12 July 2007 print
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The expanding universe of orphan drug regulation: transatlantic collaboration now in place
The European Medicines Agency (EMEA) announced it has just passed a milestone with the recent recommendation of marketing authorisation for its 40th orphan medicinal product. Things are truly moving forward in the field of rare disease medicinal products and collaboration is a part of this forward motion. The US Food and Drug Administration (FDA), the European Commission, and the EMEA have decided to expand many of their cooperative activities - including the area of medicinal products for rare diseases - in order to better protect public health, reduce regulatory burden and costs, and bring "innovative products to patients in a timely manner".

The call for further collaboration also extends to paediatric medicines, working within the framework of the recently-implemented Paediatric Regulation in the EU. It has been estimated that up to 80% of rare diseases affect children. The EMEA and the FDA are committed to developing a foundation to facilitate the regular exchange of information on scientific and ethical issues to minimise the exposure of children to unnecessary trials. The Principles of Interactions document has been created to achieve this goal and to better coordinate paediatric medicinal product development on both sides of the Atlantic. The document delineates several goals, including the development of global scientific paediatric plans compatible to both agencies. Information to be shared includes material referring to trial design issues, draft guidance documents, and safety issues such as adverse drug reaction reporting and database statistics. The two groups will be granted observer status for each others' Paediatric Committee meetings to be better kept abreast of "optimal mechanism and timing of exchanges". Monthly conferences and listings of applications and decisions are also proposed. A secure link, such as Eudralink, will be employed for the exchange of information.

It was in September 2003 that Confidentiality Arrangements between the EU and the FDA were reached in the context of regulatory cooperation and transparency, establishing a framework for "upstream regulatory cooperation including the possible exchange of information on advance drafts of legislation and regulatory guidance documents as well as non-public information" relating to the assurance of "quality, safety and efficacy of medicinal products - including orphan medicinal products authorised or under review both in the USA and the EU." To facilitate this exchange of documents and information, an Implementation Plan describing the processes of information and document exchange was finalised in September 2004. A year later, a five-year extension of the plan was signed into effect. Within this plan, article 2.1.4 calls for a regular exchange of information in the area of orphan medicines, among others, on topics including marketing authorisation applications, extensions of indications, and risk management plans.

A Transatlantic Workshop on Administrative Simplification in Medicines Regulation is being planned for late November in Brussels, Belgium.

The extension of existing collaboration can only mean good news for orphan drug development, often hindered by small clinical trial sizes and limited potential customer bases, resulting in lengthy delays and high costs. Rare disease patients, their families and stakeholders on both sides of the pond have reason to celebrate with the deepening of international collaboration.


Task Force Update
Seventh RDTF meeting discusses an array of issues
The Rare Diseases Task Force held its 7th Meeting on 20 June 2007 in Luxembourg. Presentations included an update on the scoping paper of the Commission Communication on a European action in the area of Rare Diseases (RD). The completion of a first draft of this Communication is scheduled for September 2007 after a meeting of a Communication Drafting group on 18 July. A final draft will be made available for public consultation in November 2007.

Other activities of the RDTF included designation of Ségolène Aymé, chair of the RDTF, as chair of the Topical Advisory Group for the World Health Organisation ICD revision process followed by a meeting of the WG on Coding and Classification in Paris on 2 May to establish a strategy for the revision process. On 30 May 2007, a workshop on the future of orphan drugs served as a platform for WG members to contribute recommendations in this area to the Commission Communication. The outcomes of this workshop will also serve as the framework for a discussion on rare disease prevalence during the 8th EPPOSI Workshop on Partnering for Rare Disease Therapy Development taking place in Copenhagen on 18-19 October. Progress of the DG SANCO supported RAPSODY project was also presented. Currently, preliminary analysis of a patient satisfaction survey of the provision of health care for RD is underway. A synthesis of the outcomes of 11 national workshops on European Networks of Centres of Reference (ENCR) is also underway and recommendations resulting from this process will be presented at a workshop on ENCR in Prague on 12-13 July. The programme for the upcoming Rare Diseases Research: Building on Success conference (13 September 2007 in Brussels) was briefly summarised by RDTF members. The conclusions from the conference will be presented at the European Conference on Rare Diseases in Lisbon in November 2007, for which all RDTF member are encouraged to register. The next meeting of the RDTF is scheduled for 23 October 2007 in Luxembourg and will be dedicated to discussing the first draft of the Commission Communication.


EU Policy News
Physicians and Industry form cooperation
Two non-profit international associations, the Standing Committee of European Doctors (CPME), representing the 2 million medical doctors in the EU in the promotion of the highest standards of medical training and practice, and the European Medical Technology Industry Association (Eucomed), an organisation representing some 4500 designers, manufacturers and suppliers of medical technology for the diagnosis, prevention, treatment and amelioration of disease and disability, dedicated to improving patient and clinician access to innovative and reliable technology, have forged a cooperative agreement. The "Joint Declaration on the Cooperation between the Medical Profession and the Medical Technology Industry" stresses the importance of compliance between doctors and medical technology companies at all stages of development and use of medical technology. This cooperation aims to ensure the safety of patients and the efficacy of diagnosis and therapy. The two groups consider it essential to establish jointly accepted guidelines that can serve as a framework at both European and national levels. Each interest has already adopted ethical principles to govern the conduct of their activities, which are confirmed in the joint statement.
DG Research
Simpler payment scheme adopted for non-EU FP7 participants
The European Commission has implemented a lump-sum payment option for Seventh Framework Programme non-EU participating countries. It is hoped that the flat-rate lump-sum amounts, which can be incorporated in grant agreements, will simplify the grant-agreement process as well as project administration and will ultimately facilitate the participation of International Cooperation Partner Countries. For more information.
Orphan drugs and rare diseases at a glance
The EMEA has put a new document online: Orphan drugs and rare diseases at a glance provides definitions of orphan medicinal products and lists the incentives manufacturers have to invest in orphan drug production. The document also provides information on the definition of a rare disease and provides useful links.
EMEA publishes advice document for orphan drug applicants
The European Medicines Agency (EMEA) has released a new document: Practical Information for Sponsors during the Early Phase of an Orphan Drug Application, an informal set of recommendations designed for orphan drug applicants to help the application process go smoother but that does not replace the legal requirements laid out in the EU Directives nor the guidelines available on the EMEA website. This list instead addresses issues that typically arise during the early phases of the application process, including the pre-submission meetings that are strongly encouraged and can take place via teleconference to save travel expenses; the format of the final application at the time of submission; and various items of general advice.
EMEA issues Paediatric Regulation documents, revamps website
The EMEA has issued several documents pertaining to the implementation of the Paediatric Regulation that came into effect in January of this year, including templates to use for various application requests, information concerning practical issues relating to the application procedures, calendars and timelines, and a template for letters of intent. Furthermore, the Medicines for Children section of the EMEA website has been redesigned and updated to accommodate the new Paediatric Regulation. Finally, the EMEA is establishing a new Paediatric Committee due to come into effect by 26 July 2007. The Paediatric Working Group that prepared the groundwork for the implementation of the new regulation over six years has ceased its activities. The EC has launched a Call for Expressions of Interest in becoming Commission appointees to the Paediatric Committee as representatives of healthcare professionals or patient associations, to be sent electronically to Peter Arlett at the European Commission by 31 August 2007. Further details, including the criteria for selection, can be found in the European Commission's call for expressions of interest.
EMEA welcomes new leaders
The EMEA Committee for Medicinal Products for Human Use (CHMP) has elected Dr. Eric Abadie (France) as new chair and Dr. Tomas Salmonson (Sweden) as new vice-chair for three-year mandates beginning 18 June 2007. Dr. Abadie previously was a member of the Committee for Orphan Medicinal products. The EMEA Management Board also has a new chair and vice-chair. Pat O’Mahony and Lisette Tiddens-Engwirda will serve three-year mandates as chair and vice-chair, respectively. The Management Board has requested a staff increase in anticipation of an increase in applications following the implementation of the new EU paediatric regulation.
First-in-man clinical trials guideline workshop debates high-risk definition
Following the 12 June 2007 workshop held as part of the public consultation of the draft guideline of recommendations for first-in-man clinical trials for potential high-risk medicinal products, participants were able to reach a consensus on certain points and move toward finalisation of the guideline. The draft guideline was released for a two-month public consultation period that ended in May. The workshop focused on specific points, including "how to define high risk medicinal products", and "elements of design of first-in-man clinical trials". The EMEA defines a community guideline as a document designed to provide advice on the best way to fulfil an obligation set forth by EC pharmaceutical legislation. In this case, the guideline provides counsel on managing the transition from non-clinical studies to tests in humans. Concerning the concept of the classification of high-risk, proposals were made to replace it with a risk management and mitigation approach "based on the concept of risk as a continuum for all medicinal products". Considering the particular concerns and often small number of subjects in rare disease product clinical trials, guidelines such as these will be important for orphan drug sponsors.
Gene Therapy Working Party calls for comments on genetic-based medicine documents
The EMEA Committee for Medicinal Products for Human Use has released two documents for consultation and comments following recommendation by the Gene Therapy Working Party: the Concept Paper on the Development of a Guideline on the Quality, Preclinical and Clinical Aspects of Medicinal Products Containing Genetically Modified Cells is the title of the first document.

The second document is titled, The Development of a Guideline on Clinical Monitoring and Follow-up of Patients exposed to Gene Therapy/Gene Transfer Medicinal Products. Interested parties, including members of the pharmaceutical industry, academic networks and learned societies within the EU, may send comments electronically using the templates provided. The consultation period will finish in November for the first document and July for the second.


National & International Policy Developments
Spanish geneticists campaign for official recognition
Feliciano J. Ramos, MD PhD, President of the Asociación Española de Genética Humana (AEGH), describes for OrphaNews Europe the efforts underway in Spain to have the field of Clinical Genetics officially recognised:

Spain is one of the few EU countries that does not officially recognise genetics as an independent specialty. Spanish geneticists of different backgrounds, most represented by the Asociación Española de Genética Humana (AEGH), have been struggling with government authorities for more than three decades to obtain this recognition. Many attempts to create the specialty have been undertaken. In recent years these efforts, most of which are lead and coordinated by the AEGH, have been intensifying and producing some headway. Two advancements have occurred within the last few months. In May, a no-law proposition was presented to the Spanish Senate by Socialist party deputy and pediatrician-geneticist Joaquín Bellón, requesting the government create a "Specialty in Genetics" in Spain. The proposition was passed with the approval of all political parties represented in the Senate. Some 20 members of the AEGH, including members of its directive committee, witnessed in situ this unprecedented event. Moreover, in March, after attending a workshop on Spain's new "Biomedical Research Law", ERC political party deputy Rosa Maria Bonás presented a no-law proposition to the Spanish Congress requesting the Government create a working group to study the programs and competences that would form the bases of the future Genetics Specialty in Spain. It is hoped that these two steps forward are the beginning of the final stage of our seemingly never ending journey to establish a specialty for Clinical Genetics in Spain. It is about time...

Spanish Parliament authorises therapeutic cloning
On 14 June, Spanish deputies adopted a law authorising biomedical cloning strictly for therapeutic purposes. An ethics committee will be established to ensure research follows legal and ethical guidelines as well as a commission charged with regulating the donation and usage of human cells and tissues.
Italy extends umbilical cord stem cell storage and use
The Italian Health Ministry has issued a decree consenting blood conservation intended for neonatal use or the benefit of a consanguineous person affected by a disease (either genetic or acquired) at the time of collection, for which the use of umbilical cord blood-derived stem cells is scientifically established and clinically appropriate by presentation of acceptable clinical documentation. The Lazio Region in Italy has proposed an autonomous law concerning the "Regional interventions to promote the use of hemopoietic stem cells derivated from cordonal and placental blood for therapeutic, clinical and research purposes". In families at high risk for genetically determined diseases, the charges for autologous cordonal and placental blood for the infant or a related person would have to be paid by the regional sanitary system. A 28 June disposition taken by the Lombardy Region, following a decree of 4 May 2007 issued by the Italian Health Ministry, will allow, for the first time in Italy, the free conservation of umbilical cord stem cells for private use. Requests, spontaneously made by the parents, will be approved only in the presence of a genetic disease in the family and/or of a disorder already diagnosed at the time of delivery in the neonate or a relative.

Two Italian non-profit associations, the Associazione Donatrici Italiane Sangue del Cordone Ombelicale and the Associazione M3V ONLUS are promoting umbilical cord blood donation throughout the entire nation. In addition, they are collecting money for the research of umbilical cord blood in transplants and for the creation and development of a network of umbilical cord blood banks at the national level. At a round table discussion that took place in June, geneticist and Orphanet partner Bruno Dallapiccola discussed the use of these cells as a tool for treating rare diseases. Data was presented concerning the activities of the 15 public Italian banks, where more than 22,000 cord samples have been stored and more than 600 samples used for transplants, including over 300 donations to foreign countries.

Other European news
A national British network for stem cell research
The United Kingdom National Stem Cell Network (UKNSCN) officially launched in April of this year as a direct result of a recommendation contained in a report presenting a “ten-year vision for UK stem cell research” commissioned by then-Chancellor of the Exchequer Gordon Brown in 2005. This nationally-funded network was established to “improve the coordination of stem cell research and the dissemination of research results, in addition to providing a focal point for communication with overseas researchers, the media and the general public”. The network is intended to “maximise the cross-fertilisation between those involved in the sub-disciplines of UK stem cell research” and has as its central mission the “promotion of research activities and events at the national level which help to speed the translation of basic stem cell research into therapeutic applications in the control of degenerative diseases…”. Huntington disease and amyotrophic lateral sclerosis (ALS) syndrome are just two examples of rare degenerative diseases. The UKNSCN does not fund research and does not replace already existing regional stem cell networks in the UK. The UKNSCN is attributed with playing a key role in attracting the International Society for Stem Cell Research’s annual science conference for 2009 to London, the first time this conference will be held in Europe.
Other International News
Ten new rare disease genetic tests available in the US
In the United States, the Collaboration Education and Test Translation Program (CETT), a pilot program developed by the National Institutes of Health Office of Rare Diseases, endeavours to facilitate the availability of genetic tests for rare diseases. Ten such new rare disease genetic tests thus became available to the US public in the past year: Joubert syndrome (Prevention Genetics), Cornelia de Lange syndrome (University of Chicago), cherubism (Hospital for Sick Children Toronto), X-linked chondrodysplasia punctata (University of Chicago), Kallman syndrome (GeneDx), progressive familial intrahepatic cholestasis (Baylor College of Medicine), Russell Silver syndrome (Emory University) mucopolysaccharidosis type VI (Emory University), Niemann Pick disease type A/B (Emory University) and X-linked periventricular nodular heterotopia (Harvard University). Fortunately, Orphanet confirms that all of these tests are also available in Europe.

Orphanet News
Updated Orphanet Reports Series available online
The following Orphanet Reports Series have been updated: The prevalence of rare diseases: A bibliographic study April 2007 - Issue 4 and List of marketing authorised orphan drugs in Europe May 2007
New Research Projects open for Recruitment
A Phase I-II Study: Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK, After Transplantation of Allogeneic T-Depleted Stem Cells From a Haploidentical Donor in Patients With Haematological Malignancies
Above multicentre trial in Germany
Above multicentre trial in Italy


New Syndromes
A new genetic disorder in mitochondrial fatty acid beta -oxidation: ACAD9 deficiency
The acyl-CoA dehydrogenases are mitochondrial enzymes that act in fatty acid beta -oxidation and amino acid catabolism. To date, nine members of this group of proteins have been identified and seven different genetic anomalies have been described. In this study, the authors describe three patients with ACAD9 deficiency. The first, a 14-year-old boy, died following an acute hepatic insufficiency episode reminiscent of Reye syndrome along with a cerebral stroke. The second patient, a 10-year-old girl, has presented acute hepatic insufficiency and hypoglycemia since 4 months of age. The third patient, a girl aged four and a half years, died of cardiomyopathy. Despite the variable phenotypes, the spectrum of clinical manifestations is the same as those observed in other ACAD deficits.

Read the Pubmed abstract
Am J Hum Genet ; 87-103 ; July 2007

New Genes
FGD4 gene mutations are responsible for the 4H form of Charcot-Marie-Tooth neuropathy
Charcot-Marie-Tooth (CMT) diseases are a heterogeneous group of hereditary motor and sensory neuropathies characterised by muscular weakness and wasting and feet and hand deformities. The 4H subtype is an autosomal recessive demyelinating form that was recently linked to 12p11.21-q13.11 chromosome region. Two articles describe the identification of FGD4 gene mutations in several families. FGD4 codes Frabin, a GDP/GTP nucleotide exchange factor specific to Rho GTPase Cdc42.

Read the Pubmed abstract of the first article
Read the Pubmed abstract of the second article

The American Journal of Human Genetics ; 1-16 ; July 2007
The American Journal of Human Genetics ; 158-164 ; July 2007

A gene linked to Joubert syndrome now involved in Meckel syndrome
Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterised by central nervous system malformations, polydactyly, multicystic kidney dysplasia, and ductal changes of the liver. Three loci have been linked to the disease and mutations in two genes situated in the MKS1 and MKS3 loci have been identified. Through a linkage analysis performed in eight families, a French research team identified a new locus, MKS4, carrying mutations in CEP290 gene in four familes. This gene was recently identified as causative of Joubert syndrome (JS) and isolated Leber congenital amaurosis. This study confirms that Joubert and Meckel syndromes could have a common origin despite their variable symptomatology (MKS3 mutations have already been linked to the two syndromes).

Read the Pubmed abstract

The American Journal of Human Genetics ; 170-9 ; July 2007
Gene MFSD8 is mutated in late-infantile forms of the neuronal ceroid lipofuscinoses (NCLs)
Late infantile forms of neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of diseases characterised by epileptic seizures, psychomotor decline, myoclonus, vision loss and premature death. Through a genomewide scan and homozygosity mapping, the Finnish authors identified six different mutations in MFSD8 gene, which codes a membrane protein principally located in the lysosomes and of which the function is still unknown. Furthermore, analysis of the data from other families revealed a link with three other loci, confirming the heterogeneity of the late infantile forms of the disease.

Read the Pubmed abstract

The American Journal of Human Genetics ; 136-146 ; July 2007
PLEKHG5 and NFk-B pathway are suspected in an autosomal recessive form of lower motor neuron disease
In 2006, the authors described an African family presenting an autosomic recessive form of lower motor neuron disease characterised by childhood onset, generalised muscle involvement, and severe outcome. They linked the phenotype to chromosomic region 1p36. In this study, the authors have identified a homozygous missense mutation in PLEKHG5 , provoking protein aggregation and disturbing NFk-B pathway signalisation. Both these phenomena probably contribute to the neuronal toxicity observed.

Read the Pubmed abstract

The American Journal of Human Genetics ; 67-76 ; July 2007
NR2E3 is mutated in an autosomal dominant form of retinitis pigmentosa
"Autosomal dominant retinitis pigmentosa" refers to a genetically heterogeneous group of retinal dystrophies, of which 54% of all cases can be attributed to 17 disease loci. The Belgian authors have identified mutations in NR2E3 gene in four families afflicted with autosomal dominant retinitis pigmentosa. NR2E3 codes a nuclear receptor expressed in the retina and has already been linked to Goldmann-Favre syndrome, an autosomal recessive retinopathy.

Read the Pubmed abstract

The American Journal of Human Genetics ; 147-157 ; July 2007

Research in Action
Fundamental Research
The genes implicated in Bardet-Biedl syndrome code a protein complex needed for ciliogenesis
Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder caused by primary cilium dysfunction. Symptoms include obesity, retinal degeneration, and nephropathy. Although mutations in 12 BBS genes have been identified, their cellular function remains unknown. The authors have identified a complex composed of seven highly conserved BBS proteins localised to the centriolar satellites and membrane of the cilium and required for ciliogenesis. Its function appears to be dependent on the Rab8 GDP/GTP exchange factor, already known to be involved in ciliary function. The authors propose that the mutations responsible for Bardet-Biedl syndrome may cause defects in vesicular transport to the cilium.

Read the Pubmed abstract

Cell ; 1201-1213 ; June 2007
Clinical Research
Perforin implicated in aplastic anemia
Aplastic anemia is characterised by hematopoietic stem cell destruction by activated T cells and Th1 cytokines. The authors have identified mutations in the gene coding perforin in five patients with acquired aplastic anemia, all of whom presented an abnormally low level of the protein. Normally, perforin is expressed principally in the T cytotoxic lymphocytes and natural killer cells, two cell types known to be implicated in auto-immunity. The perforin mutations may thus contribute to the development of aplastic anemia.

Read the Pubmed abstract

Blood ; 5234-5237 ; June 2007
Gaucher disease and increased risk for non-Hodgkin lymphoma, pancreatic cancer or malignant melanoma
Gaucher disease is a lysosomal surcharge illness caused by a deficiency in glucocerebrosidase (also referred to as glucosylceramidase or acid beta-glucosidase) or, in rare cases, by a deficiency in the activator protein saposin C. The disease is characterised by the presence of glucosylceramide (or glucocerebroside) deposits in the reticuloendothelial cells of the liver, spleen and bone marrow. In this study, the authors identified 1525 Gaucher disease patients using data from US Veterans Affairs hospitals. Besides yielding a large patient population, the data source allowed for follow-up for as long as 27 years. A two-to-three time elevated risk of developing non-Hodgkin lymphoma, pancreatic cancer or malignant melanoma was discovered.

Read the Pubmed abstract

Arch Intern Med ; 1189-1194 ; June 2007
Stem Cells
Human embryonic stem cells differentiate in cardiac cells in rats
In vitro, human embryonic stem cells can give rise to cardiomyocytes. To test in vivo their regenerative capacity, the French researchers injected embryonic stem cells in rat myocardium that had undergone coronary artery ligation two weeks prior. Two months after the injection, the human cells had differentiated into cardiac cells. This ability of cardiac-specified HES cells to differentiate along the cardiomyogenic pathway following transplantation into infarcted myocardium raises the hope that these cells might become effective candidates for myocardial regeneration.

Read the Pubmed abstract

Stem Cells ; Epub ahead of print ; 31 May 2007
Gene Therapy
Gene therapy suppression and replacement to circumvent mutation heterogeneity in retinitis pigmentosa
Autosomal dominant forms of retinitis pigmentosa can be attributed to mutations in the gene coding rhodopsin. More than 100 mutations in this gene have been described. The Irish research team developed a new genetic therapy approach in mice to avoid developing a specific treatment for each mutation. They injected retinitis pigmentosa mouse models with a virus delivering interfering RNA that suppressed the expression of both the normal and mutated allele of the the gene coding rhodopsin. At the same time, a virus delivering a normally functioning gene coding rhodopsin, but resistant to the RNA interference was injected. This suppression and replacement strategy improved the condition of the mice treated, confirming that this approach presents a potential solution for circumventing mutational heterogeneity.

Read the Pubmed abstract

The American Journal of Human Genetics ; July 2007 ; 127-135
Therapeutic Approaches
Parathyroid hormone improves bone growth in embryos of achondroplasia mouse models
Achondroplasia is characterised by short height and short members. It is caused by activating point mutations in FGFR3. Various studies suggest a deregulation in the proliferation and differentiation of the chondrocytes (the cells that participate in the synthesis and maintenance of the cartilage tissue) as the origin of the disease. The Japanese authors tested in vitro the effect of parathyroid hormone on growth of femurs from mouse disease model embryos. In four days the hormone reduced the differentiation and cell death of chondrocytes and improved bone growth. Thus parathyroid hormone is a potential treatment for achondroplasia.

Read the Pubmed abstract

Bone ; 13-18 ; July 2007
Calcineurin as a possible therapeutic target for T-cell acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is a malignant proliferation of lymphoid cells blocked at an early stage of differentiation and accounts for three-fourths of all cases of childhood leukemia. Calcineurin is a phosphatase enzyme implicated in T-cell differentiation. The French research team tested in vivo the effect of calcineurin inhibitors on two murine models with T-cell lymphoblastic leukaemia. They observed a rapid regression of tumours and a prolonged duration of life. Moreover, one of these inhibitors induced the death of human lymphoma and leukemia cell lines. Thus calcineurin and the cellular pathway that depends upon it, represent a new therapeutic target.

Read the Pubmed abstract

Nature Medicine ; 736-741 ; June 2007
The combination of two antibodies induce complete remission in mice with pancreatic carcinoma
Pancreatic carcinoma has a five-year survival rate of less than 20%, due in part to extreme tumour resistance to treatment. The French research team injected mice with these tumours with anti-EGFR and anti-HER2, either alone or together. Combined, these antibodies have a synergistic effect leading in some cases to complete remission. These results bring a new therapeutic hope to patients with pancreatic carcinoma.

Read the Pubmed abstract

Clin Cancer Res ; 3356-3362 ; June 2007

Orphan Drugs
Ten EMEA orphan designations for June 2007

The COMP (Committee for Orphan Medicinal Products) adopted the following 10 positive opinions on orphan medicinal product designation at its June meeting for the treatment of:

- acute myeloid leukaemia
- cystic fibrosis
- malaria
- ligneous conjunctivitis
- idiopathic thrombocytopenic purpura
- orthostatic hypotension in patients with multiple system atrophy
- orthostatic hypotension in patients with pure autonomic failure
- cutaneous T-Cell Lymphoma
- cardiogenic shock
- idiopathic thrombocytopenic purpura

Consult the European Registry for Orphan designations
Consult the Orphanet list of orphan drugs authorised for marketing in Europe

Marketing authorisation recommended for orphan drugs Atriance® and Gliolan®
The CHMP has recommended marketing authorisation for Atriance® (nelarabine), produced by Glaxo Group Ltd., for the treatment of T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic leukaemia (T-LBL) of patients in second relapse. Atriance is the 40th orphan medicinal product to receive a positive opinion. EMEA review began on 21 June 2006 with an active review time of 203 days. Atriance® is the first medicinal product for which an application was submitted using the Product Information Management (PIM) system. PIM enables the electronic exchange of the product information part of a marketing authorisation application in the European Union. Its aim is to increase efficiency of the management and exchange of the product information and to improve the quality and consistency of the published product information.

The CHMP has also recommended marketing authorisation for Gliolan® (5-aminolevulinic hydrochloride), produced by Medac, for the visualisation of malignant tissue during surgery for malignant glioma in adult patients. Gliolan is the 41st orphan medicinal product to receive a positive opinion. EMEA review began on 24 May 2006 with an active review time of 199 days.

FDA approves Letairis™ for pulmonary arterial hypertension
The US Food and Drug Administration has approved marketing for Letairis™ (ambrisentan), manufactured by Gilead Sciences, Inc. for the treatment of pulmonary arterial hypertension, a rare condition. Letairis was granted a priority review designation intended for products that address unmet medical needs. Because of the risks of liver injury and birth defects, the product will be available through the Letairis Education and Access Program (LEAP), a restricted distribution program designed to help patients learn about the potential risks of the product. Gilead Sciences has also designed a set of programs to assist patients with various reimbursement issues for Letairis™ in order to enhance patient access to the product.

News from the Patients' Associations
The Croatian Society of Patients with Rare Diseases
Rare disease patient alliances are becoming stronger all over Europe. Below, Natasa Bjelic describes for OrphaNews Europe the history and activities of the Croation Society of Patients with Rare Diseases. Orphanet partner and former Croation Health Minister Professor Ana Stavljenic-Rukavina has worked for many years in the laboratory diagnostics of rare diseases. She is an advisor to the Society and helped with the preparation of this article:

The Croatian Society of Patients with Rare Diseases is a non-profit organisation which was renamed in November of last year, continuing the work of the Croatian Society for Inherited Metabolic Diseases, which itself was renamed in 2003, succeeding the Croatian Society for Mucopolysaccharidoses and similar diseases. This process of changing names illustrates the necessity to expand the scope of our work � from one specific rare disease to all inherited metabolic diseases and, finally, to all rare diseases.

Members of our organisation include other groups that are at work solving the particular problems of those affected by rare diseases. The following organisations have joined our Society: the Croatian Organization for Osteogenesis Imperfecta, the Croatian Organization for Cystic Fibrosis, and the Association for Persons with PWS � Croatia and DEBRA Croatia.

While these organisations have worked for years on finding solutions for patients with specific rare diseases, now that we are working together as one network for rare diseases, we can achieve much more. It became essential to strengthen the cooperation of non-governmental organisations, because the difficulties of living with a rare disease are many and complex. The situation in our country is such that many medical products for rare diseases are still not registered, despite their usage in the European Union.

Our main goal is improving the quality of life for patients suffering from rare diseases as well as their families and our main activities include:

  • Supporting patients and their families in their efforts to solve their problems.
  • Organising gatherings for patients, their families and others interested in exchanging experiences and organising problem-solving efforts in relation to rare diseases.
  • Cooperating with health organisations and other relevant stakeholders in order to solve the particular issues that patients face.
  • Organising lectures and public gatherings through which foreign and domestic health experts can provide information and education, especially in terms of new developments in the treatment of rare diseases.
  • Making a centre for receiving and distributing rare disease data, using telephone technology and flyers.
  • Publishing material concerning rare diseases and the activities of our organisation.

  • We have specific targeted activities for 2007: the organisation�s office in the centre of Zagreb has been equipped and is accessible to people with disabilities. We are working on a Croatian rare disease website for our organisation, patients and their problems, which will provide essential information concerning these themes. We are also organising the first Congress on Rare Diseases in Croatia in July 2007.

    We are planning to publish written material on rare diseases � flyers and educational brochures, which we consider to be a good way of reaching people with rare diseases, many of whom are disabled. Many of our activities, such as public lectures and discussions, are directed to the general public, an effort we consider relevant to improving the quality of life for rare disease patients. Because rare disease patients are a minority in our society, it is necessary to diminish prejudices concerning rare diseases and make public the challenges those afflicted face in their every day life.

    For more information, contact the group president Vesna Skulic or Ana Stavljenic-Rukavina.

    First Person Plural!
    With the EMEA and the EC including patient groups more and more in the legislative processes for rare diseases and orphan drugs, these layled organisations are becoming more active in lobbying for recognition. They are also working together more to meet their own needs and share information. Below, British Fibrous Dysplasia patient Ann Underhill provides OrphaNews Europe with the unique opportunity to learn how a patient organisation comes into being. Here is the path she took to create the recently formed Fibrous Dysplasia Support Society:

    I have Fibrous Dysplasia (FD). In September 2006 I became the UK Liaison for the Fibrous Dysplasia Foundation, an American charity set up in 2003. Initially, I simply intended to arrange a get-together for FD patients in the UK. Using the email addresses of UK residents registered on the American website , I sent out an introductory letter to gauge the level of interest. The replies to that letter left me no doubt of the urgent need for information on how to treat FD and where to access treatment.

    In November 2006, I contacted Dr Edmund Jessop (National Specialist Commissioning Advisory Group member and leader of the Rare Diseases Task Force working group on Standards of Care) at the Department of Health. He put me in contact with Professor John Wass, Chair of Endocrinology at the OCDEM, Churchill Hospital, Oxford, and the Nuffield Orthopaedic Centre, Oxford. I met with Professor Wass in December. Our conversation focused on defining the needs of FD patients and how best to meet them.

    It was agreed that I would organise a meeting for patients with FD and their carers. This meeting, held on the 24th of March 2007 with Professor Wass in the chair, presented the first opportunity that most present had ever had to meet anyone else with the condition. Professor Wass gave a presentation on FD, which generated many questions. It was during the course of this meeting that we decided to set up the Fibrous Dysplasia Support Society. Officers were elected and a patient volunteered to create the website. Still under construction, this tool will provide a brief description of FD, an outline of possible treatments with a protocol for the medical follow up of patients, a list of UK specialists experienced in treating the condition, contact numbers and email addresses, an events diary (we are planning a second meeting on the 13th of October 2007), and any other information which would be useful to patients or the medical profession. Pr. Wass generously offered to produce a pamphlet to be used by patients and physicians containing information on FD and protocols for the long-term monitoring of the condition. A set of DVDs, recorded at the FD Foundation convention in Santa Monica, California in August 2006, and containing medical presentations given to patients, including an overview of FD/McCune-Albright Syndrome, craniofacial issues, paediatric orthopaedics, endocrine issues and drug treatments, pain and quality of life studies, and adult orthopaedic issues will be available to interested professionals.

    For further information on the Fibrous Dysplasia Support Society, please email Ann Underhill.


    Courses & Educational Initiatives
    European School of Genetic Medicine: 1st Course in Clinical Dysmorphology
    Focusing on the development of advanced counselling skills for use in a genetic health care setting and offering an introduction into spectrum, evaluation techniques, and character and etiology of dysmorphism and dysmorphic patterns in order to enable clinical geneticists to better evaluate and interpret as well as distinguish between inborn and acquired congenital developmental defects; tracing the origin back to a given prenatal period; pattern recognition and syndrome delineation. The course is a post-graduate level program directed to clinicians, either geneticists or pediatricians or neonatologists.

    Date: 9-12 September 2007
    Venue: Bologna, Italy

    Further details and to register


    What's on Where?
    1-day Conference: Clinical Research for Rare Diseases: Opportunities, Challenges and Solutions
    Date: 5 September 2007
    Venue: Washington, DC, USA
    More details

    Rare Diseases Research: Building on Success - a European Conference
    Date: 13 September 2007
    Venue: Charlemagne Building- Brussels, Belgium

    This EC conference will focus on increasing the visibility of rare diseases research and raising awareness within the 27 EU Member States and the European Parliament on the research needs in this area, providing the rare diseases community with the opportunity to express their needs in terms of research and the EC with input for future FP7 calls for research proposals.
    For more information
    To register

    4th Stem Cell Gene Therapy Conference
    Date: 13-17 September 2007
    Venue: Halkidiki, Thessaloniki, Greece
    More details

    EuroGentest Workshop on internal auditing for genetic testing laboratories
    Date: 20-21 September 2007
    Venue: Leuven, Belgium

    Registration is open for this EuroGentest workshop on internal audit for genetic testing laboratories that will feature presentations, role play, video fragments and group discussions on how to prepare, execute and report internal audits. Registration deadline: 15 July 2007

    More details and to register now

    EFGCP Children’s Medicines Working Party 3rd Annual Conference on EU Paediatric Regulation
    Date: 9 October 2007
    Venue: Brussels, Belgium

    First European Experiences & Strategic Outlook
    With a pre-conference workshop on 8 October on the background of off-label drug use in children, US and EU paedriatric legislations, and the basics of child physiology and paediatric clinical trials.
    More details on the conference and workshop.

    8th EPPOSI Partnering Workshop on Orphan Drugs
    Date: 18-19 October 2007
    Venue: Copenhagen

    This year's workshop is dedicated to exploring the topic The Reality of Orphan Medicines and will provide a platform for consensus building and the cultivation of partnerships between patients, academia, and industry as well as European and member state authorities in order to convert policy issues and scientific developments into therapies for rare diseases.

    More details and to register now

    3rd International Meeting on Congenital Disorders of Glycosylation
    Date: 18-19 October 2007
    Venue: Paris

    This international meeting on CDG is preceeded by the 3rd Orphan Focus Course on "Protein Glycosylation in Health and Disease" on Oct 16-17.

    For more details on the course
    More details on the conference

    Biology and clinical applications of cord blood cells
    Date: 19-21 October 2007
    Venue: Paris, France
    More details

    4th European Conference on Rare Diseases (ECRD 2007)
    Date: 27-28 November 2007
    Venue: Lisbon, Portugal

    This important rare disease conference will be held in English and simultaneously translated into French, German, Portuguese and Spanish.

    NB: Registration is open. Deadline for abstract submission: 31 July 2007
    More details

    15th Annual Meeting, Int'l ALS/MND Associations Alliance & 18th ALS/MND Int'l Symposium
    Date: 1-3 December 2007
    Venue: Toronto, Canada
    More details


    Press & Publications
    Genetics, Health Care and Public Policy: An Introduction to Public Health Genetics
    Setting out the basic principles of public health genetics, including basic concepts, technology, epidemiology, genetics in medicine and health services, ethical, legal and social implications, and public health policy.

    Authors: Alison Stewart, Philippa Brice, Ron Zimmern, Hilary Burton, Simon Sanderson, Paul Pharoah
    Publisher: Cambridge University Press, May 2007

    Pediatric Hematopoietic Stem Cell Transplantation
    Recognised experts provide detailed discussions of the unique issues encountered during hematopoietic stem-cell transplantation in the treatment of various disorders, including metabolic diseases and other rare disorders, and consider some of the challenges unique to treating paediatric patients.

    Author: Ronald M. Kline –Ed.
    Publisher: Informa Healthcare, 2006

    Myeloproliferative Disorders
    Providing a thorough summary of the topic with contributions from internationally recognised experts in one or more of the myeloproliferative diseases.

    Authors: Junia V. Melo and John M. Goldman –Eds.
    Publisher: Springer, January 2007


    Orphanews Europe, the newsletter of the Rare Diseases Task Force
    Orphanews Europe is supported by the European Commission's DG SANCO
    and the French Muscular Dystrophy Association (AFM)
    Editor-in-chief: Ségolène Aymé
    Editor: Louise Taylor
    Contact Us
    Editorial Board: Ségolène Aymé, Catherine Berens, Kathy Beuzard-Edwards, Helen Dolk, Anders Fasth, Edmund Jessop, Matthieu Levi-Strauss, Jordi Llinares-Garcia, Antoni Montserrat, Annie Olry, Claire Scharf-Kroener, Janos Sandor, Arrigo Schieppati, Rumen Stefanov, Domenica Taruscio, Joan Luis Vives Corrons
    For more information on the Rare Diseases Task Force
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