ࡱ> '` :bjbj .p2nnnnnnn8888d.9lph99999:::^p`p`p`p`p`p`p$GrhtpnBO::BOBOpnn99pPPPBOvn9n9^pPBO^pPPFmnno99 Y(-68OFn^pp0p,nYuOYu4oYuno:OAP+FJ3:::ppP :::pBOBOBOBO(f-d f-nnnnnn Report from Zavesca Launch Berlin, Germany, 15-17 May 2009 Background The 1st Scientific Symposium on Niemann-Pick disease type C. The Meeting introduction states: The medical community faces today two major challenges with regards to NP-C: Developing a shared and comprehensive understanding of the disease, and using this understanding as the basis for treatment guidelines that will encourage consistent and effective disease management across Europe. Agreeing on a common approach to diagnosis and screening, with the goal of achieving early diagnosis of all NP-C patients, including those who until now have been unrecognized or misdiagnosed. The Scientific Symposium is the first opportunity to participate in an interactive meeting focused entirely on NP-C, sharing experiences and listening to experts in the field. Aims and objectives / reasons for attending. As this was the first meeting of it kind since Zavesca was approved for use in NP-C it was very important to be part of it. The Niemann-Pick Disease Group (UK) has access to the largest cohort of patients and Ed Wraith is regarded as Europes biggest prescriber of Zavesca for NP-C. My aim was to get to know more people from the NPC community to encourage collaboration in research protocols and the raise the awareness of the NPDG (UK) Overview of the main talks Michael Steward- head of Global Marketing Actelion Introduced the meeting. Marc Patterson- Division of child and adolescent neurology, Mayo Clinic, Rochester, MN, USA Historical overview of NP-C. Impact of NP-C- disproportionate affect in terms of numbers affected versus impact on society, as it has a massive impact on families, community and health care systems. Many different physicians need to be aware of the disease. Diagnosing the disease- Polymorphous cytoplasmic bodies- typical of the disease. Cholesterol esterification down stream effect of primary deficit 50% of those affected have seizures- one third have cataplexy. Vertical Supranuclear Gaze Palsy- not in isolation- goes on to develop horizontal Gaze Palsy also. No reliable biomarkers currently available- work being done. There is a need to Define the place of Zavesca. Translate the lab work to the clinic. There remain problems with diagnosis- delayed, invasive, expensive, atypical, no biomarkers. The NIH data is producing conflicting data- more work needed. Zavesca alone appears to modify the progression of the disease- need to refine guidelines/treatment strategy. What is the future of combination therapy? Bench to bedside. Murine models replicate early onset severe neurological disease- may not be good model for human disease. Animal studies may reflect noise in the system- ie other factors may contribute to the results such as the effect of vigorous testing on animals. Families need to be educated about the trials and tribulations of translating animal studies into humans. Promising animal studies do not always translate into humans. Robin Lachman National Hospital for neurology and neuro surgery- London Different lipids are stored in different types of NP. NPC2- soluble. NPC1 and NPC2 interact- there is a hypothesis to support this. What about neurones? Neurofibrillary tangles- similar to Alzheimers. Ectopic dendritogenesis and axonal spheroids are being looked at by Steve Walkleys lab. These are also found in GM2 Gangliosidosis, MPS and alpha mannosidosis, NPA and NPB. Gangloside storage is important in NPC brain. Is cholesterol storage Primary or is ganglioside storage Primary in NPC? The two seem to go together but difficult to ascertain which came first. Lipid trafficking is central to pathogenesis of NPC. Molecular genetics and biochemistry of NPC becoming increasingly well understood. NPC should be viewed as Sphingolipidosis. Marie Vanier National Institute of Health and Medical Research ( INSERM), University of Lyon, Laennec Medical School, Lyon, France NPC needs to be recognised to be diagnosed. There is extreme clinical variability The neurological involvement defines the severity of the disease in 85% of patients. Visceral signs if present, always precede neurological disease. Prolonged neonatal Cholestasis icterus with hepato and splenomegaly. In 85% icterus is self limiting. Isolated splenomagaly of hepatomegaly. Neurological patients without systemic manifestations. Mutations correlate with the neurological form of the disease- not with the systemic disease. Frederic Sedel Federation of Nervous system disease and reference Center for Lysosomal Storage Disease, Paris, France. Disease can be divided into 3 types Visceral disease Deep brain Cortical Precursory signs- neurological disease. Specific signs- neonatal cholestasis. ALL neonates with cholestasis should be investigated for NPC. VSGP- seen in 80% of patients. Need to be careful when examining patients. If only the slow pursuit method is used then it will be missed. Cataplexy defined as brief episode of bilateral loss of muscle tone in face, neck, legs with intact consciousness. In patients diagnosed with neurological symptoms before the age of 25 25% have psychiatric disorders; this increases in those diagnosed after 25 to 39%. Very few disorders associate cortical and deep brain signs. Reuben Georgio. Clinical Science, Actelion Pharmaceutical, Basel, Switzerland Linear progression of the disease. No apparent deceleration of the disease. Age at diagnosis is established as the key predictor of progression rate (i.e. Fastest in earliest onset form, slower in late onset disease. Specific mention of Eds team and Clinical Research Nurse Liz Jacklin also of Marcs team in the clinical trial data. Patients with organomegaly only? There are some patients who have organomegaly and a diagnosis of NPC but who do not go on to develop neurological disease, in their 40s, 50,s and 60s- these are very rare- if they live long enough would they go on to develop symptoms? Liver transplantation- restores liver function but does not influence the course of the disease. Marc Patterson Clinical Trials Cholesterol lowering by conventional methods- diet =/- statins was of no benefit in NPC. (Patterson 1993) Mice given miglustat BEFORE they developed symptoms- there was a delay in onset and increased survival in these mice. Pathology showed some salvage of the phenotype in the treated group. Miglustat was a drug already known- had been used in HIV and Gauchers so was well placed to be used in a trial. The study Miglustat vs standard care- randomized 2:1 Horizontal Saccadic Eye Movements Primary outcome measure. Secondary measures; gait, swallowing, hearing. In NP-C, for reasons we do not understand, the vertical saccadic eye movements are affected first. Horizontal measurements were chosen as in many patients vertical are already impaired or absent. The patients on Miglustat- none deteriorated- those in the control group- did deteriorate. After 1 yr- stabilization or improvement in Primary and secondary measures. The safety of the drug was comparable to earlier trials. With prolonged use there was evidence of continued stabilization and no new toxicity. Swallowing improved or was stable after 24 months. Majority of patients classified as having stable disease. Summery- Evidence that Zavesca slows progression. The drug appears safe Guidelines in review ? Future use in combination therapies. Mercedes Pineda Hospital Sant Joan de Deu and University of Barcelona, Barcelona, Spain Retrospective Study. 25 centres worldwide Patients have much more severe disease when they started treatment Majority of patients categorised as good responders to Miglustat. The younger the patients- the worse they did. Again due to age at diagnosis being a predictor of treatment response. The speaker advocates- treatment should start early before onset of neurological symptoms. The speaker also said that children /young adults with advanced disease should not be treated as this will only prolong the agony. If the family are desperate than try for 6 months and review. Bruno Bembi Regional Coordination Centre for Rare Disorders of the Friuli-Venezia Giulia Region, University Hospital Santa Maria della Misericordia 2, Udine, Italy Clinical Management of NPC. Treat CNS manifestation Treat systemic manifestations including PAIN which is often overlooked. Specific therapy with Miglustat. CNS: Cataplexy Seizures Dystonia Insomnia Psychiatric symptoms Systemic Nutrition Dysphagia/gastroesophageal reflux Drooling- Atropine Ab-ingestis pneumonia Pain- consider and treat (paper The incidence of pain in children with severe cognitive impairments Breau LM et al Arc. Paediatric Adolescent Med. 2003 Family support Ensure multidisciplinary assistance. Provide molecular diagnosis and genetic counselling Establish continuous medical counselling Facilitate relationship with social agencies and educational system Health care System Provide a multidisciplinary therapeutic approach Stimulate and support patients school and social integration Co-operation between health care institutions and social agencies. Clinical Management Miglustat- stabilization side effects diarrhoea. Patients experiencing this should reduce carbohydrate content of food. Management of Diarrhoea diet modification- low carb diet. Dosing between meals. Anti-diarrhoeal treatment. Eugen Mengel Childrens Hospital, Gutenberg University, Mainz, Germany Registry- Improving the knowledge of NPC Several Useful registries Having a registry is an EMEA requirement There has been 2 years of development into this Actelion registry. Scientific committee- Mengel, Patterson, Pineda, Vanier, Wraith. Objectives- To determine the natural history, course and outcome review treatment experience To provide education on Miglustat prescribing. Adverse event reporting Inclusion criteria; Must have NPC Written Consent Multicentre Web-based Outcome assessment- disability status- ambulation, manipulation, language and swallowing. Safety information- Actelion will not own the data only fund it. The data will be owned by the scientific team The registry is scheduled to start in the third quarter of 2009-06-02 Analysis and data recording will be done annually. Jackie Imrie Clinical Research Nurse, Willink Biochemical Genetics, RMCH UK experience Case studies of 4 patients; 3 children 1 adult Overview of National Commissioning Group National guidelines on NCG website http://www.ncg.nhs.uk/ UK Teams for NPC- Willink Hope NPDG ? Newcastle South east Midlands National grid training scheme The NPDG (UK) Raising awareness Improving diagnosis Mutational analysis- Willink faster way Microarray analysis. Peter Bauer. Department of Medical Genetics, University of Tubingen, Tubingen, Germany Psychiatric Relationship NPC1/NPC2 testing in psychiatric patients 485 samples patients aged between 12 51 yrs Sequencing in all NPC axons/ Biochemical analysis in 17 NPC1 mutation carriers. Identified 28 patients with NPC1 and 3 patients NPC2 positive- 31 patients diagnosed with NP disease. Compound heterozygotes. R1077Q is a redundant NPC1 mutation in a Canadian sub population 28 patients with 2 NPC1 mutations. 28 different NPC1 mutations 5 novel mutations. Of the 28 patients with NPC1 the mean age of onset was 20.9 years they experienced Auditory hallucinations Depression Paranoid delusions Obsessions Is there and adult onset phenotype? Chris Hendriksz Clinical Inherited Metabolic Disorders Unit, Birmingham Childrens Hospital NHS Foundation Trust, Birmingham UK 8%- Neonatal cholestasis 10%- Acute liver failure How can we get a diagnosis quicker? Microarray technology- still validating chip. It will be 5-6 months before chip validated. 200 per patient projected cost. Arnalt Rolfs- Albrecht-Kossel-Institute for neuroregeneration, Center for Mental Health Disease, University of Rostock, Rostock, Germany. Population screening- screening groups at risk Genetic testing caveats. There is no accurate information on true incidence or carrier frequency. The test- direct sequencing of the NPC genes. Chitotriosidase in NP-C- the older the patients are the more normal the chito is. There may be a biochemical marker in the future. Possible to use in vivo laser microscopy. Overall impression of the meeting. Very useful meeting and great opportunity to get to know key members of the Lysosomal community both in the UK and further afield. I took these opportunities and spent a lot of time talking to and getting to know a number of key figures. Mainly, Paul Gisson, Chris Hendriksz, Robin Lachman, Fran Platt and Patrick Deegan As well as Actelion staff Paul Sullivan and Caroline Kelly. 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