DMD: Sarepta to Submit New Drug Application to FDA for Eteplirsen in 2014

Drug may be eligible for the agency’s accelerated approval pathway if dystrophin levels are accepted as an endpoint; confirmatory trial also planned for 2014

Article Highlights:
  • Sarepta Therapeutics, developer of eteplirsen to treat Duchenne muscular dystrophy (DMD), was told by the U.S. Food and Drug Administration on July 23, 2013, that the agency would accept a new drug application from Sarepta for eteplirsen, but that it could not commit to reviewing the drug under the agency’s accelerated approval program at this time.
  • The accelerated approval program allows a surrogate endpoint, such as dystrophin levels in muscle biopsy samples, to substitute for an endpoint that reflects true clinical benefit, such as increased life span or improved function.
  • Sarepta says it will conduct a large-scale, confirmatory (phase 3) trial of etepliren in 2014 even if the FDA does not require one.
  • Eteplirsen is designed to treat DMD that is amenable to treatment by skipping exon 51 of the dystrophin gene. Sarepta plans to target exons 44, 45, 53 and 55 next.
by Margaret Wahl on July 24, 2013 - 8:48am

In a July 24, 2013, press release and conference call, biotechnology company Sarepta Therapeutics provided an update on the regulatory pathway for eteplirsen, the company’s experimental drug for Duchenne muscular dystrophy (DMD) caused by specific mutations in the dystrophin gene.

DMD: Exon-Skipping Timeline
Laboratory development of exon skipping began in the 1990s with significant funding from MDA.

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Sarepta CEO Chris Garabedian said the company will submit a new drug application (NDA) for eteplirsen to the U.S. Food and Drug Administration (FDA) in the first half of 2014, based on a July 23 meeting the company had with the agency.

However, Sarepta does not yet know whether eteplirsen will be eligible for the FDA’s accelerated approval program.

Accelerated approval allows a drug to be conditionally approved, based on a surrogate endpoint and pending results of a large-scale, confirmatory trial. A surrogate endpoint is a measurement that “stands in” for a clinical benefit and usually can be arrived at faster than a clinical benefit endpoint, such as an increase in life expectancy or improvements in function.

A possible surrogate endpoint for eteplirsen’s benefit is the level of the dystrophin protein present in the muscle biopsy samples of trial participants. (An absence of dystrophin protein is the underlying cause of DMD.)

Sarepta reports that the FDA would not commit to declaring dystrophin an acceptable surrogate endpoint prior to the company’s submission of an NDA for eteplirsen.

"We are very excited about this announcement,” said Jane Larkindale, MDA vice president of research. “By the end of 2014, we could have the first drug specifically for DMD approved by the FDA! This is an important step forward toward that goal. Importantly, although eteplirsen would only treat about 15 percent of boys with DMD, if approved it may open a pathway for more rapid approval of other drugs for DMD, both additional exon-skipping drugs and potentially other types of drugs."

She added, "MDA's advocacy team has supported the development of accelerated approval policy through the years, and we will continue to support its use in the development of drugs for our diseases.”

Possible next steps by FDA

After the FDA receives the new drug application from Sarepta, it may:

  • allow the company to market eteplirsen prior to conducting a confirmatory trial, with the stipulation that full approval will be contingent on the outcome of that trial (i.e., allow the company to use the accelerated approval pathway, with dystrophin level as a surrogate endpoint);
  • allow the company to market eteplirsen without conducting any additional trials (i.e., grant full approval for the drug); or
  • require additional information from current and future trials before allowing Sarepta to do any marketing of etepliren.

Phase 3 trial planned for 2014

During the July 24 conference call, Garabedian said Sarepta plans to conduct a large-scale, confirmatory (phase 3) trial of eteplirsen in 2014, regardless of whether the FDA requires such a trial for approval of the drug.

He said the company will need the data from this larger trial as it moves forward with its program of exon-skipping drugs for DMD that target additional dystrophin gene exons, including 44, 45, 53 and 55.

He also said Sarepta is considering enrolling patients with DMD who may benefit from skipping these other exons but would not be expected to benefit from skipping exon 51, to serve as a control group in the confirmatory eteplirsen trial. Normally, the control group would consist of participants who could benefit from skipping exon 51 but would be treated with a placebo.

Garabedian explained that enrolling participants who could not benefit from skipping exon 51 but who could potentially benefit from skipping other exons would:

  • provide a control group for the eteplirsen trial, since these participants would, in effect, be “untreated”;
  • allow all patients with dystrophin mutations amenable to exon-51 skipping to receive eteplirsen, rather than requiring some to receive a placebo; and
  • provide information about patients with mutations amenable to skipping exons 44, 45, 53 or 55, which are future targets for Sarepta’s DMD drug development program.

About eteplirsen

Etepirsen is an exon-skipping drug that targets a part of the dystrophin gene known as exon 51. In about 15 percent of boys with DMD, skipping exon 51 with a drug like eteplirsen theoretically should result in production of functional dystrophin.

For more information

The July 24, 2013, conference call will be available for replay at Events and Presentations on the Sarepta site.

To learn more, also read Exon Skipping in DMD: What Is It and Whom Can It Help? and A Snapshot View: Drisapersen and Eteplirsen, which provides information about the two exon-skipping drugs farthest along in development for Duchenne muscular dystrophy.

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