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Therapy Development for Myotonic Dystrophy

Charting a New Course

As potential therapies for myotonic dystrophy move out of the realm of the hypothetical and into clinical testing, there is an urgent need to better understand what will be required from a regulatory standpoint to approve new therapies for this disease. Significantly, the US Food and Drug Administration (FDA) requires that the primary endpoint selected to determine if a therapy is effective must be clinically meaningful to the population it is meant to help, and must be validated as a reliable and useful measurement. Also, clinical investigators must know enough about the inherent variability of the trial population to determine inclusion and exclusion criteria and to plan trials that will be statistically robust. Finally, biomarkers used to determine if the therapy is hitting target or having a clinical effect must be well validated and accepted by regulatory authorities.

For myotonic dystrophy, we have started gathering much of this data, but we know we are not there yet. Although the “six minute timed walk” (how far a person can walk in six minutes) has been used in other neuromuscular diseases as a primary outcome, including Duchenne muscular dystrophy, it is not clear that this is the best endpoint to use to measure the efficacy of drugs developed for myotonic dystrophy. Other possibilities include different timed function tests, such as how long it takes a person to stand up from a seated position and walk a certain distance, or “Patient-Reported Outcomes” (PROs) in which people answer questions about their wellbeing in many domains. The Myotonic Dystrophy Health Index (MDHI) survey instrument developed at the University of Rochester is an example of a myotonic dystrophy-specific PRO. Although timed function tests may be more objective than a PRO, the PRO may be more tightly tied to the concept of “clinical meaningfulness.” We need feedback from the FDA about what type of endpoint would be best received for myotonic dystrophy.

We also need the FDA to understand the nuances of a complicated multi-system disease like myotonic dystrophy, where cognitive issues and multi-generational care-taking may present challenges to trial designs. We need them to understand that people with myotonic dystrophy have identified muscle weakness and fatigue, followed by daytime sleepiness, as their most challenging symptoms—myotonia is lower on the list. And very importantly, we need the FDA to know what trade-offs between benefit and risk are acceptable to this population, so that they can make decisions about drug safety that accurately reflect the needs of the myotonic dystrophy community.

To this end, on September 17th, and in conjunction with the MDF Annual Conference in Washington DC, MDF is holding a regulatory workshop titled “Myotonic Dystrophy Patient-Centered Therapy Development.” Moderated by Dr. Steven Spielberg, former FDA Deputy Commissioner for Medical Products and Tobacco, the meeting will include speakers from academia, industry, the Food and Drug Administration and other federal agencies. The specific goals of this meeting are to:

  • understand the disease burden and benefit-risk preferences of the DM patient population;
  • explore myotonic dystrophy (DM) heterogeneity in the context of the development of meaningful and measurable DM clinical endpoints, biomarkers and clinical trial design; and
  • chart a path forward by identifying concrete next steps to fill gaps in knowledge or experience needed to speed the development of novel treatments for DM.

Representatives from at least three major pharmaceutical companies and several biotechnology companies engaged in drug development for myotonic dystrophy will attend the meeting. We hope that this daylong event will serve as the beginning of an ongoing conversation with the FDA and other regulatory agencies. The better we can define a regulatory path for this disease, the more willing industry will be to commit time and funds to develop treatments for it. The results of the meeting will be submitted for publication.

For more information contact Sharon Hesterlee at sharon.hesterlee@myotonic.org or Molly White at molly.white@myotonic.org.






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