Duchenne Drug Approval Still Leaves Bad Taste for Many

Alicia Ault

November 03, 2016

The September approval of a therapy for Duchenne muscular dystrophy (DMD) continues to rankle many who say the evidence did not support it and that it may set a dangerous precedent at the agency, although specialists who work in the field say they are pleased to finally have an option for patients.

The latest critique came in the form of a viewpoint published online in JAMA on October 24.

The manufacturer's development program for eteplirsen (Exondys 51, Sarepta Therapeutics) "has provided a worrisome model for the next generation of molecularly targeted therapies: demonstrate a slight difference in a laboratory test, activate the patient community, win approval, and charge high prices, while relying on limited regulatory follow-up," write Aaron S. Kesselheim, MD, JD, MPH, and Jerry Avorn, MD, both from the Pharmacoepidemiology and Pharmacoeconomics Department at Brigham and Women's Hospital, Boston, Massachusetts.

But Kathryn Wagner, MD, PhD, director of the Center for Genetic Muscle Disorders at the Kennedy Krieger Institute, Baltimore, Maryland, said she's pleased the drug was approved. "I want the option to be able to provide Exondys 51 to my patients," she told Medscape Medical News.

Thomas Vidic, MD, a clinical neurologist and medical director at Indiana Medical Research, LLC, agrees. "I'm happy for the very narrow window of patients who are appropriate to have access to the drug," he said.

However, Dr Vidic added, "We have to approach this drug with discretion because it's going to be expensive." Sarepta has said it will charge $300,000 a year for eteplirsen.

And as pleased as he is to have something to offer the small number of patients with DMD who might benefit, said Dr Vidic, "unfortunately, the results from the trial are not as dramatic as we would like to see."

It's estimated that only 9000 to 12,000 patients have DMD in the United States, and the mechanism of action for this treatment applies to only about 13% of patients, those with mutations of the dystrophin gene amenable to exon 51 skipping.

The US Food and Drug Administration (FDA) official who ultimately approved eteplirsen, Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, said Sarepta's program was fraught with mistakes. Among them: "problems with the assays, the failure to randomize patients…a very short randomized trial," said Dr Woodcock, in an interview with Medscape Medical News.

Sarepta did provide a validated assay for dystrophin, the surrogate marker used to judge eteplirsen's effectiveness, but that assay was not instituted until after the development program was over, Dr Woodcock said.

"That's not ideal, either," she said. "But they did present that evidence at the end of the day."

Divisions Persist Within FDA

In her opinion, "the approval is a scientific decision," but one that required the maximum regulatory flexibility allowed under the accelerated approval law.

The agency officials who led the eteplirsen review objected so strongly to the approval in fact, that they asked FDA Commissioner Robert Califf, MD, to examine Dr Woodcock's decision. The appeal was brought forward by Ellis Unger, MD, director of the Office of Drug Evaluation I at CDER, and sent to the Commissioner by Luciana Borio, MD, chair of the Agency Scientific Dispute Process Review Board.

Although the review board found no procedural basis for Dr Unger's appeal, Dr Borio agreed with him that there were not sufficient data to support accelerated approval for eteplirsen, and asked that Dr Califf either review the approval or strike a panel of experts to do so.

Dr Califf elected to review the approval himself. The examination took months, culminating in a 126-page memo in which the commissioner outlined why he supported Dr Woodcock's final decision. The memo was dated September 16 but not made public until after the approval was announced on September 19.

"My decision following this review is to defer to Dr Woodcock's judgement 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," Dr Califf writes.

The parties disagreed about what might be the expected clinical effect of the level of dystrophin produced by eteplirsen in the studies, he noted, but pointed out 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 to whether the evidence supports a conclusion that the treatment has an effect that is 'reasonably likely' to predict clinical benefit.

"Given that I do not have technical expertise beyond those already involved in this decision and the record contains adequate evidence to support her conclusion, I defer to the judgement of the Center Director to approve eteplirsen under accelerate approval with the stipulations delineated in her Decisional Memo," Dr Califf concluded.

Many of Dr Woodcock's colleagues still disagree with her having used such regulatory flexibility in this case. At an October meeting of the National Organization for Rare Disorders (NORD) in Washington, John Jenkins, MD, director of the FDA's Office of New Drugs, told attendees that he did not support approval, as he saw multiple failures in Sarepta's development program.

These included a failure to validate the dystrophin biomarker, a lack of early randomization, and difficulty reconciling patient and family reports of improvement in function when the trial data showed otherwise, said Dr Jenkins.

He suggested the company had also erred in failing to make timely reports of early findings. Instead, Sarepta relied on post hoc analyses, which Dr Jenkins called "wrong, fundamentally." Such analyses "are generally hypothesis-generating exercises and should lead to a new clinical trial, not the basis for regulatory approval," Dr Jenkins said.

At the same NORD meeting, Dr Califf expanded on the rationale for his support of Dr Woodcock. It was, in part, a way of safeguarding the FDA from outside interference, a category that he said included him, since he is a political appointee.

"Setting a precedent of political appointees intervening in decisions that belong in a scientific process would risk opening the door to a potentially dangerous temptation for others, including political appointees within government and other non-FDA groups to intervene more frequently," he said.

FDA decision making is "difficult and imperfect," Dr Califf said, but allowing "political meddling would undermine confidence and introduce the kind of bias that's not helpful."

Meddling or Proper Influence?

Some critics say the eteplirsen approval was the result of just such outside meddling — in particular from patient advocacy groups who held multiple meetings with the FDA during the drug's development and who also showed up in force at the April 2016 advisory committee meeting.

But Pat Furlong, president and CEO of Parent Project Muscular Dystrophy (PPMD), a Hackensack, New Jersey-based nonprofit group, is proud of her organization's influence. "I think the pressure made a difference," Furlong told Medscape Medical News.

She believes it's time for "a new social contract," one that brings patients, the FDA, and drug developers closer together as collaborators. That's not such a wild idea: The FDA, by law, is required to work more closely with patients.

PPMD is at the leading edge. It began meeting with the FDA in 2008 to discuss unmet needs in the DMD area, along with benefits and risks of therapies in development, among other topics. Ultimately, PPMD paid a consultant to help establish guidance on development of DMD therapeutics, which the agency used as the basis for the guidance it issued, Furlong said.

PPMD is primarily funded by families, but it receives some money from industry to support its conferences and meetings, she said.

The organization is "thrilled with this approval," said Furlong, adding, "clinicians in the neuromuscular community are going to embrace this drug."

She acknowledged that cost could be a barrier. "It would be very few families that could afford that price if they were paying out of pocket," said Furlong. But she expects many patients to have insurance coverage or assistance from Sarepta.

Cigna and Blue Shield have agreed to cover eteplirsen, but one of the nation's biggest insurers, Anthem, will not, calling the drug investigational.

"Cost is a major concern," not just for families, but also to society, said Dr Wagner. She will be recommending the drug "to boys who are amenable to skipping exon 51" but still expects to need to manage expectations, she said. "I will inform the families that the drug may reduce the rate of decline but is unlikely to make the boys stronger," she added.

Dr Vidic sees a narrow window of usefulness. "Once there's too much damage, I don't think it's really going to be helping the patients," he said. He doesn't want it used by clinicians outside of the neuromuscular community and said he hopes "that parents with children with advanced disease don't pressure their doctor into prescribing it."

The safety and effectiveness of eteplirsen should continue to be closely monitored, and, preferably, a registry should be established, Dr Vidic said.

Furlong and both physicians said they're looking to the confirmatory study to provide more guidance. The FDA required Sarepta to determine whether eteplirsen truly improves motor function — something that was only suggested, not confirmed, by the data used for approval. If that benefit is not confirmed, the agency can take the drug off the market.

If that happens, "that will be a sad day," said Dr Wagner.

Critics Warn of Precedent

One of the more outspoken critics of the approval has been Diana Zuckerman, PhD, president of the National Center for Health Research, a Washington, DC-based nonprofit education and advocacy group.

Dr Zuckerman's organization testified against approval at the advisory committee meeting, believing the data did not demonstrate effectiveness. The group is concerned that now that eteplirsen is available, Sarepta will not be able to recruit controls for the confirmatory study, Dr Zuckerman told Medscape Medical News.

"You may only get people who are too poor to afford the drug, and their insurance doesn't cover it," she said. If only those who can't get the drug otherwise are the controls, "that's so unethical on every level," said Dr Zuckerman.

In her mind, the FDA allowed patient advocates to "undermine the scientific integrity of the process," she said. Dr Woodcock "was clearly moved by these kids," said Dr Zuckerman.

"We're not opposed to the paradigm shift of including patient voices," she said. "We just think the patient voices should help improve study designs and make sure that the outcome measures are the ones that matter to patients."

She contends a rise in the dystrophin was irrelevant if patients did not actually have improved walking ability or other measures crucial in day-to-day life.

Dr Zuckerman also said she's concerned the eteplirsen approval will set a bad precedent by encouraging industry to skimp on doing the hard science if approvals can be won more easily by bringing external pressure to bear.

Conversely, Ira Loss, a long-time FDA-watcher and an investment adviser with Washington Analysis, sees it differently. Because of the eteplirsen approval, "there are all these companies that are encouraged to do work in Duchenne muscular dystrophy," he told Medscape Medical News.

He pointed to recent collaborations Sarepta struck with Spectrum Pharmaceuticals and another company in the muscular dystrophy field. In addition, two other companies have submitted DMD therapies to the agency recently, he said.

Loss said the eteplirsen situation is similar to when the first drug for HIV was approved. People with AIDS had been pushing the FDA hard to get any therapy out to market. AZT, the first to reach the agency, was extremely toxic and not so effective. But in 1987, the FDA approved the drug, with just one trial that had been stopped early because of a high number of placebo deaths.

Within 3 years, there were better therapies, said Loss. "But it was getting the first one out there that got everyone else involved," he said.

Furlong, the patient advocate, said her organization had learned from the HIV community and had even consulted with ACT-UP, the group that was most associated with pressing the FDA in the 1980s and 1990s.

She thinks the eteplirsen approval "has galvanized the industry to say 'I can do it better, faster.'"

However, FDA officials are insistent that Sarepta's development program is not a good model to follow and that the approval process for eteplirsen won't become the modus operandi.

"I am confident that this unique situation will not set a general precedent for drug approvals under the accelerated approval pathway, as the statute and regulations are clear that each situation must be evaluated on its own merits based on the totality of the data and information," said Dr Califf (page 12 of his memo) in reviewing the decision.

For her part, Dr Woodcock seems glad to put it behind her. "We hope we won't see a development program like that again," she said.

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