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FDA Requests More Data on Muscular Dystrophy Drug Eteplirsen

Regulatory submission expected in mid-2015

Sarepta Therapeutics, Inc. has provided an update on its discussions with the FDA regarding its planned new drug application (NDA) submission for the approval of eteplirsen for the treatment of Duchenne muscular dystrophy (DMD).

In meeting minutes received from a pre-NDA meeting that took place in September 2014, the FDA provided updated guidance regarding the specific data to be included as part of, or at the time of, the NDA submission. The guidance states that the FDA requires additional data as part of the NDA submission, including the results from an independent assessment of dystrophin images and the 168-week data from a clinical trial (Study 202).

In addition, the guidance requests more-specific data, including the minimum duration of safety in new patients exposed to eteplirsen; patient-level natural history data, to be obtained from independent academic institutions; and magnetic resonance imaging (MRI) data from a recent study conducted by an independent academic group.

Based on these requests, Sarepta plans to submit an NDA by mid-2015, pending any additional requests for further discussions from the FDA.

Excerpts from the pre-NDA meeting minutes related to information that the FDA is requesting as part of an NDA submission included:

  • “The sponsor should include 3-month data from at least 12 to 24 newly exposed patients at the time the NDA is submitted.”
  • “Available data from the other patients enrolled in the new eteplirsen studies (Studies 301, 203, 204) should also be included at the time the NDA is submitted, even if exposure is less than 3 months in duration.”
  • “Additional data from later time points and from newly enrolled patients should be submitted in the 120-day safety update.
  • “The FDA strongly advises the sponsor to obtain and submit patient-level natural history data. The FDA is prepared to appeal to the academic groups holding the data to allow the sponsor a means to acquire the data.”
  • “The study 201/202 clinical-site inspection conducted in May, 2014, after the issuance of the April 15, 2014, guidance letter, uncovered marked disparities in the immunohistochemistry methodology and concerns about the reproducibility of the data. The lack of confirmation of robust dystrophin measurement during the site visit necessitates including the independent assessment of dystrophin-positive fibers and 168-week efficacy data from study 201/202 in the NDA.”
  • “The FDA strongly urges the sponsor to submit the MRI data with appropriate natural history controls.”

DMD is a rare, X-linked, degenerative neuromuscular disorder causing severe progressive muscle loss and premature death. The disease affects approximately 1 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.

Eteplirsen 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 phosphorodiamidate morpholino oligomer (PMO)-based chemistry and proprietary exon-skipping technology to skip mutations affecting exon 51 of the dystrophin gene. Approximately 13% of the total DMD population is amenable to exon 51 skipping. By skipping exon 51, eteplirsen may restore the gene’s ability to make a shorter, but still functional, form of dystrophin from messenger RNA. Promoting the synthesis of a truncated dystrophin protein is intended to stabilize or significantly slow the disease process and to prolong and improve the quality of life for patients with DMD.

Source: Sarepta Therapeutics; October 27, 2014.

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