Facing Disappointment from FDA's Eteplirsen Response

By now many of you may have heard the news that the FDA has called the new drug application for the exon 51 skipping drug eteplirsen premature.  They have requested instead that a larger phase III study be conducted before they will consider the application for approval.  PPMD, which provided travel support to families who participated in the trial, is deeply disappointed in this decision, but hopeful that the FDA will provide clear guidance in the near future on the quantity and quality of data that is required for it to consider an accelerated approval or an application based on phase II data.  Although accelerated approval and phase II approvals are possible, they are not common. 


In the meantime, we will continue to do everything in our power to encourage the FDA to be flexible in its review of rare and progressive diseases like Duchenne and to decrease the time and cost of conducting those trials for Sarepta and other companies engaged in or considering trials, including Halo Therapeutics, Prosensa, Eli Lilly, Pfizer, Catabasis, Reveragen, Summit PLC and PTC Therapeutics.   Sarepta has indicated in the attached release that they will likely launch their planned phase III, in consultation with the FDA, in the second quarter of 2014.


There are no words to describe the disappointment, frustration, and anger being felt in our community today. But it is important to remember that there is still progress being made and companies like Sarepta don’t stop fighting. And we won’t stop supporting them. PPMD still believes in the potential of eteplirsen.


With our upcoming Policy Forum in December, we hope you will Share Your Story with the FDA and let them know how you feel. We need to continue to put faces to this data and we need to continue to share our stories.


PPMD has been in the trenches with you for almost twenty years and we will continue to fight with you for every person living with Duchenne and for every future diagnosis. Remember that Duchenne is the enemy. This is a community of strength, hope, and one that when united, can do anything.


Sarepta Therapeutics Announces FDA Considers NDA Filing for Eteplirsen Premature in Light of Recent Competitive Drug Failure and Recent DMD Natural History Data

FDA Questions Dystrophin as a Biomarker Due to Failed Studies of Other Investigational Drugs for DMD; FDA Questions 6-Minute Walk Test Results for Eteplirsen, Suggesting Study Population Should Be Stable Over Two-Year Timeframe Due to Recent Natural History Data; FDA Requests Further Discussion on Endpoints, Design of Confirmatory Clinical Study

CAMBRIDGE, MA -- (Marketwired) -- 11/12/13 -- Sarepta Therapeutics, Inc. (NASDAQ: SRPT) today provided an update on its discussions with the U.S. Food and Drug Administration (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 Sarepta's last meeting with the agency, including a failed study with a competitive product and recent natural history data in DMD, the FDA indicated 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."

"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 chief executive officer of Sarepta Therapeutics. "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."

The FDA provided the feedback in pre-meeting comments and clarified them in a meeting with Sarepta that took place late last week to discuss the eteplirsen clinical program.

Excerpts from the FDA's pre-meeting comments on reconsidering an NDA filing included:

"Since our last meeting, a large phase 3 trial of drisapersen, a drug with a similar mechanism of action, 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."

"...the quantity of dystrophin that might be necessary to be considered reasonably likely to predict clinical benefit is even less clear; small or perhaps even moderate increases are seemingly not enough, at least in the subpopulation of boys studied so far. An adequately validated quantitative assay for dystrophin now seems a prerequisite to further consideration of the biomarker as supportive of approval. Since our last meeting, our concern about the shortcomings of your current quantification methods has grown."

"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 m for all patients."

"...the expected variability of 6MWT values appears sufficient to explain differences between arms on which the post-hoc analysis was based. Because of this, together with our lack of confidence in the capacity of your dystrophin biomarker to predict clinical benefit, we currently consider an NDA filing for eteplirsen as premature."

Additional excerpts from the FDA's pre-meeting comments on the eteplirsen confirmatory study design included:

"Recent trial failures in DMD suggest it may be productive to re-examine study enrollment criteria and endpoints."

"...it seems worthwhile to consider selection of other endpoints and/or populations for the next trial of eteplirsen. We stress that we would still accept 6MWT in an appropriately powered study; however, because 6MWT excludes both younger boys who cannot perform such a demanding test, and older boys who are no longer ambulatory, we are concerned that seemingly avoidable limitations on enrollment could undermine study feasibility. Many possible combinations of endpoints and subpopulations appear possible. Motor scales that measure a broader range of function and demand less sustained effort than 6MWT could be appropriate for a much wider range of boys, perhaps including non-ambulatory boys. To allow inclusion of a broader range of patients, a study could also be designed that mathematically combined findings from, for example, an ambulation endpoint in less advanced patients with findings from an upper-limb or respiratory endpoint in more advanced patients. We remain open to consideration of endpoints and populations you may suggest."

"...we believe that a placebo-controlled trial would be the most likely method for developing interpretable evidence of efficacy for eteplirsen, because efficacy endpoints in DMD are effort-dependent and susceptible to bias, and the natural history is highly variable and has recently improved with steroid use and advances in ancillary care. We would like to discuss the perceived barriers to conducting such a trial with you."

The FDA's request to discuss different clinical endpoints, combined endpoints, and different DMD subpopulations for a confirmatory clinical study, along with their questions about dystrophin as a biomarker and the need for a placebo-controlled study, will delay the initiation of dosing in the eteplirsen confirmatory study until at least the second quarter of 2014. A follow up meeting with FDAhas been scheduled to take place this month to discuss the confirmatory study design.

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Comment by David on November 12, 2013 at 8:29pm
I am truly embarrassed to be an American. this is unbelievable

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