Sarepta Therapeutics is a biopharmaceutical company focused on the discovery and development of unique RNA-targeted therapeutics for the treatment of rare, infectious, and other diseases.
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|Sarepta Therapeutics Announces Plans to Submit New Drug Application to FDA for Eteplirsen for the Treatment of Duchenne Muscular Dystrophy by Year End 2014|
-- Agreement reached with the Agency on eteplirsen open-label confirmatory studies with enrollment of a broader base of DMD patients later this year;
-- Company to hold teleconference at
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. 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 analysis that, if positive, will be important to enhance the acceptability of an NDA filing by addressing areas of ongoing concern in the existing dataset. Additionally, the Agency provided clear 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.
“As we announce our plan to submit an eteplirsen NDA by the end of 2014,
we are very pleased with the detailed guidance that the
Based on the Agency’s guidance, 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 between the ages of 7 to 16 years who can walk a minimum distance, and two additional clinical trials that will evaluate safety and biomarkers in DMD patients younger than 7 years and DMD patients who have advanced in their disease progression to a point they cannot walk a minimum distance or have become non-ambulant. 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.
“We are excited to have guidance from the
Sarepta plans to immediately take steps to initiate the additional eteplirsen clinical studies with the goal of beginning dosing in the confirmatory study in the third quarter, with dosing in the additional trials (i.e., younger and more advanced DMD patients) to begin later this year. Once available, detailed study eligibility criteria and clinical site information will be posted on www.ClinicalTrials.gov and Let’s Skip Ahead, an online resource center from Sarepta for the DMD community available at www.SkipAhead.com.
Excerpts from the FDA’s letter on an NDA filing included:
“…with additional data to support the efficacy and safety of eteplirsen for the treatment of DMD, described below, an NDA should be fileable (assuming other aspects of the submitted application meet applicable standards). As we are sure you appreciate, however, our willingness to consider an application for filing cannot be taken to suggest the outcome of our review. We also note that if the application is filed, you should expect public discussion of the NDA at an Advisory Committee meeting.”
“1. 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 stated 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.
“2. We have discussed the possibility of using a number of modalities to quantify dystrophin in muscle biopsies, and discussed how these biomarkers might be used as a surrogate endpoint(s) to support accelerated approval.”
In evaluating this pathway, the
Furthermore, the Agency 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.
Additional excerpts from the FDA’s letter on the eteplirsen and follow-on exon-skipping drug confirmatory studies:
“…any accelerated approval [of eteplirsen] would necessitate confirmatory studies to verify the clinical benefit. Confirmatory studies should be underway at the time of approval.”
“1. A historically-controlled trial might be acceptable to confirm clinical benefit following accelerated approval.”
“2. A randomized, placebo-controlled trial of another PMO [phosphorodiamidate morpholino oligomer] with a similar mechanism of action, directed at a different exon (e.g., SRP-4053 or SRP-4045), with a demonstration of a correlation between dystrophin production and definitive clinical benefit on 6-minute walk or another measure, could provide confirmatory evidence of eteplirsen’s clinical benefit if approval were based on a surrogate endpoint.”
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About Duchenne Muscular Dystrophy
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.
About the Accelerated Approval Regulatory Pathway
To speed the development and availability of new medicines for serious
and life-threatening diseases, the
For more information, please see “Accelerated Approval of New Drugs for
Serious or Life-Threatening Illnesses” (21
Looking Statements and Information
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forward-looking statements generally can be identified by the use of
words such as “believes or belief,” “anticipates,” “plans,” “expects,”
“will,” “intends,” “potential,” “possible,” “advance” and similar
expressions. These forward-looking statements include statements about
the timing of an NDA submission for eteplirsen in the treatment of DMD;
the potential filing and acceptance of an NDA for eteplirsen by the
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subject to risks and uncertainties that could cause actual results to
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