Rare Disease Drug Approval Sparks Controversy

New hope for a devastating disease? Dangerous precedent for the FDA? Reactions are polarized to the approval of the new Duchenne muscular dystrophy drug, Exondys 51. Some believe the FDA lowered its standards and caved to pressure from advocacy groups to approve an expensive drug that lacks convincing efficacy data. Others argue that a more flexible approach is essential for rare diseases that affect children and have few other hopeful avenues for treatment. This particular case exemplifies some of the challenges facing rare disease drug development and should be followed closely by the Rett Syndrome community.

The Disease

Duchenne muscular dystrophy (DMD) is a rare disorder that affects approximately 1 in 3,600 to 6,000 males in the US and has no effective treatment or cure. Mutation of the dystrophin gene prevents production of a muscle-stabilizing protein, causing progressive muscle deterioration beginning in childhood and ultimately leading to early death. This gene is on the X chromosome like MECP2, but unlike Rett Syndrome DMD is recessive. Girls who have a functional copy of the DMD gene along with a mutated one are spared from symptoms whereas in Rett the functional copy of MECP2 does not protect them from symptoms.

The Drug

Exondys 51 (eteplirsen) uses a mechanism called exon skipping. It is only effective in the 13% of individuals with DMD who have exon 51 deletions because it works by “skipping” over this missing portion of the gene to reinstate production of functional dystrophin protein. Administered once a week by intravenous infusion, it will cost $300,000 a year for each patient.

The Study

Sarepta Therapeutics conducted a clinical trial for Exondys a few years ago involving 12 children. 8 of the patients were randomized to 2 doses of the drug and 4 took placebo but later received the drug. The results were published in the journal Annals of Neurology in 2013, where the authors reported an increase in dystrophin protein levels from muscle biopsies and improved performance on a measure of mobility called the 6-minute walk test.

Evaluating Efficacy

Does the drug help the condition? Does the drug have harmful effects? Answering these important questions is difficult because the number of participants was so few, the treatment period was short, and there was no placebo arm (all participants eventually received drug). It’s also important to keep in mind that Exondys is only appropriate for 13% of people with DMD.

In addition, an inspection by the FDA at the study site in 2013 revealed issues with the analysis methods and indicated that the supposed benefits of Exondys were much less significant than reported. Concerns have been so great that some have called for the paper to be retracted, including the FDA commissioner himself in the report released along with the approval. While parents say anecdotally that the drug helps, the scientific evidence is questionable.

Public Advocacy & Internal Lobbying

Advocacy both external and internal to the FDA has played a crucial role in this story. An emotional public hearing was held in April where patients, family members, scientists and others presented their views on the drug (almost all were in favor of approval). Despite these moving testimonies, the FDA advisory committee voted 7 to 6 not to approve the drug based on the scientific evidence.

What saved Exondys from failure was the unwavering support of Dr. Janet Woodcock, the FDA’s head of Center for Drug Evaluation and Research. She believed that the particulars of the case called for leniency with respect to the efficacy data and lobbied for its approval. In particular, she felt that DMD had no other treatment options and that Sarepta did not have the funding to continue otherwise and “needed to be capitalized”. Ultimately she approved Exondys in spite of the advisory committee’s recommendation.

The Controversy

Documents released along with the approval reveal heated debate amongst FDA officials about how the process was handled. In August, the FDA acting chief scientist wrote a memo to the FDA commissioner Dr. Robert Califf expressing concerns about the process. Califf himself, though he ultimately deferred decision on the drug to Woodcock, expressed his view in a lengthy report that the scientific evidence for the efficacy of the drug was lacking and said that retraction of the paper in which the results of the study were published may be appropriate.

Several experts have since publically expressed their disapproval with the Exondys decision. In speaking about drug regulation for orphan diseases at a recent summit, the FDA’s director of the Office of New Drugs said that the path taken by Sarpeta for Exondys was “not a good model for other development programs”.

A scathing Journal of the American Medical Association editorial written by two Harvard physicians in October outlined the reasons why the FDA’s handling of Exondys was troubling, calling it a “worrisome model”.

Financial Considerations

The financial profit associated with an expensive designer drug like Exondys is substantial at $300,000 per year per patient. Following the approval announcement, Sarepta shares increased by more than 90%. Advocates argue, why not approve the drug when it doesn’t seem to cause harm and may benefit patients? Indeed, individuals with DMD have little to lose and everything to gain. But critics like the FDA director of the Office of Drug Evaluation point out that a drug like Exondys represents “significant and unjustified financial costs – if not to patients, to society.”

Scientific Standards

Dr. Janet Woodcock argued that we “must be flexible with respect to a devastating illness with no treatment options”. Rare, debilitating diseases like DMD (and Rett Syndrome) may mean fewer available participants, a shorter time window for treatment, unwillingness to receive placebo, and an overall urgency to expedite the drug approval process.

How can the FDA keep scientific standards rigorous while at the same time understanding that clinical trials for rare childhood disorders may need to be more flexible in some ways? What should the role of patients and their families be in the drug development process? These are questions that will need to be answered.


Although Exondys 51 has been approved by the FDA, this is not the end of the story. Sarepta Therapeutics will need to show more efficacy data or else the drug may be pulled from the market. Time will tell if this story sets a precedent for future rare disease drugs or if it is an exception to the rule.