Share this article on:

FDA: Why Eteplirsen is Not Ready for DMD

Rukovets, Olga

doi: 10.1097/01.NT.0000441297.36921.43
Back to Top | Article Outline


In a meeting with Sarepta Pharmaceuticals, the US Food and Drug Administration called an expedited approval request for the investigational Duchenne muscular dystrophy drug eteplirsen “premature,” causing the company's shares to plummet by more than 60 percent.

In October, reporting promising results from preliminary trials of investigational Duchenne muscular dystrophy (DMD) drug eteplirsen, Sarepta Therapeutics announced that it was moving forward on an expedited drug approval application. Last month, however, the U.S. Food and Drug Administration (FDA) cited new developments in DMD research which cast “considerable doubt” on the available data for eteplirsen, and called the new drug application (NDA) request “premature,” causing the company's shares to plummet by more than 60 percent.

Eteplirsen, an exon-skipping therapy, works to prevent the inclusion of the mutation-containing exon (exon 51) in the final messenger RNA in order to enable functional dystrophin production in boys with DMD and slow disease progression. So far, there have been two phase 2 trials of the drug. First, a double-blind, placebo-controlled, 24-week trial of twelve boys aged 7–13 years who were randomized to 30 mg/kg eteplirsen, 50 mg/kg eteplirsen, or placebo; then, an open-label extension study of the same participants (with placebo-treated patients initiating eteplirsen therapy).

The investigators, led by Jerry Mendell, MD, director of the Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital, presented the 96-week data from these 12 DMD patients at the 18th International Congress of the World Muscle Society in October. The therapy met its primary study endpoint — biochemical measures of dystrophin — and the medication was well tolerated, they reported. There were no clinical treatment-related adverse events. The 6-Minute Walk Test (6MWT) demonstrated that patients taking eteplirsen showed no decline in function for up to 96 weeks, representing an objective functional benefit of the drug. With these promising figures, Sarepta hoped to file for a new drug application in the first half of 2014.

But in September, a competing exon-skipping drug (drisapersen, manufactured by GlaxoSmithKline) for DMD announced its failure to meet primary endpoints on the 6MWT in a phase 3 study, despite an increased expression of dystrophin; thus calling the use of dystrophin as a biomarker into question. Before the FDA met with Sarepta last month to discuss its planned NDA filing and confirmatory clinical study, they wrote a pre-meeting memo, stating: “The disconnect between increased expression of dystrophin and clinical efficacy for drisapersen, combined with previous negative reports for PTC124, another drug thought to act by increasing dystrophin, raises considerable doubt about the biomarker, and consequentially, its ability to reasonably likely predict clinical benefit.”

The FDA also questioned the primary endpoints used in Sarepta's phase 2 studies, citing recent natural history data on DMD, which has indicated “that a baseline 6-Minute Walk Test (6MWT) ≥350 meters predicts continued general stability for such patients, not the 75- to 83-meter yearly decline you suggest in the meeting package.”

During the meeting with Sarepta, the FDA requested additional research on eteplirsen, with perhaps different clinical endpoints, combined endpoints, and different DMD subpopulations for a confirmatory clinical study. In a public conference call, Chris Garabedian, president and chief executive officer of Sarepta Therapeutics, expressed disappointment with the “FDA's decision to reconsider their openness to a potential NDA filing.” He said Sarepta still strongly believes in the eteplirsen's potential and remains committed to its development.

The FDA's requests will delay the initiation of dosing in the eteplirsen confirmatory study until at least the second quarter of 2014, Garabedian said. However, Sarepta is continuing to work with the FDA, and will be discussing the confirmatory study design in a scheduled follow-up meeting.

For its part, the FDA told Neurology Today that they “have heard from members of the public requesting an expedited review of AVI 4658 (eteplirsen).... Top FDA officials have met in person with family members to discuss their interests. We at the FDA recognize how devastating this disease is to patients and their families, as evidenced by the hundreds of letters submitted to the agency.”

The FDA spokesperson noted that although she was unable to share information about any application statuses of an unapproved drug, “please know that we will work diligently to review any request made to expedite its review.”



Back to Top | Article Outline


The vice president of research at the Muscular Dystrophy Association (MDA), Jane Larkindale, PhD, said in a press statement that the MDA shares the “community's disappointment” in the probable delay of the NDA filing for eteplirsen and in starting the confirmatory trial.

However, she stressed that this did not mean that eteplirsen was not an effective therapy, only that more efficacy data were needed to confirm the accuracy of the results. “We need to ensure we neither underestimate nor overestimate the effects of a new treatment,” Dr. Larkindale said.

Yadollah Harati, MD, chief of the Neuromuscular Section and professor of neurology at the Baylor College of Medicine, who was not involved in this research, said that he mostly agrees with the FDA's decision to delay NDA filing, and looks forward to more studies of the drug. “It appears that, unfortunately, replenishing dystrophin alone may not be sufficient enough to achieve a significant and meaningful improvement and retardation of the DMD progression,” he told Neurology Today.

There may be several “non-exclusive possibilities” for why “dystrophin expression has not been successful at predicting a clinical benefit as measured by the 6MWT,” said Thomas Crawford, MD, associate professor of neurology and pediatrics and co-director of the Muscular Dystrophy Association Clinic at Johns Hopkins University. “The dystrophin test itself may be flawed, the 6MWT test may not be a sensitive a measure as hoped, or the ‘sweet spot' for measuring benefit from that magnitude change in dystrophin doesn't match the ‘sweet spot’ for 6MWT assessment.”

Nevertheless, the delay in the approval of eteplirsen is disappointing for patients and clinicians alike, he said, and may lead to “cynicism about the project and its prospects for success.” But Dr. Crawford remains optimistic in the prospect for “meaningful intervention” for boys with DMD. “We don't know if the exon-skipping approach will work or not. But I do know that early trials often fail because investigators have difficulty getting the trials designed right.” We must learn from any mistakes, he added, “and I'm inclined to think those lessons are best learned on a therapy that, at best, was only going to be useful for a small minority of DMD patients (who at best were going to be raised to Becker MD levels of impairment).”

In rare disorders, added Dr. Crawford, “there is limited ability to test a drug post-marketing, and hence I'm inclined to think a placebo arm is essential...the need to get the key study right, the first (and maybe only) time increases that much more.”

The principal investigator on the two trials of eteplirsen, Dr. Mendell, professor of neurology, pediatrics, pathology, physiology and cell biology at Ohio State University, said that he never anticipated that the FDA would approve the NDA with efficacy data from only 12 patients. There was always an expectation, at least from the researchers, that a clinical trial with more patients would be required for approval.

“The FDA has scrutinized this data several times and never made a commitment that this was enough information to allow accelerated approval,” Dr. Mendell pointed out. The FDA said they would look at these data and consider the possibility, he said, adding that he would have been “very surprised” if the drug were approved based on this trial with a sample size of 12 participants.

Dr. Mendell noted that he believes the FDA was influenced by the results from the phase 3 trial of drisapersen, “which raises the question of why the GlaxoSmithKline result was different.” Still, he said, there have been single-site studies in the Netherlands and in the UK where “exon-skipping produced results more like ours suggesting that exon skipping does produce benefit.”

The next step now, Dr. Mendell said, is most likely a phase 3 multi-site study before approval. “When I spoke to Sarepta, this was in the planning stage and will probably take place in the near future,” but he said that he could not speak on behalf of the company.

Back to Top | Article Outline


•. Press release on eteplirsen by Sarepta Pharmaceuticals:
    •. Overview of 96-week trial data for eteplirsen:
      •. Neurology Today archive on exon-skipping therapies for Duchenne muscular dystrophy:
        © 2013 American Academy of Neurology