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news.The US Food and Drug Administration’s (FDA) Peripheral and Central Nervous System Advisory Committee (PCNSC) met to review Sarepta Therapeutics' new drug application (NDA) for eteplirsen as a treatment for Duchenne muscular dystrophy amenable to exon 51 skipping.
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The advisory committee voted 6-7 against the finding of substantial evidence from adequate and well controlled studies that show that eteplirsen induces production of dystrophin to a level that is reasonably likely to predict clinical benefit.
The advisory committee voted 3 – 7, with three abstentions, against finding substantial evidence based on the clinical results of the single historically controlled study (Study 201/202) that eteplirsen is effective for treatment of DMD.
"We would like to thank the hundreds of patients and families who participated in the discussion today, underscoring the critical unmet need of people living with Duchenne." said Edward Kaye, M.D., Sarepta’s interim chief executive officer and chief medical officer.
"We appreciated the opportunity to present our data to the advisory committee panel and will continue to work with FDA as they complete their review of the eteplirsen NDA. Today more than ever, we remain committed to our mission of bringing a treatment to the Duchenne community."
DMD is a rare degenerative neuromuscular disorder causing severe progressive muscle loss and premature death. The FDA is not bound by the Advisory Committee’s recommendation but takes its advice into consideration when reviewing New Drug and Biologic License Applications in general. The Prescription Drug User Fee Act (PDUFA) action date for completion of FDA review of eteplirsen is May 26, 2016.
In three additional voting questions, the panel voted 5 to 7, with one abstention, against whether decisions to administer the 6-minute walk test (vs. conclusions that the patient could no longer walk) were sufficiently objective and free of bias and subjective decision-making by patients, their caregivers, and/or health care professionals to allow for a valid comparison between patients in Study201/202 and an external control group.
The panel voted on the impact of the North Star Ambulatory Assessment with one panel member voting that it strengthened the persuasiveness of the findings in Study 201/202, with five voting that it weakened the persuasiveness, and seven voting that it had no effect..
The panel also voted on the impact of the other tests of physical performance (e.g., rise time, 10-meter run/walk) on the persuasiveness of the findings in Study 201/202, with the result of one panel member voting that they strengthened the persuasiveness, two voting that they weakened the persuasiveness, and ten voting that they had no effect.
The PCNSC Advisory Committee recommendation was based on a review of results from the Phase IIb clinical program for eteplirsen (studies 201 and 202), long-term outcomes (through 168 weeks) from the Study 202 open-label extension study, as well as 4-year clinical effectiveness data based on a comparison of patients in Study 201/202 to a historical control group that was designated as a major amendment to the NDA in January 2016.
About the 6-Minute Walk Test (6MWT)
The 6MWT was developed as an integrated assessment of cardiac, respiratory, circulatory, and muscular capacity for use in clinical trials of various cardiac and pulmonary conditions. In recent years, the 6MWT has been adapted to evaluate functional capacity in neuromuscular diseases and has served as the basis for regulatory approval of a number of drugs for rare diseases, with mean changes in the 6MWT ranging from 28 to 44 meters.
Additionally, published data from longitudinal natural history studies assessing dystrophinopathy, a disease continuum comprised of DMD and Becker muscular dystrophy, support the utility of the 6MWT as a clinically meaningful endpoint in DMD. These data show that boys with DMD experience a significant decline in walking ability compared to healthy boys over one year, suggesting that slowing the loss of walking ability is a major treatment goal.
About Duchenne Muscular Dystrophy
DMD is an X-linked rare degenerative neuromuscular disorder causing severe progressive muscle loss and premature death. One of the most common fatal genetic disorders, DMD affects approximately one in every 3,500-5,000 males 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
Eteplirsen is designed to address the underlying cause of DMD by restoring the messenger RNA (mRNA) reading frame, thus enabling the production of a shorter, functional form of the dystrophin protein. Eteplirsen uses Sarepta’s proprietary phosphorodiamidate morpholine oligomer (PMO) chemistry and exon-skipping technology to skip exon 51 of the dystrophin gene. Approximately 13 percent of the DMD population is amenable to exon 51 skipping.
Data from clinical studies of eteplirsen in DMD patients have demonstrated a consistent safety and tolerability profile and have also shown measurable dystrophin protein expression. Promoting the synthesis of a shorter dystrophin protein is intended to slow the decline of ambulation and mobility seen in DMD patients. There currently is no approved treatment in the United States for DMD and eteplirsen has not been approved by the FDA or any regulatory authority for the treatment of DMD.