After months of speculation, Sarepta Therapeutics Inc. hit pay dirt, gaining accelerated approval – and a rare pediatric disease priority review voucher (PRV) – from the FDA for its Duchenne muscular dystrophy (DMD) drug, eteplirsen, branded Exondys 51. The approval letter was penned by Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research (CDER).

Shares of Sarepta (NASDAQ:SRPT) soared to a 52-week of high of $56.18 before closing at $48.94 for a gain of $20.79, or 73.9 percent, with approval also turning the company into a takeover target, in the view of some analysts.

Exondys 51 is indicated to treat patients with a confirmed mutation of the DMD gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD, based on the surrogate endpoint of increased dystrophin in skeletal muscle observed in some patients treated with the drug. The label made clear that clinical benefit was not established during trials and indicated, as is customary with accelerated approvals, that continued approval in the indication may be contingent upon verification of clinical benefit in confirmatory trials.

During a conference call late Monday, Ed Kaye, senior vice president, chief medical officer and interim CEO, said Sarepta was "ready to launch," claiming the company had been prepared for commercialization since the original Exondys 51 PDUFA date in February. Kaye also disclosed that Sarepta is aiming to file its marketing authorization application with the EMA by year-end.

The net annual cost for Exondys 51 will be $300,000, taking weight-based dosing on the label into account along with compliance rates and mandatory government discounts. Sandy Mahatme, Sarepta's senior vice president and chief financial officer, took pains to explain the company's rationale, walking through the ultra-rare landscape in the U.S. before describing the "many factors" that went into setting the price as the time and cost to develop the drug, the expected number of patients on therapy and the company's need to continue funding its R&D pipeline.

With a commercial drug available, the company also expects patients to be diagnosed and treated earlier. Sarepta officials maintained their commitment to help "appropriate" patients gain access through programmed outreach to the physician and patient communities

Exondys 51 was approved with a broad label, Kaye added, with no restrictions on age or disease severity, making every patient amenable to skipping exon 51 "a potential candidate for treatment."

Mahatme disclosed the additional news that approval came with the PRV, which the company plans to sell to help finance pipeline development, manufacturing scale-up and entry into European markets.

"We've already reached out to potential buyers," he said.


Approval of Exondys 51 came with heightened drama, even considering the spectacle that has unfolded over the past two years in the DMD space. In addition to its approval letter, the FDA made public a summary review, dated Friday, addressed by Commissioner Robert Califf to Woodcock, Ellis Unger, director of CDER's Office of Drug Evaluation I, and Luciana Borio, the agency's acting chief scientist and chairwoman of the Agency Scientific Dispute Process Review (SDR) Board, about an internal dispute regarding the drug's accelerated approval. The commissioner's review suggested Woodcock personally went to bat for the drug and indicated Unger disagreed "and would decline to approve eteplirsen at this juncture," instead appealing the decision.

In his review of the dispute, Califf wrote that "Unger had an adequate opportunity to present his scientific concerns within the Center for Drug Evaluation and Research, and that Dr. Woodcock considered all relevant evidence in making her decision. In her capacity as acting chief scientist, Dr. Borio also conveyed her own views on the dispute, stating among other things that she does not believe the available data and information support accelerated approval of eteplirsen."

Califf added, "I note that, in my understanding, it is highly unusual for a center director's decision regarding a product application to be appealed to the commissioner's office."

That said, Califf indicated that he read the relevant documents – including Woodcock's decision, Unger's appeal and the recommendation of the SDR board – and "performed a thorough review of the basic and clinical science," including a briefing with Unger and the review team, discussions with Woodcock and a review of the science.

"My decision following this review is to defer to Dr. Woodcock's judgment and authority to make the decision to approve eteplirsen under the accelerated approval pathway, in her capacity as director of the Center for Drug Evaluation and Research," Califf concluded.

Both Woodcock and Unger exercised "reasonable scientific judgment in reaching different conclusions on whether the effect on dystrophin production" predicts clinical benefit, he added. "I conclude that qualified experts with extensive experience in FDA decision-making and stellar track records can assimilate the same scientific evidence and disagree about the extrapolation."

Califf acknowledged "the strain created by political and public pressures" but insisted that Woodcock did not deviate from her responsibilities as CDER's director or succumb "to pressure from the patient community, the public, the press or others."

Eteplirsen was initially set to come before the FDA's Peripheral and Central Nervous System Drugs advisory committee (adcom) in January, where it faced a hostile reception from FDA reviewers. FDA staff expressed "considerable doubt" regarding how much the drug improves dystrophin production for DMD patients and whether improvements seen in small trials could be reliably attributed to the drug. (See BioWorld Today, Jan. 19, 2016.)

A winter storm forced a postponement of the adcom, and the outlook of FDA reviewers was unchanged when the committee was set to reconvene in April. The tone of the briefing documents and the roster of panelists – which included nine voting members with expertise in neurology but only two specializing in movement disorders or DMD – along with the surprise appearance of Woodcock, seemed designed to force an even steeper battle for the candidate. (See BioWorld Today, April 22, 2016.)

At the conclusion of the epic adcom meeting, which included 52 presenters – mostly patients, family members and clinicians – during a gut-wrenching three-hour open public hearing, panelists concluded that Sarepta failed to prove its case statistically. Committee members voted 5-8 with no abstentions against accelerated approval of the drug, although Paul Romitti, professor in the University of Iowa's department of epidemiology and interdisciplinary program in toxicology, later acknowledged that he meant to vote in favor of accelerated approval, despite a desire to see a "better controlled study."

Panelists also voted 5-7 with one abstention that Sarepta failed to objectively administer the six-minute walk test (6MWT) in its single controlled Study 201/202 in 12 boys with DMD vs. historical controls. Only one panelist (after another changed his vote to an abstention) supported the notion that the North Star Ambulatory Assessment results strengthened the persuasiveness of the Study 201/202 study findings, while five voted that they weakened the study and seven that they had no effect. On the impact of other tests of physical performance, such as rise time and 10-meter run/walk, one adcom panelist voted that the findings strengthened the Study 201/202 findings, two that the data weakened the study and 10 that they had no effect.

The panel voted 3-7 with three abstentions against full approval of the drug.

Although adcom members laid most of the failure to provide the burden of proof at the feet of Cambridge, Mass.-based Sarepta, some also criticized the FDA for poorly worded questions that didn't add substantive intelligence to the discussion.


At the meeting, Woodcock seemed intent on defining the careful line the FDA was seeking to walk on eteplirsen. On one hand, she cited the agency's qualms about the 12-patient sample size, the uncontrolled nature of the study, the modest increase in dystrophin levels observed and other potential data shortcomings. On the other, she pointedly referenced the agency's duty to avoid the approval of drugs that are not effective as well as the failure to approve drugs that offer benefit. (See BioWorld Today, April 27, 2016.)

"The sponsor and FDA have attempted interpretation by comparing the results in treated children to the disease trajectory that is recorded in a number of external cohorts," Woodcock said at the time. "It's possible to reach different conclusions about these comparisons."

She acknowledged, however, that "there is agreement that eteplirsen does achieve its primary intended pharmacodynamic effect – that is, production of a truncated messenger RNA – and this is based on PCR results from muscle biopsies."

Woodcock also alluded to the challenges of reviewing drugs in DMD, which – prior to the nod for Exondys 51 – had no approved therapies.

"To me, it is remarkable that the field of exon skipping has advanced far into clinical development, generally, but without well-validated methods of determining pharmacologic success," she said.

"The translational science supporting these development programs is inadequate," Woodcock added. "This state of affairs is not atypical in rare and not-so-rare diseases, and significantly hinders the path for developers as well as the FDA."

In June, Sarepta revealed that the FDA requested additional dystrophin data as part of its ongoing review of the eteplirsen new drug application. According to the company, the agency said the dystrophin data, as measured by Western blot, could be acquired from biopsies already obtained from PROMOVI, the ongoing confirmatory study of eteplirsen. (See BioWorld Today, June 8, 2016.)

With accelerated approval of Exondys 51, the path may gain some clarity, although questions will no doubt remain for the drug, the field and the FDA. Last week, the agency's Division of Neurology Products confirmed that Robert Farkas, clinical team leader for the agency's review of eteplirsen, left his position to take a job in the private sector. In the wake of that disclosure, analysts began to handicap prospects for approval and a timetable for the agency's decision.

In her memo to Califf about the eteplirsen SDR, Borio pointed to a comment during Woodcock's concluding remarks at the adcom explaining that accelerated approval "includes a requirement for confirmatory studies for efficacy so as you've heard from the sponsor, you have to do further studies to explore and confirm effectiveness. An inherent presumption in this program of accelerated approval, which is written in the preamble to our regulation about it, is that more uncertainty is going to be tolerated initially and that in fact sometimes we will collectively get it wrong; otherwise accelerated approval would really have no different standards than regular approval."

Borio added that the FDA review team believed that, "by the end of an emotional [adcom] meeting, the framework for evaluating the data under the appropriate regulatory standards, as provided by the review team toward the start of the meeting, had been forgotten by the committee members."

Borio cited Unger's contention that Woodcock "made clear her intent to approve the drug" in a meeting with the review team on May 4, before she had reviewed drafts of the committee's final review memorandum or his review memorandum. According to Unger, Woodcock maintained that stance throughout subsequent discussions with the review team and following receipt of the additional dystrophin data from Sarepta, in part based on her perception that the review team "did a poor job framing the issues during their presentations and that the questions were confusing and poorly worded."

On July 14, according to Borio's memo, Woodcock finalized her decisional memorandum, explaining to the SDR board that her conclusion on whether the increase in dystrophin production identified by Studies 202 and 301 was reasonably likely to predict clinical benefit was based on her own "medical/scientific judgment." Borio said the director emphasized her 30 years of experience at the FDA and reiterated her position that the review team was unreasonable in its position on a threshold for predicting clinical benefit on eteplirsen.

"Her stated goal for the decisional process was to move the review team toward what she viewed as a more reasonable approach," Borio wrote. "She acknowledged that there were clear weaknesses in the data but that accelerated approval should not be limited to 'sure bet' drugs and that confirmatory trials are required for a reason."

In her presentation to the SDR Board, Woodcock also suggested that, in making the decision, "she was looking at the broader picture for the development of these types of drugs for very limited patient populations in the U.S. [between 600 and 1,300] and that there needed to be some path forward for such innovative products." Borio wrote. "She opined that Sarepta in particular 'needed to be capitalized.' She noted that the sponsor's stock went down after the [adcom] meeting and went up after FDA sent the June 3, 2016 letter. Dr. Woodcock cautioned that, if Sarepta did not receive accelerated approval for eteplirsen, it would have insufficient funding to continue to study eteplirsen and the other similar drugs in its pipeline. She stated that, without an approval in cases such as eteplirsen, patients would abandon all hope of approval for these types of products and would 'lapse into a position of' self-treatment."


The topic lit up social media Monday, with some raising concerns about the objectivity of the approval and whether the confirmatory trial will produce unequivocal data to support the drug's efficacy. In his memo, Califf noted that "the sponsor is currently conducting a nonrandomized, concurrently controlled trial in patients with mutations amenable to exon 51 skipping compared to untreated DMD patients with other exon deletions. Because of the relatively low level of protein induced, additional doses should be aggressively pursued and, if successful, a dose-comparison trial could be confirmatory. The sponsor has also planned to initiate a randomized trial with a related compound in other exons. The clinical results from these trials can inform the predictive value of the surrogate endpoint."

Later in the review, Califf added that "adequate confirmatory studies are underway and planned and are capable of further refining our understanding of the biomarker and providing evidence about the nature of the clinical benefit. The approval does not create any risk of compromising the confirmatory trials because of their nature. Therefore, I find that the probable benefits outweigh the foreseeable risks and that this application should be approved under 21 CFR 314.510."

An FDA spokeswoman confirmed to BioWorld Today that patients in the confirmatory trial will receive eteplirsen at the approved dose or higher, with none set to receive placebo.

Debra Miller, president and CEO of CureDuchenne – who vowed after the adcom to "do everything we can to help Sarepta get this drug approved" – told BioWorld Today that eteplirsen's approval capped an "absolute roller-coaster" for Sarepta, and she credited the company with staying the course despite the ups and downs. And despite "tears of joy" among the patient community following eteplirsen's approval, she lamented the DMD candidates that fell by the wayside for previous lack of FDA support, especially Kyndrisa (drisapersen), developed by Prosensa Holding NV and later acquired, and then abandoned, by Biomarin Pharmaceutical Inc. (See BioWorld Today, June 4, 2014, and Jan. 15, 2016.)

"Everybody's been watching this," Miller said. "There's been a great deal of trepidation. All of these companies had drugs that were working in at least some of the patients. With a disease that is as variable as Duchenne, companies were cautious about the prospects. I believe there's now some flexibility on the FDA's part."

Miller acknowledged potential concern by FDA officials on setting a precedent with eteplirsen's approval, "that companies would feel less need to go through a large, placebo-controlled trial." In the end, however, the decision respected the accelerated approval mandate of the FDA Safety and Innovation Act of 2012, or FDASIA, emphasizing that Sarepta "still has to go through an exhaustive trial after this," she said. "My argument has always been that if a drug is safe, and parents and physicians think it's working, approve it on accelerated approval, let the patients get the benefit and then find out through a confirmatory trial whether it's working or not."

Cowen and Co. analyst Ritu Baral pointed out that the label for Exondys 51 included the first glimpse at dystrophin data from 13 patients in the ongoing phase III PROMOVI study requested by the FDA in June. In the phase II 201/202 study, treatment with Exondys 51 led to approximately 0.9 percent of normal dystrophin expression, while the PROMOVI data, with 12 patients evaluable at 48 weeks of therapy, showed mean dystrophin improvement of 0.28 percent and median increase of 0.1 percent of normal dystrophin expression at week 48 in 12 of 13 evaluable patients.

"While these expression levels are numerically lower than in the [phase I/II], the change from baseline in dystrophin expression was found to be significant with treatment (p=0.008), which we think FDA likely viewed as the strongest indication of treatment benefit," Baral wrote. "Importantly, the label includes a description of the 201/202 study, but notes 'it is not possible to estimate dystrophin production in response to Exondys 51' from this trial due to 'insufficient information' on baseline dystrophin levels."

Baral suggested that clinician response to approval may be muted, based on prior consultant conversations, but "there would still be a willingness to use [if not outright recommend the drug] based on continued excellent safety."

RBC Capital Markets analyst Simos Simeonidis called the FDA nod "one of the most perplexing regulatory decisions in recent history," but acknowledged accelerated approval "opens the door for Sarepta's other exon-skipping compounds; Sarepta might now be a takeout candidate," given the presence of eteplirsen and the company's other earlier-stage, exon-skipping compounds for DMD "that can benefit from this very generous regulatory environment."

Jefferies LLC analyst Gena Wang was a bit more circumspect, despite an upgrade on the shares to "hold" from "underperform" and a revised price target of $50, up from $7, to reflect projected sales through 2022.

"However, we continue to see open questions at 2022 [full approval decision]," Wang wrote, citing a "weak" basis for approval on the back of questionable efficacy, questions about manufacturing capability to supply commercial and ongoing studies and a "debatable" ex-U.S. market for exon 51.

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