May 11, 2005
“Emerging therapies for Pompe disease”
Dr. Ans van der Ploeg, Erasmus MC Rotterdam the Netherlands, talked about the natural course in late onset Pompe disease. She informed the audience about the outcome and the importance of the IPA Erasmus MC Patient survey (questionnaire). For information about the outcome of the survey we would like to refer to the publications mentioned below.
The International Pompe Association (IPA) is a consortium of Pompe Patient organizations devoted to improving the welfare of Pompe Patients across the globe. Driven by a set of clear objectives and a multinational Board of Directors, the IPA, in conjunction with the Erasmus Medical Center (EMC) in Rotterdam, The Netherlands, has developed a comprehensive survey to examine the plight of Pompe patients around the globe. This survey allows Pompe patients to capture their personal journey with this disease and in doing so, helps to improve disease understanding and research for the entire Pompe Patient community.
Among these activities, the IPA, in cooperation with EMC has distributed, analyzed and published the results of a Pompe Patient survey that covers a broad set of clinical, functional and quality of life data.
The IPA/EMC Patient Survey was initiated in partnership with the Erasmus Medical Center in Rotterdam, The Netherlands, to investigate “the clinical condition of late onset Pompe patients.” These late onset patients (over 2 yrs of age) represent a large percentage of Pompe patients and exhibit a broad spectrum of clinical manifestations. Due to the heterogeneity of this affliction, more data was needed to develop a better understanding of the disease natural course in this patient population. As a means to address this challenge, the IPA/EMC Patient Survey was launched in May 2002 and to date has 300 patients participating from the Netherlands, UK, Germany, Australia, France, Canada and the US (the questionnaire is available in Dutch, English, French, and German). In terms of survey analysis and publication, there are currently three different articles
detailing observations with respect to: the path to final diagnosis, problems encountered in childhood, course of the disease, use of care facilities/providers and quality of patient life. Analysis of this data will continue as more Patient surveys are returned to the Erasmus Medical Center. Because the IPA/EMC Patient Survey represents a patient-entered, discrete assessment of patient quality of life, fatigue and functional data, it effectively complements the physician-entered, longitudinal collection of clinical data in the Pompe Registry.
Dr. Volker Straub, Neuro Muscular Centre Newcastle, UK informed us about the 137 th ENMC International workshop. An extended report of this meeting will be published in Neuromuscular Disorders and when published it will be on the IPA website www.worldpompe.org
The Pompe consortium will organize a second workshop in 2007. It is a great advantage for a rare disease as Pompe disease that specialists are working closely together in order to speed up the process from diagnosis to therapy.
Pompe disease is being accepted as the name to be used so was decided in the workshop. Pompe disease has a broad clinical spectrum and is a continuum of clinical phenotypes. Pompe disease might not always be progressive sometimes there is plateau. During the workshop amongst others diagnostic tests and assessments and procedures were discussed.
137th ENMC International Workshop
22nd - 24th April 2005, Hoofddorp, The Netherlands
Defining the standards of medical management in Pompe disease / glycogen storage disease type II
The first ENMC workshop on Pompe disease, also referred to as glycogen storage disease type II, was held in Hoofddorp from the 22nd to the 24th of April 2005. Twenty participants from The Netherlands, France, Germany, Italy, Austria, Denmark, the United Kingdom and the Untied States attended this meeting. Workshop participants covered areas of basic research, diagnostics, clinical care and therapies in Pompe disease. Another area that was discussed was nomenclature
Pompe disease is an autosomal recessive condition caused by mutations in the gene for acid a-glucosidase, an enzyme responsible for the breakdown of lysosomal glycogen. The reduction or complete loss of a-glucosidase activity leads to lysosomal glycogen storage and finally to an impaired cellular function. The effect of glycogen accumulation on cell function becomes notably effective in muscle cells, in which it compromises contractile activity. As a consequence muscle weakness is one of the predominant clinical features in patients with Pompe disease. A major focus of the workshop was dedicated to the clinical spectrum and natural course of the condition, including unusual clinical presentations and diagnostic pitfalls. It became very clear that Pompe disease is a disorder in which severity, age at onset, rate of disease progression, and extent of organ involvement can vary significantly from individual to individual. Patients present a continuum of clinical phenotypes with a severe infantile form with cardiomyopathy and early death forming one end of the spectrum, and a mild muscle weakness without any cardiac involvement and a normal life expectancy forming the other end of the spectrum. In general, the later the symptoms appear, the less severe the disease will be. But age of onset cannot always be correlated with disease severity as even milder patients can present with motor delay and weakness in early childhood and some adult patients with late onset can rapidly develop severe complains. At present the residual enzymatic activity seems to correlate best with disease progression. The less the enzymatic activity the worse is the clinical course of the disease. Despite the fact that muscle is the most severely affected tissue and most of the adults with Pompe disease present with limb girdle and respiratory weakness, there have been a few reports with involvement of the cerebral vessels in the brain. It is too early to conclude whether this observation is of diagnostic relevance. The heart does not seem to be involved in adults with Pompe disease.
Diagnostic markers that can help to indicate Pompe disease, are an elevated serum creatine kinase activity (CK), lactate dehydrogenase (LDH) and transaminases as well as tetrasaccharides in serum und urine. An air-dried blood film stained with periodic acid Schiff’s reagent (PAS) might show lymphocytes with glycogen positive vacuoles. A muscle biopsy with signs of a vacuolar myopathy and glycogen storage is indicative for Pompe disease but a normal muscle biopsy in milder patients does not rule out the condition. Muscle imaging might be helpful to select the muscle for a biopsy. Magnetic resonance imaging (MRI) and computer tomography (CT) investigations have shown that muscles of the trunk and the hamstrings are more severely affected in adults with Pompe disease than the femoral quadriceps or distal muscles. The measurement of enzymatic activity in fibroblasts is currently the gold standard for the diagnosis of Pompe disease, but enzymatic activity can also be reliably measured in muscle tissue, lymphocytes and, depending on the method, in mixed leucocytes or dried blood spots. The diagnosis of Pompe disease can finally be confirmed by mutation analysis. The consortium came to the conclusion that some of the proposed screening tests for Pompe disease have still to be validated but the use of dried blood spots looks very promising.
The assessment of patients with Pompe disease should include manual muscle testing using the scale established by the Medical Research Council (MRC scale) and tests for muscle function (e. g. 10 m walking). Furthermore, the lung function of patients should be tested in an erect and a supine position twice a year. A drop of the vital capacity > 20% indicates diaphragmatic weakness. Respiratory management plays a fundamental part in the care of Pompe disease whereas dietary therapy has been of limited benefit to the patients. For future clinical trials it will become more and more important to also apply quantitative muscle tests (e.g. dynamometer), disability scales and quality of life measurements. The workshop participants have established diagnostic algorithms for the severe infantile form (‘classical’ Pompe disease) of the condition, the juvenile form and the adult form. Future tasks for the consortium will focus on the preparation and monitoring of clinical trials for enzyme replacement therapy.
This workshop was organised by Prof. V. Straub (Newcastle, UK) and Dr. A. van der Ploeg (Rotterdam, The Netherland).
Other participants were: Dr. Allan Lund (Denmark), Dr. Anna Pichiecchio (Italy), Prof. Arnold Reuser (The Netherlands), Dr. Bruno Bembi (Italy), Dr. Benedikt Schoser (Germany), Dr. Christian Schwake (Germany), Prof. Corrado Angelini (Italy), Dr. David Hilton-Jones (UK), Prof. Francesco Muntoni (UK), Dr. Irene Maire (France), Prof. Luciano Merlini (Italy), Prof. Marc Nicolino (France), Dr. Marloes Hagemans (The Netherlands), Prof. Olaf Bodamer (Austria), Dr. Otto van Diggelen (Netherlands), Dr. Pascal Laforet (France), Dr. Priya Kishnani (USA), Ria Broekgaarden (Representative from IPA, The Netherlands).
(Summary of Nantes Conference continued...)
Prof. Marc Nicolino from Lyon France, talked about the “clinical appearance update on enzyme replacement therapy”. Pompe disease is a continuum of disease severity with one enzyme deficiency. It is a rare disease and there are different clinical presentations of symptoms of infantile Pompe disease such as: progressive muscle weakness, progressive cardio-myopathy, respiratory and heart failure, death usually in the 1e year of life (median 8.7), feeding difficulties, failure to thrive, pneumonia, sleep-apnea. Early ERT treatment showed a clear response in cardiac and skeletal muscles and survival. However the effect on skeletal muscles was variable related maybe to the severity of the disease on onset of the therapy.
Additional studies were needed. The so called 1602 and 1702 trial.
The response on ERT in the 1702 trial (children older then 6 months of age, a very sick population) was good. 11 of 15 patients were still alive at the end of the trial, they showed a good cardiac response and 40 % showed gains in motor development. The general conclusion is that the results are concordant with early ERT trials.
The 1602 trial (children under 6 months of age) showed 80 % ventilator free survival and a response in cardiac and skeletal muscle. Early treatment and early onset maybe the key.
Both trials showed no major safety problems.
Dr. Pascal Laforet from Paris, France talked about “management of Pompe disease in France and outcome of an international study LOPOS”.
In a small study 21 patients were included. 75 % had mild symptoms in childhood.
45 % had respiratory problems and 2 patients had acute respiratory problems. The results corresponded with the results of the IPA Erasmus Survey.
Dr. Laforet brought forward that the diagnosis is an important issue. Sometimes people show clinical symptoms like people with Limb Girdle Dystrophy. And misdiagnosis is an issue to consider.
In the LOPOS study, an observational study of late onset patients, worldwide 58 (36 woman and 22 man) patients were included in 5 sites in Europe (France and the Netherlands and 3 in the USA). The average age was 43,5 years. Mean years of onset 29. Functional assessments were tested and clinical presentations were characterized. The conclusion was that the assessments were reliable. The results of the study will contribute to the LOTS, the late onset trial that will start in the end of the year.
Dr. Barry Byrne Florida USA talked about “Gene therapy in Pompe disease”.Several studies have been performed. AAV vectors (Adeno Associated virus) lead to permanent gene transfer. In mouse models, when vectors (viruses) were brought in to the muscles glycogen clearance was shown in heart and liver. The manufacturing of AAV factors takes much time. AAV 8 and AAV9 could be more efficient in transduction of cardiac and skeletal muscles. Why gene therapy? Because of the intercellular route of delivery, gene transfer to motor neurons may have an effect.
More info about gene therapy can be found at:
After the presentations there was a forum discussion.
- There was a question about the prediction of the development of the disease. There is not a 100% correlation between enzyme deficiency and the development of the disease . You need more parameters to predict the natural course. The best way to measure is in fibroblast. Genetic mutations are important. More of a 100 mutations are known.
- Is the disease more rare then thought? This was the perception clinicians participating in the ENMC workshop had. However there could be more patients, not yet diagnosed or misdiagnosed.
Genzyme IPA Question and Answer session Nantes 11th of May 2005
Randall House president of the IPA opened the session. The IPA stands for 34 countries and represents more then 750 patients worldwide. The IPA is diligently trying to find more patients. During the last year the IPA worked closely together with Erasmus MC . Recently IPA came in contact with Health Ed. Together with this organization Pome information will be developed. The burden of illness study is done by Med Tap in collaboration with IPA. Also there were direct IPA contacts with Genzyme representatives, as well as between the IPA board and Genzyme. In 6 telephone conferences different importantt issues were addressed.
Mr. Frank Ollington – Genzyme presented the state of the art of Myozyme. The goal of Genzyme is to treat patients with Pompe disease world wide. The manufacturing facilities in Geel and Waterford will be opened in the upcoming months. This means that in time there will be additional capacity.
The focus in the upcoming period will be on the late onset population.
It is a pivotal moment, Genzyme is preparing for launch and commercializing of its product. Different issues are important such as the 16.02, 17.02 trial and the sibling trials, the expanded access program, the LOPOS and LOTS study, but also treatment infrastructure, product approval, disease awareness and reimbursement.
130 patients are on treatment, in trials or the expanded access program. For late onset patients the program has recently been reopened. Per quarter there is the possibility to treat a limited number of patients in each region.
The filing of data for market registration by the EMEA and FDA is an important mile-stone. The perspective is that in 2006 in the spring in Europe and mid year in the US there will be final regulatory approval from the EMEA and FDA. Important issues such as the submission of the label to regulatory authorities, the product package with the final labels, and the distribution plan will be adressed.
There is a lot of work to do for patient organizations, specialists and Genzyme; building up an infra structure of expert centers, developing uniform treatment guidelines, disease awareness. Patient organizations like IPA and its members play an important role: IPA Erasmus survey, information, early interaction with governments, Pompe disease information, patient stories etc. Newborn screening is also an important issue.
We discussed several issues, such as:
- The IPA asked for transparency of the pricing of Myozyme.
- Counselor. The IPA stressed the importance of a counselor in the hospital. People do not know what to expect. A counselor can help them to deal with their fears, expectations and hope when they are participating in the LOTS.
- The IPA asked for measures to prevent de-blinding in a placebo controlled double blind study (LOTS).
- The hope for a broad label. There is a risk that the EMEA and FDA will restrict the label to the infantile population.
- The importance of registration. It is important that people are known. The Pompe registry was being recommend.