Sarepta Therapeutics said today it plans to submit a New Drug Application (NDA) to the FDA by year’s end for eteplirsen for Duchenne muscular dystrophy (DMD)—one of two drugs seeking to become first to reach the market.

Sarepta said it will proceed on the basis of a guidance letter from the FDA. The agency concluded that “with additional data to support the efficacy and safety of eteplirsen for the treatment of DMD, an NDA should be fileable.” The letter also outlined examples of additional data and analysis that it said will, if positive, enhance the acceptability of an NDA filing by addressing areas of ongoing concern in existing data. 

The letter outlined two potential pathways to accelerated approval for eteplirsen, and served as the final meeting minutes for four meetings that took place between the agency and company between November 2013 and March 2014.

Under one pathway, data from the drug’s Phase IIb clinical trial statistically significant improvement in the 6 Minute Walking Distance (6MWD) could be considered a finding on an intermediate clinical endpoint that could have the potential to support accelerated approval. However, FDA added that it had “significant concerns” regarding Sarepta’s ability to draw valid conclusions based on Study 201/202 data on walking performance and other data. The agency also identified areas relating to the interpretation of the existing data set that will be addressed as part of an NDA review once the NDA is filed, Sarepta said.

Under the other pathway, FDA and Sarepta have discussed modalities of quantifying dystrophin in muscle biopsies, and how biomarkers might be used as one or more surrogate endpoints toward accelerated approval.

The agency added, though, that it was “uncertain whether the existing dystrophin biomarker data will be persuasive enough to serve as a surrogate endpoint that is reasonably likely to predict clinical benefit.” FDA proposed surmounting that hurdle through “a collaborative effort in which we will work to better understand the methods and analyses used for the existing biomarker data.” The agency also promised to work with Sarepta “on methods for the collection of additional data that could be more reliable,” the company added.

Sarepta says it will defer to FDA in deciding details of which pathway or pathways to pursue.

“We plan to compile additional data based on the FDA’s guidance with the goal of submitting an NDA for the accelerated approval of eteplirsen before the end of the year. It is up to the FDA to determine whether to review, and potentially approve, an NDA on the basis of a surrogate endpoint such as dystrophin or an intermediate clinical endpoint such as the 6-minute walk test,” Sarepta told GEN in a statement.

However, Sarepta did say it would launch three new Phase III clinical studies this year:

  • A clinical trial with predefined efficacy endpoints for ambulatory patients between the ages of 7 to 16 years who can walk a minimum distance,
  • A trial that will evaluate safety and biomarkers in DMD patients younger than 7 years
  • Another trial evaluating safety and biomarkers in DMD patients who have advanced in their disease progression to a point they cannot walk a minimum distance or have become nonambulant. 

Additionally, Sarepta plans to initiate a placebo-controlled study with one or more of its follow-on DMD exon-skipping drug candidates by the end of the year.

FDA also offered guidance on an open-label, historically controlled confirmatory study of eteplirsen, as well as initial guidance on a placebo-controlled study of one or more follow-on DMD drug candidates. Either could be considered an acceptable confirmatory study to verify the clinical benefit of eteplirsen under an accelerated approval, the agency told Sarepta.

“We are very pleased with the detailed guidance that the FDA has provided us on a potential eteplirsen approval pathway and their support of a historically controlled eteplirsen confirmatory study,” Chris Garabedian, Sarepta’s president and CEO, said in a statement. “We also appreciate that the FDA shares our urgency in dosing a broader base of eteplirsen patients and has encouraged us to begin the clinical program with our follow-on exon-skipping drugs as soon as possible.”

Eteplirsen is Sarepta’s lead exon-skipping drug candidate in development for the treatment of patients with DMD who have a genotype amenable to skipping of exon 51. In results from a Phase II study disclosed last year, boys who had taken eteplirsen showed a 6MWD improvement of 46.4 meters compared to placebo.

Exon-skipping is also the thinking behind the other Duchenne DMD drug in development, Prosensa’s Drisapersen (previously known as GSK2402968 and PRO051), an antisense oligonucleotide which induces exon skipping of exon 51.

Prosensa has promised to continue development of drisapersen after GlaxoSmithKline terminated its collaboration with the company late last year and returned rights to the drug following the failure of a Phase III trial.  That trial showed the drug offered no statistically significant improvement in the 6MWD test compared to placebo. Worse, there was no treatment difference in three key secondary assessments of motor function: a 10-meter walk/run test, a 4-stair climb and the North Star Ambulatory Assessment.

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