By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved the first drug to treat patients with Duchenne muscular dystrophy (DMD). Eteplirsen, an antisense oligonucleotide, was granted fast-track and orphan designations and was approved under the accelerated approval pathway.1 This pathway provides earlier patient access while the sponsor conducts a clinical trial to confirm anticipated clinical benefit. Eteplirsen is marketed as Exondys 51.


Eteplirsen is indicated for the treatment of DMD in patients who present with confirmed mutation of the DMD gene that is amenable to exon 51 skipping.2


The recommended dose is 30 mg/kg once weekly.2 Eteplirsen is available as 100 mg (2 mL) and 500 mg (10 mL) single-dose vials.


Eteplirsen is the first FDA-approved drug for DMD.


The clinical benefit of eteplirsen has not been established. The most frequent adverse events were balance disorder (38%), vomiting (38%), and contact dermatitis (25%).2


DMD is caused by deletion in the dystrophin mRNA reading frame, leading to lack of expression of dystrophin protein, important in keeping the muscle cell intact. Eteplirsen is a 30-nucleotide-long phosphorodiamidate morpholino oligomer that induces skipping of exon 51 in DMD pre-mRNA by selectively binding to the exon of dystrophin pre-mRNA, restoring the open reading frame. This results in expression of a less functional (truncated) dystrophin. Eteplirsen was evaluated in three clinical studies in patients with confirmed mutation of the DMD gene that was amenable to exon 51 skipping. Study one randomized 12 subjects (four each) to eteplirsen 30 mg/kg, 50 mg/kg, or placebo for 24 weeks. The primary endpoint was an increase in dystrophin production and the six-minute walk test. After 24 weeks, there were no significant differences in placebo or either treatment arm. Study two included all 12 subjects from study one and continued for an additional four years. Four subjects previously on placebo in study one were randomized to 30 mg/kg or 50 mg/kg in study two. The primary endpoint was the six-minute walk test. No significant difference was demonstrated between treated subjects compared to an external control. Improvement in dystrophin levels was difficult to assess due to insufficient baseline levels (muscle biopsy) from study one. In study three, 12 subjects with baseline muscle biopsies were treated for 48 weeks at 30 mg/kg. The pre-treatment level of dystrophin was 0.16% ± 0.12% of that in a healthy subject compared to 0.44% ± 0.43% after treatment. Only one subject experienced an increase > 1% of that in a healthy subject. This represented a statistically significant increase of 0.28% but is not thought to be clinically meaningful. It is believed that 10% is needed to be a clinically meaningful level.3


DMD is an X-linked recessive neuromuscular disorder, resulting in the absence or near-absence of dystrophin protein in the muscle cells. This leads to muscle damage, loss of physical function, and ultimately premature death due to respiratory and/or cardiac failure. Eteplirsen has been shown to marginally improve dystrophin levels, albeit as a less functional version, but only in those patients with a mutation amenable to exon 51 skipping (approximately 13% of all DMD patients). Clinical benefit has not been demonstrated. There was much debate whether there was sufficient efficacy evidence to support FDA approval based on dystrophin levels. In addition, there were concerns about flaws in the sponsor’s program, including poor quality of many of the biopsies.3 The results of study two were published, but after further FDA review, the improvement in dystrophin levels were considered to be “greatly overstated.”3,4 The FDA advisory committee voted against approval; however, the FDA appeared to acquiesce to public pressure and granted an accelerated approval. The sponsor currently is recruiting for a 48-week confirmatory study with the six-minute walk test as the primary endpoint and percent of dystrophin positive fibers and maximum inspiratory/expiratory pressure percent predicted as secondary endpoints.5 The cost for eteplirsen is $480 per 30 mg. This translates to $15,840 per week for a 33 kg patients and $24,000 per week for a 50 kg patient, or $823,680-$1,248,000 per year.


  1. FDA News Release. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. Available at: Accessed Oct. 27, 2016.
  2. Exondys 51 Prescribing information. Sarepta Therapeutics. September 2016.
  3. FDA. Scientific dispute regarding accelerated approval of Sarepta Therapeutics’ eteplirsen — commissioner’s decision. Available at: Accessed Oct. 28, 2016.
  4. Mendell JR, Goemans N, Lowes LP, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol 2016;79:257-271.
  5. Confirmatory study of eteplirsen in DMD patients (PROMOVI). Available at: Accessed Oct. 28, 2016.