Making Sense of Antisense Oligonucleotide-Based Therapies in Muscular Dystrophies

23 April 2021

Good news for the Duchenne Muscular Dystrophy (DMD) community. On June 8th, BioMarin announced the filing of a Marketing Authorization Application to the European Medicines Agency for Drisapersen, an antisense-mediated exon 51-skipping compound able to target the most prevalent genetic mutations responsible for the lack of production of functional dystrophin. The European filing follows the submission of a New Drug Application to the US FDA for Drisapersen back in April 2015.

Normally, dystrophin bridges cytoskeletal proteins to extracellular matrix and stabilises muscle fibres during contraction. The lack of its production in DMD leads to muscle damage, progressive muscle wasting, severe disability and premature death between the second and third decades due to cardiac or respiratory failure.

Given the lack of available specific treatments for this life-threatening disease, the regulatory filing of a new treatment raises expectations for longer life expectancy and better quality of life for patients. Furthermore, an approval in this group of rare diseases will undoubtedly represent a massive boost to ongoing scientific efforts by BioMarin and other pharma companies developing similar compounds.

Clinical development in rare diseases poses unique challenges for all stakeholders: patients, families, investigators, sponsors and regulatory authorities. These challenges include having to habilitate inexperienced clinics to conduct the trials, establishing strong connections with advocacy groups, and meeting enrollment timelines in the face of competition from other studies, while ensuring the safe conduct and integrity of the study. Research organizations that have a track record of success in delivering on rare disorder studies have developed dynamic, flexible and proactive project teams who display a highly collaborative attitude toward participating sites and patient advocacy groups. Networking is crucial for research in the rare disease field and the implementation of the European Concerted Research Action back in 2012 (COST Action BM1207, is a significant step forward to facilitate the development of new exon-skipping drugs.

DMD is an exceptionally rare disease which affects approximately 1:5000 male births. To complicate things even further, the two most advanced antisense oligonucleotide compounds aiming at restoring dystrophin expression (Drisapersen, BioMarin; and Eteplirsen, Sarepta) target genetic mutations which are only present in about 13% of subjects with DMD (1). If the treatments being developed are successful, future clinical development programs will likely target even less prevalent mutations, narrowing down the number of eligible subjects for clinical trials and making the use of placebo-controlled studies difficult in the development of new therapies. It is therefore necessary that new regulatory models and drug development paradigms be developed to ensure the practicality of exon-skipping development programs for small or ultra-small subset of patients.

It is encouraging that the regulatory environment is also evolving for the development of new drugs for this and other rare diseases. A significant milestone was achieved in February 2013 when the European Medicines Agency released the first draft Guideline on the Clinical Investigation of Medicinal Products for the Treatment of Duchenne Muscular Dystrophy (link to PDF). The document suggests that alternative study designs for confirmatory trials might be considered. Similarly, the US-FDA recently released a draft guideline on DMD (Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment, Guidance for Industry, June 2015 (link to PDF), which explicitly raises the potential use and acceptability of external controls in DMD clinical trials.

In the near future, and in close collaboration with regulatory bodies and patient advocacy groups, we envision the implementation of registration studies using data from contemporaneous subject cohorts who have received similar standards of care as those subjects in the trial. Several natural history studies are ongoing at the moment to support these efforts, some of them designed for and funded by Pharma Companies working on exon skipping candidates. Research on primary outcome measures is evolving along the same lines. Studies aiming to establish whether patients with distinct groups of mutations have different profiles of changes on the 6-Minute Walk Test (6MWT) (2)(3)(4) and the North Star Ambulatory Assessment Test (NSAA) (5) have been recently published. Their results seem to support the design of clinical trials with small numbers of eligible patients.  In addition, we believe that successful recruitment of low-prevalence, mutation-specific patient populations will likely benefit from a thorough analysis of proprietary databases integrating investigator-performance metrics and central laboratory results from genetic testing.

This is an encouraging time for patients with DMD and their families, and we are lucky to be participants in this extraordinarily fast-moving field of treatment development in rare diseases

Dr. Jesus Garcia-Segovia is Senior Medical Director within the Neuroscience Group for our Medical and Scientific Services and member of the Expert Working Group on Oligonucleotide-based Therapeutics

  • Annemieke Aartsma-Rus et al. Theoretic Applicability of Antisense-Mediated Exon Skipping for Duchenne Muscular Dystrophy Mutations. Hum Mutat 30, 293–299, 2009.
  • Pane M, Mazzone ES, Sormani MP, Messina S, Vita GL, et al. (2014) 6 Minute Walk Test in Duchenne MD Patients with Different Mutations: 12 Month Changes. PLoS ONE 9(1): e83400. doi:10.1371/journal.pone.0083400
  • Mazzone ES, Pane M, Sormani MP, Scalise R, Berardinelli A, et al. (2013) 24 Month Longitudinal Data in Ambulant Boys with Duchenne Muscular Dystrophy. PLoS ONE 8(1): e52512. doi:10.1371/journal.pone.0052512
  • Pane M, Mazzone ES, Sivo S, Sormani MP, Messina S, et al. (2014) Long Term Natural History Data in Ambulant Boys with Duchenne Muscular Dystrophy: 36-Month Changes. PLoS ONE 9(10): e108205. doi:10.1371/journal.pone.0108205
  • Ricotti V, Ridout DA, Pane M, et al. The North Star Ambulatory Assessment in Duchenne muscular dystrophy: considerations for the design of clinical trials. J Neurol Neurosurg Psychiatry Published Online First, March 2nd, 2015; doi:10.1136/jnnp-2014-309405