Edition of 16 April 2014

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Editorial

EMA publishes its work programme for 2014: potential for rare diseases

The European Medicines Agency has published its annual work programme for 2014 which shows great potential for developers of orphan medicinal products and the rare disease community.

The Agency has identified key objectives in the area of evaluating activities for human medicines 2014, all of which should help in bringing more orphan medicinal products into the market. The Agency will aim to increase the success rate for marketing-authorisation applications through a more active use of scientific advice and other pre-application support to encourage the development of new medicines, especially in areas of unmet need, such as orphan medicinal products. The Agency will also work towards facilitating the use and development of emerging technologies and approaches in developing new medicinal products in addition to improving international cooperation in pre-authorisation support, especially in the area of scientific-advice. This was also reflected in their recent workshop on worldwide orphan medicinal designation

Broadly, the Agency aims to offer support for innovative methodologies, such as biomarker qualification, as well as for the development of new approaches and medicines, such as stem-cell technology. In addition to providing advice to sponsors applying for orphan medicines, paediatric medicines, advanced therapies, the Agency also envisions providing greater support to the HTA throughout the “lifecycle of the medicinal product”. The Agency will also work towards further facilitating the early stages of medicines development, implementing the clinical trials legislation, enhance cooperation within the European medicines network and with other European and international partners with increased transparency as one of their key focus. These goals and objectives outlined in EMA work programme for 2014 will prove to be greatly beneficial in faster access of OMP’s to patients.
Read the EMA Work Programme 2014

Spotlight on...

Pre-Conference Tutorials: ECRD highlight not to be missed

The 7th edition of the biennial European Conference on Rare Diseases & Orphan Products on 8-10 May 2014 has announced a packed programme with a wide variety of interesting topics. This conference, organised by the European Organisation for Rare Diseases (EURORDIS) and DIA Europe, is the only event dedicated to providing the state-of-the-art of activities in the field of rare diseases, in areas as far ranging as research, medical and social care, and access to orphan drugs. It provides a unique forum for the rare disease community, bringing together actors from across all diseases and stakeholder groups in Europe and beyond and providing a perfect opportunity to exchange knowledge and experience.

A highlight of the ECRD will be the Pre-conference tutorials which will take place on Thursday 8 May, 2014 from 14:30-17:00. These tutorials include discussions on topics that are current and relevant for all the stakeholders that plan to attend this conference. The first tutorial aptly named HEALTH TECHNOLOGY ASSESSMENT 101 FOR RARE DISEASES will introduce the participants to the principles of health technology assessment, describe the methods of economic evaluation, illustrate the unique circumstances surrounding rare disease evidence, provide an overview of the different approaches for assessing rare disease drugs across countries and discuss other factors which may contribute to funding decisions.
For further information on HTA

RD-CONNECT: AN INTEGRATED PLATFORM CONNECTING DATABASES, REGISTRIES, BIOBANKS AND CLINICAL BIOINFORMATICS FOR RARE DISEASE RESEARCH is the second tutorial which also promises to be extremely useful to the attendees. It will provide information on the RD-CONNECT platform and will guide clinicians, researchers, patient advocacy groups and industry on how this platform can be utilised to obtain the best results. The tutorial aims to provide information on how to set up and manage a registry or a biobank for a disease, study rare disease biospecimes. It will also provide information on how RD-Connect can be exploited to plan a rare disease trial as well as to analyse exomes for diagnostics and discovery.
For further information on RD-CONNECT

The third tutorial titled SUPPORTING THE PATHWAY TO TRIALS FOR RARE DISEASES: CLINICAL TRIAL DESIGN AND OTHER CONSIDERATIONS divided into two parts will provide information on clinical trial management for orphan drugs. The first part will endeavour to impart knowledge on the design and analysis challenges faced during clinical trials of orphan drugs due to the small recruitment numbers as well as provide examples of appropriate trial design and analysis for these groups with the help of Integrated DEsign and AnaLysis of clinical trials (IDeAL project). During the second part, TACT, the TREAT-NMD Advisory Committee for Therapeutics will share their illuminating experience and provide advise on drug development on the drug development pathway for neuromuscular diseases.
For further information on the IDeAL project
For further information on TACT

Last but not the least, A HIDDEN TREASURE TROVE: HOW TO GET THE BEST OUT OF ORPHANET DATA will provide in-depth knowledge on the ORPHANET website; the broad range of data it offers and how the information on ORPHANET can best be utilised to benefit your purposes be it in advocacy, public health, research, developmental strategy, to name a few. Information on how a successful partnership/collaboration with ORPHANET will also be imparted.
Go to the ORPHANET website

These pre-conference tutorials will indeed prove to be vital to prepare you for what will be a stimulating and exciting conference.
Further information on the EURORDIS website

EU Policy News

EMA

National & International Policy Developments

Other European news

Other International News

Patient Protection and Affordable Care Act in the United States helps out survivors of paediatric cancer

An article published in Journal of Clinical Oncology reports on the benefits that the Patient Protection and Affordable Care Act (ACA) enacted in 2010 will bring for patients who have suffered from childhood cancer in the US. The act will prove to be a blessing for these survivors as the incidence of childhood cancer have increased significantly from 1975 to 2006, with a concomitant increase in the number of survivors (pegged at more than 320,000 individuals in the US). The authors have described the situation of these individuals as grim as they have not only have faced the difficult experience of developing cancer during the formative years, they are bound to face more health challenges during their lifetimes. So far, in the US, difficulty acquiring health insurance is a common problem for adult survivors of childhood cancer due to insurers denying insurance to individuals with pre-existing conditions.

In this article the authors have explained how the advent of ACA has brought renewed hope for paediatric cancer survivors where they can no longer be refused coverage nor will their coverage be cancelled as a result of pre-existing medical conditions. Furthermore, these adults may remain on their parents’ private health insurance plans up-to the age of 26 years and finally “states can choose to raise the minimum eligibility requirements for Medicaid to 133%of the federal poverty level, with this coverage expansion financed in full by the federal government for the first 3 years”. Although enacting ACA brings many optimistic changes, the authors caution that its a long road before these survivors are adequately served by the US government. The problems revealed by the authors include ACAs provision limited to essential health services only. Therefore, childhood cancer survivors will likely face difficulty having screenings related to cancer care follow-up, which is not considered essential according to ACA, to be covered without experiencing financial burdens.

The authors ask the clinicians to be “mindful of potential plan benefit limitations and advocate for their patients to be reimbursed for procedures performed according to COG screening guidelines” and impress upon the readers the importance of future studies of childhood cancer survivors to gain a better understanding of the impact of the ACA.
Read the open access article

Guidance Documents and Recommendations

Bioinformatics, Registries and Data Management

Screening and Testing

Ethical, Legal & Social Issues

Increased information flow leads to changing usage of internet for information

The Genetic and Rare Disease Information Center (GARD) is a major provider of Web-based information on genetic and rare diseases. Little is known about the type of Web-based information individuals seek about genetic and rare diseases or their reasons for seeking. A paper published in JMIR Research Protocols describes the types of Web-based information sought about genetic and rare diseases and the reasons for seeking it from GARD by examining inquiries from 2006 and 2011. The authors randomly selected email and Web-based inquiries posed to GARD in 2006 and 2011 and examined them using content analysis. The results showed that most often in both years, individuals sought basic disease information and information about treatment while some requested information about their disease prognosis and made requests for specialists and information related to undiagnosed symptoms. The growing interest in current knowledge and the increasing information dissemination is requested in the fact that inquirers were significantly more likely to have seen a health care provider before contacting GARD and to ask about clinical research studies in 2011 than in 2006. Also seen was a gender difference between the two years as a majority of the inquirers were women in 2011 and men in the 2006 sample. The authors believe that the findings from this study indicate that lay people contacting a genetic and rare disease information center most often seek information about disease prognosis, finding a specialist, and obtaining a diagnosis for symptoms. They highlight the unique characteristics of individuals searching the Internet for genetic and rare diseases information, include a growing interest in participating in clinical research studies and a desire to supplement or better understand information discussed during a visit with a health care provider and believe that these efforts represent advancements in patient self-advocacy.
Read the open access article

EU Project Follow-up

New Syndromes

New Genes

Research in Action

Clinical Research

Gene Therapy

Therapeutic Approaches

Diagnostic Approaches

Patient Management and Therapy

Orphan Drugs

Finding a home for an orphan (drug): a biontrepreneurs guide

An article published in Nature Biotechnology has provided an analyses on whether the regulatory incentives on orphan drugs have helped bioentrepreneurs with an orphan drug focus reap financial rewards based on the likelihood of investment from big pharmas. The authors do this by identifying “the important acquirers, average price of purchase and at what stage orphan disease companies get bought”, which they believe should “inform bioentrepreneurs about the orphan drug space and their potential futures in it”. The authors identified 98 mergers and acquisitions using the HBM Partners Mergers and Acquisitions Report and analysed the conditions where companies with an orphan focus are acquired

Interestingly, the authors found that, on average, companies with and without an orphan designation (ODN) on their lead compound were bought within eight years of their founding. However, companies with an ODN compound were bought at phase 3 of the drug trial, while companies without an orphan focus were bought during the phase 3 trials, signifying a shorter time for drug development for orphan drugs but not a shorter time for acquisition. The authors postulate that this may be caused either due to the perceived market risk of orphan drugs or because of the reluctance of bioentrepreneurs with an orphan focus to sell their company after the phase 2 trial. Additionally, the authors discovered that from “(a) financial standpoint it is about as attractive to develop drugs for a rare disease as it is for a more common illness”. Keeping this data in mind the authors advice bioentrepreneurs with an orphan-focused company that their "financing status should allow for the complete development of a compound in-house”.

Other useful information provided by the authors includes some useful statistics on the behaviour of big pharmas on acquiring and developing orphan products. They report that during 2008-2012 Pfizer was the biggest acquirer, followed by Gilead, Roche and Shire, while neither Novartis, GlaxoSmithKline nor Roche acquired a company but did develop many ODNs during this period. Thus the authors warn that “although most pharmaceutical companies have in-house ODN programs, only a subset of big pharma is interested in acquiring orphan-designated drugs”. The authors recognise the challenges bioentrepreneurs face while starting a company with an orphan focus and believe that this analysis should provide them with some indication as to how they can make the best out of their investment.
Access the article

Regulatory News

Political and Scientific News

Grants

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Courses & Educational Initiatives

What's on Where?

OrphaNews, The Newsletter of the Rare Diseases Community.
OrphaNews is supported by the European Commission's DG SANCO (EUCERD Joint Action N° 2011-22-01)
and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Ségolène Aymé
Editor: Divya Unni
Editors for Scientific Content: Catherine Pouzat, Sophie Höhn
Contact Us
Editorial Board: Ségolène Aymé, Kate Bushby, Catherine Berens, Barbara Cagniard, Virginie Hivert, Helena Kaariainen, Odile Kremp, Yann Le Cam, Jordi Llinares-Garcia, Antoni Montserrat, Charlotte Rodwell, Jaroslaw Waligora

INTERNATIONAL CORRESPONDENTS
Orphanet Partner Country Representatives: Kristine Hovhannesyan (Armenia), Hugh Dawkins (Australia), Till Voigtlander (Austria), Rumen Stefanov (Bulgaria), Ana Stavljenic-Rukavina (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), John Rosendahl Ostergaard (Denmark), Vallo Tillmann (Estonia), Riitta Salonen (Finland), Joerg Schmidtke (Germany), Helen Michelakakis (Greece), Zsuzsanna Lengyel (Hungary), Andrew Green (Ireland), Annick Raas-Rothschild (Israel), Bruno Dallapiccola (Italy), Tomoko Kodama (Japan), Jana Lepiksone (Latvia), André Mégarbané (Lebanon), Vaidutis Kucinskas (Lithuania), Yolande Wagener (Luxembourg), Abdelaziz Sefiani (Morocco), Gert-Jan van Ommen (Netherlands), Stein Are Aksnes (Norway), Malgorzata Krajewska-Walasek (Poland), Jorge Sequeiros (Portugal), Cristina Rusu (Romania), Dragica Radojkovic (Serbia), Laszlo Kovacs (Slovakia), Borut Peterlin (Slovenia), Francesc Palau (Spain), Désirée Gavhed (Sweden), Loredana D'Amato Sizonenko (Switzerland), Ugur Ozbek (Turkey), Dian Donnai (UK)
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Photo credit : Serimedis http://www.serimedis.inserm.fr/ (unless otherwise stated)

Editorial

EMA publishes its work programme for 2014: potential for rare diseases

Spotlight on...

Pre-Conference Tutorials: ECRD highlight not to be missed

EU Policy News

EMA

Biomarkers to define orphan medicines designation an EMA perspective

National & International Policy Developments

Other European news

International Workshop on European Reference Networks: Recommendations and Criteria in the Neuromuscular field

Other International News

126 million slated for paediatric cancer research in United States

Patient Protection and Affordable Care Act in the United States helps out survivors of paediatric cancer

Guidance Documents and Recommendations

Genetic deafness: American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis

Aggressive B-cell non-Hodgkin lymphoma: National Institute for Health and Care Excellence guidance for pixantrone monotherapy

Bioinformatics, Registries and Data Management

Establishment of a vasculitis registry in Poland

Screening and Testing

Childhood Heritable Diseases: looking forward

Ethical, Legal & Social Issues

Increased information flow leads to changing usage of internet for information

EU Project Follow-up

The ODAK project: safe treatment for Acanthamoeba keratitis, a rare eye disease

New Syndromes

Progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures caused by compound-heterozygous mutations in QARS

Intellectual disability with additional variable features of brachycephaly is associated with de novo loss-of-function mutations in SETD5

An overgrowth syndrome with intellectual disability is due to mutations in DNMT3A

A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP

A novel syndrome involving the central nervous system and connective tissues is caused by a missense mutation in fibulin-1

A novel inherited disorder of the endoplasmic reticulum-associated degradation pathway linked to mutations in NGLY1

A novel immunodeficiency syndrome associated with partial trisomy 19p13

Intellectual disability, macrocrania, patellar dislocation, and celiac disease due to TBC1D7 loss-of-function mutations

New Genes

Retinitis pigmentosa due to homozygous nonsense mutation in KIZ

Stormorken-like syndrome, tubular myopathy and congenital miosis caused by gain-of-function mutations in STIM1 and ORAI1

Progressive familial intrahepatic cholestasis due to mutations in TJP2

Amelogenesis imperfecta caused by mutations in ITGB6

Megacystis-microcolon-intestinal hypoperistalsis syndrome linked to heterozygous de novo and inherited mutations in ACTG2

Cardiodysrhythmic potassium-sensitive periodic paralysis caused by a mutation in KCNJ5

Familial epilepsy with polymicrogyria due to a homozygous missense mutation in FIG4 in a consanguineous Moroccan family

Familial infertility associated with a homozygous frameshift mutation in ZP1 in six family members

Early infantile epileptic encephalopathy due to NECAP1 loss of function in six affected individuals of a multigenerational consanguineous family

Distal hereditary motor neuropathies caused by recessive mutations of HINT1 in two patients

Borrone dermato-cardio-skeletal syndrome linked to mutations in SH3PXD2B in two families

Acromesomelic dysplasia, Grebe type associated to homozygous missense and nonsense mutations in BMPR1B

A novel mitochondrial muscle myopathy linked to deleterious mutation in FDX1L gene

An individual with blepharophimosis - epicanthus inversus – ptosis syndrome and additional phenotypic features without FOXL2 mutation presented mutations in KAT6B

Recessive azoospermia caused by truncating mutations in TAF4B and ZMYND15

Research in Action

Clinical Research

Soft tissue sarcoma: the use of intensified doxorubicin and ifosfamide is not recommended unless the specific goal is tumor shrinkage

Follicular lymphoma: rituximab monotherapy should be considered as a treatment option for asymptomatic and advanced-stage patients

B-cell chronic lymphocytic leukemia: obinutuzumab combined with chlorambucil improved outcomes in patients compared to rituximab combined with chlorambucil

Rett syndrome: insulin-like growth factor 1 is safe, well tolerated and ameliorates certain breathing and behavioral abnormalities

Amyotrophic lateral sclerosis: cervical and dual-targeted intraspinal transplantation of neural stem cells is feasible and well-tolerated

Choroideremia: retinal gene therapy with and adeno-associated viral vector encoding REP1 is consistent with improved rod and cone function

Neuromyelitis optica: allogeneic hematopoeitic stem cell transplantation results in clinical and radiological improvement

Diazoxide-resistant diffuse hyperinsulinism: clear glycemic response to sirolimus in infants and no major adverse events during one year follow-up

Idiopathic aplastic anemia: eltrombopag restores hematopoeisis that can be sustained on discontinuation of drug

4-hydroxybutyric aciduria: adaptive behavior does not improve significantly with taurine intervention

Sporadic idiopathic steroid-resistant nephrotic syndrome: ofatumumab for rituximab-resistant pediatric patients

New insight for aortic dissection in Marfan syndrome patients: aortic root replacement or repair should be recommended

Gene Therapy

Mucopolysaccharidosis type 7: a helper-dependent canine adenovirus vector harboring a human GUSB expression cassette corrected neuropathology throughout the dog cerebrum

Huntington disease: intrajugular vein injection of adeno-associated viral vector serotype 9 prevented weight loss, atrophy and inclusion formation in key brain regions in mice

Junctional epidermolysis bullosa: the adeno-associated virus serotype DJ fully reversed the blistering phenotype both in vitro and in skin grafts

Metachromatic leukodystrophy: long-term correction of biochemical and neurological abnormalities in mice model by neonatal systemic injection of an ssAAV9

Therapeutic Approaches

Pelizaeus-Merzbacher disease: lonaprisan partially rescued the upregulation of proapoptotic genes and reduced microgliosis, astrogliosis and lymphocyte infiltration in mouse model

Erythropoietic protoporphyria: the in vivo correction of a common single splicing defect with antisense oligonucleotide-based therapy would improve the patients’ condition

Rhodopsin autosomal dominant retinitis pigmentosa: Hsp90 represents a potential therapeutic target but sustained Hsp90 inhibition might adversely affect visual function

Osteosarcoma: selective inhibition of BET bromodomain epigenetic signaling interferes with the bone-associated tumor vicious circle

Osteosarcoma: silencing microRNA-133a with locked nucleic acid (LNA) reduced cell invasion, and administration of LNA with chemotherapy prolonged survival in mice

Glioblastoma: the combination of Gint4.T and an epidermal growth factor receptor-targeted aptamer is better at slowing tumor growth than either single aptamer alone

Thrombotic thrombocytopenic purpura: plasmin, a thrombolytic agent, may help treating microangiopathies and may be useful to bypass inhibitory antibodies against ADMTS13

Graft versus host disease: the JAK inhibitor tofacitinib prevented weight loss, mucocutaneous lesions and reversed the disease in a murine model

Myeloproliferative neoplasms: therapy with PU-H71 and ruxolitinib improved blood counts, spleen weights, and reduced bone marrow fibrosis compared with ruxolitinib alone in mice

Diagnostic Approaches