EMA DMD Workshop

25 Sep 2009

London, UK

"TREAT-NMD Workshop on the development of antisense oligonucleotide therapies for Duchenne Muscular Dystrophy"

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TREAT-NMD in collaboration with the parent advocacy groups, UPPMD, AFM, PPMD, MDA, the regulators FDA and EMA and the international neuromuscular community, organised a meeting at EMA headquarters in London on 25th September 2009, to discuss the issues surrounding the development of antisense oligonucleotide (AO) therapies for DMD. There were 40 active participants representing six countries and included scientists, clinicians, patient and pharmaceutical industry experts. Regulatory organisations present included the US Food and Drug Administration (FDA) and the European regulator, European Medicines Agency (EMA) who supplied members from their various committees including, Medicinal Products for Human Use (CHMP), Orphan Medicinal Products (COMP), Advanced Therapies (CAT) and the Paediatric Committee (PDCO). Also in attendance was a member from Comite Permanent des Medecins Europeens (CPME: Standing committee of European Doctors) representing the National Medical Association of 27 European countries.

The aim of the meeting was to gain both legislative guidance from the regulators and to identify an appropriate strategy for taking forward the AO therapeutic approach in a sensible time-frame for it to be a positive benefit for patients. There were several objectives:

  1. It was currently understood by TREAT-NMD partners that a minimum of 150 patients would be required to perform a clinical trial. Since DMD is a rare orphan disease can smaller patient cohorts be used in randomised controlled trials?
  2. The AO therapeutic approach is suitable to treat > 80% of DMD patients, but over 30 different AOs would be needed to treat the full range of mutations. Under current regulations each AO is classed as an individual medicinal product and thus must undergo safety and toxicology studies. After the safety evaluation of one/two AOs with a given chemistry in both animals and clinical trials, would it be acceptable to presume similar toxicity profiles for AOs with a different nucleotide sequence and go straight into man with the proviso of 2-4 week toxicity studies?
  3. Where double exon skipping is required, would additional trials need to be performed to test the combination over individual use?
  4. Advice was sort for the spectrum of clinical and biochemical outcome measures required to confirm patient benefit.

Data was also presented which educated the regulators in muscle disease mechanism, exon skipping methodology, current standards of care available and AO pharmacology, to aid the regulators in formulating appropriate guidelines. Similarly, the meeting opened with a parent of a DMD sufferer, who presented both the parent’s and the teenage patient’s perspective of day-to-day living with DMD. This contributed greatly towards the regulators understanding of the condition.

The meeting was heralded a success by all present and set a precedent for AO therapy to treat disease. The regulators expressed their recognition of the collective enthusiasm, praising the collaborative approach implemented to tackle this novel and challenging treatment programme. Moreover, they were clearly amenable to aiding future progress by suggesting frequent future meetings with them. Suggestions for influencing both the speed and safety of the therapeutic stratagem were made throughout the meeting and the take home messages for the way forward are summarised below:

  • The regulators recognised that it was necessary to perform randomised clinical trials with fewer than 150 patients where rare orphan diseases are concerned.
  • Representatives stipulated that both patients and their parents/carers should be consulted in the design of all aspects of future clinical trials since they are in the best position to know how their life can be improved.
  • Natural histories need to be revised and expanded to include neonates and non-ambulant boys.
  • A validated goal attainment scale is suggested for the outcome measures.
  • There is a need to identify the most appropriate surrogate marker (e.g. dystrophin) that illustrates functional benefit.
  • It is important to demonstrate that the resulting increase in dystrophin level achieves acceptable functional clinical benefit.
  • Disease stabilisation is an acceptable therapeutic option.
  • More safety and toxicology data are required on more than one AO with the same chemistry to allow extrapolation of data to other AOs.
  • AO therapeutic treatment in DMD represents first in child therefore the AO safety data must temporally the chronic treatment programme.

This meeting can be seen as the beginning of a long-term on-going liaison between the neuromuscular community and the EU and FDA regulators, so as to achieve a rational strategy for implementing AO therapy to DMD boys in a safe and timely manner.

The development of antisense oligonucleotide therapies for Duchenne muscular dystrophy: Report on a TREAT-NMD workshop hosted by the European Medicines Agency (EMA), on September 25th 2009
F. Muntoni , on behalf of the meeting steering committee, and of the TREAT-NMD Network
Neuromuscular Disorders 20 (2010) 355–362



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