SMA outcomes and clinical trial readiness

Location: Heemskerk

Co-sponsored by the SMA Foundation, ZonMw, Cure SMA and SMA Europe


Twenty-four researchers and industry representatives from 9 different countries (USA, Spain, Italy, France, Germany, Switzerland, Sweden, the Netherlands, United Kingdom), two representatives of SMA Europe (one patient, one parent of 2 SMA affected children) and one representative from SMA Foundation, met in Holland on the weekend of the 7th- 9th of November 2014. They came together to update current knowledge on clinical trials and outcome measures for spinal muscular atrophy (SMA). The workshop was conducted under the leadership of Richard Finkel, Enrico Bertini, Francesco Muntoni and Eugenio Mercuri.

SMA is one of the most common neuromuscular diseases and -since last ENMC workshop on this condition held in 2007- there has been noticeable improvement on the understanding of its pathogenesis and natural history. Moreover, some clinical trials have been recently completed or are ongoing, and others are at advanced planning stages. This progress has highlighted the need for a better definition of outcome measures and to improve clinical trial readiness.
In this workshop, participants presented new data related to the fundamental deficiency of the SMN protein and where high levels of SMN are required. In severe SMA mice pathological changes can be detected outside the central nervous system but it remains unknown how relevant these changes are for the human condition

Novel information was provided on experimental therapeutic developments in different animal models, also focused on defining when during development the pathological process has its onset and at which stage restoration of SMN protein is likely to result in a beneficial response. New information on involvement of regions of the nervous system other than motoneurons was presented, including neuropathological data in children with SMA type 1 showing pathological alteration in the thalami. Information on electrophysiological and serum biomarkers was presented, including their correlation to clinical outcomes, both in preclinical models and in SMA patients. Differences in diagnostic tests being used worldwide and in gene modifiers were discussed.

A significant portion of the workshop was devoted to the discussion on the different functional tools available to capture the heterogeneous nature of the disease, which spans from severe SMA type 1, to milder SMA types 3 and 4. Information on differences in the clinical course of disease in the childhood types was discussed, together with the challenges to capture meaningful and reliable information in a population that ranges from severely affected infants, to children who are able to sit, to young adults who can walk. The importance to keep these populations separate for trial design was highlighted by all participants.
Gaps in knowledge and need of further development and validation work were identified, especially linking different levels of functional abilities of affected individuals, and on the correlation between some of the functional and surrogate measures to minimally clinically meaningful differences. The discussion also included the important question what “clinically meaningful” means to patients, parents, doctors and scientists.
A series of collaborative strategies to address these points were discussed and agreed, and these will be summarized in the full workshop report is submitted for publication to Neuromuscular Disorders (pdf).


Richard Finkel, Francesco Muntoni, Eugenio Mercuri, Enrico Bertini, Arthur Burghes, Karen Chen, Mencia de Lemus, Jean-Yves Hogrel, Omar Khwaja, Jan Kirschner, Marion Main, Elena Mazzone, Jackie Montes, Danielle Ramsey, Thomas Sejersen, Charlotte Summer, Kathryn Swoboda, Danilo Tiziano, Brian Tseng, Ludo Van der Pol, Carole Vuillerot, Brunhilde Wirth, Anna Wittchen, Danny Yeh.

Formation of a European network to develop a European data sharing model and treatment guidelines for Pompe disease

Location: Naarden, The Netherlands

This workshop was co-sponsored by the Dutch ZonMw, Genzyme Europe BV, the International Pompe Association, Amicus Therapeutics and BioMarin Europe Ltd.



Pompe disease is a rare inheritable muscle disorder for which since 2006 enzyme replacement therapy (ERT) is available. Studies in infants showing improved survival were key to the market approval of this drug. Since 2006 several studies in children and adults have also shown effects of this treatment. Harmonized criteria to start or stop ERT for the whole spectrum of patients with Pompe disease are needed.

This workshop brought together a panel of physicians and researchers from various European countries with clinical experience in treating and following larger groups of patients with Pompe disease, or doing research in this disorder, as well as a patient representative.

Aims of the workshop

The aim of this workshop was

  1. To establish a European Network on Pompe disease
  2. To agree on a minimal dataset (of outcome measures)
  3. To make recommendations on start and stop criteria for ERT for adult patients.

What was achieved?

  1. A European network was formed. The network is initially comprised of the participants of the meeting, but will over time be expanded to involve more European countries, and later possibly also experts from countries outside Europe. Areas the network intends to work on include: data sharing, developing recommendations on starting and stopping ERT, standards of care, harmonisation of outcome measures and responses to questions from health authorities.
  2. Agreement was reached on a minimal dataset to be collected for adult patients. For infants and children a workgroup was set up.
  3. Consensus was reached about recommendations for start and stop criteria for adult patients. These will be prepared for publication.

A full report is published in Neuromuscular Disorders (pdf)


Chronic respiratory insufficiency in Myotonic Dystrophies: management and implications for research

Location: Naarden, The Netherlands

Workshop organisers: Dr VA Sansone (Italy) and C Gagnon (Canada)

Myotonic Dystrophies are the most frequent muscular dystrophies of adulthood. Patients with myotonic dystrophy type 1 (DM1) die primarily from respiratory complications in mid-life and patients with the congenital form of DM 1 may require a stoma in the trachea at birth (invasive ventilation). Myotonic dystrophy type 2 (DM2) also affects multiple organs, but the degree and severity of respiratory involvement has not been investigated in detail. Although respiratory involvement is a major concern in the myotonic dystrophies,  respiratory care has been limited by the complex pathophysiology of respiratory involvement and by specific clinical characteristics of DM patients.

Patients progressively develop respiratory muscle and diaphragm weakness which affects their ability to ventilate efficiently, especially at night while lying in bed. This leads to low blood oxygen levels and high blood carbon dioxide levels, initially during the night and then even during the day. Patients slowly habituate to the abnormal blood gas levels. It is however not only the muscle component and obstructive sleep apnea which come into play, but there are several complex central nervous system (CNS) pathways which interfere with synchronous activity of respiratory and abdominal muscles. Especially during the night, which disrupts sleep patterns, thus worsening ventilation. Management is therefore challenging. The choice of the type of non-invasive ventilation (NIV), such as C-PAP, BiPaP or Auto-SV, needs to be tailored for each patient.  These complex underlying mechanisms of the disease are largely responsible for excessive daytime sleepiness and fatigue which are frequent in DMpatients.

The cognitive and behavioral features of these patients are such that there is lack of awareness of chronic respiratory insufficiency and patients seldom complain of symptoms of respiratory involvement. When cough assistance rehabilitation programs or non-invasive ventilation are prescribed, compliance is limited and respiratory management becomes very challenging.

This workshop provided a platform for experts in myotonic dystrophy and in respiratory care from across Europe, Canada and USA to share best practice. It allowed to start to work together on a common standardized pathway of respiratory care for these patients when first seen and during follow-up. The combination of experts in myotonic dystrophy and experts in ventilation also created a platform to adapt existing consensus care recommendations for cough assistance and domiciliary non-invasive ventilation in these patients. Specifically, it was very important to merge knowledge in respiratory care with that of the muscular and multisystem additional aspects of the disease, including the ability to manage the cognitive and behavioural characteristics of these patients.

The workshop heard from clinical experts on the issues of fatigue and excessive daytime sleepiness and on how specific CNS pathways may play a role in the development of chronic respiratory insufficiency, disturbed sleep and reduced awareness. The issue of the patients not reporting symptoms was discussed and there was general consensus that this is a major limitation to care and management.The relationship between cardiac and respiratory involvement was also addressed with specific focus on the arrhythmic risk in patients with or without ventilation. Each country representative provided indicative data on the frequency and severity of respiratory involvement and on the pathway of care and management in these patients. Similarities and differences were discussed. It was noted that the efficiency of the healthcare systems in different countries in providing respiratory care are dependent on existing structures and/or specific persons and existing pathways and the extent to which these enable coordination and interdisciplinarity. This indicated that respiratory assessments, management and the quality of care is highly variable and could sometimes be quite fragile. It was also noted that the use of cough-assistance devices and respiratory rehabilitation programs varied widely amongst the different countries. This session played an integral part in identifying gaps in existing care and helping to adapt existing recommendations and move towards a consensus statement for respiratory care, specific for myotonic dystrophies regarding recommendations for the diagnostic work-up, succession planning and monitoring. The workshop also heard  personal experience from an Italian patient and spouse and from a Dutch patient and spouse and from organisations representing patients – the Myotonic Dystrophy Support Group. This patient´s voice was essential to help in defining ways to overcome and manage the lack of awareness of symptoms, to better address the need for respiratory care and to improve compliance.

To summarize, the main points of discussion were:

  • The importance of accessibility for patients with myotonic dystrophies to a neuromuscular centre with experience in non-invasive ventilation or referral by a neuromuscular or myotonic dystrophy healthcarer to a respiratory center with experience in non-invasive ventilation to allow co-ordination of care.
  • The importance of dedicated healthcare pathways to define respiratory care during screening visits and during follow-up assessments were also discussed.
  • It is critical to understand that patients with myotonic dystrophies require more time from the healthcarers during clinical assessments, administration of questionnaires, explanation of specific healthcare pathways and treatment options, and during training. In order to improve compliance to treatment
  • Specifically, the workshop allowed to:
  • Provide a basic screening respiratory protocol to assess patients at baseline (when first assessing respiratory function) including a symptoms check-list and a list of recommended respiratory laboratory tests for screening, applicable by myotonic dystrophy experts and non-experts. The symptoms check-list includes a list of questions with adequate wording for myotonic dystrophy patients to increase the patients’ understanding of symptoms.
  • Discuss uncertainties and benefits and side-effects of NIV and lack of knowledge of its effects in the long-term given the lack of natural history studies in respiratory involvement in myotonic dystrophies. Consensus was reached on the need to launch NIV when specific criteria are present. The workshop allowed to adapt existing recommendations for launching of NIV (ACI Respiratory Network Domiciliary Non-Invasive Ventilation in Adult Patients : A Consensus Statement) making them specifically applicable to these patients.
  • Address additional management issues including: peri-operative management, secretion management, weight control, physical exercise program and patient and carer education, training and acclimatization. Existing emergency care plan could be implemented in all countries to help improve management of these patients.

To determine future areas of research including natural history study to understand the course of the respiratory involvement and outcome measures validation.
Margaret Bowler from the Myotonic Dystrophy Support Group and the patients representatives will help in diffusing information and results obtained from the workshop discussions.

A full report is published in Neuromuscular Disorders (pdf)

Adults with DMD

Location: Naarden

Care for a novel group of patients: Adults with DMD. Scope of the problem and need for care recommendations

Workshop organisers: Dr. J. Rahbek (Denmark), Dr. B. Steffensen (Denmark), Dr. I. de Groot (The Netherlands), Prof. K. Bushby (United Kingdom)

Due to recent improvements in the treatment of late-stage Duchenne in the last few decades, many children with Duchenne are now living long into adulthood with the condition.  This has led to a current “unforeseen generation” of adults living with Duchenne who are now in their 20s, 30s and 40s.  This workshop provided a platform for experts in adult Duchenne care from across Europe and North America to share best practice and work together to update the existing consensus care considerations to include this novel group of patients.

The workshop heard from clinical experts on the issues faced by adults with Duchenne in areas of cardiac and respiratory management, nutrition and gastro-intestinal problems, as well as issues of pain and fatigue, bone health, upper body function, emotional and psychological health.  The workshop also heard from organisations representing parents and adults – the Dutch Duchenne Parent Project, Parent Project Muscular Dystrophy and DMD Pathfinders, including two expert patients living with Duchenne who shared personal and peer experiences.  This patient voice played an integral part in identifying gaps in existing care and helping to shape the care considerations update.

It was noted that the efficiency of the healthcare systems in different countries in supporting adults with DMD are dependent on existing structures and/or specific persons and the extent to which these enable coordination and interdisciplinarity.  This indicated that the quality of adult Duchenne care could sometimes be quite fragile and should be supported by succession planning, monitoring and review.

Some of the issues identified which will form the basis of updated care considerations include:

  • The importance of seeing Duchenne as a childhood onset chronic disease with patients treated as such, including the consideration of interventions such as cardiac devices and transplant where appropriate
  • The need for continued emphasis on meeting existing best-practice standards in cardiac and respiratory care, as well as the importance of access for each adult patient to a neuromuscular centre to allow co-ordination of care
  • The importance of healthcare pathways to define care in an emergency, which should include details of advanced directives agreed by the patient and a contact point with specialist neuromuscular centres available at any time.  It was felt that emergency/advanced healthcare pathways was a more useful approach than references to “end of life” care.
  • The value of extending steroid treatment for current steroid patients into adulthood
  • The need for a holistic, patient-centered approach to care which emphasises the strong interplay between cardiac, respiratory and nutritional care
  • The importance of ongoing monitoring and a stepped approach to tackling under-nutrition in adulthood.  This should include monitoring and treatment of dental problems which can exacerbate nutritional issues.
  • The importance of access to specialist physiotherapy and equipment for adults with Duchenne to address issues of pain, contractures, sitting balance and the maintenance of arm and hand function

Issues were also raised by patient groups regarding the need to place Duchenne care in a social context which responds to the significant differences between childhood and adult life, rather than simply extending pediatric care roles.  This recognises the fact that adults with Duchenne are living increasingly diverse lives but typically identify with a perspective of non-difference, wishing to be treated in line with their non-disabled adult peers.  It was agreed that:

  • Care for adults with Duchenne must ensure access to support is available around issues of everyday adult life, including: social inclusion and independent living, education and career development, sexual health and care, peer and romantic relationships, enhancing self-identity and self-esteem, and risk-taking behaviours.
  • It is critical to understand that the medical/healthcare system, the family, and the adult with DMD, are three different groups with often different values and interests.  It is important the care is led by the adult’s wishes however sensitivity is required to support all parties through the transition to adulthood and beyond.  This is best supported by transition preparation, education and emotional support which starts at diagnosis and continues throughout the patients’ life.
  • When a multifaceted health care plan is being issued and coordinated, it is very important that there is a key person that speaks on behalf of the adult with DMD and their needs and interests – if the adult is unable to do so.

It was also identified that there are many issues where data on issues of adult care is lacking.  It was recognised that in these areas it is important for clinical experts to be clear about uncertainty concerning benefits and side effects, or lack of knowledge in an area – including the question of life expectancy.  It was agreed that further research is needed:

  • To identify the potential of e-health, remote care and outreach to address the challenges faced by this population in travelling to specialist centres
  • To develop a full, evidence-based natural history profile of Duchenne in adulthood. A small group will be set up to develop a protocol for investigation for a natural history study to include an in depth medical review and seek funding for this
  • To increase understanding of gastro-intestinal and endocrine problems experienced in adults with DMD
  • To support the extension of existing therapies or new therapies currently in development into adult age by testing them in an older population

The workshop also identified considerable potential for further follow-up work in regards to care for this group of patients beyond these research needs.  It was recognised as critical that this builds on existing engagement with patients to increase registry participation, peer support and advocacy provision – especially when it comes to difficult transitional periods.  Engagement with regulators and commissioners across Europe and North America is also needed in order to respond comprehensively to the needs of this growing patient population.

A full report is published in Neuromuscular Disorders (pdf)

Pathology Diagnosis of Idiopathic Inflammatory Myopathies

Location: Naarden, The Netherlands

This workshop was co-sponsored by the European Science Foundation and the Dutch ZonMw Foundation


The idiopathic inflammatory myopathies (‘myositis’) are not one single disease but encompass a group of diseases with variable clinical characteristics. A muscle biopsy is usually needed for a precise diagnosis. The identification of disease subgroups is extremely important for assessing treatment options and prognosis in the individual patient, yet classification criteria have not been standardized and validated.  A first ENMC workshop on myositis muscle pathology was held in 2012 and led to recommendations for a minimum diagnostic set of histopathological stainings and a working document on how to best define and score disease signs. At the end of the first workshop, participants agreed unanimously that continuing toward a standardized diagnostic work up is absolutely crucial to better patient care in the future.

The group of world experts on muscle pathology of patients with myositis now reconvened in Naarden to fine-tune the propositions from the first workshop.  Consensus was sought on how and what to analyze in muscle biopsies of patients suspected of having an inflammatory myopathy and how to provide accurate description of disease subtypes. It was discussed how to translate these recommendations into a comprehensive diagnostic tool that could be widely implemented. A virtual microscopy platform was used to validate the drafted morphological criteria in digitalized muscle biopsies from 24 selected patients which were assessed prior to the workshop. At the end of the workshop a consensus text was drafted stipulating the work up of muscle biopsy specimens and a working document for scoring pathological features. It was concluded that important progress was made toward the final goal being the drafting of a standardized scoring procedure for the idiopathic inflammatory myopathies. Participants reaffirmed their willingness to continue efforts in this respect.

A full report is published in Neuromuscular Disorders (pdf)

Biomarkers in DMD

Location: Naarden

This workshop was co-sponsored by the American Parent Project Muscular Dystrophy, the Dutch ZonMw Association and Genzyme Europe BV

Biomarkers are defined as cellular, biochemical, molecular alterations or features  that are measurable in biological material and that can provide information on physiological or pathological processes. Biomarkers may be used in differential and early diagnosis, and in monitoring of disease progression, regression, or therapeutic response. Duchenne Muscular Dystrophy (DMD) is a severe hereditary muscle disorder due to a wide variety of dystrophin gene mutations and presenting with variable clinical severity.

Recently novel experimental drugs have been developed for DMD and several trials are ongoing, raising the urgent need of having fine tools for measuring the trial outcomes as well as for optimizing the selection of eligible patients. Biomarkers are appealing since may show earlier response to treatment and may not necessarily require invasive sampling, allowing their assessment at multiple endpoints.

This ENMC workshop was focused on biomarkers in DMD and aimed at sharing experience and results among the international Community working on DMD and other neuromuscular disorders. 26 EU and USA experts participated, and among these almost all partners of the BIO-NMD EU project attended. Given the rarity of DMD and other NMDs, this large and intercontinental collaborative cooperation is needed to address this topic, also accordingly to the IRDiRC ( initiative.  Specific representative of regulatory bodies, EMA and FDA, were not present, but the EMA perspectives and biomarkers rules were presented by an EMA-affiliated. The remaining representatives were from academic medical centers from EU and North America.

Duchenne Parent Project representatives (EU and USA) attended. Prosensa and Sarepta Pharma-companies also attended.

The workshop focused on the following main topics:

  • The need for biomarkers
  • Setup of biomarker studies
  • Existing Genomic biomarkers in DMD
  • Existing Proteomic biomarkers in DMD
  • Clinical biomarkers in DMD
  • Complexity of finding biomarkers in DMD : confounding factors, specific phenotypes
  • Planning the future – Breakout sessions

A comprehensive overview on biomarker research in DMD, highlighting both established and yet unpublished data, was presented. EMA rules and mechanistic pathways underlining biomarker discovery and development were presented clarifying the role biomarkers may have in clinical trials (surrogate/accompanying) or disease stratification (diagnostics/prognostics).

Types of biomarkers, discovery tasks, strategies and clinical applications were extensively presented. A session was dedicated to the already known DMD biomarkers (DNA, RNA, proteins) and their potential role in clinical trials. The utility of biomarkers can be influenced by genetic, phenotypic and environmental factors (disease severity, steroids, mutation types, genetic modifiers) and examples of these and the complexity of their interpretation were presented.

A significant part of the workshop was dedicated on planning the future research to implement some of the early findings on biomarkers into clinical applications. Potential collaborations, the need for early dialogue with the FDA and EMA, and efforts for research harmonization were intensively and fruitfully discussed.

The following conclusions were reached:

  • Biomarkers are a very timely subject in the study of rare diseases, and much progress has been achieved, especially in the discovery field
  • The NMD community has defined several exploratory biomarkers that need to be validated in larger patient cohorts
  • The qualification of biomarkers by the regulatory agencies, and their application in clinical trials is highly demanding (time/cost/effort) and requires cooperation and dialogue between all parties.
  • The regulatory definition of biomarkers, and the requirements for their use in clinical trials, must be correctly communicated to both investigators and to patient advocacy groups in order to avoid false perceptions of their utility for drug approval.
  • The role of industry is vital, since in the majority of cases a biomarker may not only facilitate orphan drug designation but may also be concurrent to drug approval. Similarly, if a biomarker is proposed independently of a specific therapeutic agent, the EMA/FDA qualification process may require the industry’s effort.
  • A database should be developed which catalogues ongoing DMD biomarker studies as well as biomaterial that can be shared/used for large validation studies.
  • RD-connect EU project and IRDiRC initiative are positioned to help organize such a database and disseminate information.
  • Several collaborations and future common applications for research projects were initiated.
  • All participants enthusiastically and openly shared data, ideas, critiques and future view, making this a productive WS that achieved its goals and outlined future plans.
  • We expect that the pursuit of the above will be of  a great value as outcome, in terms of for research and, clinical applications , and will be of for the benefit of patients and their families.

A full workshop report is published in Neuromuscular Disorders (pdf)