US grants accelerated approval for first Duchenne muscular dystrophy drug with Sarepta's Exondys 51

The FDA on Monday granted accelerated approval to Sarepta Therapeutics' Exondys 51 (eteplirsen), making it the first drug cleared in the US to treat patients with Duchenne muscular dystrophy (DMD), sending the company's shares up as much as 91 percent. Specifically, the once-weekly intravenous therapy is indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which the FDA said affects about 13 percent of the population with DMD. 

Sarepta interim CEO Edward Kaye said the approval "represents a major milestone in the treatment of DMD for patients amenable to skipping exon 51 by targeting the underlying genetic cause of the disease, the lack of the dystrophin protein." He added "we will continue to leverage what we have learned from Exondys 51 to facilitate future development of potential new treatments targeting additional exons."

According to Sarepta, Exondys 51 will cost an average of $300 000 a year, which the company noted was a net price based on the patient's weight. Kaye suggested that the price of the drug was "in the middle of the range" for rare disease treatments, noting that the drugmaker had factored in its research costs, as well as the expense of future drug trials. "Given the sensitivity to pricing we have tried to be what we think is very reasonable given all of the costs for this," Kaye added.

The FDA's decision goes against a controversial advisory panel recommendation earlier this year not to support approval for Exondys 51. Sarepta's application was based largely on data from a 12-patient Phase II trial showing that at three years of treatment, patients had slower disease progression compared with untreated matched historical controls, while the drug continued to be well-tolerated. However, members of the advisory panel in April voted 7-3, with three abstentions, that the study did not provide enough evidence of Exondys 51's efficacy (for related analysis, see ViewPoints: Sarepta's AdCom - plenty of emotion, not enough data). Prior to the vote, an FDA staff report had questioned the reliability of the study's findings.  

In June, Sarepta revealed that the FDA requested additional dystrophin data from biopsies obtained in an ongoing confirmatory study of Exondys 51. Meanwhile, the recent departure of an agency official said to have been critical of the drug fuelled speculation that it could be nearing approval.  

According to the FDA, its decision to grant accelerated approval was based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The agency said data submitted by Sarepta "demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients," but noted that the drug's clinical benefit, including improved motor function, has not been established. The FDA added that as part of the review process, it "considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy."

However, even once approval for Exondys 51 had been decided by Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research (CDER), the decision was challenged internally at the agency, prompting FDA commissioner Robert Califf to conduct a review in order to settle the dispute. Califf noted that it was "highly unusual" for a CDER director's decision to be appealed to the commissioner's office, but ultimately sided with Woodcock in the matter, saying this "unique situation" was unlikely to set a precedent for drug approvals. Meanwhile, Woodcook stated that "accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial that the company must conduct after approval." 

In July, the FDA declined a request by Santhera Pharmaceuticals seeking accelerated review of its investigational DMD therapy Raxone (idebenone). Previously, the agency issued a refuse-to-file letter to PTC Therapeutics for Translarna (ataluren) for the treatment of nonsense mutation DMD and also rejected BioMarin Pharmaceutical's filing for the DMD therapy Kyndrisa (drisapersen).

For related analysis, read ViewPoints: "Just this once" – FDA's decision to relent on Sarepta's Exondys 51 pleases DMD patients, but concerns drug safety advocates.

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