Clinical trial readiness in nemaline myopathy

Number 250
Date 6 September 2019

Location: Hoofddorp, the Netherlands

Title: Clinical trial readiness in nemaline myopathy

Date: 6 - 8 September 2019

Organisers: Dr J. C. Bönnemann (USA), Prof. U. Schara (Germany), Prof. L. Servais (France), Dr C. Wallgren-Pettersson (Finland)

Translations of this report by:
Dutch by N. Voermans
Finnish by Dr. C. Wallgren-Pettersson
French by Ms M. Annoussamy
German by Prof. U. Schara
Italian by Dr G. Tasca

Participants: Ms M. Annoussamy (France), Prof. A. Beggs (USA), Dr C. Bönnemann (USA), Mrs. S. Colquhoun (UK), Prof. N. Darin (Sweden), Dr J. Doorduin (The Netherlands), Dr G. Dziewczapolski (USA), Dr T. Evangelista (France), Dr A. Ferreiro (France), Dr E. Michael (Sweden), Dr C. Moreno (Brazil), Dr F. Munell (Spain), Dr S. Neuhaus (USA), Mr. C. Park (UK), Dr A. Roos (Germany), Dr A. Sarkozy (UK), Prof. U. Schara (Germany), Prof. L. Servais (UK), Dr G. Tasca (Italy), Dr N. Voermans (The Netherlands) and Dr C. Wallgren-Pettersson (Finland)

Description of the workshop:

The 250th ENMC workshop entitled “Clinical trial readiness in nemaline myopathy” took place from the 6th to the 8th of September 2019 in Hoofddorp, The Netherlands. A multidisciplinary group of 21 persons from 10 countries (Brazil, Finland, France, Germany, Italy, Spain, Sweden, UK, The Netherlands and USA) attended the workshop, including 19 clinical and basic science researchers, and two patient representatives.


Nemaline myopathy (NM), or rod myopathy, is a rare pediatric neuromuscular disorder, characterised by genetic and clinical variability. Nemaline myopathy is most commonly caused by mutations in either the NEB gene, which determines the structure of a protein known as nebulin, or a mutation in the ACTA1 gene, encoding a protein known as skeletal alpha-actin. There are several other rare genes that are also known to cause nemaline myopathy.

Nemaline myopathy is characterised by, in its most classical form, a congenital onset, which may be severe, and a slowly progressive constellation of symptoms including hypotonia, bulbar weakness (meaning weakness of the face and swallowing muscles), muscle weakness affecting the arms and legs, as well as weakness of the respiratory musculature, leading to respiratory insufficiency which can, at times, be very severe.

Currently, there is no treatment for nemaline myopathy and the emergence of novel therapeutic approaches in the field, such as gene editing, has prompted a much-needed discussion between basic science researchers and clinicians regarding clinical trial readiness in the nemaline myopathy population.

Clinical testing of therapeutic approaches for nemaline myopathy can be challenging, as there are several known genetic causes and some of the underlying genetic mechanisms are still being determined.  To this end, the goal of this ENMC workshop was to discuss trial design and develop a well-planned and meaningful Natural History Study (NHS) approach, integrating practical outcome measures with the long-term goal of setting the stage for the nemaline myopathy patient population towards clinical trial readiness.

To ensure that NHS data can support future clinical trials, the design of the NHS should be aimed towards key clinical features typical of NM, which can be reproducibly obtained across multiple sites to maximize good use of the patients’ time and, importantly, encourage broad patient participation.  Outcome measures for nemaline myopathy were carefully considered in both the adult and pediatric populations and stratified according to the ambulant or non-ambulant status of the patient. Domains of importance to include are: motor/strength outcome measures, respiratory function measures, and bulbar (or swallowing) function measures.

In addition to careful natural history study design, it will be important for experts in the field to agree upon sharing any currently existing natural history data in order to identify key patient populations, which can later be targeted for therapeutic intervention at pivotal points in the disease course.  It will also be important for current experts in the field to share information about their current nemaline patient cohorts.

Moving forward, we will need to engage with local academic trial sponsors as well as potential commercial partners to assist in the support of international NHS efforts in nemaline myopathy.  It is also important to meet with the key regulators and payers, both in the USA and also in Europe, to ensure that decisions made along the translational pathway will forward the goal of obtaining meaningful natural history data that can be segued into future clinical trials.

The aim of the workshop:

  • Discuss patient cohorts in each country
  • Discuss Natural History viability in each country
  • Determine countries to participate in NHS
  • Determine which inclusion criteria will be most beneficial for NHS moving forward
  • Determine optimal mechanisms for funding across USA, European, Brazilian and Canadian medical centers
  • Increase collaboration worldwide
  • Build upon work carried out by others, e.g. share natural history data, learn from previous NHS in rare neuromuscular disease
  • Harmonise procedures across countries (e.g. outcome measures, registries)
  • Create a trial network and define rules of inclusion in Natural History, with the goal of being as inclusive as possible to allow for future technological advancements in therapeutics, enabling fairness to both common and more rare genetic mutations in nemaline myopathy alike.

Meeting participants shared their expertise in research on a range of clinically meaningful endpoints, specifically as they relate to pediatric and adult patients with nemaline myopathy.

The limited availability of natural history data through unified, validated outcome measures that can be reliably used to make decisions in clinical trials is one of the most significant barriers to drug discovery and development in neuromuscular disease, and also specifically for nemaline myopathy.

This ENMC workshop was dedicated to address this key gap by taking advantage of clinical and scientific expertise from neuromuscular physicians, academic scientists and patient representatives from around the world.

The consensus from the workshop was to meet this need through the establishment of a NHS network across several sites and expert medical centres across the USA, Canada, Brazil and Europe. This network would serve to develop NHS in each prospective location with the goal of sharing this data to inform future clinical trial design and patient treatment paradigms.

The following key deliverables were achieved:

  1. Harmonisation of disease classification/diagnosis clinically, genetically and pathologically
  2. Determination of formal inclusion criteria for natural history studies, for both pediatric and adult patients
  3. Consensus on outcome measures (motor, respiratory and bulbar function) for both pediatric and adult patients taking part in natural history studies across all sites
  4. Commitment to open sharing of data and samples together with lessons learned across the nemaline myopathy community, from patient advocacy group representatives
  5. Agreement to work in partnership with the USA, Canada, Brazil and Europe

Road map for the future:

Moving forward, the USA and Canada will have a plan in place for a collaborative natural history study data collection in nemaline myopathy, utilizing the Muscular Dystrophy Association (MDA) Network.  European countries, and also Brazil, will work to develop a similar framework for their NHS.

The Community is now significantly better prepared to initiate the development of natural history studies across continents, setting the community up for clinical trial readiness.

The members of the Steering Group for the Consortium have been appointed and progress will be reviewed within six months of this meeting.

A full report is published in Neuromuscular Disorders (PDF).