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    Controversy surrounds Exondys 51 approval: What to know


    Although only 22 novel drugs were approved in 2016—fewer than half the number the previous year, according to the FDA’s Center for Drug Evaluation and Research—one drug leaves a cloud of controversy behind it: Exondys 51 (eteplirsen) for Duchenne muscular dystrophy (DMD). The new medication, approved September 19, 2016, is for patients with a confirmed mutation of the dystrophin gene that is amenable to exon 51 skipping—13% of the population with DMD, according to the FDA.

    Despite a recommendation against approval from an independent advisory committee of scientists, the FDA granted the drug an accelerated approval based on a surrogate endpoint—whether Exondys 51 could increase dystrophin, a protein promoting skeletal muscular movement.

    The FDA determined that the application meets the requirements for accelerated approval based on the effect of the drug on the surrogate endpoint—increased dystrophin production in skeletal muscle observed in some eteplirsen-treated patients—which was concluded to be reasonably likely to predict clinical benefit. 

    “In appropriate situations, the agency exercises flexibility when evaluating treatments for serious and life-threatening conditions,” says an FDA spokesperson.

    The approval, however, comes with a provision—a follow-up trial from Sarepta Therapeutics, the drug’s manufacturer. It will be a two-year, randomized, double-blind controlled trial assessing motor function, in which two dose levels of eteplirsen—the approved dose of 30 mg/kg weekly and a significantly higher exposure—will be tested in patients with mutations amenable to exon 51 skipping. If the trial is unable to prove that clinical benefit, the FDA could withdraw approval.

    Criticisms and concerns

    The approval surprised many who claimed the research was flawed in studying just one genetic mutation in a small population of 12 boys. After three trials, the level of dystrophin in muscle biopsies improved by a median of only 0.1%, according to the FDA.


    The trials for Exondys 51 worry Kaiser Permanente, says Sameer Awsare, MD, associate executive director, Permanente Medical Group, because of the small number of participants; however, he realizes that DMD is a rare disease only affecting a small population.

    “We are not clear about the benefit of the drug,” he says, referring to the 0.1% increase in the amount of protein added to a patient’s system after taking the drug—the surrogate measure used to test the drug in trials.

    In addition, the six-minute walk test used to determine how far a patient with DMD can walk in that timeframe—a key tool in the trials—did not indicate any significant clinical difference after taking the drug—a reason he says the FDA did not approve Exondys 51 at first.

    “We are concerned when the FDA hesitates to approve a drug—whether the process could possibly be broken,” he says.

    Next: Formulary or not?


    Mari Edlin
    Mari Edlin is a frequent contributor to Managed Healthcare Executive. She is based in Sonoma, California.


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