Novazyme visit

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.

1997: Lift off!

Looking back, 1997 was an absolutely pivotal year.

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

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

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

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

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

Enzyme Therapy for Glycogen Storage Disease Type II: Dream or Reality?
by Arnold JJ Reuser, Biochemist, Clinical Genetics Erasmus University, Rotterdam and Ans T van der Ploeg, Paediatrician, Sophia Children's Hospital, Rotterdam

A number of recent events have brought the answer to this question near. When Dr. Kevin O'Donnell asked us for the latest news, we thought it would be nice to put these recent events in a historic perspective.

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

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

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

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

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

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

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

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

Although the final results of this technical, costly and emotional adventure are still uncertain we should feel encouraged that after so many years of waiting a realistic and promising attempt at enzyme therapy for GSDII will be taken.

I can hardly describe the sense of excitement at this time. It really seemed that the fledgling Pompe community could, at last, dare to hope.

1996

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.

1994 continued

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.