Data Trumps Anecdotes, Emotion At Sarepta Panel

At a highly charged April 25 meeting of the FDA's Peripheral and Central Nervous System (PCNS) Advisory Committee, which concluded with angry shouting from parents and patient advocates, a majority of panelists said Sarepta Therapeutics Inc. failed to provide sufficient efficacy data for its Duchenne muscular dystrophy drug eteplirsen to win US approval – accelerated or standard, although the votes were much closer on the former than on the latter question.

Now, though, it's up to the FDA on whether it will take that advice – with all eyes on Janet Woodcock, director of the Center for Drug Evaluation and Research, who on more than one occasion during the more than 11-hour-long meeting emphasized that even though the statutory standard for efficacy was clear, the agency has some flexibility, particularly when it comes to a rare, life-threatening disease like DMD, a progressive muscle degenerative condition that primarily affects boys, who often don't live beyond 30 years.

Indeed, Woodcock even pointed out the FDA has been "instructed" to take the patient community's views into account when asked by one PCNS panelist whether the committee should consider the testimony they heard at the meeting from the more than 50 people, including young boys with Duchenne who participated in Sarepta's trial, or were not able to do so, their parents and other advocates, including a member of Congress, Rep. Mike Fitzpatrick (R-PA), who pressured regulators to approve eteplirsen, noting he carried a letter with him signed by 108 of his Capitol Hill colleagues.

Earlier in the day, Woodcock even suggested it may be worse for the FDA not to approve a drug for a "devastating" disease that's actually effective – declaring the consequences would be "extreme" for patients – although she emphasized regulators were still grappling with eteplirsen's efficacy benefit.

Robert Temple, deputy director of the FDA's Office of Drug Evaluation I, noted that while regulators had raised a lot of questions about Sarepta's single trial, known as Study 201/202, with specific concerns about whether there was "improper influence" – pointing out the difficulty of controlling bias in historical control studies – he also told panelists they "may have heard testimony from patients that they didn't think that would alter the level of effort that people made."

"So those kinds of factors are certainly things that are up for discussion," Temple said.

While "a lot of people don't like historically controlled trials," he said those types of studies "can be an adequate and well controlled."

Ellis Unger, director of the FDA's Office of Drug Evaluation I, told PCNS members they had to "try to reconcile what you heard from the patients" with the "actual hard data you've been analyzing today."

But it was the comments from one committee member, Chiadi Onyike, an associate professor of psychiatry and behavioral sciences at Johns Hopkins University in Baltimore, that stirred outrage from the audience of patients and parents.

Onyike insisted Sarepta's 12-patient study failed on "scientific grounds" to prove efficacy and the anecdotal testimony from patients and parents during the open public hearing "wasn't properly measured in the study."

So, Onyike said, "I hope you would consider as a patient community participating fully in controlled trials so you are not in this position in the future" – remarks that drew immediate fire from Duchenne advocates.

Sarepta management had explained the reason they hadn't conducted a placebo-controlled trial for eteplirsen was because at the time they launched the 12-patient study, there wasn't enough of the drug manufactured. And by the time there was a larger supply of the experimental medicine, patients already heard reports about its efficacy and so it became "unfeasible" since no patient wanted to risk getting the placebo.

But Sarepta leaders pointed out the firm has a confirmatory Phase III trial, known as PROMOVI, underway, which plans to enroll up to 80 patients with genetic deletions amenable to correction by exon 51 skipping in the treatment arm and 80 in the untreated group not amenable to exon 51 skipping.

Analysts, however, questioned whether that trial would satisfy the FDA.

Votes

The PCNS voted 7-6 that Sapreta had failed to provide substantial evidence from adequate and well-controlled studies that eteplirsen induced production of dystrophin – a protein essential for normal muscular structure and function and the lack of which is at the heart of DMD – to a level that is reasonably likely to predict clinical benefit.

In other words, the committee voted against an accelerated approval of eteplirsen.

The initial vote on that question was 8-5, but one panelist, Paul Romitti, a professor of epidemiology and toxicology at the University of Iowa, said he'd "hit the wrong button," and voted "no" when he meant to vote "yes," so the change made it an even tighter split among the PCNS panelists – something that may give Woodcock some leeway to work with if she's truly inclined to get eteplirsen to patients sooner rather than later, as some analysts have speculated.

The committee voted 7-5, with one abstention, the decisions to administer the 6-minute walk test, versus conclusions that the patient could no longer walk, failed to be sufficiently objective and free of bias and subjective decision-making by patients, their caregivers or their health care professionals to allow for a valid comparison between patients in Study 201/202 and an external control group.

A majority of the panel said they believed there was no effect of North Star Ambulatory Assessment results on the persuasiveness of the findings in Study 201/202.

An even greater number of the committee said they thought there was no effect of the other tests of physical performance, like rise time or the 10-meter run or walk, on the persuasiveness of the findings in the Sarepta trial.

For the final question, the panel voted 7-3, with three abstentions, the clinical results of Sarepta's s single historically-controlled study failed to provide substantial evidence that eteplirsen was effective as a treatment for DMD.

Billy Dunn, director of the FDA's Division of Neurology Products, noted the "emotion and passion in the room was clear" and tried to reassure the patients and parents at the PCNS meeting "we listened carefully" to their testimony and would take the information "under serious consideration."

The panel's rejection was just the latest blow to the DMD community. In January, FDA's snubbed BioMarin Pharmaceutical Inc.'s DMD drug Kyndrisa (drisapersen), and the next month, the agency refused to file PTC Therapeutics Inc.'s new drug application for Translarna (ataluren).