Summary of the GSD (UK) Patient Conference and IPA Meeting

Category: IPA Conferences
October 10, 2004

October 9-10, 2004
Birmingham, UK

On 9th and 10th October, the AGSD (UK) held its annual patient conference. This year we were more ambitious than usual in that the Pompe Workshop extended into a second day. Families and speakers arrived on the Friday night and we held an informal conference dinner on the Saturday evening. These two evenings were as important as the conference itself as it gave families the chance to socialise and exchange views on coping with Pompe Disease.

I really want to thank everyone who contributed to the event: All the speakers were excellent this year, and all gave talks that were easily digestible by the layperson. We had many more patients represented than in previous years, which benefited not only themselves, but everyone present. Many professionals commented on how wonderful it is to meet patients and the general feedback I received was that the weekend was both very informative and thoroughly enjoyable.

Allan Muir, AGSD (UK)

Summary of the GSD II Programme

(by Allan Muir)

Saturday 9th October

The day started with a light-hearted presentation on last year’s charity bike ride. Colin McArthur gave an excellent off-the-cuff talk about our adventures in Vietnam and also introduced his plans for the next ride in Costa Rica, March 2006.

The first medical presentation of the general session was from Chris Hendriksz, Birmingham Children’s Hospital (UK). Chris gave an overview of all GSD’s in a humorous yet informative fashion and his talk has helped us all better understand the problems faced by families affected by GSD types other than our own.

Our second general speaker was Ruth Geall from the Muscular Dystrophy Campaign. This is a charity that represents many more patients than the AGSD (UK); over 30,000 patients and over 60 diseases. The MDC has a wealth of experience and resources at their disposal to help MD patients. Ruth offered to work more closely with the AGSD (UK) which will, I’m sure, be an enormous help to us; we are simply too small to offer the level of service that they can provide.

Dr. Mark Davidson, Genzyme Europe, gave a review of the Pompe trials programme. He outlined the milestones achieved over the last 12 months and discussed the product registration procedure for Myozyme in the European Union (EU). Specific milestones he quoted were:

  1. Completed enrolment of 2 key infantile-onset studies; 1602 & 1702
  2. Started up a programme in late-onset Pompe patients
  3. Broadening of clinical experience with Myozyme through international expanded access programmes
  4. All patients now transitioned to Myozyme
  5. Launch of the Pompe disease registry
  6. On track to submit Marketing Authorisation Application (MAA) for Myozyme in EU in December 2004

Mark then described each of the studies in more detail and talked about the current observational study for late-onset patients and how its data will be used to define the clinical study, due to start in mid-2005. The expanded access programmes were also discussed and we learned that by the end of this year Genzyme expect to be treating a total of around 50 Pompe patients.

Dr. Ed Wraith, principal investigator at the UK trials centre, Willink Unit, Royal Manchester Children’s Hospital, described the natural history of Pompe disease without treatment. He then contrasted this with the results from ERT clinical studies. After a historical perspective he gave interim study results:

1702 trial (6m to 36m): Twelve out of fifteen patients were alive after six months of treatment. Ten patients were not invasively ventilated at baseline; eight patients were still alive and free of invasive ventilation at six months of treatment. The ventilator-free survival time is 80%

1602 trial (less than 6m): All eighteen patients are alive. They are distributed over five sites (France, UK, Israel, USA, Taiwan). Age at onset of ERT ranged between 0.8 and 6.2 months. Duration of ERT ranges between 3 and 15 months. Current Ages range from 5.4 to 20.3 months. 16 of the18 children are invasive ventilation-free and of those over 15 months, 5 out of 9 are able to walk.

These are very encouraging results and show great improvement over previous trials. This is probably due to a combination of improvements to both the enzyme and clinical management. Lessons have been learned from earlier trials and the ERT now appears to be very well tolerated.

Prof. Timothy Cox, Addenbrookes Hospital, Cambridge University, gave an impassioned and comprehensive talk, covering all the arguments for providing and funding therapies for rare disorders. He especially urged family support groups, such as ours, to raise our profile by joining international organisations and tackling our problems of access to therapies at a political level. He gave some excellent advice and he is an invaluable companion to have on our difficult road towards funding for Myozyme throughout the UK.

Ellie Gunary, MPS Society, stepped in at very short notice to relate her experience of ERT funding difficulties in the UK for patents with MPS I and Fabry Disease. This is hugely relevant to us as we expect to be in the same position in little over a year’s time. Ellie led us through the whole process including Judicial Reviews an appeal processes and gave us heart from the fact that the MPS society has only lost one Primary Care Trust (PCT) appeal out of 9.

We then heard three gene therapy presentations. The first two speakers are colleagues of Barry Byrne who sadly couldn’t make the conference this year. (Thanks to Clive Tonks for this piece).

Dr Cathryn Mah. Topic: Adeno-associated virus vector mediated gene therapy for the treatment of Pompe’s Disease.

Catheryn reported that her laboratory had used a knockout mouse model for Pompe’s. The mice showed muscle weakness, cardiomyopathy and hepatomegaly. As a vector for the gene for acid maltase, they chose a strain of an adeno-virus that was non-pathogenic for humans.

The vector and gene were mixed with a gel that was painted onto the diaphragm of affected mice. They then demonstrated that strips of diaphragmatic muscle contracted more strongly.

Other strains of vector were developed which worked when injected intravenously. They found that different strains differed in how effective they were in different tissues. For example, one strain was more effective in targeting skeletal muscle, while another was better with cardiac muscle. The improvements in knockout mice, using the best vectors were persistent to the age of 11 months, elderly for a mouse. The expression of the gene was seen within 5 days of injection.

Dr Kerry Cresawn. Topic: Indirect correction of affected tissues in Pompe’s Disease using recombinant adeno-virus vectors and potential immune mediated effects.

Liver, heart and skeletal muscle were affected to different degrees by different vectors. Two of those most affecting liver were injected directly into the portal vein of knockout mice. This specifically targeted the liver and caused it to manufacture large amounts of acid maltase, which leaked into the blood stream. This enzyme was then taken up by other tissues such as heart and skeletal muscle and those tissues the showed improvement. Surprisingly, there was little immune response to the enzyme and so it seemed likely that using the liver as an enzyme factory could be one way forward.

Dr Andrea Amalfitano concluded Saturday’s presentations with an interesting overview of his work (thanks to Peter Constable for this report):

Andy started by discussing the advantages of gene therapy over other forms of treatment, these are:

  1. Widespread and rapid effect.
  2. Long-term efficacy.
  3. Easy dosing schedule (no more than every 6 months and possibly as long as a year)
  4. Augments enzyme replacement therapy (ERT).
  5. Could replace ERT.
  6. Easier production than ERT chemicals

ERT means that the enzyme must be infused directly into the bloodstream and as little as 2% of the enzyme can get to where it is. Gene replacement therapy can be produced automatically in the right place or so that the body doses itself.

There are two means of getting the virus into the body, it can be injected directly into the muscles, this achieves very high enzyme levels but it doesn’t infect the muscles evenly. It can spread from the muscle and is taken up by the liver & spleen. Alternatively, the virus can be injected into the blood stream where it is targeted to infect the liver. The liver is very efficient at producing GAA and can become a “factory”, releasing the protein into the bloodstream for the muscles to take up.

He has discovered that older mice are less responsive than younger mice. In neo-natal GAA-KO mice after treatment the levels of GAA were up to one hundred times over what would be found in a natural population, this effect appeared long lasting and the GAA was taken up, and importantly, was effective in, the heart, diaphragm and quadriceps (thigh muscle). This implies that it has been taken up by all other skeletal muscles.

Immune responses to the therapy were highlighted and ways around some of these reactions. Killer cells will try to engulf and remove the virus as it is injected, steroids can suppress the response and only have to be given for a few hours around the time of infusion. Also, enhancers can be administered along with the virus, although an immune response it initiated a state of equilibrium is reached with virus, GAA and antibodies all circulating in the blood.

The next step is to move to primate trials, however, these are extremely expensive. Dr Amalfitano does not believe that the treatment will be approved without this. Although he did say that as other gene replacement therapies are approved the authorities may allow viral treatment as a block and only require approval for the gene itself. Gene replacement therapy does offer real hope to sufferers and their families.

I [Allan Muir] concluded the day with a discussion of the AGSD (UK) Pompe group’s activities over the last 12 months. This was, in part, a plea for help from the membership in light of the extra work I see in the months ahead. Thankfully I received several offers of assistance from a number of new members. Also I introduced our new Webmaster, Peter Westwood, to the group; Peter will be taking control of over the coming months and will be relaunching the site sometime soon.

The day finished one hour later than scheduled, but nobody seemed to complain, I didn’t like to cut any of the presentations short, as they were all so well delivered and captivated the audience.

Sunday 10th October

Randall House, Chairman of the IPA opened the second day of presentations by describing the huge collaboration between the IPA and Genzyme. He then invited Frank Ollington, Senior Vice-President of Genzyme Therapeutics, to present the current status of the Pompe Development Programme.

Presentation by Frank Ollington: Frank opened by describing how Genzyme is a patient focussed organization and that conferences such as these are very special events for him. Meeting families and patients was clearly very important to him, especially the little baby who had been cooing and gurgling throughout the Saturday presentations; another spectacular success story from the Manchester ERT trial site. (I really must thank the parents for bringing their daughter; it made the conference a very, very, special occasion for me too).

The Pompe programme development goal is to develop and gain regulatory approval for an enzyme replacement therapy for Pompe disease; so as to make drug therapy available to as many patients as possible, as soon as possible, globally. Frank showed how the programme was designed to build on current progress with manufacturing, trials, the expanded access programme and the Pompe Registry, leading to regulatory submissions in Europe, then the US, and then Globally. He also stated that it was Genzyme s intention to invest in the future by developing next generation drug therapies, improved diagnostic screening procedures, and healthcare infrastructure.

Summarising the programme he said that the Genzyme development program is making good, steady progress; indeed all aspects of the program have progressed substantially in the past year. Specifically he reported that their regulatory submissions are planned for December 2004 in EU and mid-2005 for USA. These will be followed by a Biologics License Application, after which other global filings will take place. He presented a timeline for the potential sequence of events involved with the EU submission, concluding with a possible decision from the European Medicines Evaluation Authority (EMEA) during January or February 2006.

In conclusion he outlined last year’s achievements: The 2000L plant is on schedule, the trials and LOPOS, EAP enrolment have all gone very well. The Pompe Registry has over 20 sites enrolled and some have IRB/Ethics approval. He stated his goals for the future as being:

  1. Continue to increase understanding of disease and standard of care
  2. Ongoing success in developing ERT and obtaining regulatory approvals
  3. Development of diagnostic technology and treatment centres to accelerate the provision of better care
  4. Build the body of knowledge necessary to support appropriate reimbursement of ERT upon approval
  5. Second Generation ERT and Gene Therapy.

Despite being so upbeat, Frank did warn that due to the unusual nature of the filing, there is still much risk in the programme. Particularly with the application for a broad label. This is because much of the data presented is based on infantile trial data; it may be difficult to automatically gain approval for all sufferers in the first application.

Presentation By: Professor Volker Straub, from the International Centre for Life, Newcastle-upon-Tyne, UK (Thanks to Martin Johnson for this report): Whilst Pompe is a lysosomal storage disease, it presents more similarities to neuromuscular diseases (NMD) than to other metabolic diseases; hence most diagnosis of Pompe is by neurologists and not metabolic specialists. Prof. Straub s personal view was that the NSCAG NMD centres would be more appropriate locations for diagnosis than LSD centres. Diagnosis is the basis for treatment, and too many misdiagnoses are occurring, mostly as a result of lack of awareness you can’t make a diagnosis that you don t know. Typical symptoms of Pompe Disease such as respiratory distress and weakness are non-specific.

Two ENMC workshops are to be organised, with the aims of delineating the natural history of Pompe Disease and establishing standards for diagnosis, follow-up assessment, clinical management, and the therapeutic approach Treatments are likely to include physiotherapy, prompt intervention in the event of chest infections, diet, non-invasive ventilation, ERT and Gene Therapy. Measures of success of treatment will include muscle strength, structure and function; biomarkers such as CK level; life expectancy and quality of life. Prof. Straub noted that PCT’s might ask for specific evidence of improvement in quality of life measures in order to fund treatment, and he emphasized the importance of a multi-disciplinary approach, and of support groups working with medical specialities.

Finally Prof Straub discussed the necessary characteristics for newborn screening to be viable:

  1. A treatment must exist
  2. The treatment must prevent early onset symptoms
  3. The screening test must be highly specific – no false positive results
  4. The test must be highly sensitive – no false negative results
  5. it must be easy to perform
  6. it must be cheap.

Volker said that all these conditions could be satisfied for screening Pompe Disease and that very cheap blood-spot diagnostic tests are currently under development.

The final presentation was due to be presented by Julia Fox-Rushby of MEDTAP International. Unfortunately Julia could not make the conference for personal reasons. As we had her slides Julie Kelly (Genzyme UK) and I decided to present the Burden of Disease Study on her behalf. The aim of the study is to assess the annual economic burden of illness associated with caring for people with severe Pompe disease. A questionnaire will be sent to willing volunteers and will ascertain:

  1. Direct Costs
  2. Medical costs to health providers
  3. Medical and non-medical costs to families or patients
  4. Indirect costs
  5. Productivity losses borne by families or patients.

This is the first study of its kind and will help decision makers to know how much it costs to care for a Pompe sufferer in the absence of treatment. It will also help to assess the financial impact avoided by the health service when a patient remains healthy through ERT; it will helps to assess part of the value gained to society by avoiding these illnesses.

The study is in three parts:

  1. an information review (complete)
  2. a physician s survey (underway)
  3. a patient (or carer) survey (ready to start).

The study is for patients in UK, Netherlands, Sweden, Germany, Canada, USA, Australia, Brazil and will include patients older than18 yrs or main carers of patients less than 18 yrs. This is not a survey only for patients who are able to walk more than a few 100 metres AND who require no additional help to breathe.

Or to put that another way:

This is a survey only for patients who are unable to walk more than a few 100 metres OR who require additional help to breathe.

There was some debate as to the precise meaning of these criteria and we hope to have them more accurately defined in the near future. The survey is intended for those severely affected by Pompe Disease, and those who will suffer a considerable financial burden because of it.

Specifically excluded are patients who are currently part of a clinical trial.

To our embarrassment we were unable to answer some of the posed questions, but hopefully the main aims and structure of the study were communicated. The survey will be available very soon and if you are interested and able to participate or you know others who might be willing to help, contact details were given:

Phone +44 (0) 20 7299 4550 (ask for Lesley) or email

There followed a session where individuals gave short presentations on the activities of their patient support groups; Ria Broekgaarden gave an excellent talk on the VSN, the Dutch Patient Association for Neuromuscular Diseases. Ria’s talk was very interesting and was summarised as patients can play an active role both on a national and an international level and collaboration offers solutions.

Helmut Erny representing the German GSD group talked about the accidental diagnosis of his son, now 16 and still well. He described the organizational changes (into GSD Types) currently taking place in the Selbsthilfegruppe Glykogenose Deutschland e.V. Helmut talked about the annual meetings they organise for patients to discuss such subjects as respiratory equipment and wheelchairs and emphasised the importance of patient contact. Last year the SHG-Glycogenose organised the exceptional IPA Pompe Conference in Heidelberg.

Marylyn House ran through the history of the AMDA, formed in 1995 after their daughter Tiffany s diagnosis. The AMDA have run a number of ambitious projects and conferences over the years and are hoping to hold a Pompe conference in San Antonio in 2006.

Once again I want to thank all those who contributed to the success of our Birmingham (UK) Conference. My only regret was that I didn’t t have time to chat more to people, a feeling shared by others, I know.

Thank you Allan!

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