the Duke product was more effective than the transgenic, and the doses of these patients was to be reduced to 5/mg/kg/week. To put this into perspective, at that time the patients in the transgenic infantile trial were receiving 40mg/kg/week and those in the juvenile trial were receiving 20/mg/kg/week. Ultimately, after many discussions, the transition

I can’t speak to all that was said behind closed doors during this time. What I can say is there was a genuine concern regarding the transition and how patients would do. The team in the Netherlands wanted more information to make sure it was safe to transition their patients. But, the ability to wait for this information was taken out of their hands by upcoming events . . .

The transgenic method of production had been foregone in favor of the CHO method of production, so the production of the transgenic product ceased (and the fate of rabbit herd remains a mystery). That meant that there was a limited amount of supply left. The transition could only be delayed for as long as the supply held out. Then things got more complicated: a decision was made by the Pompe Leadership Team at Genzyme to begin using a new brand of vials, and the vials started to break. The breaking vials meant that the need to transition was sped up. There was no more time to make sure the transition would be smooth and not have adverse consequences for the patients.

By summer of 2003 most of the transgenic patients had been, or were in the process of, transitioning to the Duke product. The next hurdle that had to be faced was the dose. Within 6 months it was clear that the lower dose was not effective–patients were deteriorating where as before they had been improving. After many conversations Genzyme finally agreed to increase the dose (a further increase was later agreed to) and by summer 2004 the transgenic patients were once again receiving the same dose they had received while on transgenic (see my story on the Patients page of the AMDA website for an account of how I deteriorated during this time).

Unfortunately, by that time severe damage had been done to some patients. I personally remember seeing and talking to one of the patients in the original infantile trial. After a year and a half on treatment this patient was able to be off of the ventilator for several hours a day and could move her arms a little. These were drastic improvements. When the dust had settled after the transition, she was no longer able to be off of the ventilator and her condition had drastically declined. I can’t help but wonder what her life would be like today if her dose had not been reduced.

**I say “team” because if you ever talk to Drs. van der Ploeg or Reuser they will never take credit for the things they have accomplished—instead, they say it was the “team” that did it. This is, to me, just one of many of the examples of what drives them and their work. For the Dutch “team” it is not about notoriety or recognition. They have spent decades researching and working on Pompe for the sake of science. But, more importantly, for the sake of the patients the science will help.

The 2001 AMDA conference - Tiffany House

2010-01-21T22:00:00.002Z

L to R: The late Jose Valentin and friend, The Houses

As Kevin has already related, the weeks leading up to the 2001 AMDA Patient Conference were filled with turmoil and uncertainty.

I suppose the best place to start is, as always, at the beginning. The conference was the culmination of nearly a year of planning and organizing. By early September everything was planned and we were ready to go–eager to host the first ever Pompe patient meeting in the United States. It was going to be the first time that there was a conference for Pompe patients, and devoted only to Pompe disease—and from the responses we had gotten patients were planning to turn out en-mass.

Then, the tragedy of 9/11. As you will probably all remember, this was a time of turmoil and uncertainty in our country. BUT, despite statements made by Novazyme/Genzyme the AMDA never waivered in our decision to hold the conference. Kevin has already mentioned the statement posted to the GSDnet by Julie Smith of Genzyme on behalf of John Crowley (Novazyme) and Jan van Heek (Genzyme)—can you imagine our shock when we opened that email? We swiftly, and firmly, responded by saying that the conference was NOT cancelled and that we were still expecting a very good turnout from the scientific community. The exact message that was posted is as follows:

Dear All,

Thank you for your response. It was a complete shock to us to check our emails and find that the AMDA conference had been cancelled. We are flabbergasted that these two companies have taken it upon themselves to decide when and where a patient conference should be held.

We want to go ahead with the meeting. We have confirmations from keynote investigators that they will definitely present information to the patients at the meeting. These dedicated scientists/physicians are truly friends of the patients and have the patients' best interests at heart. The patients have a right to gather, exchange information, and to be informed about results from the ongoing trials. They also have the right to question the corporations about timelines and patient criteria for participation in new trials.

If we let Novazyme/Genzyme dictate all phases of what patients and patient organizations have a right to know and do, then we become putty in the hands of these "CORPORATE GIANTS".

We have all been affected by the bombings in the US, and we certainly understand anyone's apprehension with boarding an airplane. But if the corporations wanted to come--there are other means of travel available in the US. They can make other arrangements as are many of the patients. Many patients have told us that they want this meeting to take place and that they want to come to this meeting in spite of many obstacles; health, travel delays, etc. If patients have this much determination, then Novazyme/ Genzyme should be willing to come also to address this gathering.

Until Novazyme/Genzyme's announcement, we had 150 participants. As recently as Friday, both of these corporations had 20 people registered to attend.

Are there other motives for not wanting to attend?????

Novazyme and Genzyme stated that they were the sole sponsors of the AMDA Patient Conference. THIS IS NOT TRUE! AMDA has funded 2/3 of the conference. Genzyme has funded 1/3 of the conference. Novazyme has contributed nothing.

The following institutions were contacted today by AMDA and have vowed their support. They will make presentations at the conference.

Duke University-presentation on the CHO Trial

Rotterdam--presentation on the Transgenic Trial

Germany--presentation on the CHO trial and the Transgenic Trial

Presentation by the FDA--approval process for orphan drug products

Australia--presentation on diagnostics

UK--presentation on patient advocacy

Patient--presentation by a patient in a current clinical trial for Pompe's Disease

Marylyn House
AMDA

Kevin has spoken as to the possible motivations for “cancelling” our conference, but you would have to ask those who made the decision to know for sure. What I do know is, despite the lingering concerns caused by 9/11 the patients and scientific community demonstrated their strength and perseverance and showed up on the first day of the conference. My mom (Marylyn House) remembers talking to Dr. Reuser and thanking him for attending. He replied that his wife said he should come–it was too important not to. I share that anecdote because I think it is important to realize that it is not just the scientists, themselves, who are dedicated to our disease — it is their families, too.

That leads us to the conference itself. There were some really great presentations. What I remember most were the presentations by Duke (made by Dr. Amalfitano) and Erasmus (made by Dr. van der Ploeg). In particular, I remember the slides showing how the infants did on the different treatments (CHO vs. transgenic). What struck me the most about these slides was that both doctors presented slides that had graphs of the progress of the patients on therapy. The Duke slide showed three patients that showed an impressive improvement. However, after this initial improvement 2 of the 3 patients (or lines) sharply dropped off and then stabilized. As I recall, the decline was to baseline (or slightly below). In contrast, the slide from Erasmus showed steady improvement for all patients–albeit different degrees of improvement (one patient had a pretty drastic improvement while another had a very slight improvement).

You may think that I am biased as I was on the transgenic product–but I’m not. What I am talking about is interpreting a black and white graph of how the patients did. I am by no means trying to degrade the accomplishments of the Duke team–the babies were alive which they would not have been without treatment. All I am saying is that, to me, it was very apparent that patients on the transgenic enzyme seemed to do better.

I remember talking to Dr. Amalfitano after his presentation about my feelings. I can’t recall his exact words but they were along the lines of: “who are we to say that stabilization isn’t good.” He’s right. I firmly believe that in a disease like Pompe the first goal that needs to be reached is stabilization. Anything else is a bonus. But, at the time, I was having a hard time reconciling the graphs I saw with Genzyme’s decision to pursue the CHO method instead of the transgenic.

Now that I am older and wiser ;-) I understand that CHO was the quickest way to bring treatment to Pompe patients around the world. Personally, though, I wouldn’t be surprised if the transgenic product rears its head again one day in the future . . .

A break from our normal schedule

2010-01-21T21:50:00.001Z

One of the things I really hoped to do with this blog was to include the perspectives of other members of the international Pompe community. I am therefore delighted to say that I now have a number of contributions that I will be posting to the blog. I to begin with I have contributions from Tiffany House (of the AMDA and IPA) and Maryze Schoneveld van der Linde (of the VSN and IPA). Both people with stories to tell and who were (and are) in a good position to observe events. I thank them both for their excellent contributions and encourage others to contribute their own.

2002 concluded - last thoughts on John Crowley

2010-01-20T23:48:00.001Z

I described 2002 as the John Crowley era. In fact, it was the only time that John was directly involved in the Pompe project. As far as I can judge, he did a competent job and left a more patient-centred approach that continues at Genzyme to this day. That is his real professional achievement, I think, and it's not a bad legacy to leave. It's one he should be proud of.

However, was John responsible for the development of a treatment for Pompe disease, as The Cure implies and Extraordinary Measures more-than-implies? No, absolutely not.

John Crowley is, I believe, a good man and a good father. He is one of the worldwide Pompe family. He has a prodigious talent. However, for me, The Cure is the story of a talent wasted. The story of Novazyme, in particular, is essentially the story of a gigantic displacement activity. It's what kept John busy while the rest of the world got on with developing a treatment for Pompe disease.

I can't help but wonder what might have been. What if John had been more of a team player and that amazing energy and talent had been used within the international Pompe community? What might have been achieved then? Looking through my notes in writing this blog, I saw that John Crowley was originally down to attend the IPA founding conference in 1999 but did not come. What if he had? What might we all have achieved then? What if...?

I'm glad - beyond glad in fact - that John's children were finally able to take part in a trial of ERT. As I've said before, my heart sings every time I hear of a child or adult I know of starting treatment. And I'm glad that he and his wife have had the courage to tell the story of what it is like to cope with seriously ill children. That makes The Cure a moving book at times and, by all accounts, Extraordinary Measures a moving film. It's a story that many parents coping with seriously ill children will identify with and one that deserves to be more widely known and understood. It's a great thing that they have helped raise awareness in this way. I just wish that they would tell the real story of the development of a treatment for Pompe disease too.

Pretty soon - already, in fact - new Pompe patients will simply accept that the treatment is there and not give much thought to how it came about. That's as it should be, I guess. However if The Cure and Extraordinary Measures fill the vacuum, then a great disservice will have been done to the researchers who really did help develop the treatment and to the international patient community who played a part in it. That's why The Cure is, ultimately, a disappointing book. It's a shame, because with a bit more competent research - and, perhaps, a bit more generosity of spirit - it could have been a great book. Another 'what if...?'

That's why it's important that the real story is written down, so that it is not forgotten and is there for those who do want to know. One day, that story will be told by the great book that it deserves - until then, this rather sloppily written blog will have to do. But I digress.*

*Proving my point about sloppy writing. See what I did there?

2002 - the IPA patient registry

2010-01-20T23:02:00.001Z

Aside from the continuing development of ERT, the IPA was involved in another important project , starting in 2002. This was the establishment of a Patient Registry as Erasmus University, Rotterdam.

Looking ahead to clinical trials with late onset patients, it was acknowledged that the 'natural history' of pompe disease in adults was poorly documented. This meant that, for example, it would be more difficult to show a positive effect of ERT, because there was no baseline to compare patients against. Arnold Reuser and Ans van der Ploeg came up with the innovative idea of a Patient Survey. This would consist of a professionally authored questionnaire to be completed by patients with the anonymised data held at Erasmus University, to be analysed and published. The IPA helped fund the work and ensured that patients themselves had some ownership of their own data. The survey has led to a number of publications, with researcher Marloes Hagemans as the lead author (listed at the link above) - a very valuable contribution to our understanding of Pompe disease.

Yet another ground-breaking success story from the Rotterdam team - and another example of the patient community taking control of their own destiny.

2002 - continued

2010-01-20T22:41:00.001Z

2002 continued the established pattern of regular liaison between Genzyme and the IPA.

Where possible, there were public reports of these meetings. For example, the visit of the IPA Executive to Genzyme HQ, on 16/17 April 2002 led to a positive joint statement. This was followed by accounts of the teleconference in September 2002 and a further update in December 2002. Of course, these were only the public face of continuous contacts at various levels.

On of the main decisions, early in 2002, was to progress to commercialisation using Genzyme's own in-house enzyme, priduced using their own cell line. We were therefore in the position where the eventual product was not that used in either the first clinical trial in Rotterdam or the second trial at Duke University. Of course, the actual enzyme was very similar - what changed was simply the method of production. After all, insulin used today is not produced in the same way as that used in Banting and Best's Nobel Prize-winning work on developing a treatment for diabetes. It doesn't lessen their achievement one bit. Likewise, the fact that Genzyme now produce alpha-glucosidase in their own cell line does not detract one iota from the ground-breaking achievements of the pioneering Rotterdam team, or the following trial at Duke.

Genzyme agreed that the clinical trial patients should continue to receive the enzyme they received in the trial (Pharming for Rotterdam, Synpac for Duke) until an orderly transition could be arranged. It's fair to say that this was the cause of a great deal of discussion and concern. Patients who had done well, particularly with the Pharming enzyme, were - understandably - apprehensive about switching to another product. A particular issue was the fact that the Pharming enzyme was given at a higher dosage and it was felt that a benefit was lost on transfer to the lower dosage Genzyme product. Some of those directly involved may care to comment here.

Genzyme continued to make progress with production, bringing more bioreactors on stream. 2002 progressed according to plan, with a series of further trials being announced in November 2002. At the same time, it was announced that John Crowley would be leaving Genzyme. There's a little more about this in The Cure but essentially he had not been able to separate his personal and professional situations. I don't blame him for that - I don't think there's anyone in the world who could have done so. His replacement was Frank Ollington, who I would credit as being the person who brought the project to fruition. Frank's attitude was - I paraphrase wildly - "I don't give a rat's ass if you like me - my job is to make this product happen." And he did.

2002 - The John Crowley era

2010-01-17T23:14:00.001Z

Reading through the huge number of emails, tele-conference transcripts and written notes from 2002, I find it hard to reconcile them with the account of this year in The Cure.

In fact, I think that the account in The Cure, in its rush to airbrush the patient community out of the picture, sells John Crowley short somewhat.

In general, I do think that John succeeded in bringing some of the Novazyme philosophy to Genzyme. In a lengthy transcript from 26 February 2002, of a teleconference between John Crowley, Jan van Heek and the IPA Board, I am struck by the new-found openness shown by Genzyme. They went into great detail about their plans - information that was in confidence and commercially sensitive. Regulatory-sensitive too. There was a lot of trust, openness and good humour. Something had changed for the better and was going right. I, for one, am happy to give John Crowley the credit for that.

The exciting news was that good progress had been made with manufacturing. By the end of 2002, supply of enzyme was no longer expected to be a bottleneck, opening the way to larger trials.

This new positive relationship (a complete change-around from the nadir of September 2001) was cemented by a visit of the IPA Board to Genzyme's HQ near Boston, in April 2002.

We were back on track.

A small personal note on 2001

2010-01-17T22:29:00.001Z

I can't end the account of the events of 2001 without noting a small but significant personal change for me. I stood down as the Pompe representative on the AGSD-UK Executive. Partly because I was just worn out with it really. Partly because I had always seen my involvement as finite - I would do it until a treatment was available. That day was was now not so far off. And partly again because I was in the happy position of having a good successor in Allan Muir.

I've already sung Allan's praises once, so I won't embarrass him by doing it again. Except to note that he is one of those people who seems to radiate calm, when everyone else is in a flap. A quality I can only admire.

From now on, the rest of this blog (at least the bits written by me) will be somewhat detached from the UK scene. I retained my involvement with the IPA for another couple of years though (before cunningly diverting that to Allan too).

I therefore only have first-hand experience of two more years - 2002 and 2003.

Why Genzyme are one of the world's greatest companies

2010-01-17T12:05:00.001Z

I've been slightly harsh about Genzyme in my last few postings, so I'd like to re-dress the balance somewhat.

Sure, they had a run of 3 bad decisions - buying Novazyme, trying to prevent a patient meeting and putting John Crowley in charge of the Pompe project. However, in the grand scheme of things, those were aberrations that should not detract from the big picture. And I'm in no position to be too critical since, as I've admitted, I was happy enough with two of those decisions at the time.

None of the above means that Genzyme is a bad company. They're not bankers, for goodness sakes. They're just not perfect, that's all.

The big picture is this. Genzyme is a company that does well by doing good. Their products add greatly to the sum total of human happiness and, in many cases, transform patients' lives for the better. They bring hope to people who had none. Sure, it's a business and if it didn't make a profit they wouldn't do it - and they can certainly show some corporate ruthlessness in the pursuit of that profit.

However, I've met many Genzyme employees over the years and two things have struck me about every single one of them. Firstly, they have all been impressive performers - the recruitment bar is clearly set high. Secondly, I always got the impression that it was more than just a job. They believed in what they were doing and were motivated by a genuine desire to help patients. If a company has those fundamentals in place with their staff, it won't go far wrong.

Genzyme have also been generous in their provision of treatments to those parts of the world which cannot afford them, indicating a humanitarian streak. I'm not saying that they are corporate saints - but they are certainly on the side of the angels.

That's enough good things about Genzyme for now. I may well be critical of them again - but I wanted to put that criticism into its proper context.

The conference itself

2010-01-16T18:23:00.001Z

After all that drama, the conference itself was great. I met many people whom I 'knew' from email, some for many years by this time. I realised that we had perhaps become a little blaze about our European meetings where we now took it for granted that leading researchers and company representatives would attend and keep us up to date. For many attendees, there had been nothing like this before. There were presentations from all the key scientific players. Genzyme/Novazyme were there and clearly eager to build bridges following their latest gaffe. for my part, I was only to happy to do what I could to help them. At the time, I saw them as simply having made a silly mistake - least said, soonest mended. A really positive experience for all concerned and well done to the Houses for organising it (and funding most of it).

The show-stopper was Ans van der Ploeg's presentation of the Rotterdam juvenile trial - the first results we had seen of ERT in anyone other than infantile patients. And what results. A young man in a wheelchair was shown getting up and jumping out of it, amongst other activities. Very dramatic. The other results had also been positive, though not as good. However one patient from that trial - Tiffany House - was able to make a presentation to the conference herself which we may take as a positive outcome in itself.

During the conference I had a breakfast meeting with John Crowley. I hadn't had the chance to catch up with him since the Novazyme interview and was eager to speak with him. John told me that he had sold to Genzyme because he had decided that this was the best way to get the Novazyme treatment to patients. Furthermore, now that he was in charge of the overall Pompe project, he would be bringing Novazyme's patient-oriented approach with him. He told me that he was keen to maintain the dialogue with the IPA. This was all music to my ears. Bear in mind that, at this point, I had no idea that the Novazyme product was a complete dud. As far as I was concerned, John was one of the 'Pompe family' and the fact that he was in charge now could only be good for us and for the project. As it turned out, I was wrong.

Not because John Crowley is a bad man - he is not. But because of what seems blindingly obvious in hindsight - no-one on Earth can be expected to take objective decisions on something that their own children's lives depend on. I didn't see that at the time because I wasn't capable of thinking objectively either.

Three in a row for Genzyme.

AMDA Patient Conference 28-30 September 2001

2010-01-16T17:50:00.005Z

The AMDA had organised some pioneering scientiifc conferences, as desribed earlier. However their first patient conference was held on 28-30 September, 2001. That link leads to a good summary of it, including photos, so I won't repeat that here.

I'll get to the conference itself in a moment, however before doing so I need to recount a bizarre incident from the run-up to it: on 24 September, Genzyme/Novazyme tried to cancel the AMDA's conference. Why exactly did a pharmaceutical company think that it was within their remit to cancel a conference organised by a patient group? Well, here's what they posted to GSDNet, via Novazyme staffer Julie Smith:

The tragic events of the last two weeks have had a profound impact on us all. Its repercussions have been felt worldwide and now it has affected a Pompe meeting that we had all very much looked forward to.

As you all know, the AMDA has announced that the scientific portion of the Pompe conference has been cancelled. There are still plans for an abbreviated patient meeting in Texas to go forward on September 29th.

In view of current events, we think that the AMDA decision to cancel the scientific meeting is wise. The AMDA’s decision mirrors Genzyme’s own internal concerns as evidenced by the strict travel guidelines that substantially limit travel to all except the most urgent situations and only for limited numbers of Genzyme employees. We likewise, however, understand the patient community's desire to come together and to not let these unsettling times delay such an event. Still, as the sole sponsors of the Pompe patient meeting, we at Novazyme and Genzyme do not think that it is prudent for this meeting to go forward as originally planned. There are three key reasons for this view:

1) Safety: We have full confidence in our nation's ability to provide for our national defense and ensure our security. Nonetheless, in the next several weeks as a U.S. retaliatory strike inevitably begins, we believe that the most secure places for patients, physicians, researchers and our employees will be in our own homes and communities.

2) A number of key physicians and researchers have already confirmed that they will not attend including Drs. Reuser, Kishnani, Slonim, Byrne, Tift, Canfield, Nicolino, among others.

3) A number of patients and their families (as well as physicians) have already cancelled their travel plans in view of the AMDA's initial decision to cancel the entire meeting.

We are firmly committed to building our relationship with all Pompe patients, physicians and their families and to keeping an open line of communication. There are two steps we propose to build on this commitment.

1) Initiate a series of patient “Town Hall” meetings across the U.S. and in Europe this fall as circumstances change and travel becomes less restricted in order to promote an exchange of current information and issues.
2) Organize a scientific symposium in early 2002 in coordination with the International Pompe Association and a well-recognized academic institution, such as the U.S. National Institutes of Health.

Also, for those of you who decide not to attend this weekend's conference and who have non-refundable airline tickets, Genzyme will reimburse the non-refundable portion to you. Be safe and God Bless you and your families.

John F. Crowley Jan van Heek
President & CEO Novazyme Pharmaceuticals Executive VP, Genzyme Corp.

My first reaction was "What the...?".The 'tragic events' referred to were, of course, the terrorist atrocities of September 11. These were, to say the least, unsettling. However air travel has returned to normal and, as far as I knew from my discussions with Marylyn House, the AMDA conference was still very much on. So I was surprised but the thought never occurred to me for a moment that the Genzyme/Novazyme statement was made without the support of the AMDA - let alone that it contained some outright falsehoods. I was rapidly brought up to speed by Marylyn and made the following response:

Here are three key reasons why I think the Novazyme/Genzyme view is wrong:

1) This is a conference of the AMDA - a patient group. It is absolutely not the business of the pharmaceutical industry to go around cancelling patient conferences because it doesn't suit them. The AGSD(UK) conference is next month - is that also to be cancelled if it doesn't suit the companies?

2) There will still be significant scientific input, alongside the patient contributions.

3) I am by no means convinced that San Antonio is likely to be a hotspot of military or terrorist activity in the event of the ground war starting this week.

I can't emphasise enough how disturbing I find this. My first assumption was that the Novazyme/Genzyme email had been issued with the full co-operation of the AMDA. I now understand that this is not the case. The idea that the patient organisations can have their activities dictated by the companies is one that needs to be nipped in the bud right now.

For my own part, I will be travelling to Texas to attend the meeting, as long as the AMDA is holding it.

It quickly became apparent that this was the consensus view. Not only that, it appeared that the scientific speakers (The Netherlands, Germany and Australia as well as the US) were all still intending to attend. So why on earth did Genzyme think that they could curtail the activities of patients in this way?

The charitable explanation is that Genzyme were sensitized following the loss of a key member of staff on 11 September. Lisa Raines had been VP in charge of government relations at Genzyme and had been on the plane which was used to attack the Pentagon. People were undoubtedly - and understandably - upset at the loss of a friend and colleague in such circumstances. If so though, why not just say so?

However, there is also a less charitable explanation. Randall and Marylyn House's daughter, Tiffany, had been part of the juvenile trail carried out at Rotterdam (following anonymous selection). This undoubtedly led to them taking a robust position on the continuance of provision of the Pharming enzyme to those who had taken part in the trials of it. That certainly didn't suit Genzyme. Was this seen as a chance to reduce the influence of the Houses?

There is also an even less charitable explanation. A press release from Genzyme on 27 September announcing the completion of their acquisition of Novazyme revealed that John Crowley was now in overall charge of the Pompe project. Did he see this as an opportunity to stick one to the Houses? It's an ungracious thought, I admit and there is absolutely no mention of this period at all in The Cure, so no corroborating evidence there. In fact, the only mention of patient groups in that book at all is of John's introduction of people from his own Children's Pompe Foundation creation to Genzyme staff. In retrospect, perhaps an indication that he would have difficulty in separating the personal from the professional. Did that difficulty extend to grudges too, I wonder?

Whatever the reasons, Genzyme tried make a mistake that would have been on a par with their buy-out of Novazyme (albeit less expensive). Yep, that bad. Fortunately, they were faced down by the patient community. With hindsight, this assertion of patient independence was a pivotal moment.

Oh, and Genzyme and Novazyme did come to the conference in the end, along with everyone else.

2001 continued

2010-01-16T16:48:00.001Z

Things seemed to be on a pretty even keel, even if progress was not quite as fast as we might have liked.

Then came the news of the Genzyme/Novazyme merger in August 2001. I have already dealt with the Novazyme story in earlier posts and don't propose to re-hash the whole sorry story again here.

This was swiftly followed by the news that Pharming had gone into receivership. Thankfully, as noted before, they survived to fight another day. Genzyme acted to ensure that there was a continued supply of the rabbit enzyme for those patients receiving it, though it was clear that they would now be even more keen in transitioning those patients to the CHO enzyme as soon as possible.

Nevertheless, it raised a lot of concerns - we appeared to have been on one course and now everything was, once again, up in the air. Thankfully, an AMDA patient meeting was scheduled for September 2001, in San Antonio, Texas. As well as being the first opportunity for may US patients to get together, Genzyme had undertaken to participate and answer questions.

The Duke results

2010-01-16T16:28:00.001Z

Although the results were now widely known, it is worth noting that March 2001 saw the publication of the results of the Duke University trial led by YT Chen, using the Synpac enzyme. There was the inevitable press release from Genzyme/Pharming and a paper published in Genetics in Medicine. Only the abstract is available free unfortunately.

This largely (with the caveat previously mentioned) confirmed the results from the Rotterdam trail.

It was also a real achievement for Yuan-Tsong Chen and his co-workers. Known to all as 'YT', Chen was (still is) a well known and well-liked figure amongst US patients. This was partly because his interest in the glycogen storage diseases extended to types I and III, the liver-based GSDs. These are very different from Pompe and, thankfully, more treatable. YT had the reputation of being a diligent and committed doctor, as well as a good scientist.

One name missing from the list of authors for the Duke paper was Johan van der Houe. He had been a collaborator in the earlier Chen papers and retained a close interest in the subject. He had returned to his native Belgium, where he was involved in the clinical trials. I had met Johan at a number of meetings of the years - he was, in fact, one of my earliest and most helpful scientific contacts. His commitment and contribution deserves to be noted and this seems like a good place to do so.

Genzyme up their game - into 2001

2010-01-16T16:07:00.002Z

What can we tell from the previous posts on the AGSD-UK 2000 conference?

Firstly, Genzyme confirmed that they had opted for the CHO method of production, rather than the rabbit method. As far as we could tell, this was simply because the rabbit method was not feasible. In hindsight, it's hard to argue with that and the fact that they committed to continue rabbit production for those already receiving it did help to soothe some nerves.

However, things were not so straightforward. Despite assurances that the two products would be identical, some doubts remained. The emerging findings from YT Chen's Synpac trial showed an important difference from the Rotterdam trial. Chen found that the initial effectiveness of the treatment was lost when the patient began to generate antibodies in response to the enzyme. The Rotterdam team had observed the same antibody response but had not found any difference in the effect of the treatment. This led to some uneasiness that a superior product was being ditched for commercial reasons, however compelling.

On a more positive note, it was clear that Genzyme now recognised the importance of working with the patient community. On an international level this would be through the IPA.

So, we now had a known destination - a Genzyme treatment, produced by their 'standard' CHO cell method - and an undertaking from Genzyme to keep us informed of progress on getting there. It was clear to us that they were committed to do so.

There were monthly telephone conferences with the IPA Executive. However, much of these discussions were 'in confidence' and we were keen to let the wider community know what was going on.

Genzyme therefore agreed to an interview with Paul Kaplan, who was in charge of the overall Pompe project. I canvassed for questions via GSDNet beforehand, to try to make sure that as many of people's concerns as possible were answered. The interview took place on 29 March 2001 and was reproduced in the Pompe's Bulletin, as well as GSDNet and the IPA website.

Reading it again for the first time in years, I am impressed with how open Genzyme were willing to be and how on top of the subject Paul Kaplan was. It was a telephone interview, so he might have had a team standing by to pass answers to him. It doubt it though - he was just good at his job. I'm also struck by how accurate his roadmap to availability turned out to be. He reckoned on approval in 2003. He wasn't too far out.

The next day, Genzyme/Pharming announced a multi-centre clinical trial, using the CHO enzyme.

We now knew exactly what was needed before ERT became widely available as a treatment - and why. We knew it wouldn't - couldn't - happen overnight. But we knew that we were very much on our way.

Oxford 2000- part 2

2010-01-07T21:29:00.003Z

AGSD-UK's Oxford 2000 conference (part 2)

Aside from the researchers we also had a strong representation from Genzyme and Pharming (who were the sponsors of the conference). In attendance were Jan van Heek, Gene Williams, Willem va Weperen and Phillipe Houten (I'm guessing here -I forgot to write Phillipe's second name down - d'oh!).

The first two had attended an IPA executive meeting the night before and had expressed a desire to be more open and communicative with the patient community. I therefore gave them the opportunity to answer a few of the questions that have been in people's minds since the switch to the CHO method of production: are there any differences in the results for the two methods? what are the benefits to us? What are the time-scales for trials? What is the availability of enzyme?

Genzyme: ERT is working and this is very encouraging. The question for us now is how can enough enzyme be made for more trials and beyond. It is good to know that, from Genzyme's experience, it is possible to get Government/insurance to pay for such products.

It was a difficult decision to switch manufacturing from the rabbits to cell culture. We have not been good at communicating this and in future would like to work better with patient groups.

We know that the product works and now need to work on appropriate doses etc. Time lines are under review and more questions arise as we go along. We promise to publicise any changes.

Questions

Q: We know that the milk based enzyme is efficient and non-toxic. can it not be made commercially viable? There is as yet no data for the cell-based enzyme.

A: We have looked at the unpublished data from Y T Chen and our believe that both products will behave similarly is supported by the data. (A. Reuser commented that tests with mice had shown no differences, however there was no comparison with humans yet. As the two trials had been set up differently, it was difficult to make an exact comparison - the types of patient, doses etc. may have been different, amongst other uncertainties. Conclusion - there is no evidence that suggests that they don't work equally well.)

In June, in Boston, all sorts of experts convened and reviewed the data. It was concluded that more trials were needed to satisfy the requirements of the regulatory authorities.

Lots of enzyme is needed and manufacturing must be scaled up dramatically

Q: Will it be easier to produce commercial quantities using cell manufacture?

A: Easier and faster. We have 60 different people working on the Pompe programme. The uncertainties are that we have no manufacturing capacity yet and no regulatory approval yet.

Q: Why not do trials which would be approved quicker?

A: Can't do it until ERT is proved to work, to the satisfaction of the regulatory authorities. At the beginning we didn't know the dose that would be required. A lot of material is needed to be effective, therefore a large manufacturing capacity is required. At least 50 people working on doing that.

We decided that this way was faster, more durable and gave more product to get to patients.

The key now is to get trials started to get us to the first end point - regulatory approval.

We need to select patients, treat them and then analyse and present the esults. All that takes time.

We now understand the importance of getting timely information to patients.
We are meeting with the FDA in October to discuss the next trial.

Q: Is this just for the USA?

A: Our intention is that the data will be produced in such a way that it is acceptable to all the different authorities. It will be a multi-centre trial in around 5 locations - not confined to the USA. We will communicate details to patient groups via the IPA.

Q: What are the plans for future trials?

A: The constraint is supply of enzyme. There may not be enough until late 2001. this is under discussion and review. We are working hard on this issue.

Q: Is the switch to CHO the solution to the problem of enzyme availability or the cause?

A: The solution. It will be quicker.

Q: What will happen to the patients receiving the rabbit milk enzyme at the moment?

A: We met some of the patients in Rotterdam. We are committed to provide the rabbit enzyme to them until 2001 [implication was until CHO supplies are available - KOD].

Q: In the early days we were told that rabbits could produce enough enzyme, then that cows would be used. Is that off the agenda now?

A: We think that there will be enough CHO capacity to meet demand. The cow platform is being preserved and the rabbit line just in case the CHO production does not work. All you can do is to make the best decision you can on the basis of the available data - and at the moment that means CHO.

Q: Would it be better to develop the products in parallel?

A: We've kept the one we don't want to implement as the back-up. If we used it we'd need to go back to the start with the regulatory authorities. However we do not expect CHO production to fail at this stage.

Q: Is it still worth getting regulatory approval for the rabbits on a small scale adult trial?

A: We are convinced that the data available shows proof of principle. However we have also concluded that the regulatory bodies would not give approval on the basis of the existing data. The big issue for us is how can we increase the availability of the product. CHO is the fastest way of doing this.

Q: Any information on costs?

A: Need to show treatment works first of all. Have experience of persuading insurance companies/governments to pay for ERT.

Q: Can you give information on trial dates?

A: This is ongoing. Earliest will be early 2001, followed by another 6-9
months later.

Q: Allowing for all obstacles how long till regulatory approval?

A: At least 5 years for all approvals.

Oxford 2000 part 1

2010-01-06T19:50:00.013Z

Every year I say the Pompe's workshop was the biggest and best so far, and this year's was no exception. Just under 50 people attended the workshop,held on Saturday 9 September 2000 at the Oxford Belfry Hotel.

As well as UK patients and families, we also had participants from Denmark,The Netherlands, Germany and the USA. These included some representatives from Genzyme and Pharming, of whom more later.

To begin with, we had the star of the show - Ans van der
Ploeg. She was accompanied by Arnold Reuser, Marian
Kroos and Hannerieke van den Hout. Yes,we had the cream
of Pompe's research attending the one little meeting. I can't
tell you how pleasing it was to see not only the research
leaders but also Marian Kroos, whose name has co-authored
many research papers and has been Arnold Reuser's
collaborator for many years, and Hannerieke van den Hout,
who has been deeply involved in the clinical trial and is the
'first author' on the Lancet paper.

I introduced the proceedings by mentioning the change in
attitude towards enzyme replacement therapy for Pompe's,
from it being effectively a dead duck to a successful
clinical trial. I pointed out that this was due to the work
carried out in the Netherlands, in large part by people
present today.

Dr van der Ploeg gave a good account of the ERT trial
on infants. She began by saying that she had said in every
talk for the last 10 years that enzyme replacement therapy
was a possibility. Now, for the first time, she could
present real evidence of it working.

She presented the results of 36 weeks of treatment for
the 4 infants. The inclusion criteria were: showing
symptoms of Pompe's, including heart enlargement; less
than 10 months of age; alpha-glucosidase deficiency;
muscle biopsy diagnosis.

The ages at diagnosis were 1, 4, 0.5 and 6 months, and
at inclusion, 3, 7,2.5 and 8 months.

Patients 2 and 4 had lost a great deal of muscle function
and required oxygen.

After 12 weeks, all 4 babies had an alpha glucosidase
activity within the 'normal' (i.e. non-Pompe's) range.

Muscle biopsies (images shown) illustrated that glycogen
storage had been markedly reduced. Heart size was
also reduced.

Muscle function showed improvement. One child is still on
a ventilator and one is now walking.

Conclusions:

The treatment is generally well-tolerated.

The treatment prolongs life.

Therapeutic effects were observed.

Muscle function and cardio-respiratory function were both
stimulated.

And perhaps most importantly - it is easier to prevent than
to cure, therefore treatment should be started early.

[Applause]

Questions

Q: The dose was increased 3-fold during the trial. Are
you satisfied with the current dose?

A: Yes. Enzyme activity is normalised, which is a good
sign that the dose is correct.

Q: Is it possible that not all muscle activity would be
recovered?

A: Yes, it is possible - some muscle fibres may be
beyond repair. Recovery may be a very long process
for severely affected patients.

Q: Did any patients show an antibody response to
the enzyme?

A: Yes but this did not appear to have an effect on
the treatment.

Q: Does enzyme get to the lysosomes?

A: Yes - we know this because glycogen is removed
from the lysosomes by the enzyme.

Q: Is it possible that measuring enzyme activity may
overstate the amount there, since you may be measuring
enzyme that is in the rest of the cell too?

A: Theoretically this is possible, however alpha
glucosidase is only active at the acid pH of the lysosomes,
not the neutral pH of the rest of the cell. In the end, the
best measure of enzyme activity is that the glycogen is
removed and muscle function improves. This has been
shown by the trial.

Q: What the implications for the late onset types?

A: Too early to say but treatment holds promise. It will
be a long process but hopeful for the future for ALL
Pompe's patients.

Q: Can you say anything about the status of juvenile trials?

A: The trial has started but it will take longer than with the
infants to make certain that measurements and improvements
are actually due to the treatment. There is a need to gather
reliable statistics and data.

Q: Is a controlled diet more important in the later onset forms?

A: There are many hypotheses. It is certainly very important
to have enough protein for muscles. Keeping busy/moving
is a good way to help muscle strength.

[Prolonged applause]

Back on track - progress on the real treatment

2010-01-06T19:45:00.004Z

After that excursion to plant Novazyme, we go back to the development of a treatment for Pompe disease.

The results of the clinical trials, corporate shenanigans and subsequent buy-out of Synpac had left patients feeling uneasy. The Rotterdam (and Duke) results had been promising yet the corporate turbulence had confused the picture. What exactly was going on? Could we still rely on genzyme? What was going to happen next?

At the AGSD-UK conference, held in Oxford in September 2000, we got some answers.

An attached IPA meeting ensured a good international presence and genzyme sent over a high-powered delegation, including Jan van Heek, second in command of the company. That itself sent a message that they meant business.

What follows in the next couple of posts is the account that originally appeared on GSDNet at the time, complete with some contemporary photographs.

Novazyme's results

2010-01-03T19:55:00.009Z

Before the visit, Randall House and I had to sign confidentiality agreements that meant we couldn't share the evidence we were given. However, I note that the agreement is now out of date, so here it is.

What follows is a series of photographs of tissue from Pompe mice, 3 from a set of 9 we were given, all treated with a stain that shows up glycogen deposits as purple. On the left hand side is tissue from mice treated with the 'standard' alpha-glucosidase (Standard GAA). On the right hand side is the same type of tissue from mice treated with just 2 mg/kg of the Novazyme product (HP GAA) just 6 hours before.

Did you notice what we noticed? That's right - the glycogen in the mice treated with the Novazyme product has completely disappeared. After just 6 hours! And at a dose of only 2mg/kg!

The Novazyme blurb goes on to note that the appearance of the tissue from the mice treated with the standard enzyme was similar to that from untreated Pompe mice, while the tissue from treated with the Novazyme product looked like that from normal mice.

You have to admit that, even now, that looks pretty convincing. Heck, right now, looking at it all, I'm prepared to be convinced all over again. As I now know from reading The Cure, John Crowley knew exactly how convincing such photos could be, as they made a big impression on him during his visit to Pharming in 1998.

This is the same evidence that, according to The Cure, was shown to Genzyme during the discussions to persuade them to buy out Novazyme. Which they did - for $137.5 million (with the promise of $87.5 million more if it worked). Bearing in mind that Genzyme only paid $20 million for the Synpac product (a real product that had been shown to work) and $17 million to buy into Pharming (ditto) this was a breath-taking sum. A very impressive achievement on John Crowley's part.

And what did Genzyme get for their $137.5 million? Fast forward to November 2003and the IPA Conference held in Heidelberg, Germany. I asked what was happening with the Novazyme product. William Canfield answered. He said that it had not proven possible to replicate the promising results shown with the Novazyme product and that the impressive photographs (above) were simply "an artefact" because the procedure had been carried out wrongly. In fact, here is the full question and answer, lifted from the DVD of the conference:

So there you have it. The evidence which had helped persuade Genzyme to part with $137.5 million was "an artefact". A flaw in the process had failed to stain the glycogen still in the tissue samples of the mice treated with the Novazyme product, while staining that in the tissue samples from the mice treated with the other enzyme. In other words, those convincing pictures shown above, which suggested that Novazyme's highly phosphorylted enzyme was superior to the others, were false, because of a "mistake" by Novazyme in conducting the test. Hey, it could happen to anybody.*

The noise of jaws dropping around the room was audible.

There were only 3 possible explanations for this astonishing state of affairs.

1) Novazyme was engaged in an intentional fraud.

I think we can rule out that one. I don't believe that anyone involved was less than sincere and, my own demonstrable gullibility notwithstanding, I see no evidence to suggest otherwise.

2) The Novazyme product was as good as they said, those results were genuine and Genzyme are covering them up.

Again, I don't think so. Apart from anything else, the sheer number of people that would have to have been involved makes it unlikely that it wouldn't have leaked out. The idea that Genzyme are keeping a genuinely fantastic product in some big hangar like the one at the end of Raiders of the Lost Ark is just plain risible.

3) Novazyme made an incredible, unintentional, undetected mistake and then managed to fool themselves.

We have a winner. The thing that I had failed to take into account was that if anyone wanted to believe John Crowley more than me, it was John himself.

John Crowley's achievement here was to persuade Genzyme to part with $137 million for a dud. Vaporware. I take my hat off to him, however I think we have to ask - couldn't Genzyme have put all that money to better use? Developing their proven Pompe treatment, say? Just a thought.

In any event, I hope this account scotches any notion that Novazyme had anything to do with the development of a successful treatment for Pompe disease. Clearly, the evidence shows that it did not. Indeed, the existence of Novazyme, in particular the resources Genzyme used to acquire it, may well have delayed the availability of that treatment.

As I said at the start, this is not a story from which anyone comes out well. However, while I hold my hand up and admit that I let my emotions get the better of my judgment regarding Novazyme, at least I didn't blow $137.5 million on it. What were Genzyme thinking? If I was one of their shareholders, I might have some sharp questions to ask.

If you listened carefully in Heidelberg, you could hear the distant sound of Pharming's Schadenfreude laughter.

*That said, fair play to William Canfield - it probably wasn't his personal mistake and he didn't have to be so honest about it. But he was. The hallmark of a true scientist.

Novazyme visit

2010-01-03T17:11:00.003Z

Gosh, I was excited by that Novazyme visit. All of my scepticism was blown away. I found them to be open, engaged and committed. Their approach was refreshingly patient-centred, compared to that of Genzyme. I came away from that visit on a real high - Novazyme had the right people and the right product! I remember saying to Randall House that I didn't understand why their product worked but that the evidence we were shown was so compelling that it obviously did.

Here's what I wrote on my return:

"The major impression I have of Novazyme is movement.Have you ever seen one
of those stop-motion films of a flower bursting into bloom? It was just like
that. It is a place where things are happening, not one at a time but in
parallel and at great speed. Everywhere, people are working away. Every
conceivable nook and cranny is put to use to store equipment or consumables
or has been commandeered for lab space. Here, a high grade facility - there,
an office - there again, walls are being knocked down and a new facility
built.

I have never seen so many people all working on Pompe's disease. There were
more here, I think, in one place than were at the AMDA conference for
researchers in Bethesda, which pulled in people from all over the world.
Amazing.

Like Trae a few weeks back, Randall and I spoke at one of their regular
'Lunch and Learn' meetings, where they invite a speaker to talk about an
aspect of Pompe's. This struck me as a very good idea and illustrative of
the Novazyme approach and corporate culture. But I'm getting ahead of
myself - the detailed stuff can wait for the interview transcript.

As you know, some work has already been presented regarding Novazyme's
product. A question I had when I went over was how solid was the scientific
base for the company. This is dealt with in the interview but I'll give my
opinion here. From the evidence I saw, yes, they have something special -
astonishing, in fact. Obviously, what we saw was a company presentation and
not a peer reviewed paper, so caveat emptor, to an extent. However, I think
it is unlikely that the wool was being pulled over our eyes. Two reasons for
that.

Firstly, they were incredibly open - to the extent of showing us information
on their costs (yes, we signed a non-disclosure agreement but all the same,
it's a gesture of trust).

Secondly, and most importantly: John Crowley. He's one of us, remember, and
his motivation is certainly not to make money.

So, interesting times ahead.

I hope that little taster will last you until the interview transcript:-)

Lastly, a few riders on all of the above:

Those are my own views - I'm not presuming to speak for Randall.

I'm making no judgements about which company has the best ERT product - just
noting that it is now very much a two horse race.

The transcript of the interview referred to was published on the IPA, AGSD-UK and AMDA websites and can be found in the AGSD-UK's Pompe's Bulletin (now a glossy full-colour production).

In retrospect this was astonishingly naive. Particularly so when the above is read in conjunction with The Cure. From that book we learn that what we were told about the intention to hold a clinical trial was false; John Crowley had already decided to sell Novazyme. In fact discussions had already taken place at Genzyme HQ. So what the heck was the point of it all?

What makes me particularly uncomfortable is the thought that my enthusiastic report and the associated interview might have, in however small a way, been have responsible for nudging Genzyme into the disastrous decision to buy out Novazyme. Note the section below, in particular:

IPA: Gaucher disease? You’re really planning to compete with Genzyme’s big product?

Novazyme: the decision isn’t driven by a desire to go head to head with Genzyme. We believe that we have a product which will be an improvement on Cerezyme (the Genzyme ERT for Gaucher) and which may help patients with difficulties that product does not help.

In retrospect, it kind of looks like a signal doesn't it?

Hindsight is a great thing. Before we move on though, it is worth taking a look at the evidence presented to us that we found so convincing at the time.

Novazyme

2010-01-03T13:40:00.064Z

I didn't see this one coming - though they, arguably, saw me.

Let me say at the outset that the Novazyme story is not one in which anyone (including me) emerges with any credit at all. It was, in my view, a time and resource wasting piece of nonsense that quite possibly delayed the wider availability of a treatment for Pompe disease. That's only my own opinion, of course; you can judge for yourself.

I will now tell the story from the beginning. You may feel aggrieved at knowing the ending already. But think of it as watching a magic show. You know that what you're going to see unfold is an illusion but the entertainment is in trying to work out how it was done.

After some rumblings and rumours, Novazyme burst onto the scene in October 2000 via a press release announcing that they had US 'orphan disease' designation for a planned Pompe disease treatment.

A website followed in early November 2000, which was 'patient friendly' and generated some discussion about Novazyme and what they were doing. My own thoughts at the time, as published on GSDNet, were:

What I've personally found difficulty doing here is to separate my opinion of John Crowley (a good guy and one of us) from Novazyme (a hungry new company competing in a tough market). In other words, we need to give Novazyme the same critical appraisal as we have given Genzyme and Pharming.I think it's important to do this. Having tried to do so, I find I'm left with a number of unanswered questions about Novazyme. These principally boil down to 'where's the beef'.

They say that their method of phosphorylating alpha-glu leads to increased uptake. That's good - but where's the evidence? They mention animal studies - but these don't appear to be published. Are they going to be published and, if so, where and when. If not, why not? The alarm bells set ringing by this rang a good deal louder when a saw the graph on their website. It shows uptake of 'well phosphorylated' enzyme versus 'poorly phosphorylated' enzyme. The phosphorylated enzyme does much better. The
conclusion that we're invited to draw is that this is a comparison of Novazyme's product against..well, against what exactly? Pompase? the transgenic enzyme? Bog-standard unphosphorylated alpha-glu? We are not told which, sceptic that I am, leads me to think that the last option is the most likely answer. I hope I'm wrong - only Novazyme can tell us and they've chosen not to.

The second thing we need to consider is this. Given that the existing enzyme brings levels back up to normal in Pompe's patients, would any increase in uptake make any difference clinically? Is there any evidence from animal models that this is the case?

These are the questions we need answered, I think.

I should have printed that out and stuck it on my wall as a reminder not to let my enthusiasm become detached from the evidence.

Naturally, I was keen to get the story from the horse's mouth and eventually had a telephone conversation with John in February 2001. What he told me sounded astonishing.
He said that Novazyme had already carried out a fibroblast (cell culture) study comparing the Novazyme super-enzyme against the equivalent to that used in the YT Chen study. They had found that their enzyme was 99% phosphorylated, compared with only 3% for the "Synpac equivalent". This meant, John told me, that treatment could be carried out with only one hundredth of the Synpac dose - or one thousandth of the Pharming one. Many more patients could therefore be treated with the same amount of enzyme - because the Novazyme product was so much better!
John went on to say that they had considered 3 different contractors for manufacturing their product but had concluded that the best way forward was to construct their own. Their target was to begin clinical trials by Autumn 2001. I was slightly sceptical about all this - if something sounds too good to be true, it generally is. However, John then said something that brought me on board: "Kevin, no-one will ever be deprived of this drug because they cannot afford it."

This had been a real concern for the patient community - the Genzyme Gaucher treatment was, after all, the most expensive drug supplied by the UK's National Health Service. But here was someone talking our language! One of us! In charge of a new go-ahead company with a fantastic product! It just couldn't get any better than that, could it?

In February 2001, Novazyme announced the opening of their new facility in Oklahoma. Hot on the heels of that, in April 2001, Novazyme announced successful results using an animal model. This showed an 'unprecedented' response to ERT using the Novazyme product. Just two doses had cleared accumulated glycogen from the mice and restored muscle function!

This was beginning to look like business. So when Novazyme offered me the opportunity to visit them on Oklahoma (along with Randall House) I jumped at the chance. Who wouldn't?

Things get complicated

2010-01-02T16:57:00.002Z

Out of the blue, on 19 April 200, came a press release from Genzyme, announcing that they were buying the rights to the Synpac product. under the deal it seemed that Genzyme paid $20 million to Synpac and Pharming paid $10 million to Genzyme. It looked like the Genzyme/Pharming joint venture would now commercialise ERT using the Synpac product ie one produced in fermenter vessels using chinese hamster ovary (CHO) cells.

What on earth was going on? What would happen to patients already receiving the rabbit enzyme? Why was this happening? Was the Synpac enzyme better?

Rumours abounded. The Duke/Synpac trial results had not yet been published however it was put about that the results (based on 3 patients) were better than those for the Rotterdam trial. As it turned out, this was not the case. However it ushered in a period of great uncertainty for patients.

It is true that enzyme production in rabbit milk was more difficult than originally anticipated. The rabbits did not produce as much enzyme as hoped and the Rotterdam trial showed that more enzyme was needed than originally thought too. The initial estimate that one rabbit would produce enough for one patient was now looking very optimistic indeed. However, they could be seen as a stop-gap until a larger milk producer - cows - could be brought on-stream. That did not seem to be in the game plan though.

And while all the above may have been true (though not necessarily the show-stopper it was all purported to be) it is certainly true that the move to CHO production suited Genzyme. They had a track record of enzyme production by that method and manufacturing-scale facilities already in use for their Gaucher product. This turn of events locked Pharming into the CHO method for the joint project with Genzyme. As the path to commercialisation became longer, the drain on Pharming's resources became too much for the small company and they went into receivership on 10 August 2001 . A potential long-term competitor to Genzyme was removed; Pharming slept with the fishes (as far as the Pompe project went anyway - they survived receivership and are still a going concern).

Of course, I am in no way suggesting that this is an outcome that Genzyme were actively working towards - it's just the way things turned out.

There was certainly no lack of commitment to the success of the joint venture, as evidenced by the recruitment of Paul Kaplan, who had a 10-year record in drug development, to lead it into the next phase.

I'm getting ahead of myself there though. All this was still to unfold. For now (and for the next few years) the IPA was involved in a battle to ensure that those on the Pharming trial continued to receive the Pharming enzyme, on which they were doing demonstrably well.

It was unsettling - things just didn't seem to be progressing to the timescale that patients would have liked. There was a suspicion that this might be due to the lack of competition.

Then, all of a sudden, there was competition again - in the form of Novazyme, a new company headed by John Crowley.

The notes of IPA meetings at the time show that

A milestone

2010-01-02T14:23:00.001Z

Following the release of the Pharming/Genzyme results, we held an IPA telephone conference on 20 March 2000. This marked an important milestone.

One of the items concerned the extension of the trial mentioned in the press release - round 8 babies would be treated at Essen, in Germany. At the moment they had no-one and were actively recruiting. If I can add a personal note, this meant that, after 7 years of speaking with distressed parents from all over the globe, such parents could now be given something a bit better than sympathy. There was now a treatment, it had been shown to be of some benefit - and there were places available on a clinical trial right now. I felt a weight lifting. How much more must that have meant to doctors giving the diagnosis and the parents who received it.

We also agreed to co-operate with the Rotterdam team in drawing up a database of Pompe patients and their clinical progress and symptoms.

We were now waiting for two things - the results from the Duke/Synpac trial and the plan to commercialise the alpha-glucosidase product. The latter turned out to be more complex than we could have imagined at the time.

Pharming trial results: it works!

2010-01-02T14:12:00.002Z

Pharming/Genzyme issued a press release on 15 March 2000.The link goes to the archived version on the International Pompe Association website.

It noted that after the trial had run for 36 weeks, the 4 babies in the trial were now aged 12 to 17 months. For a disease where infants did not generally live to see the first year, this was in itself remarkable.The press release also spoke of improvements in heart and skeletal muscle. However, there was no actual data. And here was a conflict between scientific integrity and commercial pressures. The Rotterdam team put out their own statement, via Erasmus University, saying that Pharming/Genzyme had been wrong to release the results, as they had not yet been subject to peer review. Notwithstanding the relief with which the press release was received, the Rotterdam team were absolutely correct; the proper place for announcing scientific results is in a journal following peer review. This was particularly true when the results meant so much to desperate families across the globe. It was important to get it right.

A formal publication did follow. Recombinant human alpha-glucosidase from rabbit milk in Pompe patients was published in one of the world's most prestigious medical journals, The Lancet, on 29 July 2000 (Vol 356, pp 397-8). This paper is a real piece of history and, as with the 1991 paper demonstrating that ERT should work in theory, you would be justified in printing it out and putting it on your wall. You can download it from The Lancet's website for free (you will have to register, however this is worth doing as you will then have access to The Lancet's entire searchable archive). Even if you refrain from framing it, please do read it.

In one of life's pleasing coincidences, 29 July is my birthday. I can honestly say that this was the best birthday present that I have ever received and we drank the IPA wine to celebrate.

The paper contained the data and detail missing from the press release, however the overall message remained the same - this was an effective treatment. All children were still alive, all patinets showed progress. The two who had started treatment before the age of 3 months were now out-patients and were breathing without the aid of a respirator. The most prominent effect was on heart size, which had reduced quite dramatically. it was also noted that the required dose was larger than initially thought - during the trial it was increased from 15-20 mg/kg to 40 mg/kg. At this dose, alpha-glucosidase activity was in the normal range for all 4 patients. I've emphasised that because it seemed to confirm that William Canfield's argument at the AMDA conference had been wrong; there was no need to 'bolt on' extra mannose-6-phosphate residues in order to get enzyme activity up to normal levels.

Presciently, the authors added " We recommend that treatment be started early."

The authors were Hannerieke Van den Hout, Arnold J J Reuser, Arnold G Vulto, M Christa B Loonen, Adri Cromme-Dijkhuis, Ans T Van der Ploeg. It was very pleasing to see Christa Loonen included amongst the authors. However this publication represented a particular triumph for Ans van der Ploeg and Arnold Reuser. They had taken enzyme replacement therapy from a lab-based concept to a working treatment making a difference to real children. Decades of work on "a disease no-one has ever heard of" had resulted in some remarkable progress. This was not only the first paper to demonstrate an effective treatment for Pompe disease, it was also one of the first (if not the first) paper showing the efficacy of a transgenic medicine.

Yes, the premature announcement by press release was not ideal. Yes, there were many twists and turns in the road to commercialisation ahead. However, let us pause now in this narrative to reflect on the remarkable progress this small but extremely talented and fiercely dedicated team had made.

At last, a treatment for Pompe disease - and it worked!

The rest of 1999

2009-12-27T17:06:00.001Z

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

2009-12-27T16:54:00.002Z

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

2009-12-27T15:37:00.002Z

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..

Kevin

IPA Founding Conference part 3

2009-12-27T15:32:00.003Z

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)

Friends,
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
day.

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)

Friends,

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.

Bye,
Gezinus

IPA Founding Conference part 2

2009-12-27T14:11:00.001Z

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.

Towards a Therapy for Pompe Disease: founding IPA conference

2009-12-22T15:43:00.005Z

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.

The dark horse enters the race

2009-12-21T19:54:00.002Z

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

2009-12-21T19:34:00.003Z

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!

2009-12-21T18:05:00.004Z

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
participation.

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
US?

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
2001.

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.

December conference postscript

2009-12-20T23:10:00.006Z

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

2009-12-20T22:41:00.004Z

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

2009-12-20T21:22:00.001Z

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.

The first clinical trials

2009-12-15T00:04:00.003Z

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.

The 1998 scene

2009-12-14T19:42:00.002Z

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.

The birth of the International Pompe Association

2009-12-13T17:22:00.003Z

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.

A two-horse race

2009-12-12T23:37:00.002Z

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

2009-12-12T22:29:00.008Z

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

2009-12-12T21:14:00.001Z

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.

1997: Lift off!

2009-12-03T23:09:00.074Z

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.

The AGSD-UK

2009-12-02T00:08:00.002Z

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.

Postscript

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.

GSDNet

2009-12-01T22:18:00.002Z

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.

AGSD-UK helps fund Rotterdam group

2009-11-29T16:48:00.002Z

The UK Pompe patients, organised within the AGSD-UK, had a clear goal. We wanted to raise funds and raise awareness, in order to help the Rotterdam group take their work on ERT forward.

In 1996, there was an opportunity to do exactly that.

The problem for the Dutch group (I am putting words into their mouths here, for which I apologise) was to find a way to make the jump from their ground-breaking experiments that demonstrated that ERT could work in principle, to clinical trials. The funding required for that (£ millions) seemed like an insurmountable problem, however they took the sensible approach of taking one small step at a time. For example, a collaboration with John Hopwood's lab in Australia had resulted in the development of cells which produced alpha-glucosidase (complete with the critical sugar residues attached) and which were suitable for growing in a production vessel.

The strategy was therefore to use the Hopwood cell line to produce enough alpha-glucosidase to treat one or two patients and hope that a pharmaceutical company would then take it up. This was, to say the least, an approach fraught with uncertainty. However it is also true to say that there was no alternative.

To produce the enzyme, it was proposed to use a new company started by a former student (Martin van der Vliet) of Arnold Reuser's, called Biocell technology, who would build a small-scale fermenter. However this work, while being done at a bargain rate, still needed funding- and, despite applications to grant-awarding bodies and biotechnology companies, none was forthcoming. That was where the AGSD-UK were able to step in and fund the building of the fermenter via a grant of £10,000. Here's a photo of it below (that's the old AGSD-UK logo in the corner):

This was a great day for the UK Pompe patients - at last we were taking an active part in shaping our own destiny. At the same time, the AMDA were funding similar work at Y T Chen's lab in the US (along with other projects).

I think that the AMDA had also offered to fund the Rotterdam work, however Arnold Reuser and Ans van der Ploeg opted to receive the money from the AGSD-UK instead, a route that involved them in a bit more hoop-jumping. Why? I don't know for sure but here are my guesses. Firstly, they knew how much it would mean to us to do it. Secondly, it always makes sense to keep a diverse range of funding options open - and they knew that the AMDA route would still be open to them in the future. Thirdly - and this is a complete guess on my part - Arnold had a shrewd idea that by allowing us to become a funder, it would give us a seat in future discussions on the development of ERT.

£10,000 is, of course, in the grand scheme of things a small amount (though it represented a lot of hard work and generosity by many people). However, I believe that it had an effect out of all proportion to the amount. Again, I am departing into the realm of conjecture here - what follows represents my opinion only and I am not going to present any evidence to back it up:-)

The reactor was indeed used to produce enzyme that was used in experimental work. However it also demonstrated to Erasmus University (and Sophia Children's Hospital) that the Pompe group were capable of raising funds from overseas to further their work. I think that would have helped to boost their profile. Most important of all, the Rotterdam group had been in discussions with a biotech company called Pharming, regarding the production of alpha-glucosidase in the milk of transgenic animals. These discussions had been going on for a while and were inconclusive. However the advent of a new funding source (conveniently omitting that it was a small charity with limited resources) may have helped to push Pharming into a decision to commit to the project. It's a great theory - but I have absolutely no idea if it's true!

Soon after, Pharming did indeed commit to the Pompe project. And that decision was the key to making things happen.

1996

2009-11-29T15:45:00.002Z

A quick summary of where we were at in 1996.

In retrospect, this was a pivotal year though it didn't seem so at the time. The patient group in the UK was growing slowly. The Pompe's Bulletin newletter was circulated to any patients, doctors and scientists that we could think of. The patient groups in different countries began to reach out to each other via the internet. Another common link was Arnold Reuser's group on Rotterdam - their willingness to engage with the growing patient community was crucial to its development. They struck a careful balance between their compassion and their professionalism. There was a growing sense of beginning to come together for a common purpose. Little did we know that things were about to kick off in a quite astonishing way. But that's for 1997:-) First a couple of articles on 1996.

House improvements

2009-11-14T19:02:00.007Z

I have tried to make this a roughly chronological account but I'm going to go off piste here because I can't give a good portrait of Randall and Marylyn without looking ahead.

In front of me is my first written communication from the Houses. Dated 29 August, 1995, it expresses sympathy for our loss of Calum, introduces Randall, Marylyn and their daughter Tiffany (then just a 12-year-old slip of a girl) who has Pompe (they have two other children, who do not), shares their conclusions so far and a sheaf of information on diet, including a paper by Pompe patient Donald Ewers. In hindsight it has all the hallmarks that mark out the Houses: compassion for others, sharp analysis and - above all - a drive to translate those things into action. It's a bit of a cliché but I found a lot of the American pioneer spirit in the Houses.

We talked on the phone and exchanged emails and gradually built up a relationship. My dealings were mainly with Randall, whose no-nonsense approach impressed me. We were fairly guarded with each other at first, as we worked out each other's agendas. It's probably true to say that I respected Randall before I liked him - though I came to like him a great deal. He is straight-talking - not given to exaggeration or soft-soaping. I found that if he said something, he meant it and if he said he would do something, he did it. I quickly realised that the Houses' resources were in a different league and that the most useful thing I could do was to be as open as possible and hope that it was reciprocated (it was).

Randall's words to me were along the lines of "We are not super-wealthy but we do have some means. We would like to use that means to find a treatment for this disease." Little did I realise then how much they would do. I also didn't fully appreciate at the time what those words meant. The Houses owned (still do, I think) a manufacturing business that they had devoted years to building up. That "some means" came from hard work and toil. I think it was, to a significant extent, their life's work up to that point. And yet they unhesitatingly put it at the service of finding a treatment for Pompe disease. In my view, their contribution to the development of a treatment for Pompe disease is as much their life's work as building their successful business.

I think I suggested that to have maximum effect they should found a patient organisation (the AGSD-US was, for whatever reason, less amenable to a devolved Pompe group than the UK version) , rather than act as individuals, and also have a scientific advisory board, to ensure that their money was spent wisely. We were both agreed that enzyme replacement therapy was the way to go. I don't know whether I had any actual influence, however Randall and Marylyn founded the Acid Maltase Deficiency Association (AMDA) as a patient organisation. They used that as their base to do some remarkable things.

Firstly, they built the AMDA as a source of advice and information for hundreds of people affected by Pompe disease. Secondly, they did something that had never been done before. They gathered together, at their own personal expense, Pompe experts from all over the globe and hosted a conference for them in San Antonio, Texas. This was on March 21-22, 1996. The talks read like a who's who of the Pompe world. It was followed by a second, even bigger, conference on June 22-23, 1997.

Organising these conferences was an imaginative and far-sighted act. As important, I think, as the funding that the Houses put into research (again, a significant amount - nearly $5 million to date, according to the AMDA website). They were obviously scientific conferences, not patient ones, however the Houses were kind enough to send me video recordings of each conference, which allowed me to keep right up to date with what was happening. A characteristic piece of generosity on their part.

Looking at the 1996 programme now, I am amused to note that the session started at 7.00 am with breakfast and registration. That's approximately 2.5 hours earlier than most scientists are used to, so I guess Randall and Marylyn were putting their own work ethic stamp on proceedings from the start (1997 had a more leisurely 7.30 am start). The programme was designed by one Tiffany Laurel House, who now heads up the AMDA.

In the founding of the AMDA and the gathering of US patients together, and bringing together scientists, Randall and Marylyn were playing the major role in creating a worldwide Pompe community. In extending those connections to industry (I'm really getting ahead of myself now) they helped found a new model in the development of treatments for rare diseases, one in which patients, researchers, doctors and companies interact. The development of ERT for Pompe was possibly the first instance where an informed patient community said to industry, in effect, "We are your future customers, this is our condition and this is the treatment we would like you to develop." But more of that later.

For now, it's enough to say that Randall and Marylyn changed the game. In a very real sense, they made ERT happen. They made it happen while being part of an international community. And they made it happen not just for Tiffany but for all Pompe patients.

Postscript
I don't think I actually met Randall until 1997, at the AGSD-UK's annual conference. Here's my earliest memory of him. We had introduced ourselves and I noted that he was wearing a formal business suit, unlike my scruffy self. I was fussing about trying to make some sense of the organisation of the Pompe session out of the customary AGSD-UK chaos. There was a group of parents who had found some space on the floor in order to feed/change their young children. Next time I turned around, Randall had hunkered down on the floor, amongst the crumbs, in his business suit, in order to talk with them. That's my abiding image of Randall House. Sorry, I can't tell you what brand of suit it was - or what kind of watch he was wearing.

Making connections

2009-11-14T17:27:00.002Z

The UK group was definitely stirring and I had a growing mailing list that I could send paper newsletters to. However I realised that there were probably patient groups and individuals in other countries going through exactly the same process - but how could I contact them?* The answer seems simple now - just use Google, d'oh! Unfortunately, in 1995 Google was yet to be invented. I had internet access at work though and was keen on the idea of using a website as a sort of shop window.

A bit of history/nostalgia. My first web browser was something called Lynx which was entirely text-based. I then started using something called Mosaic which had the startling innovation of allowing you to see pictures and text. I got a hold of it by email - you got sent the code for it in chunks and had to manually piece them together to make a functioning piece of software. Happy days. But I digress.

I put together a rudimentary website for the AGSD-UK and included the full text of my Pompe patients' guide. A friend at work kindly hosted on his webspace (cheers, David). But how could people find it? I emailed it around to anyone I could think of but there were no search engines as such. However a couple of students at Stanford University had used their university account to set up a sort of index for interesting websites, so I listed it there. They had called their site Yahoo. It'll never catch on with a name like that, I thought.

Anyways, I gradually made contact with people from other countries - individuals from Germany and the US to begin with. Then I got a phone call from a guy in the USA that I'd never heard of but who had come to the same conclusions as me and was determined to do something about them. His name was Randall House and he, along with his wife Marylyn, changed everything.

*I realise on looking through my papers that the original list of names I was given by Ann Philips contained one non-UK contact - Helen Walker from Australia. I'm surprised by that and also to find that I've now been in touch with Helen for 15 years! More about the Ozzies later.

Ans van der Ploeg's visit to the AGSD-UK conference

2009-10-06T21:05:00.008+01:00

As mentioned in an earlier post Dr Ans van der Ploeg had agreed to speak at the 1995 AGSD UK conference, which was held in Birmingham on 28 May.

This was a very exciting prospect. For one thing, it would give the other Pompe families the opportunity to see that the Dutch team were not a figment of my imagination. The impact of a real person standing in front them talking about her promising research was not to be under-estimated. It would also mark something of a departure of the AGSD-UK, with a main talk at the conference being given over to Pompe disease, rather than one of the liver-based GSDs.

In short, I was anxious for it to go well. So when Hugo Del Mar, son of AGSD-UK co-founder Sue Del Mar, offered to pick up Dr van der Ploeg from the airport in his new two-seater sports car, I was delighted. "That will impress her!", I thought. I reflected on this example of my innate shallowness later, as I watched a fairly heavily pregnant Ans van der Ploeg extricate herself from the tiny sports car...

Ans van der Ploeg (yes, the one on the right) receiving an award for her pioneering work on Pompe disease.

The talk itself was excellent and well-received. It strengthened the resolve of the Pompe group to do something to support the work of the Rotterdam team and fund-raising began in earnest, though there was, at that point, nothing specific to support. Nevertheless, from that time on, we had a real goal.

Dr van der Ploeg was, needless to say, charm itself and dealt with her and her unborn child being squeezed into a sports car with her customary sang-froid. Many people (most, even) would have found pregnancy a more than adequate reason to cancel the talk. However - and this is typical of the whole Rotterdam team - having made a commitment to patients, she did not want to disappoint, regardless of the personal inconvenience.

Ans van der Ploeg is blessed with cleverness, good looks and a list of achievements that includes - aside from the minor matter of developing a treatment for Pompe disease - such things as national cross-country skating.

Normally of course, such a super-abundance of talents in one individual would draw the disapproval of all right-thinking people, given that so many of us have to get by with none at all. However, like everyone else, I am prepared to make an exception in Ans' case, as she has put her considerable abilities towards the service of others - and with such good effect.

The Hal Brodhurst Trust

2009-10-06T19:57:00.008+01:00

The Hal Brodhurst Trust has an honourable corner of the Pompe story that deserves to be remembered.

Hal was the son of Robin and Desiree Brodhurst and suffered from infantile Pompe disease. When he was 6 months old, Hal had a radical treatment, a combined heart and bone marrow transplant, carried out in July 1993. The surgeon was the heart transplant pioneer, Sir Magdi Yacoub. Sadly, the treatment was not effective and Hal died four months later.

His parents established the Hal Brodhurst Trust in July 1994, in order to help fund research into Pompe disease. The aims of the Trust were:

1. To advance education by the promotion of research into the causes and treatment of glycogen storage disorders with particular concern for type 2 Pompe's Disease on terms that the results of such research are published. 2. to relieve the sickness of people suffering from glycogen storage disorders with particular concern for type 2 Pompe's Disease and in particular and without limitation to promote the establishment of a unit dedicated to the treatment of glycogen storage disorder patients at a United Kingdom hospital.

They raised funds which were put at the disposal of Magdi Yacoub, who established a small team at Harefield Hospital, near London. A Pompe Disease workshop was held there on 31 March 1995 and I attended on behalf of the AGSD-UK. The focus very much reflected Sir Magdi's own interests, with several talks on transplantation. Arnold Reuser also made a presentation. Robin and Desiree conducted themselves with their usual quiet dignity.

Something that particularly sticks in my mind is that Sir Magdi said that his research strategy would be to sequence the Pompe mutations, find out what had gone wrong and then find a way of making the mutated enzymes work again. I was astonished by this because it was vanishingly unlikely to work (I still do think that, regardless of the fact that an analogous approach is being pursued by Amicus Therapeutics) . Being a great man in one field is no guarantee of being right in another one. But I digress.

The team at Harefield, led by Ann Child of the Institute of Child Health in London, looked at Pompe tissue samples from across the UK and carried out DNA sequencing. The work was published in the journal Human Mutation in 1998. The paper, by Clare Beesley, described some novel mutations causing Pompe disease (including the one I carry, if I remember rightly). After that, the Trust faded from view and, as far as I know, no longer exists.

Partly, this was a reflection of the limitations of charities dedicated to one child. With the best will in the world, by their very nature they find it difficult to draw the wider support needed for the longer haul. This reinforced my view that the AGSD-UK route was the right one for whatever contribution I was able to make. It also brought home to me the importance of a Scientific Advisory Board to give broad-based specialist advice.

However, and most importantly, the Hal Brodhurst Trust had the considerable achievement of funding the first UK research into Pompe disease. An important milestone and a lasting memorial for Hal.

1995

2009-10-06T19:45:00.005+01:00

Right, back to our trawl through the dusty archives. At the risk of eliminating all suspense, here are the things that happened: There was a UK Pompe meeting organised by the Hal Brodhurst Trust; Ans van der Ploeg came to the AGSD UK Conference; I started a website for the AGSD-UK, with Pompe information; and last but not least, I had my first contact with a US couple called Randall and Marylyn House. All important in their different ways. I'll do them as separate blogs over the next week or so.

1994 continued

2009-09-26T20:19:00.004+01:00

I'm really going through my big folder of emails, faxes, scribbled notes of phone calls etc. and trying to unpick what actually happened, so this narrative might seem a bit disjointed. Hopefully, others will now chip in with their own recollections to help fill in the gaps (hint).

For me personally, the big thing that happened with regard to this story was that I started building the Pompe Group in the AGSD-UK. There are several letters from people I met at the Newcastle conference, giving information, other contacts to follow up and so on. Email was not really widespread at this time, so most contact was by letter.

The main things I have are:

I persuaded the AGSD-UK to set up a Scientific Advisory Board, onto which Arnold Reuser and Ans van der Ploeg were invited, amongst others. This helped to provide some professional ballast for the AGSD-UK, while increasing its profile amongst medical and scientific professionals. You know, I still think that was a good move. Well done me;-)

The second thing was that the AGSD-UK set up a specific Pompe fund. This was to become a focus for fund-raising by the Pompe families (and still is).

The creation of the SAB was followed up by inviting Dr Ans van der Ploeg to speak at the next AGSD conference, to be held in Birmingham in May 1995. This invitation was in September 1994, so 8 months in advance. I'm flagging that up for a reason, so pay attention.

There was so much happening that I started a Pompe-specific newsletter - The Pompe's Bulletin - to use a a tool to keep people in touch and to spread the word. Initially 4 sides of A4 text, it has since become a high-quality, professional production. Of course, that only happened once I stopped having anything to do with it. You may see the start of a recurring theme here. Having said that, those newsletters, alongside the US equivalent produced by the AMDA (about to enter our story) are a pretty good historical record of events.

However, I can't let the round-up of 1994 pass without mention of the fact that we knew we were going to have another child and that our child would not have Pompe disease. chorionic villus sampling (CVS) is a technique that allows a sample of placenta to be tested for the presence of (in our case) alpha glucosidase. We had the test at 11 weeks. Not a great experience because you see the foetus on the screen, just like a normal ultrasound. We were trying not to look because, after all, we might have had to terminate the pregnancy. We knew that the sample was to be sent to Manchester and the test carried out there and were told to expect a result in a week or so. The hospital phoned the next day to give us the all clear. They must have had a courier waiting right there and then to take that sample to Manchester, where someone was waiting to - right there and then - start work on it.

The staff at the hospital were wonderful with us - though I don't think I've met anyone employed by the National Health Service who treats it as 'just a job'. They did everything they could to make things as easy for us as possible and treated us with great kindness. Hopefully we were able to show our gratitude at the time. However, there were a lot of people in that chain from Edinburgh to Manchester and back, who did well by us, and who we'll never know. People who are doing the same thing day in, day out for others. Our thanks to all of them from the very bottom of our hearts.

Euan was born in January 1995. The knowledge that we were having a healthy child made the last part of 1994 a very happy time for us.

So, the UK Pompe group was beginning to stir in 1994. This was only the start - the next year would see the start of an international network.

A visit to Rotterdam

2009-09-21T21:53:00.015+01:00

Give a guy a big nose and some weird hair and he is capable of anything. Frank Zappa*

I have previously talked about the scientific research into Pompe disease. However, one of the things I hope to do in this story is to try to give a picture of some of the people involved, as they appeared to me. As you might gather from the Frank Zappa quote above, this is a personal and slightly irreverent account of my first meeting with Arnold Reuser.

In late June 1994, I went to Amsterdam, to attend a scientific conference (the 4th International Congress of Plant Molecular Biology, since you ask). Elaine came with me. Of course, I immediately thought that it might be possible to combine this with a visit to the laboratory in Rotterdam which was carrying out Pompe research. So I wrote to Arnold Reuser saying that I would be in The Netherlands and hoped that it would be possible to come and visit him, though I understood that it might not be convenient.

He called me up to say that he would be happy for me to visit and when he heard that my wife was coming to Amsterdam with me, he invited us both to his house for dinner. And so, on 25 June (after the conference session, lest my employers be reading this) , we found ourselves taking the train to Rotterdam. Bear in mind that Arnold and I didn't know what each other looked like - no websites with photos in those days. However, Arnold gave some helpful advice as to how to identify him: "Well, people do say that I have a big nose. And I will be wearing a pink scarf." He was right - we spotted it from the other side of the railway station. The scarf I mean. It was enormous and circled him several times - an excellent ice-breaker.

We had a very nice meal with Arnold and his wife Mariette. During this, I learned a lot about Arnold and his work and about Pompe disease in general. As I had guessed, funding was precarious. However, he was clearly a determined and dedicated man. His Head of Department used to visit his office every few months or so and say, in effect, "Hey, when are you going to stop working on a disease no one has ever heard of?" I suspect that doesn't happen now. Yet he persevered, on a shoestring, but was at something of an impasse. He wanted to take ERT to the next stage and yet knew that this would more resources than had been available to him so far. He said that Ans van der Ploeg was now a medical doctor at the nearby Sophia Children's Hospital and was also still very much interested in Pompe disease.

Naturally, we wanted to help but, at that stage, had very little to offer except encouragement. I hope that the knowledge that there were people outside of The Netherlands interested in his work did make a difference, however small.

As Elaine and I made our way back to Amsterdam, we reflected on the evening. Of course, it was fascinating to speak with someone who was so knowledgeable about Pompe disease, the condition that had become so important to us. And it is one thing to be familiar with someone's work through their scientific publications and quite another to meet a living, breathing human being. However, there was something else too. The sad fact is that, when you lose a child, some people you know will cross the road to avoid you. It's not because they are bad people and mean to be unkind - it's just that they don't know what to say and, well, it isn't a pleasant thing to speak to grieving parents. Yet here were two strangers who had invited us into their home and had wanted to know about Calum. It must have been difficult for them, particularly since their youngest child was then the same age as Calum. It's a kindness that we've never forgotten.

One other thing. When leaving, I had handed Arnold a copy of a pamphlet I'd written for patients called Recent Advances in Research into Pompe Disease (correct, a snappy title - soon changed to Pompe Disease - a Guide for Families, still available from a website near you). I asked him if he wouldn't mind giving me some comments sometime. When we got back to our hotel in Amsterdam, there was a fax waiting, with encouraging comments in it. This had been sent at 10.30 pm. As I was to discover, Arnold's routine was often to work all day, go home to have dinner with the family and put the kids to bed - and then go back to the lab to do even more work.

So, what had I learned? I knew that there was a small but very determined group in Rotterdam who deserved our support - financial (though we had little in the way of that) and moral. For the first time, I had a sense that this was not a hopeless cause, that there was a battle going on that the AGSD-UK could try and play a part in - and that we had an ally. There would soon be others.

*Sorry Arnold, it was too good a quote to miss:-) This was from one of Frank Zappa's last interviews - fellow Zappa fans can find it here

My first AGSD-UK conference

2009-09-19T16:53:00.006+01:00

When Calum was diagnosed, one of the few things the hospital could do for us, was to give us a leaflet for an organisation called the Association for Glycogen Storage Disease (UK) (and also for the Research Trust for Metabolic Diseases in Children, now Climb) .

We called Ann Philips, the President, and she put us in touch with other families who had had a baby with Pompe's. It was an enormous comfort to speak to them - other people who understood what it was like to have lost a child to this rare disease. So we decided to go to their annual conference, which was being held in Newcastle on 29 May, 1994.

The organisers, Henry and Janet, couldn't have been kinder to us and they - and Ann - made us feel very welcome. Most of the conference dealt with the other types of glycogen storage disease - reasonably enough, as that reflected the membership. However, at some point, the Pompe families met together. I don't have a note of everyone who was there, however it certainly included the Harringtons (who had also lost a child to Pompe's and became good friends of ours) the Critchleys and Allan and Barbara Muir. Allan is the current UK Pompe supremo and (I'm jumping the narrative gun a bit here) has made a much better job of it than I ever did. If you are doing a job that really matters to you, then I can wish you no greater blessing than to have a successor who does it better. It's certainly been a source of great happiness for me - cheers, Allan!

But I digress. At that small gathering I spoke about the ERT research and we gave ourselves a target to raise funds to help it. I also found myself on the executive of the AGSD, representing the Pompe group.

Without really thinking about it, I'd made a decision that whatever efforts I made regarding Pompe disease, it would be as part of this group. In retrospect absolutely the right decision (how I wish they were all like that). The alternative was to start a new group specifically focused on Pompe disease. However being part of a larger group brought the advantages of critical mass (for example, tagging on to a group big enough to organise a proper conference) and opened me up to the constructive criticism of others. Both important things.

Of course, I didn't realise then quite how much of my life this was going to take up for the next 10 years or so... It is not an exaggeration to say that this was a meeting that changed my life.

The very next month, I was to have another important meeting.

Tidying up before the next phase

2009-09-19T16:32:00.003+01:00

Before I get into the story of the patient community and its involvement in the development of ERT, there are a few loose ends to tidy up.

Back in 1993, there were three groups looking at ERT. Arnold Reuser's in Rotterdam (of which more soon), Y T Chen's at Duke and Frank Martiniuk's in New York.

Frank Martiniuk had some interesting work and always gave me the impression of someone who was prepared to push things forward. For some reason (luck, politics, who knows) his group was not one of those that eventually participated in trials of ERT. I met him briefly - just to shake his hand really - at a Pompe conference some years later. However I'd like to thank him, not only for his efforts at pushing forward research into what was then a deeply unfashionable field, but also for an act of generosity that was much appreciated by me at the time.

Following my trawl through the literature, as described earlier, I wrote to him and asked him how his work was going. I didn't get an immediate reply, however I did receive in the post a large bundle of papers related to his work. It must have cost a fortune to post from the USA, never mind the time and trouble it took to put it together for me. I read it all avidly and still have it. Thanks, Frank.

The story so far...

2009-07-03T09:56:00.003+01:00

Sitting down to write this up has brought back many, many memories. Consequently, it's taking me longer than I thought to sift though files of letters, emails etc.

While I do that, here's a quick summary of where we've got to so far:

Pompe discovered the disease
Hers explained it
Reuser and van der Ploeg worked out a way to treat it with enzyme replacement therapy.

That is the main narrative. Anything you read that purports to be the story of the development of ERT and doesn't have those names in it is not an accurate account. Simple as that.

Now, before I get into the patient group stuff (which is where I really will need some help, as we will be entering a more subjective realm) let me take the scientific story one step further.

As I showed in my last post, the Dutch team had shown that ERT could be made to work. What was needed though, was a supply of phosphorylated enzyme (because it has to be the phopshorylated version to work - you remember that, right?). It turns out that they had the start of the answer to that problem because Arnold Rueser's laboratory had cloned the gene for the enzyme.

This was a huge step forward because once you have the gene in a test tube, you can work at inserting it into other cells. For example, a standard type of cell used in laboratory and other work are chinese hamster ovary cells. These are the type that are used by Genzyme in their huge fermenters. Imagine huge amounts of those cells, all producing that vital enzyme. That's what cloning the gene opened up.

So having cloned this gene - and opening the way to eventual commerical production of the enzyme - the Dutch did a remarkable thing. They gave it away.

They gave it to Y T Chen's team at Duke University and to John Hopwood in Australia (with whom they had a continuing collaboration). That led to the creation of two cell lines producing phosphorylated alpha-glucosidase.

Thanks to an act of scientific generosity, the future was opening up.

The Turning of the Tide

2009-05-17T14:19:00.006+01:00

Writing about Calum brought back a lot of memories. It was the saddest time of our lives. However, from now on, the story becomes brighter. Not that there isn't pain and sadness ahead for many - to this day, in fact. But from here on in, I'll be talking about the development of a treatment for Pompe disease. This is where hope first appears in this narrative. This, my friends, is the turning of the tide.

To quickly recap: Pompe discovered and described the disease. Hers explained it. What follows is the story of how Arnold Reuser and Ans van der Ploeg worked out how Pompe disease could be treated - and went on to demonstrate that their theory actually worked.

As we have seen, following Hers' discovery of lysosomal storage diseases, many attempts were made to treat Pompe disease by enzyme replacement therapy. None worked because enzyme was simply soaked up by the liver - it did not reach the muscles, which is where it needs to go, in order to shift glycogen. The whole concept of enzyme replacement therapy therefore fell out of favour. The situation seemed hopeless.

However, Arnold Reuser, a researcher at Erasmus University in Rotterdam, and his then PhD student, Ans van der Ploeg, had other ideas. They looked again at enzyme replacement therapy. In particular, they made use of the recent discovery that enzymes made their way into the lysosome using a receptor for the sugar mannose-6-phosphate. They reasoned that enzymes with this sugar attached - phosphorylated enzyme - might be more efficient at getting to the lysosome than the enzyme previously used in enzyme replacement therapy. The mannose-6-phosphate would effectively act as an address label, ensuring that the enzyme reached the lysosomes in the muscles. An interesting theory - but was it right?

Their first experiment was to take cell lines isolated from Pompe patients - human muscle cells grown in a dish in the laboratory. These cells showed the classic Pompe symptom of glycogen accumulated in the lysosomes. Reuser & Van der Ploeg added the phosphorylayed enzyme - and the glycogen was degraded.

This was obviously an important step forward, however it was not enough to demonstrate that this approach would work. After all, cells growing in a thin layer in a laboratory dish are one thing - living organisms with blood, liver and muscle are quite another. And this presented a seemingly imovable obstacle. The phosphorylated enzyme was difficult to produce and only small amounts -extracted from bovine testes - were available. This was not enough to treat a child, even if permission had been obtained for such a speculative approach. The only animal model known at that time was a type of cattle - which would require even more of the enzyme. How could this be resolved?

The answer came in a series of experiments which I can only describe by using one of the highest words of praise in the scientific lexicon: elegant.

Reuser and Van der Ploeg realised that they only had enough enzyme to use on mice. However, these mice did not have Pompe disease and therefore had normal levels of alpha-glucosidase and no glycogen accumulation. So how could they be used to demonstrate uptake of the enzyme? The solution was to use antibodies that reacted with the phosphorylated enzyme produced from bovine testes but not against the normal mouse enzyme.

The bovine enzyme was administered to the mice, and the increase in alpha-glucosidase activity in different tissues measured. It was possible to work out how much of this activity was due to the bovine enzyme using the bovine-specific antibodies. Firstly the whole tissue activity was measured, and then the activity when the antibodies had reacted with the bovine enzyme. By comparing these two figures, it was possible to see how much of the activity was caused by the mouse enzyme and how much was due to the added bovine enzyme. This also showed that the bovine enzyme had made its way to the various tissues, including heart and muscle.

Reuser and Van der Ploeg found that the addition of the bovine enzyme to the mice resulted in a 43% increase in enzyme activity in muscle and 70% in the heart.

They noted that even after 6 days, enzyme activity in mice was 10-20% above normal. As enzyme activity of more than 20% of normal does not usually result in Pompe symptoms, they concluded that, in some cases at least, a slight increase in alpha-glucosidase activity might be enough to prevent glycogen storage.

These results were published in February 1991. The paper is entitled Intravenous Administration of Phosphorylated Acid Alpha-Glucosidase Leads to Uptake of Enzyme in Heart and Skeletal Muscle of Mice. Thanks to the wonder of the internet, you can read the whole paper online at the website of the Journal of Clincial Investigation

The paper also notes that the amounts of enzyme required would be very large - beyond what it was then possible to produce. However the speculated - correctly - that it might be possible to produce it using the cloned human gene for the enzyme.

With characteristic understatement, Reuser and Van der Ploeg concluded that "...we think that the original idea of enzyme replacement therapy for treatment of lysosomal storage diseases deserves new attention."

I'll say! While the paper was in preparation, results showing the success of such an approach on Gaucher disease (another lysosomal storage disease) were published. Gaucher disease was something of a special case, for reasons too complicated to go into here, however it underlined the feasibility of the approach.

Here's a suggestion. If you are affected by Pompe disease, follow that link and print out that paper. Read it and try and understand it (go on, it's not as difficult as it might look). Put it in a nice folder. Even better, frame it and put it on your wall. That paper is an important part of your life story because, building on what went before, it made a treatment for Pompe disease a real possibility for the first time. Cherish it.

Calum

2009-04-24T20:48:00.007+01:00

The morning glory that blooms for an hour, differs not at heart from the giant pine that lives for a thousand years.

Buddhist proverb

It was Friday 28 May, 1993 and one of the happiest days of my life. I was driving across the border from England into Scotland, to a new home in Edinburgh - the city I had always wanted to live in - and to my dream job, running my own molecular biology laboratory. Best of all, I had my family in the car with me - my wife Elaine and our two-month old baby son, Calum. Life was sweet. Yet within a few short months that sweetness turned to dust in my mouth.

Everything was fine for a couple of months. I busied myself with settling in to my new job, while Elaine and Calum went house-hunting. Then Calum seemed to be getting a lot of colds and sniffles, which took longer and longer to go away. It never occurred to us for one moment that something could be seriously wrong. Even when, at six months old, Calum was hospitalised with pneumonia we didn't think it was anything other than a temporary blip. In hindsight we were incredibly naive - but what does anyone know with their first child?

An x-ray showed an enlarged heart and, even then, we didn't think anything other than "So he shouldn't play rough sports? Guess he'll just have to be geeky like his dad!" Unknown to us though, alarm bells were beginning to ring at the hospital and blood tests were taken "Just routine, nothing to be concerned about..." And we weren't concerned. We found a house (next to a park - and a school - perfect!) and started fixing it up prior to moving in.

Then we got the news that brought our world crashing down around our ears. On a follow-up hospital visit we were told that the blood tests showed Calum had something called Pompe disease which was a type of glycogen storage disease. It was untreatable and fatal; children with this disease did not usually live beyond their first birthday.

We just couldn't believe it. We thought that there must have been some terrible mistake. Our beautiful child, the light of our lives, going to die? How could such a thing be possible? And whoever heard of an untreatable disease in this day and age - those doctors really needed to keep up with what was happening in the world of medicine!

For the next two we weeks we frantically found out everything we could about Pompe disease and what little information there was available was not good. Everything confirmed what the hospital had told us; there was no hope. None. While we were still in shock, Calum declined quite rapidly and he went back into hospital. He died at the Sick Children's Hospital in Edinburgh, on 18 November 1993, just two weeks after we were given the diagnosis.

We used the Buddhist proverb from the beginning of this article as his epitaph. We both think of him every day and will always mourn the life that was lost. But we will always be grateful for the life that we had.

...

The hospital hadn't been able to help us with a treatment however they did one thing for us that was very helpful, both then and in the years ahead, and which was life-changing. They passed us details of two patient groups that helped families in our position. One was the Research Trust for Metabolic Diseases in Children (now known as Climb ), an umberella group for metabolic diseases, and the other was the Association for Glycogen Storage Disease UK, which dealt specifically with the glycogen storage diseases. Both organisations founded by remarkable women who responded to the illness of their own children by creating organisations that helped others. We will be forever indebted to Lesley Greene (Climb), Ann Philips (AGSD-UK) and the families they put us in touch with, for helping us through the darkest time of our lives. More of them later.

Following Calum's death we wanted to raise some funds for research into Pompe disease and I also had the idea that, as there was so little information available on Pompe disease, I would use my scientific background to write something aimed at parents. I felt that this was important because we had been desperate to understand what was happening to Calum and as I had watched Elaine (a bright person without a science background) struggle with concepts like genes, enzymes and lysosomes it was brought home to me what a privilege it is to be a scientist. It now gave me the opportunity to make a contribution that others were not in a position to make. I had thought that I would pull together what information there was and write up something for the AGSD. A sort of 'thank you' that would also be of a help to any future parents in our position. I didn't really see that there would be much that could be done beyond that.

The librarian at my work, Lynda, pulled a few strings to get me into the medical library at Edinbugh University and so I started carrying out a literature search on Pompe disease, helped by my cousin Aidan, who was a med student at the time. It was just the kind of mind-numbing, time-consuming task that I needed. In the far off days of 1993, younger readers may be surprised to learn, this was all done as a paper chase - looking up entries in publications like the citation index, then walking to shelves of actual hard-copy journals to look up the articles and see if they were of any interest. And if they were useful, you wrote the reference (by hand) on an index card and put it in a little desk file. Describing this to anyone under the age of 30 elicits a response that can only be compared with the old 'For mash get smash!' advert. But I digress.

And then something astonishing happened. Right then, in that library, amongst those dusty shelves of journals, I felt the sun come out. Because there, in my hands, was a paper that showed that Pompe disease was not the hopeless case that I had thought. A team of people in The Netherlands had been carrying out some ground-breaking research. They had worked out how Pompe disease could be treated and had designed some ingenious experiments to show that their idea could work.

I realised that I would be able to do more than just write an article for other parents to help them understand how their child was dying. I could write something explaining how this disease could be beaten. This was no longer a hopeless cause - it was a cause that could and must be won.

And the first step was to try to explain to other people just why what this Dutch group had done was so important. Which is something that I am going to do again in the next article.

The long plateau

2009-04-13T19:58:00.004+01:00

Following Hers discovery of lysosomal storage diseases - the second great milestone in the Pompe disease story - there followed a long period where there were no major advances. That's not to say that work was not being carried out. Research continued and small but important additions were added to our store of knowledge.

It was discovered that Pompe disease could affect older children and even adults (where it was at that time given the name acid maltase deficiency) with progressive muscle weakness but no heart enlargement. Diligent, essential work (such as that by Christa Loonen) described the 'natural history' of Pompe disease patients. There were important advances in related fields too - lysosomes became better understood and better molecular biology tools and techniques were developed. The world was moving on.

There were attempts at a treatment too. Soon after Hers discovered lysosomal storage diseases, it had been suggested that enzyme replacement therapy might be a potential treatment. As early as 1965, this was tried for Pompe disease, firstly using enzyme prepared from the fungus Aspergillis niger and later with enzyme derived from human placenta. All attempts failed; the enzyme was simply soaked up by the liver and did not reach the muscles.

I would like to make a tangential point here that I may return to later. It is often said by animal rights proponents that if scientists were not able to use laboratory animals, they would soon find alternative methods. Well, there was clearly a tremendous will amongst the scientific and medical community to find a treatment for Pompe disease, as evidenced by the pretty desperate attempts at enzyme replacement therapy. Yet for a quarter of a century, there was no progress. Looks like absence of animal models does not, after all, magically lead to progress by other methods.

But I digress. By the late 80s, the stage was set for the third great leap forward - one that would lead to a treatment for Pompe disease. Once again, it would take place in the Netherlands.

However, before I get to that, in the next instalment I'd like to leap ahead to 1993, with some personal background. It's an indulgence, I know, however it will also help me to tell the story.

Christian de Duve, Henri-Gery Hers and serendipity

2009-04-07T18:33:00.012+01:00

"In the field of observation, chance favours only the prepared mind"

Louis Pasteur

J C Pompe had described a disease which had the symptom of glycogen accumulation, particularly in the heart, due to an 'inborn error of metabolism'. In the years that followed, further research on glycogen metabolism made the cause of the disease more mysterious, rather than less.

Gerty and Carl Cori were pioneers in this field and discovered the missing enzyme in von Gierke's disease. Indeed, they won a joint Nobel Prize for their work on glycogen metabolism. In 1957, G T Cori listed what are now known as glycogen storage disease types 1-4. Only in the case of Pompe disease was the missing enzyme unknown. The key to solving the puzzle of what caused Pompe disease lay in a seemingly unrelated discovery taking place elsewhere.

US stamp issued in honour of Gerty Cori (the formula is wrong, unfortunately...)

In 1955 Christian de Duve and co-workers were investigating the effect of insulin on the liver, when they came across some odd results, in the shape of some intra-cellular particles which seemed to have digestive properties. Intrigued, they stopped their work on insulin and investigated this phenomenon. de Duve named these particles lysosomes and so began a long period of research by his group and others. This was an important discovery. The idea that cells themselves had compartments (now known as organelles) with particular functions was now firmly established. Thus was the idea of the lysosome as the 'recycling plant' of the cell established. Prof de Duve was awarded the Nobel Prize for his discoveries in 1974.

I wrote to Professor de Duve a few years ago, asking him if it had ocurred to him that his discovery of lysosomes might have some medical significance. He replied that it had not - it was curiousity-driven 'blue skies' research. However that connection was made by one of his original co-workers, Henri-Gery Hers.

After the discovery of lysosomes, most of de Duve's team joined him in this exciting direction, however Henri-Gery Hers retained his interest in carbohydrate metabolism and founded his own research group instead. This ultimately led him to become involved in research on glycogen metabolism. Following the death of Gerty Cori, he decided to take up her research on identifying the missing enzymes responsible for the glycogen storage diseases.

In the course of this he examined samples from patients from around the world, including some with Pompe disease. This confirmed the puzzle that in pompe disease all of the known enzymes for the metabolism of glycogen were present and correct - yet there was still massive accumulation of glycogen.

That was still not his main line of research. Hers was trying to develop a test for the enzyme responsible for glycogen storage disease type 3. Unfortunately, his test turned out to be for an enzyme that was at normal levels in his GSD 3 samples. Fortunately, by chance, he had included some Pompe samples in his experiment - and his test showed a deficiency in all of those cases. He had discovered the enzyme deficiency responsible for Pompe disease.

That wasn't all though. Hers knew that his new enzyme, an alpha-glucosidase, worked best at an acid pH. This set him thinking about his previous work on lysosomes which had an acid environment - could this new enzyme be situated there? He went on to establish that it was. He further deduced that the normal function of this enzyme was to break down glycogen inside the lysosomes and that, in its absence, glycogen would accumulate, as it was isolated from the normal enzymes for glycogen metabolism found in the rest of the cell. In 1965 he established the concept of lysosomal storage diseases, based on his Pompe disease research.

All in all, a remarkable piece of scientific detective work. Yes, there was an element of serendipity involved, however Hers was quick to realise the significance of what he found. Truly chance favours only the prepared mind.

Thanks to de Duve and Hers, the cause of Pompe disease was now known over 3o years after its discovery. The next task was to find a way to treat it - that would take an equally long time.

Joannes Cassianus Pompe 1901 -1945

2009-04-04T17:35:00.037+01:00

I can think of no better place to start the story of Pompe disease than with Joannes Cassianus Pompe, the scientist who first described the disease which now bears his name. It is important to note that the disease had undoubtedly been around for a very, very long time, prior to its discovery. In fact, I would say (warning: people often look askance when I say this and your attention is drawn to the disclaimer at the right) that it was around in the time of the dinosaurs. "Evidence?", you cry? Well, if it is found in both mammals and in birds (and it is) it's a fair bet that it was found in the common ancestor of mammals and birds - which pre-dates the dinosaurs. All of which makes its eventual discovery all the more impressive as a piece of scientific observation and detective work.

In putting together this article, I have drawn heavily from information and images supplied by Dr R C C Pottkamp of the Netherlands Institute for War Documentation, whose help I very gratefully acknowledge.

The image above is a contemporary drawing of the great man. I scanned it, with permission, from the 1979 PhD thesis of Christa Loonen (The Variability of Pompe's Disease: A clinical, biochemical and genetic study of glycogen storage disease type 2, or acid maltase deficiency - also drawn on here) one of the dedicated band of Dutch scientists and doctors who did so much to take forward Pompe's work. But more of them later.

Joannes Cassianus Pompe was born in Utrecht on 9 September 1901. He studied medicine at the University of Utrecht and during this time came across the symptoms of what is now known as infantile Pompe disease, which he described in his 1932 publication Over idiopathische hypertrophie van het hart. On December 27, 1930, Dr Pompe had carried out a postmortem on a 7-month old girl who had died of pneumonia. He found the enlarged heart now known to be charactertic of the infantile form of the disease and had some microscope slides prepared. These showed that the muscle tissue was distorted into an oval mesh.

He realised after detailed examination, that this appearance was due to the accumulation of something forcing the muscle tissue to distort in that way. This isn't as obvious as it appears now - when you look at fishing net, would you conclude that it has been forced into that shape by the air filling the holes? He then tried to discover what the accumulated substance was and had the idea that it might be glycogen. Subsequent testing showed that to be the case.

Pompe was perhaps guided in that direction by his colleagues Professor Snapper and Dr van Creveld. They had published a paper in 1928 desribing what is now known as Von Gierke disease, or glycogen storage disease type 1. In fact, the girl on whom Pompe carried out his post-mortem had been the patient of Professor Snapper. You can imagine that these colleagues might have encouraged Dr Pompe in establishing the idea that here was a second type of glycogen storage disease, also an inborn error of metabolism. It is interesting to speculate (and that's all it is, pure speculation on my part) that having missed out on 'naming' glycogen storage disease type 1, Snapper and van Creveld were keen to promote 'Pompe disease' as the name for the new type (there was some competition, as a German pathologist, W Putschar, made the same discovery, just a few months later!).

Dr Pompe graduated in 1936 in the subject 'cardiomegalia glycogenica', indicating that this had been a continuing subject of study for him. After a spell at the St. Canisius Hospital in Nijmegen, he was appointed as Pathologist at Hospital of Our Lady (OLCG) in Amsterdam, where he worked from June 1939 until his death.

The workplace was appropriate as he was known as a very devout Catholic, as well as an admirer of Sophocles and the Dutch poet Vondel. The overall picture is of a 'renaissance man' - a man of both science and the arts, as well as a dedicated family man. He was also, as we shall see, a hero, for Pompe, no doubt led by his strong Christian beliefs, became active in the wartime in the wartime Dutch resistance.

To the right is a photograph of Dr Pompe in the uniform of a Captain of the Dutch army (Medical reserve), thought to have been taken in 1939-40. Following the Nazi invasion of the Netherlands on 10 May 1940, he was mobilised and was involved in the fighting that lasted until 15 May.

Following the fall of the Netherlands, Dr Pompe became involved with the Dutch resistance. At first he was involved in finding hiding places for Jews. Through this he made contact with the operator of an illegal transmitter.

Pompe's laboratory was somewhat isolated from the rest of the hospital. So much so that at least two men who were hidden in the OLVG worked in the laboratory during the daytime! He therefore suggested that it would make a good hiding place for the transmitter and in sometime in November-December 1944 it was installed in the animal house (where the experimental animals were kept) beneath his laboratory. The transmitter was used to send messages to the UK on behalf of the resistance.

The transmitter was eventually detected by the Germans and on Sunday 25 February 1945, at 10 am, 40-50 members of the German Military Police entered the hospital and made straight for the animal house. The wireless operator, Pierre Antoine Coronel, was broadcasting at the time and tried to resist. He was subject to summary execution in the courtyard of the hospital. After the war, a street was named after him in Amsterdam - Coronel Street. Several hospital staff were arrested.

During the raid, Dr Pompe had been at Sunday mass and on returning to hospital was warned by patients of what had occurred. He went home to tell his wife that he needed to go into hiding. While leaving the house he was arrested in front of his wife and children, who were threatened with rifles.

While some of the imprisoned staff were eventually released, Dr Pompe, Louis Berben (the man in charge of the animals) and a male nurse, Piet van Doorn, were kept in jail.

On April 14, 1945, the resistance blew up a railway bridge near St Pancras, destroying an army train in the process. As a reprisal, 20 Dutch prisoners, including Dr Pompe and Louis Berben were shot. They were taken in a sealed truck to a meadow near St Pancras and, at around 9pm on 15 April, shot in two groups. The bodies were buried in a mass grave in the sand dunes near Overveen. On the same day, Piet van Doorn was also shot, in retaliation for another attack on a railway.

A monument was erected to the victims after the war (colour photographs below, courtesy of Maryze Schoneveld van der Linde's brother).

In addition, a tile panel was erected above the main entrance of the OLVG, in remembrance of Dr Pompe and the other employees who were shot. This is currently held in storage, following redevelopment of the hospital.

Apologies if the reader feels I have gone on at too much length here. However, I have to confess that I am in awe of such bravery in the face of seemingly insurmountable evil and so wanted to give a fuller picture of the man who is at the start of our story - his intellect and his courage. Truly, there is much to admire about Joannes Cassianus Pompe.

One last comment. I have been gathering this information for some time and have found myself almost reluctant to write it up. The reason is that the German patient group are amongst the leading lights of the international Pompe community and I would be unhappy if this article were thought to be, in some way, anti-German. It is certainly not intended to be so. It is worth bearing in mind that the first country to fall victim to the Nazis was Germany itself (over 3 million German citizens were imprisoned by the Nazis and around 77,000 executed), that they were aided and abetted by home-grown Nazi movements and sympathisers in other countries and that perhaps the bravest of all the anti-Nazi movements was the German resistance. Lastly, I don't think we need to think too hard to realise the fate of any family touched by genetic disease under a Nazi regime.

Introduction

2009-04-01T06:43:00.003+01:00

Where to begin?

Just 16 years ago, Pompe's disease (glycogen storage disease type 2, acid maltase deficiency) was still an untreatable condition, invariably fatal in infants and relentlessly progressive in older children and adults. That is all changed now. The story of how that change came about is a remarkable one. It's a story that I have been threatening to write a book about for the last 6 years and have signally failed to do so! This blog is an attempt to put that right and to do so in a way that allows the wider Pompe community to add to, comment on and correct what I have written.

I have to confess that this blog is also, in part, a reaction to Geeta Anand's book, The Cure, soon to be the basis for a Hollywood film. It's not a bad book. It's the inspiring story of one man, John Crowley, whom I rather like and admire. What it is not is the story of the development of a treatment for Pompe disease. In fact, in that respect, the book is akin to reading a history of World War 2, told entirely from the perspective of Switzerland: "Skiing good. Apparently the neighbours are fighting about something or other. Most importantly, we have invented Toblerone!"

The Cure misses the main narrative out altogether, along with most of the important milestones in the development of enzyme replacement therapy. However the most glaring omission is the complete absence of any mention - any mention at all - of the role played by the international patient community in bringing about the availability of a treatment. The alliance between patient groups, researchers and industry is a model for the development of treatments for other rare diseases.

This is a story that needs to be told and I will attempt to do that justice here, though I hope I will have some help. I have a large file of material that I intend to work my way through - I know that others have their own archives and I hope that they will contribute from them. The result may not be strictly chronological but I hope that it will be as objective as possible.

Lastly, a quick word about myself. I'll post the story of my involvement later, however, just to be clear at the outset, I have no claim to have played any significant part in the events that will be described here. What I did have, was a ringside seat during what was a very exciting time. What follows is the view from that ringside seat.