In the wake of a decision by Sarepta Therapeutics Inc to delay submission of a new drug application (NDA) for eteplirsen, its promising new experimental agent for Duchenne muscular dystrophy (DMD), until the middle of next year, the US Food and Drug Administration (FDA) has taken the unusual step of issuing a statement explaining its position.
According to Sarepta, the delay in seeking drug approval is necessary to accommodate inclusion of additional data requested by the FDA. However, the delay is raising concerns among patients and clinicians who were anticipating the drug application to be submitted by the end of this year.
In its statement, the FDA said it understands "the dire urgency of the situation and the importance of our actions to the DMD community."
It also said that since April, it "has been working intensively to help Sarepta provide the additional data and analyses needed to support an NDA."
If approved, the drug is expected to treat about 13% of patients with DMD in the United States.
Although Sarepta researchers are "disappointed" by the delay, "we also understand the FDA's need to be comfortable with the dataset," Christopher Garabedian, president and chief executive officer of Sarepta, told participants of a "business update" teleconference in late October.
"We believe that our drug will stand up to that level of rigor and scrutiny of the FDA and we will satisfy their request as expeditiously as possible without compromising quality."
Assuming Sarepta's submission is ready by the middle of 2015, eteplirsen could be approved in the first half of 2016, if the NDA is filed under a priority review.
DMD is a rare degenerative neuromuscular disorder causing severe progressive muscle loss and premature death. It affects about 1 in every 3500 boys born worldwide. The disorder is caused by a mutation in the gene encoding the protein dystrophin. Eteplirsen induces skipping of exon 51 in the dystrophin pre-messenger RNA to correct this mutation.
To date, Sarepta has seen encouraging results of studies investigating eteplirsen. At the American Academy of Neurology annual meeting earlier this year, company representatives shared 120-week results of an open-label extension trial of eteplirsen that included boys aged 7 to 13 years who were initially randomly assigned to receive placebo or eteplirsen, 30 mg/kg or 50 mg/kg, for 24 weeks, after which they all took the study drug during the open-label phase.
In earlier published results to 24 weeks for 12 boys (Ann Neurol. 2013;74:637-647), the percentage of dystrophin-positive fibers was increased to 23% of normal in the patients receiving 30 mg/kg eteplirsen, with no increase in placebo-treated patients (P ≤ .002). Even greater increases occurred at week 48 in the treated cohorts, suggesting that dystrophin increases with longer treatment.
The newer results appeared to reinforce the importance of treatment timing. On the 6-minute walk test (6MWT), the four placebo/delayed boys had dropped 20 meters from baseline before eteplirsen treatment was initiated at 24 weeks, but then became stable by about week 36.
At 120 weeks, their 6MWT distance was –79 meters. The six patients receiving continuous treatment had a 120-week 6MWT distance of –14 meters, which represented a between-group difference of 65 meters (P ≤ .006).
Meanwhile, late last year, the FDA deemed the drug's approval premature. In April of this year, the agency provided a "guidance" letter for the NDA submission indicating steps to take for drug approval. However, a clinical site inspection carried out in May reportedly uncovered disparities in methods used to measure dystrophin and concerns about the reproducibility of the data.
The FDA confirmed in its recent statement that the need for additional data and analyses was reinforced by an inspection of the clinical site where dystrophin analyses were conducted. "It is important to note that the agency did not find any evidence of fraud at this site, as has been perceived by some," the statement noted.
For its part, Sarepta said that it did a comprehensive dystrophin analysis that included objective computer-generated dystrophin-positive fibers and dystrophin intensity by immunofluorescence, as well as Western blot, and staining for other glycoproteins and other assessments of the muscle tissue.
"We believe that the controlled blinded manner in which this was conducted shows that there is significantly more dystrophin after treatment than was there at baseline before treatment," said Garabedian in the conference call. Physicians and researchers "are convinced by our data set," he noted.
He added that the company will provide high-resolution images for review by trained pathologists at three independent laboratories.
The independent assessment was among a list of additional data for the NDA submission that the FDA included in a recent "updated guidance."
According to a Sarepta press release, the additional requested (or strongly advised) information also includes 3-month data from at least 12 to 24 newly exposed patients; available data from other patients enrolled in new eteplirsen studies, even if exposure is less than 3 months; additional data from later time points and from newly enrolled patients to be submitted in a 120-day safety update; patient-level natural history data (eg, to determine whether the study results for the 6MWT are different than expected in the natural history); and MRI data from a relatively large ongoing study.
The FDA also indicated to Sarepta that additional discussion will be necessary to determine what would constitute a complete NDA.
"The specific guidance on safety and a minimum number of patients and a minimum duration of exposure was not described in the April guidance nor communicated until last week," said Garabedian during the conference call. He added that this additional information can't be completed and compiled into "submission ready form" until the middle of next year.
"To be clear, this request was not based on any new safety concerns or signals from the approximately 3 years of continuous exposure data compiled to data in our phase 2b study, which accounts for more than 30 patient-years of eteplirsen safety," he said.
He added that this is believed to be "the longest continuous treatment of any group of boys across any DMD drug to date."
Garabedian indicated that although not mandated, the company plans to carry out a fourth biopsy in patients with DMD to strengthen its data set and help demonstrate "that long-term benefit is sustained biochemically with our drug." Not all study patients have volunteered for this additional biopsy, presumably because it involves an uncomfortable procedure and represents a hardship for some boys.
"We still believe we have produced one of the most robust and meaningful dystrophin datasets that have been compiled to date in the Duchenne muscular dystrophy space and have provided extensive support of a biochemical effect and a confirmation of eteplirsen's mechanisms of action as a foundation to support the clinical outcomes seen to date," commented Garabedian in the conference call.
The FDA said it has been "consistent" in communicating the necessity of submitting data from the ongoing open-label trial of eteplirsen in an NDA along with data from natural history studies that could show treated patients had slower decline in physical function. It has also consistently advised that data from additional patients would be critical to the assessment of the safety and efficacy of eteplirsen.
The agency indicated that it is willing to conduct a "rolling review" of Sarepta's NDA. Under such a review, the FDA can assess portions of an application as they are completed. The FDA said it expects the NDA for eteplirsen will qualify for a priority review.
Before it decides on approval, the FDA plans to present the NDA to a public advisory committee to get advice from outside experts and stakeholders on the adequacy of the data. It's possible, it said, that the drug will get "accelerated approval," a mechanism whereby drugs may get approved before definitive evidence of effectiveness is available.
Sarepta representatives expect to meet again with the FDA later this year.
Eteplirsen is not the only contender in the race to develop the first disease-modifying therapy for DMD. Also in the running is another exon-skipping drug, drisapersen (Prosensa Holding). The two drugs use a somewhat different technology to correct the genetic flaw causing DMD.
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Cite this: FDA Addresses Duchenne Muscular Dystrophy Drug Delay - Medscape - Nov 12, 2014.