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New Trials Will Assess Muscle Disorder Drug After FDA Criticism

Agency says previous data may not support approval of eteplirsen

Sarepta Therapeutics, Inc. has announced that it plans to submit a new drug application (NDA) to the FDA by the end of 2014 for the approval of eteplirsen for the treatment of Duchenne muscular dystrophy (DMD).

Eteplirsen is an exon-skipping drug candidate in development for the treatment of patients with DMD who have a genotype amenable to skipping of exon 51.

The plan to submit an NDA for eteplirsen by the end of 2014 is based on a guidance letter from the FDA that proposed a strategy regarding the submission of an NDA for eteplirsen under a potential accelerated approval pathway. The agency stated that “with additional data to support the efficacy and safety of eteplirsen for the treatment of DMD, an NDA should be fileable,” and outlined examples of additional data and analyses that, if positive, will be important to enhance the acceptability of an NDA filing by addressing areas of ongoing concern in the existing dataset.

In addition, the FDA provided 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, which, like the open-label study, could also be considered an acceptable confirmatory study to verify the clinical benefit of eteplirsen in the event of an accelerated approval.

Sarepta plans to initiate several additional clinical studies with eteplirsen later this year in exon-51–amenable genotypes. These studies will include a clinical trial with predefined efficacy endpoints for ambulatory patients aged 7 to 16 years who can walk a minimum distance. Two additional clinical trials will evaluate safety and biomarkers in DMD patients younger than 7 years and in DMD patients who have advanced in their disease progression to a point where they cannot walk a minimum distance or have become non-ambulant. In addition, 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.

In its guidance letter, the FDA stated: “The clinical data from Study 201/202 [Phase IIb clinical trial program] on 6-minute walk could be considered a finding on an intermediate clinical endpoint that could have the potential to support accelerated approval.” Related to this first pathway to accelerated approval, the agency also noted that they have “significant concerns regarding our ability to draw valid conclusions based on the Study 201/202 data with respect to walking performance and other data,” and 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.

In its guidance letter, the FDA also commented: “We have discussed the possibility of using a number of modalities to quantify dystrophin in muscle biopsies, and [have] discussed how these biomarkers might be used as a surrogate endpoint(s) to support accelerated approval.” In evaluating this pathway, the FDA expressed concerns about methodologic problems in the assessments of dystrophin and “remain skeptical about the persuasiveness of the (dystrophin) data.” As a result, the agency is “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.”

Further, the FDA suggested that “another approach to demonstrating an effect of eteplirsen on dystrophin protein production would be to obtain a fourth muscle biopsy in patients who are continuing in Study 202,” which could serve to enhance the acceptability of an NDA filing and accelerated approval.

Under either potential application of the accelerated approval pathway, the FDA’s letter included comments expressing both a desire for more eteplirsen safety and efficacy data and a willingness to consider supplemental data in an NDA filing or during an NDA review (following the NDA filing) from the ongoing Study 202, and early safety and biomarker data from a confirmatory eteplirsen study. The agency also encouraged Sarepta to collect safety and biomarker data with eteplirsen in a broader population of patients, including DMD patients who were younger, older, and non-ambulant and previously treated with drisapersen.

Source: Sarepta Therapeutics; April 21, 2014.

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