Eteplirsen Approval Reflected FDA's Conflict On Accelerated Approval – Former Sarepta CEO

The regulatory review of Sarepta Therapeutics Inc.'s Duchenne muscular dystrophy drug Exondys 51 (eteplirsen) highlighted FDA staff's conflicted feelings about the accelerated approval pathway, the company's former CEO said Dec. 14.

"I think it's fair to say that there are probably some within the FDA who see the accelerated approval pathway as a bit of a headache," Chris Garabedian said at the FDA/CMS Summit in Washington, DC.

Garabedian suggested there is an inherent conflict between the "reasonably likely to predict clinical benefit" standard for accelerated approval, and the statutory requirement for sponsors to demonstrate substantial evidence of efficacy. "There's an irreconcilable conflict in those two statements," he asserted, noting that FDA has said "we're not going to lower our standards for accelerated approval."

Garabedian also suggested that a lot of the agency's anxiety around accelerated approval stems from the potential for confirmatory trials to fail.

"If the new data comes out and doesn't support it, we're going to have a bigger problem if we try to pull a drug from the market that you're hearing a parent say is working for their child," Garabedian said.

The former Sarepta exec said the eteplirsen experience shows that FDA and sponsors need to figure out where accelerated approval fits into the development paradigm for rare diseases, where patients are few, endpoints are novel and natural history data are lacking.

Weighing Accelerated Approval Vs. Placebo Controls

Garabedian's remarks came during a panel discussion on FDA and patient advocacy in the wake of the eteplirsen approval.

FDA granted accelerated approval to eteplirsen in September. The controversial decision to approve was made by Center for Drug Evaluation and Research Director Janet Woodcock, who overruled the objections of review staff and other senior CDER officials. Woodcock concluded that the small amount of dystrophin produced by eteplirsen was reasonably likely to predict a clinical benefit under the accelerated approval standard, and FDA Commissioner Robert Califf deferred to her decision. (Also see "Sarepta's Eteplirsen Approved After Contentious Internal FDA Debate" - Pink Sheet, 19 Sep, 2016.)

Internal agency documents show that while Woodcock viewed eteplirsen's approval as an exercise of the flexibility envisioned for the accelerated approval pathway, other agency officials saw it as a lowering of the efficacy bar and a threat to the substantial evidence standard. (Also see "Accelerated Approval After Eteplirsen: A Lowered Bar Or A Unique Event?" - Pink Sheet, 20 Sep, 2016.)

Garabedian was CEO of Sarepta from January 2011 until his resignation March 2015. His ouster largely was seen as an effort by the company to smooth both its strained relations with FDA and the regulatory pathway for eteplirsen. (Also see "Hoping To Smooth Relations With FDA, Sarepta Moves On From CEO Garabedian" - Pink Sheet, 1 Apr, 2015.)

Those strained relations resulted, in part, from differences in how FDA and Sarepta viewed the advice the agency gave to the company, and in the company's public disclosures about its data and interactions with FDA.

"The issue is you need to resolve are you going to consider this for accelerated approval or not, and if you're not should you shift to a placebo-controlled study?" – Former Sarepta CEO Garabedian

Garabedian said it was a "misnomer" that FDA told Sarepta to do a placebo-controlled trial and that the company refused. "You have to do what FDA asks, it's their choice," he said. "They gave us guidance at the end of the day to please do an open-label study."

Internal review documents show that while FDA repeatedly encouraged Sarepta to conduct a placebo-controlled trial, the agency ultimately agreed to other study designs, such as a historically controlled trial, in light of concerns expressed by the company and patient community that a placebo-controlled trial would not be feasible. (Also see "Exondys 51’s Development: Was Placebo-Controlled Trial Possible?" - Pink Sheet, 16 Nov, 2016.)

"Now the reason that was such a controversial decision was you can't on the one hand say we'll consider accelerated approval and your drug could be on the market next year, and we want you to do a placebo-controlled study," Garabedian said.

"No one was debating the fact that no one is going to stay in a placebo-controlled study when you've got a terminal, progressive, irreversible condition and you don't even know if you're drug is working. You're going to drop out and then you have no data," Garabedian said. "So even FDA wasn't contesting that."

"The issue is you need to resolve are you going to consider this for accelerated approval or not, and if you're not should you shift to a placebo-controlled study?"

No Lowering Of The Bar

Garabedian also rejected any suggestion that the eteplirsen approval would lower the bar for other drugs. "I think from a program standpoint we raised the bar," Garabedian said, describing the eteplirsen clinical program as the most rigorous ever conducted for a Duchenne drug.

His comments seemingly stand in stark contrast with the views of agency staff, including Woodcock and Califf. In internal memos and public statements, FDA officials have described the eteplirsen development program has seriously flawed and one that should not serve as a model for other drugs. (Also see "No More Sarepta-Like Development, FDA Officials Say" - Pink Sheet, 20 Oct, 2016.)

With its accelerated approval of eteplirsen, FDA "did differentiate, they didn't lower the standards," Garabedian said.

He pointed to the agency's decision on two other Duchenne drugs that predated the eteplirsen approval: a complete response letter for BioMarin Pharmaceutical Inc.'s Kyndrisa (drisapersen) and a refuse-to-file decision for PTC Therapeutics Inc.'s Translarna (ataluren).

"They said no to another drug with a similar mechanism because the data wasn't there," Garabedian said. "They said refuse to file to another drug that was dystrophin producing. I don’t think if you talk to those companies they would say they lowered their standard."