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Sarepta Moving Forward with Duchenne Confirmatory Trial Following FDA Guidance

APRIL 21, 2014
RDR Staff

Sarepta Therapeutics plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) by the end of this year for its drug eteplirsen to treat patients with Duchenne muscular dystrophy who have a genotype amenable to skipping of exon 51.

Last fall
, the FDA informed the company that the design of their phase2b study with eteplirsen would likely not good enough to be the confirmatory study needed to submit an NDA with accelerated approval and that the company needed to come back with an improved study design – preferable one with a placebo group.

After several meetings with the FDA, the company is now ready to move forward with its plans to create a clinical trial that the FDA will likely approve. In a press release, Sarepta stated, “The plan to submit an NDA for eteplirsen by the end of 2014 is based on a guidance letter from the Agency that proposed a strategy regarding the submission of an NDA for eteplirsen under a potential Accelerated Approval pathway and served as the final meeting minutes for four meetings that took place between November, 2013 and March, 2014.”

While details of the clinical trials are yet to be finalized, Sarepta did state their goal is to begin dosing patients for the confirmatory study in the third quarter of 2014, with dosing in the additional trials (i.e., younger and more advanced DMD patients) to begin later this year.

Study Design to Include Untreated Group, not a Placebo Group

During a conference call, Chris Garabedian, CEO and Dr. Ed Kay CMO of Sarepta provided some hints on the design of the confirmatory study.  The FDA originally suggested that the confirmatory trial be a placebo-controlled randomized clinical trial since none of the trials by Sarepta to date have had a comparator group. Finding a middle ground between the studies they have done in the past (small patient population with one treatment group, very impressive long term efficacy data) and the request from the FDA for a placebo controlled arm, the company plans to design a trial that has an untreated cohort arm. The cohort will be Duchenne boys with mutations that would not benefit from eteplirsen (i.e., exon 51 skipping treatment) but likely have a similar natural history. 

This trial design compromise makes ethical sense given that the drug in question is being tested at a time period when the boys are in rapid decline of their walking ability. To ask one of them who are eligible for the drug to not receive it and risk the loss of ambulation forever seems unnecessarily cruel.  At the same time, it is not 100% certain that the boys with the other mutations show the same decline in muscle function.  A bit of a gamble on Sarepta’s part but an understandable one.

Another major concern with creating a placebo-controlled arm, according to Mr Garabedian, is that design would delay the potential approval of the drug by several years and the company feels that the plethora of additional data they plan to submit to the FDA from their ongoing studies should be sufficient to show that the drug is safe and effective.

The confirmatory trial will enroll 60-80 patients with Duchenne muscular dystrophy who would benefit from exon 51 skipping treatment. Of those 60-80 boys, the primary endpoints will be limited to those boys who are ambulatory and able to walk 300-400 meters in the 6-minute walk test at baseline.  Other studies are also been planned to include younger patients as well as older boys who are no longer ambulatory.

During the conference call, Dr Kaye also noted that patients previously treated with Prosensa’s drisapersen - and who meet the inclusion criteria for the study - will also be eligible for the study.

About Duchenne Muscular Dystrophy  (From Sarepta’s press release)

DMD is an X-linked rare degenerative neuromuscular disorder causing severe progressive muscle loss and premature death. DMD affects approximately one in every 3,500 boys born worldwide. A devastating and incurable muscle-wasting disease, DMD is associated with specific errors in the gene that codes for dystrophin, a protein that plays a key structural role in muscle fiber function. Progressive muscle weakness in the lower limbs spreads to the arms, neck and other areas. Eventually, increasing difficulty in breathing due to respiratory muscle dysfunction requires ventilation support, and cardiac dysfunction can lead to heart failure. The condition is universally fatal, and death usually occurs before the age of 30.

About Eteplirsen and Sarepta’s Proprietary Exon-Skipping Platform Technology

Eteplirsen is Sarepta's lead drug candidate and is designed to address the underlying cause of DMD by enabling the production of a functional dystrophin protein. Data from clinical studies of eteplirsen in DMD patients have demonstrated a broadly favorable safety and tolerability profile and restoration of dystrophin protein expression.
Eteplirsen uses Sarepta's novel phosphorodiamidate morpholino oligomer (PMO)-based chemistry and proprietary exon-skipping technology to skip exon 51 of the dystrophin gene enabling the repair of specific genetic mutations that affect approximately 13 percent of the total DMD population. By skipping exon 51, eteplirsen may restore the gene's ability to make a shorter, but still functional, form of dystrophin from messenger RNA, or mRNA. Promoting the synthesis of a truncated dystrophin protein is intended to stabilize or significantly slow the disease process and prolong and improve the quality of life for patients with DMD.

Sarepta also has seven additional PMO-based exon-skipping drugs in earlier stages of development that are intended to treat other genetic sub-groups of DMD patients by skipping exons 53, 45, 50, 44, 52, 55 or 8. Overall, Sarepta’s current pipeline of exon-skipping drug candidates has the potential to treat nearly half of all patients with DMD. In addition, the company is committed to exploring the potential of its technology in the future to address all patients with DMD who may be candidates for an exon skipping therapy, even those with rare genetic mutations.

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