Maryze's story - Part 8

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

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

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

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

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

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

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

 

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

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

 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.