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FDA Says NDA Filing for Muscular Dystrophy Drug Eteplirsen Is ‘Premature’

Agency raises doubt about clinical trial (November 12)

Recently, Sarepta Therapeutics, Inc., a developer of RNA-based therapies, has been having discussions with the FDA regarding its planned New Drug Application (NDA) submission and confirmatory clinical study with eteplirsen for the treatment of Duchenne muscular dystrophy (DMD).

Citing recent developments since the company’s last meeting with the agency, including a failed study with a competitive product and recent natural history findings in DMD, the FDA has indicated that the new data raise “considerable doubt” about both the dystrophin biomarker and the supportive clinical efficacy assessed on the 6-minute walk test (6MWT) in the phase IIb clinical study of eteplirsen. As a result of these recent data, the FDA stated that they “currently consider an NDA filing for eteplirsen as premature.”

Eteplirsen uses phosphorodiamidate morpholino oligomer (PMO)-based chemistry and exon-skipping technology to skip exon 51 of the dystrophin gene, thereby facilitating the repair of specific genetic mutations that affect approximately 13% of the total DMD population.

Excerpts from the FDA’s comments on reconsidering an NDA filing included the following:

  • “Since our last meeting, a large phase III trial of drisapersen, a drug with a similar mechanism of action [to that of eteplirsen], was reported to be negative, despite increased expression of dystrophin. 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.”
  • “Recent natural history data in DMD indicate 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. Thus, considerable doubt is also cast on the efficacy support provided by your ongoing open-label study (4658-us-202, 96-week data submitted), in which baseline 6MWT was > 350 meters for all patients.”

Source: Sarepta Therapeutics; November 12, 2013.

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