Action Plan 2017 - 2019

2017-2019 Grid of Action PlanTREAT-NMD has always worked to a clearly defined "description of work", with agreed deliverables, milestones and expected achievements. This milestone-driven approach clearly drove the network's progress forward, therefore it was considered crucial to maintain this momentum by establishing new goals and defining the priorities and direction for future collaborative work across the NMD field.

The first (2011-2013) and second (2014-2016) ‘Action Plan’ built around the network’s core tools and resources has now been updated and the details of the outcomes achieved since the end of our EU funding can now be found here.

The TREAT-NMD Executive Committee, Taskforce and Secretariat have worked on updating and defining a new set of priorities in the form of this third work plan document that will take the network through to 2019. As well as the tasks described in the Action Plan, additional projects led by network participants will continue to make use of the network tools. Anyone interested in contributing to these tasks or proposing new areas of activity for the network is invited to contact the named coordinator.

Activity

Coordinator

Animal Model - Standard Operating Procedures (SOPs)

Markus Rüegg and Raffaella Willmann

Achievements (2014-2016)

With the funding provided by the AFM grant, a total of 17 protocols were finalized and uploaded on the CureCMD website (curecmd.org) and linked to the TREAT-NMD website.

Future plans (2017-2019)

Aim 1) Natural history database

With the financial support of Duchenne Parent Project Netherlands, this project was started in January 2016. Parameters to collect from a core of six labs are: CK, grip strength, histology, hanging test, locomotion, force assessment, CNF, fiber size, fibrosis, and cardiac function. Measurement units, devices, mouse ages, mouse gender, and mouse origin (commercial or in-house breeding) will be specified in the data collection.

Aim 2)  Stakeholder-workshop

The workshop will be organized to discuss with journal publishers, funding agencies, researchers and clinicians how to improve the quality of published efficacy studies, and how to encourage and fund horizontal studies and reproducibility studies. An application for such a workshop was submitted in March 2016 to ENMC.

Aim 3) Highest priority pathways for treatment targets in mdx

The purpose of this study, started in 2008 on initiative of PPMD USA, was to create a database of studies on drug efficacy in the mdx mouse model and identify pathological pathways that best respond to treatments and drug therapies, to finally encourage focused research on such targets, considering also repurposing of available drugs that act on those pathways. To finalize this project, it is now necessary to update the database and summarize the results of the analysis in a publication that would be of great benefit to the mdx research community and may foster a more focused development of promising treatments for Duchenne Muscular Dystrophy. Duchenne Parent Project Netherlands supports this project that started in January 2016.

All activities are coordinated and followed up by the Swiss Foundation for Research on Muscle Diseases with the collaboration of the TREAT-NMD chair and vice chair (Aim 2) and of members of the TACT committee and TREAT-NMD Task force (Aims 1, 2 and 3).

 

Biobanks: EuroBioBank

Mary Wang

Achievements (2014–2016)

EuroBioBank (EBB) continues to operate and every six months publishes a Sample Catalogue that lists the biological samples available for research (February 2016 edition: 148,000 specimens). The number of stored samples have increased steadily in the past two years, as well as a broadening of sample material categories. More than 950 rare diseases are currently presented in the EBB catalogue, where 55% are diseases of the nervous system (according to ICD-10 classification). The standard operating protocols (SOPs) were updated and uploaded to the EBB website in 2015. Between 2014 and 2016, the EBB network welcomed two new biobank members, thus bringing the network to 23 rare disease biobanks and 3 institutional partners.

As an associated partner of RD-Connect, EBB held a training workshop on biobanking for beginners and contributed to the development of sample workflow, SOPs, and the evaluation process for the inclusion of new RD biobanks. In 2015, together with RD-Connect, EBB also partnered to provide samples for a PhD fellowship project funded by Kindness for Kids (Germany).

Future plans (2017-2019)

At the end of 2015, EBB came to a firm agreement with RD-Connect to act as the de facto biobank in the EU infrastructure project. The partnership signifies the adoptation of latest informatic technologies for the creation and searchability of the sample catalogue, streamlined sample workflow, and compliance to the latest ELSI principles. Many of the EBB biobanks are registered in their respective national node within BBMRI-ERIC, and a close link is maintained at the network level in the context of RD-Connect with BBMRI-ERIC. This connection ensures sample data are interoperable and promotes synergy in other ongoing initiatives in biobanking. The integration of EBB with RD-Connect is expected to take place between 2016 and 2017. EBB also plans to work closely to ELIXIR, to voice the need of rare disease biobank community in terms of infrastructures for biological information in Europe.

Biomarkers

Alessandra Ferlini

Discovery of new biomarkers

There is a clear need for tools to better monitor patients in natural history studies and clinical trials. In the neuromuscular field, scientists and clinicians work together towards the identification of prognostic and predictive biomarkers as well as candidate surrogate endpoints to be used in disease monitoring and clinical trials. Most of the work focused on DMD and SMA, but new data have been obtained and released for other muscular dystrophies (LGMDs, FSHD and DM) as well as for inflammatory myopathies.  Evidences, ranging from the quantification of specific molecules in circulation to non-invasive imaging and electrophysiology, are now available to investigators as research tools to support primary endpoints in clinical trials. This has been greatly facilitated by EU projects and consortia such as Neuromics, RD-Connect and NeuroNext, which allowed for the sharing of samples, expertise and technology. More research and validation of the obtained results is needed in order to develope tools into qualified biomarkers.

Achievements (2014-2016)

  • Stakeholder workshop at the European Medicine Agency (EMA) organized by COST Action BM1207 ion collaboration with the SCOPE-DMD project. London, 29th April 2015
  • “Making outcomes work” workshop organized by SCOPE-DMD and BIO IMAGE-DMD consortia. London, 26th May 2016
  • Scotton C, Passarelli C, Neri M, Ferlini A. Biomarkers in rare neuromuscular diseases. Exp Cell Res. 2014 Jul 1;325(1):44-9. Review
  • Notable collaborative papers from the biomarker network

Future plans (2017-2019)

  • To date a larger number of exploratory and candidate biomarkers have been discovered and a primary goal during the next two years is to apply sharing policies, In order to maximize clinical translatability of these knowledge
  • An ENMC workshop on DMD biomarkers has been approved and will take place Jan 20-22 2017 in Naarden the Netherlands. This meeting is organized by Annemieke Aartsma-Rus, Alessandra Ferlini, Elizabeth McNally and Lee Sweeny and will focus on prioritizing identified markers for further validation and developing mechanisms to enable sample sharing and ensure good custodianship of samples
  • A meeting on biomarkers in rare diseases organized via RD-Connect, Neuromics, EuRenomics and IRDiRC is also being considered

Care & Trial Site Registry - CTSR

Jan Kirschner and Kirsten König

Expansion of CTSR and data quality

The CTSR has grown steadily in the past two years with 39 new centres registering. The registry now contains 329 sites seeing 66 000 patients altogether, of which 313 centres treat neuromuscular diseases and 80 treat neurodegenerative diseases. We have intensified curation of the database to further improve data quality and to avoid duplicate entries. A further change to the web application allows secondary users to edit the data. Many centres have made use of this feature and 78 secondary users have registered since January 2014.

Quality of sites and collaboration with research networks and patient organisation

In 2014 and 2015, seven feasibility reports were delivered to the pharmaceutical industry and three surveys for patient organizations were conducted.The sites were motivated through these ongoing activities to update their data leading to the improvement of the data quality, which can be monitored by the progress bar value: now 201 sites have at least 6 points on this scale, whereas two years ago it was 151. Accordingly, the mean number of patients per registered site has risen from 150 to 200.

Future plans (2017-2019)

In the next two years we aim to acquire new neuromuscular centres to improve the worldwide coverage of the CTSR. Data curation and regular interaction with sites is an ongoing process. The possibilities for usage of the CTSR are numerous, i.e. to gather information for identifying centres of excellence for the European reference network or find partners for research. For more information please click here.


Ethical Issues - Project Ethics Council

Elizabeth Vroom

Since 2013 the Project Ethics Council (PEC) has continued to be responsive and proactive regarding ethical issues in translational research in NMD. To identify, discuss and respond to questions and organise a conference call at least every 6 month or more often if needed.

PEC responses can be found here on the TREAT-NMD website.


Collaborative Research Networks – Duchenne Muscular Dystrophy Francesco Muntoni & Virginia Arechavala-Gomeza

Organisation of regular meetings

Using funding from COST Action BM1207, workshops on exon skipping have been organized on delivery (Leiden 2013, Bilbao 2016), delivery to the central nervous system (Madrid 2013, Bilbao 2016), animal models (Munich 2015), safety (Stockholm 2014), chemistry (Stockholm 2014) and regulatory challenges (London 2015). Additional workshops will be organized in 2017 (last year of COST funding). Topics are chosen by partners involved in the work as needed.

Harmonisation of biochemical outcome measures (dystrophin and exon skipping quantification)

To address the lack of harmonisation in the methods to quantify dystrophin restoration after antisense treatment, an international consortium of research groups performed a cross-validation of methods using blinded samples provided by a single lab. This was published recently (Anthony, Neurology 2014) and was presented at an FDA workshop on dystrophin quantification (March 2015). Current work focuses on cross-validation of methods to quantify exon skipping levels.

Scientist laboratory exchange visit

The scientist exchange visit enables early stage researchers to pursue research at a host laboratory for up to 90 days, whilst also facilitating and enhancing networking, as well as promoting harmonisation within the field. If you are considering applying for the exchange visit, please visit the websites of the respective Actions to see whether you are eligible.

Collaborative Research Networks - Facioscapulohumeral Muscular Dystrophy Silvere van der Maarel and Rabi Tawil

Overview and achievements

With increasing interest by pharmaceutical industry in Facioscapulohumeral Muscular Dystrophy (FSHD), there is a push to ensure that components of clinical trial readiness are in place to facilitate the conduct of future trials.  To that end two clinical trial readiness workshops were held in Leiden in April 2013 (sponsored by the whil Foundation) and in Rochester, New York in May 2015 (sponsored by the FSHD Champions, a consortium of international FSHD lay organizations). More recently, an FSHD Research Summit, held in Portland, Oregon in March 2016 (sponsored by Friends of FSH Research), addressed translational challenges in FSHD as well as trial readiness issues.

Future Plans (2017-2019)

  • Formation of an FSHD clinical trial network (USA)
  • Development of standards of care and management and best practice guidelines on genetic diagnostics
Collaborative Research Networks– GNE myopathy Hanns Lochmuller

Overview and achievements

The John Walton Muscular Dystrophy Research Centre (Newcastle University) and Ultragenyx Pharmaceutical are working in collaboration on several projects studying different aspects of GNE myopathy. This public-private partnership between both parties was established in 2012 to conduct a GNE Myopathy Disease Monitoring Program (GNEM-DMP). Since its launch in March 2014, the online patient registry (www.gnem-dmp.com) has seen its number of participants grow to 230, who join from across 28 different countries worldwide.  The online registry has also recently moved to a new IT platform which will allow for further advancements in the way that participants interact with the study team, as well as providing a platform for increased participation from the wider research community.

The multicenter natural history study continues recruitment across sites in the UK, Canada, USA, Bulgaria and France with the objective of gaining a better understanding of natural progression of the disease over a long period of time. Recruitment to the Phase III Clinical Trial of aceneuramic acid extended release (Ace-ER) tablets for the treatment of GNE myopathy is currently ongoing, with the recruitment process in its final stages.  This placebo-controlled study will collect information on the safety and efficacy of Ace-ER and it is taking place across 13 different study centers internationally.


Future plans (2017-2019)

At present the key area of focus centers around the completion of recruitment to the Phase III clinical trial, utilizing the strategic patient identification process developed within the team. The online registry is about to begin the first stages of a collaboration with the Japanese national registry for GNE myopathy, where both registries data sets will be combined in order to get a robust description of the clinical presentation and natural progression of the disease. From this combined data set, it is planned that a manuscript will be prepared and published. Promotion of the study continues through poster and oral presentations at major neuromuscular meetings, as well as through the study newsletter which has just completed its fourth edition (available in over 10 different languages).

Collaborative Research Networks– Limb-girdle muscular dystrophy Stojan Peric

Overview and achievements

The ultimate goal of the collaborative efforts in Limb-girdle muscular dystrophy (LGMD) is to develop curative therapy for LGMDs and over the last several years there has been a significant increase in joint research on LGMD. However, there still remains a number of topics that required elucidation.  A number of ENMC workshops on LGMD have been conducted in the recent years including; titinopathies, clinical trial readiness for FKRP dystrophy, dystroglycanopathies (2016) and calpainopathy (2013).

The number of LGMDs types has become so large that current classification and nomenclature are not adequate to keep up with dynamic changes in basic science. Thus, a workshop about new classification and nomenclature will be organized taking into account pathophysiological processes of LGMDs.

The Care and Trial Site Registry (CTSR) contains basic data about patients population (including more than 4000 LGMD patients) providing valuable data for different research studies and clinical trials. The following clinical trials were completed in the last several years including:

  • MYO-029 in patients with different types of muscular dystrophies (phase I/II)
  • Deflazacort in LGMD2B (phase II/III)
  • Gene transfer therapy in LGMD2C and 2D (phase I)
  • NeoGAA in LGMD2V (phase I)

Ongoing trials include: coenzyme Q10 and Lisinopril in muscular dystrophies (phase II, III), gene transfer therapy for LGMD2D (I/IIa), and cell therapy in LGMD.

Future plans (2017-2019)

A number of individual research groups are working on the development of non-invasive biomarkers in LGMD. Further collaborative research is necessary in the field of biomarkers.

Collaborative Research Networks – Myotonic Dystrophy Baseil van Engelen & Stojan Peric

Recent years have seen a major increase in collaborative research on myotonic dystrophy (DM). The first multicenter therapeutic trial of a targeted therapy for DM was initiated in December 2014, at seven North American centers.

A natural history and biomarkers is in progress in Québec, Canada over the 15 years with 115 patients. The subjects were assessed by an interdisciplinary team including epigenetic, cognitive, muscle, cardiac, pulmonary functions and environmental factors.

OPTIMISTIC, a EU funded collaborative project between 4 DM1 centres, in the Netherlands, United Kingdom, Germany and France. This multi-centre, randomised trial designed aims to compare an intervention comprising cognitive behavioural therapy (CBT) plus graded exercise therapy against standard care. One of the goals is the creation of a clinical trial infrastructure for European DM1 trials, including the collection of natural history data from a large cohort of DM1 patients.

A multicenter study of natural history and biomarkers is in progress at 6 centers of the Myotonic Dystrophy Clinical Research Network in the U.S.  The study has enrolled over 100 subjects for serial studies of muscle function and biochemical analysis of muscle biopsy samples.

In September 2015, a  Patient-focused Drug Development meeting devoted to myotonic dystrophy was held in the U.S, sponsored by the Myotonic Dystrophy Foundation. The meeting had broad participation by experts from the clinical research community, Food and Drug Administration and industry.

Harmonising Research Efforts through Networking

Annemieke Aartsma-Rus

Organisation of regular meetings

Using COST funding 2 or 3 workshops on exon skipping will be planned each year. The topics will be chosen by partners involved in this work as needed.

Meetings on “Brain delivery of exon skipping compounds” (Madrid January 2014, organised by Aurélie Goyenvalle, Matthew Wood and Annemieke Aartsma-Rus) and “Antisense oligonucleotide chemistry and toxicology” (Stockholm April 2014, organized by Samir el Andaloussi, Mike Gait and Annemieke Aartsma-Rus) have already taken place.

Exchange of scientists between laboratories

Exchanging scientists between laboratories is a good way to facilitate and enhance networking and to harmonise the field. Within COST Actions there is funding available for short term visits of (early stage) researchers to another laboratory (5 – 90 days, see www.exonskipping.eu/stsm for more information). All researchers working in countries (not Institutes) linked up to a COST Action are eligible for this. Within the TREAT-NMD Alliance, there are currently two COST Actions active, one on exon skipping (www.exonskipping.eu, coordinated by Annemieke Aartsma-Rus) and one on MRI (coordinated by Volker Straub). If you are considering applying for an exchange visit using COST funding, please visit the websites of the respective Actions to see whether you are eligible.

Harmonisation of biochemical outcome measures (dystrophin quantification) - Francesco Muntoni

University College London and Leiden University Medical Center are now embarking on a similar effort to compare protocols to quantify exon skipping levels. This will be sponsored by COST.


MRI - Standard Operating Procedures

Volker Straub

The work that TREAT-NMD has started on MRI/MRS as outcome measures in neuromuscular diseases has been taken on by a comprehensive working group that applied for funding through the European COST program. The project proposal entitled “Applications of MR imaging and spectroscopy techniques in neuromuscular disease: collaboration on outcome measures and pattern recognition for diagnostics and therapy development” was funded for 4 years and is chaired by Prof Volker Straub (Newcastle University) and co-chaired by Prof Pierre Carlier (IoM, Paris). The start date of the program was 1 January 2014. Additional information is also available on the following websites: MYO-MRI and COST ACTION BM1304.

The main aim of the imaging program is to advance novel MRI and MRS techniques for both diagnosis and quantitative monitoring of neuromuscular diseases through sharing of expertise and data, joint development of protocols, opportunities for young researchers and creation of an online atlas of muscle MRI and MRS.

Secondary objectives will be achieved via four Working Groups (WGs), each of which has a specific focus, defined outcomes and agreed deliverables.

Improvement of diagnosis and understanding of muscle pathology

Knowledge about the onset of muscle pathology detected by imaging, about the degree of progression, the spectrum of selective involvement across the whole body and about modifiers of these parameters is still very sparse for the majority of NMD. This lack of information might delay the diagnosis of patients with NMD and impede our understanding of disease mechanisms.

Specific objectives: 1.1
: Hold 2 WG meetings per year that coordinate the collection of an agreed number of standardized MR images for defined diseases. 1.2: Establish and validate a secure Information Technology (IT) platform to share medical images between experts. 1.3: Establish an online inventory of muscle MR images with associated standardised clinical and genetic data from NMD prioritized by the consortium (including a spectrum from pre-symptomatic to advanced, whole-body images, where appropriate cardiac images). 1.4: Define regions of interest (ROI) for each disease, indicating the optimal muscle to biopsy or to be used for outcome measurements in a clinical trial setting (showing most reliable change over time). 1.5: Develop a user friendly digital NMD atlas of muscle MR images with public access.

Development of multicentric outcome measures (OMs)

The most important reason why quantitative muscle MRI and MRS is currently not applied routinely across trial sites in multicentric studies is because of the lack of standardized and validated MR protocols for both data acquisition and data analysis. Trial participants therefore either need to all travel to a single centre or there is a risk that data is not comparable across centres. Protocols may need to be tailored for specific diseases. There is also a global lack of young researchers, (MR physicists and radiographers) with expertise in this area, and given its rapid growth it is essential to encourage new researchers to specialise in this field. Enabling STSMs for young researchers to gain expertise in different departments is crucial to catalyse development of expertise in the “next generation”.

Specific objectives: 2.1:
Hold 2 expert WG meetings per year that serve to develop SOPs for imaging protocols relevant for quantitative muscle imaging in natural history studies and clinical trials. 2.2: Publish optimised protocols for Dixon acquisition (Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation, IDEAL vs non-IDEAL, and fat spectrum simulation) and T2 acquisition using new approaches (partially Spoiled Steady State Free Precession, pSSFP, acquisitions) validated in a multicentric, cross-platform setting. 2.3: Hold 1 training school per year for MR staff from different centres at a central location, coordinated by the Action’s Dissemination and Training Committee (DTC). 2.4: Offer up to 4 STSMs per year for ESRs to train in muscle imaging at centres of excellence. ESRs from Eastern Europe will be encouraged to make use of the offer as will those who are working in neuromuscular centres with an interest in clinical trials. Applicants are selected by the DTC. 2.5: Provide expert site visits for onsite training on outcomes of WG1 and WG2 to ensure implementation of the relevant protocols. 2.6: One international conference on neuromuscular imaging as a show case for European translational research in rare diseases.

Exploration of new contrasts, new targets and new imaging techniques for NMD

New imaging techniques and contrast agents evolve with the development of improved MR technology and need to be tested against established protocols for their added value in the quantitative assessment of muscle pathology.

Specific objectives: 3.1:
Hold 2 expert consensus WG meetings per year to confidentially share pre-clinical and clinical data with the intention to develop joint protocols for new imaging techniques. 3.2: Publish joint reports on experimental validation of new contrasts relevant for the diagnosis and/or assessment of NMD and recommendations for their application by non-experts.

Exploration of strategies for muscle imaging texture analysis

Muscle architecture disorganization is a frequent end-stage feature of chronic NMD and particularly of muscular dystrophy. These structural changes translate into abnormal dispersion of the NMR signal distribution within muscles. The NMR signal heterogeneities result in increased standard deviation of muscle signal intensities. This very simple index has been shown to identify dystrophic muscle in animal models and to normalize when dystrophin expression is restored. However it does not take into account possible particular spatial distribution of muscle signal intensities. Texture analysis algorithms may reveal topographical patterns and improve diseased muscle characterization.

Specific Objectives: 4.1:
Hold Working Group meetings of experts to define strategies of muscle texture analysis and to define the best NMR contrast for these techniques to be applied. 4.2: Compare results obtained with different approaches and determine their merits for monitoring disease evolution. 4.3: Publish joint reports and manuscripts on the relative performances of all techniques tested.


Diagnostics for Neuromuscular Disorders and New Gene Identification: Next Generation Sequencing

Kathryn N North & Nigel G Laing

Establishing and providing next generation sequencing (NGS) diagnostic services

The establishment of next generation sequencing (NGS) will play an important role in diagnosis of neuromuscular disorders. In order to establish centres of NGS excellence providing diagnostic services, each country needs to design and deploy NGS diagnostics to suit their own health system. These centres must be allied with networks of clinical and pathological excellence with experts in each of the groups of diseases to facilitate the exchange of information and promote excellence in clinical practice.

Through clear communication with stakeholders (including clinicians and patients), we aim to identify and proactively respond to issues relating to NGS, including equity of access and cost per patient in each country, in addition to ethical issues surrounding the applications of NGS in clinical practice.

Current initiatives

A number of TREAT-NMD initiatives are currently being investigated in various collaborations. This includes investigation of molecular diagnostics by exome sequencing and sequencing of targeted gene panels in the European Union Framework Program 7 project “NEUROMICS” and by NEUROMICS Australia.

In Australia, different methods of establishing next generation sequencing nationwide, including funding options, are currently being explored by Neuromics Australia, the Australasian Neuromuscular Network, The Melbourne Geomics Heatlh Alliance and the Australian Genomics Health Alliance.

Several NGS projects in LGMD have been conducted so far including the MYO-SEQ project. This project has used PhenoTips software for entering phenotype data in accordance with the standardized terminology and hierarchy of the Human Phenotype Ontology project. This is very important to establish connections between phenotypes and genotype data in the era of NGS.


Outcome Measures

Eugenio Mercuri

TREAT-NMD has continued the work aimed at refining existing functional measures in DMD and SMA and promoting discussion with regulatory authorities to define a roadmap of measures to be used in different trials according to age, inclusion criteria and mechanism of action of the drugs. TREAT-NMD continues to use its experience and expertise (based on DMD and SMA work) to find the most suitable measures for other muscle disorders (CMD, DM, FSHD, GNE, LGMD, FKRP, Congenital Myastenia) that share some clinical features but have distinct patterns of muscle involvement and progression.

Achievements - DMD

  • Development of a patient reported outcome measure (PROM) - provides additional information on activities of daily living that cannot be captured in clinic using observer rated scale like the PUL
  • Non ambulant boys: longitudinal data has been collected using the PUL and the relationship with variables such as age, baseline values and steroid therapy are being established
  • Young infants with DMD: work has been performed to confirm the suitability of developmental scales longitudinally to assess the early phases of motor and general aspects of development (Myotools /accelerometer)

Achievements - SMA

An international effort has been made in the last 3 years to review existing scales and develop revised version that take into account the issues raised by the Rasch analysis. An international effort has also identified trajectories of progression in type 2 and 3 SMA

Achievements - LGMD

There is a special interest for MRI as a non-invasive biomarker in LGMD. COST Action BM1304 MYO-MRI is ongoing (2014-2018), and includes 20 countries. Besides this, the results of collaborative studies on muscle MRI in LGMD2I and LGMD2L, and cardiac MRI in LGMD2B and LGMD2I have been recently published.

Future Plan (2017-2019)

  • Further refine existing measures and natural history data in DMD, SMA, CMD, DM, FSHD, GNE, LGMD, FKRP and Congenital Myastenia
  • Obtain better information on the progression of the disorder in patients at different ages and different severity and to establish how these measures can predict important clinical endpoints such as loss of ambulation
  • Find the best statistical method to identify trajectories of progression that better predict the severity of progression
  • Establish the possible effects of regional differences in standards of care across countries and evaluate their effect on natural history
  • Continued work on non ambulant and very young DMD to obtain enough longitudinal data to identify possible trajectories of functional impairment

TREAT-NMD is promoting a registry of outcome measures that will collect information on the existing long term longitudinal studies in DMD and other different diseases. Furthermore, TREAT-NMD, in collaboration with advocacy groups and several clinical networks, is promoting discussion to find a consensus on a common muscle MRI protocol, that would allow data sharing and comparability of the results of the individual studies.


Patient Registries

Hugh Dawkins

Summary of Priorities

  1. Currency and quality of the registries’ data - Continued curation, and keeping the data up to date
  2. Global registry hosting and platforms - Help smaller groups by providing platforms to increase interoperability
  3. TGDOC meeting in Leuven 19th - 20th September 2016 - Discuss the planning, topics and format of the meeting
  4. Enquiries and support from industry - Increase the number and diversity of enquiries from industry. Explore potential funding models
  5. Post marketing surveillance (PMS) - Continue to ensure curators are engaged with PMS developments
  6. Global Unique Identifier (GUI) - Worked on by RD-Connect, TGDOC to remain informed and aware

TREAT-NMD Global registries enquiry information

 

Overview - Limb-girdle muscular dystrophy (LGMD)

The number of LGMDs types has become so large that current classification and nomenclature are not adequate to keep up with dynamic changes in basic science. Thus, a workshop about new classification and nomenclature should be organized taking into account pathophysiological processes of LGMDs.

Patient registries are available for several LGMDs: 2A, 2B, 2C and 2D, 2I, congenital muscle disease (including 2I, 2K, 2M, 2N, 2O), and 2V (late-onset Pompe disease). They are mostly run by patient organizations.

Further collaborative efforts are needed to include more patients in existing registries and to form registries for other LGMD types.

Regulatory Interactions - Issues

Annemieke Aartsma-Rus, Steve Lynn & Nathalie Goemans


TREAT-NMD has been involved in interactions with regulatory agencies since 2009, when a large stakeholder meeting was organized (hosted at the European Medicines Agency (EMA)). Networking activities with regulatory agencies is currently funded by COST Action BM1207 (www.exonskipping.eu).

In 2013 a workshop was organized in collaboration with patient advocacy groups to discuss the draft EMA guidelines (London, UK). In 2014 a small workshop involving researchers, clinicians, regulators and patient representatives was organized to discuss challenges for exon skipping development and biomarkers (Leiden, the Netherlands). A lay summary of this workshop was drafted and can be found here.

A large stakeholder meeting to discuss DMD therapy development, natural history and outcome measures was organized by COST Action BM1207 and SCOPE-DMD in 2015. This meeting was hosted by EMA and involved representatives from academia, industry, regulators and patients and parents. The meeting was recorded and can be viewed on the EMA Youtube channel. The briefing document for this meeting can be found here. A stakeholder meeting to discuss this is organized by SCOPE-DMD and Bioimage-NMD on May 26 2016.

A publication about stakeholder interaction between patient representatives, academics, industry and regulators will be published shortly. TREAT-NMD will continue to interact with regulatory agencies on a regulatory basis, e.g. to validate developed outcome measures for upper limb function and MRI.

The EMA has set up an initiative to make better use of existing patient registries and facilitate the establishment of high-quality new registries as a source of post-authorization data for regulatory decision-making. This initiative starts with a pilot-phase to test different components of the patient registry strategy and to see whether it meets regulators’ and other stakeholders’ data and information requirements. TREAT-NMD has formally notified the EMA of its interest in collaborating with the EMA on this initiative and in the production of its recommendations following the pilot phase.

For spinal muscular atrophy (SMA), the last meeting with EMA on outcome measures and clinical trial readiness was held in 2007. With the results of the first clinical trials in SMA becoming available and many other trials ongoing or in the pipeline, there has been increasing pressure from advocacy groups, industries and the whole SMA community to plan a meeting with regulatory agencies to discuss the state of art on outcome measures and natural history and possible challenges and bottlenecks. An ENMC Workshop to discuss the available outcome measures for SMA and suitability to the criteria requested by regulators, were discussed at a recent ENM workshop held in November 2014 (Finkel et al., 2015). TREAT NMD , in collaboration with SMA Europe and other advocacy groups is planning to propose a new meeting with EMA in the next year.


Care Guidelines- Spinal Muscular Atrophy Thomas & Richard

Achievements (2014-2016)

TREAT NMD was involved in the organization of a European Neuromuscular Centre (ENMC) International workshop (February 19th-21st 2016), aimed at revisiting the consensus statement of standards of care in spinal muscular atrophy (SMA). Participants included clinical researchers and representatives of patient advocacy groups from different countries. The workshop focused upon eight topics related to different aspects of diagnosis and care. For each topic there were 2/3 leaders who prior to the workshop selected at least ten international experts on that topic who participated in a discussions prior to the workshop. Recommendations were put forward from each group when more than 70% of experts agreed.

Future Plans (2017-2019)

  • Further clarification of certain aspects of subjects or recommendations as discussed and identified by groups
  • Final recommendations of each working group will be completed by Summer 2016
  • A comprehensive summary of final recommendations will be published and a family-friendly version will also be made available to the public via the internet

TACT

Kathryn Wagner

Review Meetings

TACT will continue to hold review meetings every 6 months.

Reaching out with TACT model to other rare disease groups

TACT is committed to spreading the model for accelerating drug discovery in rare diseases based on our experience. To this end we will regularly review and publicise TACT activities and will continue to reach out to other rare disease groups via personal contacts and relevant conferences. The current examples are:

  1. A paper describing the TACT model and achievements has been submitted as a commentary to Science Translational Medicine
  2. TACT members hosting a pre-conference tutorial on the TACT model for therapeutic review in rare diseases at the ERCD meeting in Berlin in May 2014.
  3. Members of other rare disease networks to attend TACT as observers covered by Confidential Disclosure Agreements. A member of the Beyond Batten Disease Foundation attended the meeting in May 2014.

Sustainability

TACT will seek funding to ensure a minimum of 3 year stability – core funding for a co-ordinator and twice yearly meetings. Various members of the Core committee and the Secretariat will be tasked with approaching specific organisations for funding.


Education Stephen Lynn

Achievements (2014–2016)

TREAT-NMD has been involved in several educational efforts and outreach initiatives. TREAT-NMD has been able to use EU funding awards to co-organize conferences in Brazil, China and several Eastern European countries to provide information about TREAT-NMD tools, the Care and Trial Site Registry (CTSR), care guidelines etc. In collaboration with international patient organizations, results were also disseminated to patients and parents.

In September 2015 and 2016 TREAT-NMD organized an expert masterclass on DMD that focused on genetic diagnosis, natural history, outcome measures and therapy development (these events was supported by an educational grant awarded by PTC Therapeutics).

Future Plans (2017–2019)

Following on from the success of the DMD expert masterclasses, TREAT-NMD plans to organize a thrid masterclass in 2017. Furthermore, we hope to oganise the first SMA expert masterclass in 2017/2018.

If you are interested in co-organizing an educational meeting or masterclass with TREAT-NMD, please contact us.

TREAT-NMD Secretariat

Website & communications resources

The TREAT-NMD Secretariat is responsible for:

  • continued updating, maintenance and development of the TREAT-NMD website
  • publishing and distribution of the monthly TREAT-NMD newsletter
  • development of the social media communications across the network
  • updating and maintenance TREAT-NMD’s Intranet area and mailing lists
  • monitoring, analysis and dissemination (when required) of the amount of internet traffic to the website
  • processing new membership applications to the TREAT-NMD Alliance when required
  • providing advice and assistance to associates and collaborators who want to include information on the network website
  • continually monitoring developments in technology - implementation will be considered if deemed to be 'of value' to the network
  • making available up-to-date TREAT-NMD promotional materials to various bodies, committees and individuals associated with the network

Support service to the TREAT-NMD Alliance and its Committees

The TREAT-NMD Secretariat will continue to provide an efficient and coordinated support service to the TREAT-NMD Alliance, specifically to the TREAT-NMD Executive Committee, TREAT-NMD Global Database Oversight Committee (TGDOC), and the TREAT-NMD Advisory Committee for Therapeutics (TACT).

Management of industry interactions
The TREAT-NMD Secretariat will continue to act as the first point of contact within TREAT-NMD with regards to industry interactions.

Liaison with registries
The TREAT-NMD Secretariat will continue to manage communication with the TGDOC members and registry curators. The Secretariat will provide support to coordinate studies and enquiries coming from industry and academic researchers to the global registry. The Secretariat will work together with the TGDOC chair on the planning and organisation of the TGDOC and Curators meetings.

Liaison with patient organisations
The TREAT-NMD Secretariat will continue to liaise with patient organisations.

Organisation of regulatory interactions
The TREAT-NMD Secretariat will continue to be responsible for planning and organisation of workshops and meetings with regards to regulatory issues.

Publications related to the network
The TREAT-NMD Secretariat will continue to work on the publications related to the activities of the network.

 
12 Apr 2017