FDA Panel’s 7-6 Vote Against Sarepta’s DMD Drug Underlines Battle Between Science and Patient Advocates

April 26, 2016
By Mark Terry, BioSpace.com Breaking News Staff

Yesterday, after a 12-hour series of discussions and presentations, the U.S. Food and Drug Administration (FDA)'s Peripheral and Central Nervous System Advisory Committee (PCNSC) voted 6-7 against a recommendation for Cambridge, Mass.-based Sarepta Therapeutics ’s eteplirsen for Duchenne Muscular Dystrophy (DMD). Now the FDA will make a final decision on May 26 whether to approve the drug. The FDA typically follows the recommendations of its advisory panels, but not always, and the political pressure in this particular case is extreme, and has the potential to seriously affect where the scientific bar is placed for drug approvals.

Originally the FDA was to review Sarepta’s New Drug Application (NDA) for eteplirsen for DMD on Jan. 21. It was postponed until yesterday because of an impending snowstorm on the east coast.

DMD is a muscle wasting disease caused by mutations in the dystrophin gene. Dystrophin is a protein that plays a central role in muscle fiber. The disease is progressive and typically causes death in the mid- to late-twenties. It mostly affects boys, about 1 in every 3,500 to 5,000 male children.

In the lead-up to yesterday’s hearing, advocacy pressure ratcheted upward. In March, 36 experts in DMD signed a letter to the FDA urging the agency to approve the drug. It was written by two co-directors of the Center for Duchenne Muscular Dystrophy at UCLA, M. Carrie Miceli and Stanley Nelson. In February, 109 members of Congress sent a letter to the FDA urging it to accelerate approval of a DMD drug—any DMD drug, apparently.

The primary issue the FDA has with the drug is the size of the study and lack of placebo controls. The study only involved 12 boys, and the data on two of them, who did not respond to the drug, is essentially being disregarded by Sarepta, claiming that they weren’t expected to respond to the drug because they are at a later stage of the disease. There were no real placebo controls to compare the results to. Arguing that it was “unethical” to withhold a potentially effective drug from the boys, the company utilized historical data from European studies.

FDA clinical team leader Ronald Farkas told the advisory committee that the FDA “consistently and strongly encouraged” placebo-controlled trials for the drug and “expressed strong doubts regarding the interpretability of comparison.”

Underscoring the political aspect of the meeting, the first public speaker was Pennsylvania Representative Mike Fitzpatrick, a Republican, noting the 100 or so lawmakers that had signed the letter to the FDA. There were 52 public commentators at the hearing, including several boys with DMD and their parents. Of them, 51 urged approval.

One of the boys was Billy Ellsworth, who testified from his wheelchair, saying, “I’m going to beat this bloody disease but I need your help. FDA, please don’t let me die early.”

The public speakers lasted about three hours, with the remaining nine hours spent on primarily technical discussions. Eric Bastings, an FDA official, told the panel there was “no apparent correlation between muscle levels of the protein dystrophin and a change” in how the boys did on a walk test, which is a primary way of evaluating the progression of the disease.

The ultimate 7 to 6 vote pretty much indicates that seven of the panel members didn’t believe the trial showed the drug worked. It’s important to note that the vote doesn’t mean the drug doesn’t work—it means that the clinical trials have not yet proven that it works. There were additional votes. Seven of the panelists voted that the drug was not effective. Three voted that it was, and three abstained from voting.

“The data wasn’t there to approve on the basis of one poorly controlled trial,” said Caleb Alexander, a researcher at the Johns Hopkins Bloomberg School of Public Health and the panels chair.

Although it’s up in the air for the final vote in May, at least one analyst, Steve Brozak, with WBB Securities, expects it will. “Everyone was visibly moved by the audience and their testimony, and that is not going to go unnoticed. It’s not just political pressure. It’s advocacy pressure of the sort that I’ve not seen since the days of HIV and AIDS. And that can make the difference here.”

Advocates for the drug are arguing that since the drug is safe, why not make it available to the DMD patients? What do they have to lose?

“The worst thing you can do is deny access to a drug and then find out it works—too late, after we have lost a generation of boys,” Debra Miller, chief executive officer of CureDuchenne said to the panel.

That’s an arguable point. It would definitely be tragic if that were the case, but equally and perhaps more tragic if, because of the small size of the drug, there were as-yet unseen adverse side effects, or the drug was essentially no better than a placebo. There would likely also be significant litigation exposure for Sarepta and physicians if that did turn out to be the case.

The FDA is charged with setting a scientific bar for the safety and efficacy of approved drugs, which in some cases can be very difficult to define. Situations like this one are enormously challenging for the scientists and regulators involved, as well as for the patients, families of patients and patient advocates.

In his opening remarks at the meeting, Billy Dunn, the director of the FDA’s division of neurology products, noted that the FDA was legally required to approve drugs only if “substantial evidence” of their effectiveness was found. “These words are not vague words to be defined according to whim or fashion. Anecdote and emotion do not change the data with which we are confronted, no matter the attendance.”

Earlier this year, the FDA turned down San Rafael, Calif.-based BioMarin Pharmaceutical ’s application for Kyndrisa for DMD. And in January, Cambridge, Mass.-based Akashi Therapeutics halted its DMD trial for HT-100 because one of the patients developed serious, life-threatening health problems.

France’s Anagenesis Biotherapies is opening a U.S. facility in Boston and will work on a DMD drug.