14th December 2011
A holiday message from the network co-ordinators

This is the final newsletter of TREAT-NMD as an EU-funded project*, and a time to look forward to the new phase of TREAT-NMD in 2012 and beyond. Our first newsletter of the New Year will be sent out on Wednesday 25th January.

In our capacity as the network’s coordinators for the five years of EU FP6 funding, we’d like to take this opportunity to thank all our partners, members and supporters from all different stakeholder groups across the world, including the many dedicated people who have provided their vision and support throughout the EU-funded project through its formal committees: the Science and Technology Advisory Council, the Global Database Oversight Committee, the Project Ethics Council, the TREAT-NMD Advisory Committee for Therapeutics, and the Governing Board. In our public consultation in 2010, ‘facilitating international collaborations between research groups’ was identified as the top achievement of the network by 91% of respondents, and it is thanks to the dedication of so many people across the world that we have exceeded the original scope of the EU project and taken great strides forward in the global collaboration that is essential to bring new therapies to patients. This collaboration has resulted in resources for the community ranging from patient registries and the care and trial site registry to biobanks and care standards, and from standard operating procedures for preclinical research to outcome measures for clinical trials. These resources are used by people in more than 140 countries via the TREAT-NMD website.

Although ongoing funding for the international collaboration has been difficult to find, much of this work is continuing thanks to project-specific funding, institutional support and the commitment of those involved and we hope it will attract further funding in the future.

We are moving into an important phase of consolidation. There are many outputs from the work of the network that need to be further developed and expanded. From 2012, the TREAT-NMD Alliance will be managed by an executive committee, the members of which will be elected from members of the academic Task Force and patient organisations. This executive committee will take on the coordinating role for the new TREAT-NMD and will continue to be supported by staff in the Newcastle office for communication and administrative management. We’re very grateful to the Task Force for overseeing this transitional period and guiding the future academic work of the network, and we look forward to informing you about the result of the elections early in the New Year.

This is also an interesting and busy time as far as grant opportunities are concerned, with several applications relating to neuromuscular diseases having successfully passed the first evaluation stage for the European Commission’s 2012 call for proposals in the health field. Projects include exploiting cutting-edge -omics technologies to drive forward new therapies and find the genetic causes for more undiagnosed neuromuscular and neurodegenerative diseases, applications for clinical trials and natural history studies in neuromuscular conditions, an infrastructure project for creating a global integrated platform connecting registries, biobanks and clinical bioinformatics for rare disease research, as well as proposals for knowledge sharing in clinical management. The result of these applications will be known in April 2012.

There are many exciting things happening in the neuromuscular field. We have learnt through leading the network that collaboration brings great results and can draw together consensus where none previously existed. Sometimes this means putting aside individual interests and it has been great to see this can happen. Collaboration and successful networking requires for us at times to be both selfish and altruistic which is an interesting balance! We would like to thank you all again for the privilege of coordinating such an exciting and dynamic network, which has been tremendously enjoyable despite the challenges, and to wish you all a Merry Christmas and all the best for 2012.

Katie and Volker

* TREAT-NMD was supported through Priority 1 (Life Sciences, Genomics and Biotechnology for Health) of the European Union's Sixth Framework Programme (FP6) under contract number LSHM-CT-2006-036825

Collaborative clinical outcome measures
consensus article published
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In September 2009 TREAT-NMD and EMA co-sponsored a workshop on the “Development of Antisense Oligonucleotide Therapies for Duchenne Muscular Dystrophy”. An ongoing priority highlighted at this meeting was the need to establish international consensus in developing age appropriate clinical outcome measures.

In response, an international consortium was established in late 2009 to work towards a data driven, international consensus defining the most appropriate clinical outcome measure as a function of age, to use in clinical trials in DMD.  

The group, comprising of 25 academic investigators, pharmaceutical sponsors, patient organisations and regulatory agencies involved in DMD therapeutics met for the first time in Washington DC USA on the 28th and 29th June 2010.  Data were presented from eight multicenter longitudinal datasets, representing nearly 1900 patients over a 20-year time period, confirming that it is feasible to use repeated evaluations performed at multiple sites to address several core issues in drug development for DMD. A meeting report has recently been published in Clinical Investigation.

The second meeting saw 26 participants from Europe and the US come together on the 10th and 11th July 2011, in Baltimore, MD to continue discussions and to build upon the work that was done at the first meeting. The full meeting report is available here.

The meetings were coordinated by Children’s National Medical Center and TREAT-NMD and supported by CureDuchenne, the Foundation to Eradicate Duchenne, Ryan’s Quest, Parent Project Muscular Dystrophy and MDA.

The group remains committed to working together on a number of collaborative projects and are preparing for the next, of what is planned to be an annual meeting. By continuing to collaborate we are confident that we can accomplish the goals set out and make a lasting impact in clinical trial research in DMD.

Final report from the NMD-chip project
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The EU-funded NMD-Chip project* formally finished in September 2011. The aim of the project was to design, develop and validate new sensitive high throughput DNA arrays to efficiently diagnose patients affected by NMDs. The tools originating from this project are designed to assess all known genes implied in a group of disease at one time, as well as to efficiently analyse chip data through optimised read-out bioinformatics tools, within 72hrs to one week. Besides the development of these new high-throughput molecular diagnostics tools, NMD-Chip also fosters knowledge of NMDs by accelerating the discovery of new disease-causing mutations using a candidate gene approach.

The scientific strategy was to design 4 types of chips, 2 for known NMD genes, and 2 for candidate genes. In each case, both CGH arrays to detect CNV (insertions or deletions), as well as Sequence Capture arrays for massive re-sequencing and point mutation detection, have been set up.

Today, at the end of the project, the two first generations of CGH NMD-chips including all the known genes have been validated, and it is proposed that they become part of the diagnostics workflow to progressively replace the current techniques. The capture chips have been compared with the "in-solution" capture tools that have emerged as an alternative solution during the past two years. Due to the rapid advances of technology, this part of the work has not been completely resolved and it is still unclear whether one approach is better than the other. The CGH chips have been validated on previously characterised DNA with several deletions or insertions in LAMA2, DYSF, CAPN, DMD, PMP22, COL6A genes and others. Several uncharacterised patients have been provided with a molecular diagnosis, thus making the project a success.

A full final report on the project is available via the “more” link below.

*NMD-CHIP was supported through FP7 under contract number 223026

TACT review update
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TACT evaluated three proposals at the review meeting held on 15-16th October 2011 in Lisbon, Portugal. The TACT reports with recommendations were sent to the applicants within 6 weeks following the meeting and the available corresponding non-confidential reports, approved by the applicants, have now been uploaded to the TACT webpage on the TREAT-NMD website.

Over the last 2 years TACT have reviewed 11 applications and has secured funding for at least the next three years. The next meeting will be held in the USA from 28-29 April 2012 and the deadline for applications is the 27th January 2012.

TACT evaluated three proposals at the review meeting held on 15-16th October 2011 in Lisbon, Portugal. These were:

1. Marc B. Blaustein, MPP, Halo Therapeutics, LLC
A randomised, double-blind, placebo-controlled, multiple-dose, dose-escalation study to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of HT-100 in patients with Duchenne muscular dystrophy.

2. Fabrizio Dolfi, PhD, NicOx SA
A 6-month multicenter, randomised, double-blind, placebo-controlled, Phase IIa proof of principle study of naproxcinod (HCT 3012) 750 mg bid in patients with Becker Muscular Dystrophy (BMD).

3. Chris N Airriess, PhD, California Stem Cell
Human Embryonic Stem Cell Derived Motor Neuron Progenitors for the Treatment of Motor Neuron Disease.

The TACT reports with recommendations were sent to the applicants within 6 weeks following the meeting and in some cases within 3 weeks. The available corresponding non-confidential reports, approved by the applicants, have now been uploaded to the TACT webpage on the TREAT-NMD website. Anyone interested in the full TACT report should contact the applicants directly.

To date TACT have held 4 review meetings in Europe and the US and have reviewed a total of 11 program applications from both academic investigators and industry in the following areas: DMD, BMD, SMA and CMD. Of the 11 compounds reviewed 7 were from industry and 4 were from academic applications; 4 were for novel compounds and 7 were for repurposed drugs; 8 were small molecules and 3 were biologics; 3 were preclinical stage applications and 8 were clinical stage applications. Therefore, after only 2 years, TACT believes that it is fulfilling its remit to be useful to many different groups at varying stages of the drug development pathway.

The TACT and the Secretariat would like to acknowledge gratefully the support received from PPMD, who have integrated the TACT review process into their own evaluation for funding process, kindly provided 50% of the costs for the two 2011 meetings and offered to continue funding in the next year. We would also like to thank the commitment from Children’s National Medical Centre, Foundation to Eradicate Duchenne and Cure Duchenne to help support future meetings, which is much appreciated and will allow the work of the TACT to continue for at least the next three years.

The next TACT review meeting will be held in Arlington, Virginia, USA on 28th - 29th April 2012. Anyone wishing to submit a proposal for this meeting should contact the TACT secretariat (emma.heslop@ncl.ac.uk) before 1st January 2012 in order to discuss this further. The deadline for applications is 27th January 2012.

Facing the challenges of clinical trials
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Two especially interesting and topical articles which review the current practice, challenges and some potential solutions for clinical trials have been published in the academic press in recent months. Writing in Muscle and Nerve, Robin Conwit and colleagues (Conwit et al., 2011) discuss problems facing clinical trials for neuromuscular diseases – such as the rarity and wide geographical distribution of patients.

Adding more muscle and nerve to clinical trials

Robin A. Conwit, MD, Minal J. Bhanushali, MD, John D. Porter, PhD, Petra Kaufmann, MD, MSc and Laurie Gutmann, MD

ABSTRACT: In this review we illustrate both the fundamentals and challenges of randomized clinical trials in neuromuscular disorders and suggest directions for prospective efforts to improve the design, conduct, rigor, and objectivity of these trials. Current research in clinical trials for neuromuscular disorders and key issues affecting these trials are reviewed. This perspective addresses the planning of clinical research, level of preclinical data needed to justify trials, patient recruitment and retention, and opportunities to access federal funding and infrastructure in support of clinical trials. The need for innovation in trial design and conduct, rigorous standards for the preclinical efficacy and safety data that support trial rationale, novel collaborative paradigms, objective interpretations of outcomes, and sharing of the lessons learned from trials in any one disorder among all neuromuscular trialists are imperative to improving the heretofore limited success in delivering novel, safe, and effective therapies to patients burdened by neuromuscular disorders.

Muscle Nerve 44: 695–702 (2011), doi: 10.1002/mus.22130

This material is reproduced with permission of John Wiley & Sons, Inc.

© 2009 Wiley Periodicals, Inc.

Meanwhile, Nature features a news article from Heidi Ledford (Ledford, 2011) which also discusses some of the challenges faced. She presents four particular strategies which some researchers, ‘have come up with to give clinical trials a better success rate.’

Translational research: 4 ways to fix the clinical trial

Heidi Ledford

Published online 28 September 2011, Nature 477, 526-528 (2011), doi:10.1038/477526a

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14th December 2011
TREAT-NMD newsletter - 14th December 2011