FDA has asked Sarepta Therapeutics for additional information about dystrophin production and safety before it will consider accepting an application for accelerated approval of its exon-skipping drug
The U.S. Food and Drug Administration (FDA) has said it will consider accepting an application for accelerated approval for eteplirsen, an experimental drug for Duchenne muscular dystrophy (DMD), after it reviews additional data from clinical trials of the drug.
The FDA has requested that Sarepta provide additional information from existing data on eteplirsen to help the agency make a decision on whether or not the data are sufficient for a new drug application (NDA) filing under the accelerated approval regulatory pathway.
This pathway allows the agency to approve a drug based on the use of a surrogate marker, a measurement that can stand in for accepted measurements of disease progression. Standard measures of a drug’s success (such as survival time or duration of walking ability) can take far longer to reach in a clinical trial than a surrogate measurement (such as dystrophin production) which can be shown more quickly. The accelerated approval pathway is designed for situations where time is critical for people with the disease.
The surrogate marker being proposed for eteplirsen is the percentage of fibers producing the dystrophin protein, which is missing in DMD. The FDA needs additional data to help it determine whether the dystrophin measurements, in conjunction with the clinical data (such as the distance a child walks in six minutes), are reasonably likely to predict clinical benefit.
"We are encouraged by our interactions with the FDA and their Division of Neurology Products, and we view their request for more data as a reflection of the thorough and comprehensive approach that the agency takes in evaluating a new surrogate marker," said Chris Garabedian, president and chief executive officer at Sarepta.
In an April 15 conference call, archived on the Sarepta website, Garabedian said he believes that a follow-up meeting with the FDA will be scheduled, if not completed, by the end of June 2013. At this meeting, the company expects to learn whether or not an accelerated approval application for eteplirsen can be submitted.
The accelerated approval mechanism was added to FDA regulations in 1992 for treatments for serious or life-threatening illnesses. It allows regulators to measure a drug's effect in a clinical trial by using a surrogate marker, or surrogate endpoint, rather than a true endpoint, which would take much more time to show.
Accelerated approval comes with the requirement that the company continue to study the drug post-approval to confirm its benefit and safety. However, patients can have access to the drug prior to completion of the post-approval studies.
Eteplirsen is an exon-skipping drug, delivered intravenously, that is designed to coax muscle cells to ignore, or "skip," exon 51 of the dystrophin gene. In people with DMD who have specific dystrophin gene mutations, it’s hoped that skipping exon 51 can allow production of a smaller-than-normal, but still functional, dystrophin protein.
The drug has shown continued benefit with respect to walking ability, via the six-minute walk test, 74 weeks after the start of a phase 2b, 12-person trial. Results related to dystrophin production have likewise been encouraging.
Garabedian said Sarepta hopes to start a phase 3 trial of eteplirsen in DMD early in 2014. If the accelerated approval mechanism is used, this phase 3, confirmatory trial will be necessary for additional, post-approval data gathering. If the accelerated approval mechanism is not acceptable to the FDA after it conducts its additional data review, then the phase 3 trial will be needed before the agency allows any type of approval for eteplirsen.
On April 11, Sarepta announced it had entered into a licensing agreement with the University of Western Australia — where MDA is supporting molecular biologist Steve Wilton for exon-skipping research — for intellectual property rights to the university's portfolio of exon-skipping drug candidates for DMD. The deal will allow Sarepta to develop additional exon-skipping drugs.
Discussions of exon skipping in general, as well as Sarepta's exon-skipping drug eteplirsen and the exon-skipping drug drisapersen (in development by other companies) will take place at the MDA Scientific Conference, to be held in Washington, D.C., April 21-24.
MDA's support of exon skipping
MDA has supported the development of exon skipping through its basic research program since the 1990s and continues to provide this type of support. In addition, the Association provided supplemental funding for a clinical trial of eteplirsen to neurologist Jerry Mendell at Nationwide Children's Hospital in Columbus, Ohio.
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