FDA Says New Drug Application Filing for Eteplirsen is Premature

Sarepta Therapeutics says the U.S. Food and Drug Administration has changed its view of a possible accelerated approval pathway for Duchenne MD drug eteplirsen

The FDA isn't ready to pursue an accelerated approval for exon-skipping drug eteplirsen.
Article Highlights:
  • The FDA had previously said it might consider an accelerated approval pathway for eteplirsen, an experimental exon-skipping drug for Duchenne muscular dystrophy (DMD).
  • An accelerated approval pathway would have hastened the approval of eteplirsen, although a confirmatory study of the drug's safety and effectiveness after approval would still have been required.
  • The FDA says recent data about the natural history of DMD and data from other drug trials have cast doubt on the validity of two of the outcome measures relied upon in the eteplirsen trial: dystrophin protein levels and the six-minute walk test.
  • Sarepta says it remains committed to eteplirsen and will work with the FDA on a possible redesign of the confirmatory trial, while at the same time continuing to explore with the agency the possibility of moving the drug through an accelerated approval pathway.
  • MDA shares the community's disappointment that eteplirsen's regulatory pathway may be delayed.
by Margaret Wahl on November 12, 2013 - 2:46pm

Update (Dec. 10, 2013: Sarepta has posted webcasts of a presentation given Dec. 2, 2013, at a Deutsche Bank BioFEST conference; and of a presentation given Dec. 4, 2013, at a Piper Jaffray Healthcare conference. In those presentations, Chris Garabedian said the door on a possible accelerated approval pathway for eteplirsen is not completely shut. Discussions with the FDA about this and other matters related to eteplirsen are continuing.

The U.S. Food and Drug Administration (FDA) has changed its view of an early "new drug application" (NDA) for experimental Duchenne muscular dystrophy (DMD) drug eteplirsen, Sarepta Therapeutics announced today. This does not mean the drug does not work. However, it does mean that more testing is required before an NDA can go forward.

"We share the community's disappointment," said Jane Larkindale, MDA's vice president for research. "However, we understand the need for caution, and we support Sarepta's plan to follow the FDA's guidance, while moving forward as quickly as possible with eteplirsen and other drugs in the DMD pipeline."

In a Nov. 12, 2013, press release, the Cambridge, Mass., biotechnology company said the FDA now believes that consideration of eteplirsen under the agency's accelerated approval program would be premature.

In October, Sarepta announced it was on track to submit an accelerated approval application for eteplirsen to the FDA during the first half of 2014 and that it hoped to start a confirmatory trial of eteplirsen during the first quarter of 2014.

About eteplirsen

Eteplirsen's mechanism of action is exon skipping, and its target is exon (section) 51 of the dystrophin gene. Mutations in the dystrophin gene and a lack of the dystrophin protein underlie DMD. Eteplirsen is designed to restore production of a smaller-than-normal, yet still functional, dystrophin protein in patients with specific dystrophin gene mutations.

FDA concerns and requests

In its Nov. 12 press release, Sarepta reported that the FDA:

  • questions the use of dystrophin protein levels as a biomarker because of failed studies of other investigational drugs for DMD [presumably because dystrophin protein levels did not correlate with functional effects in these trials];
  • questions data from the "six-minute walk test," or 6MWT, a functional outcome measure relied upon in the eteplirsen phase 2b trial, noting that new natural history data for DMD show study participants would have had stable 6MWT results over a two-year time frame even without eteplirsen treatment; and
  • requests further discussion on the endpoints (outcome measures) and other aspects of the design of the forthcoming confirmatory trial of eteplirsen.

MDA's reaction

"We share the community's disappointment that there will be a probable delay in filing for approval of eteplirsen and in starting the confirmatory trial," said Jane Larkindale, MDA's vice president for research. "However, we want families to understand that the FDA is not saying that eteplirsen doesn't work. The agency is saying it wants to make sure that we are measuring any effects of eteplirsen accurately — which is important not just for this drug but for all drugs to come.

"We need to ensure that all clinical trials are done rigorously to ensure that we neither underestimate nor overestimate the effects of a new treatment," Larkindale said, noting that the FDA's decision reflects this important point. "MDA is committed to finding ways to measure treatment effects accurately."

MDA has been supporting the development of exon skipping for DMD since the 1990s. A current MDA grant to molecular biologist Steve Wilton at Murdoch (Australia) University may allow the strategy to be applied to a larger percentage of the DMD population.

Sarepta's reaction

"We are very disappointed with the FDA's decision to reconsider their openness to a potential NDA filing based on our current data and the resultant impact this change may have on our efforts to achieve an earlier approval of eteplirsen," said Chris Garabedian, president and CEO of Sarepta.

"We strongly believe in the potential of eteplirsen to address a serious unmet medical need in DMD, and we are committed to its development. Our team at Sarepta recognizes the urgency of families who are seeking new treatments, and we will continue to work with the FDA on an acceptable confirmatory study design and, in parallel, seek to address their concerns regarding a potential NDA filing based on our current dataset."

A Nov. 12 conference call featuring Garabedian and Ed Kaye, the company's chief medical officer, is available for replay on the company's website. The call may be accessed by dialing (888) 895-5271 in the U.S. or (847) 619-6547 outside the U.S. and entering passcode 35957586.

On the conference call, Garabedian said that Sarepta does not agree with the FDA's assessment of the eteplirsen trial data. "The 96-week data are not typical of what has been seen in natural history literature or clinical studies," he said. "We believe that eteplirsen is safe and effective based on our data."

Garabedian said Sarepta plans another meeting this month (November 2013) with the FDA but that the earliest a confirmatory study could start would now be the second quarter of 2014. The delay of the clinical trial and the request from the FDA to revisit enrollment criteria and endpoints, he noted, could push the timeline for approval of eteplirsen out two years or more.

"We will work diligently with the FDA to agree on the design of a confirmatory study and, in parallel, we will try to persuade them [concerning] an early filing strategy," Garabedian said. "We are not giving up on this."

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