FDA Advisory Panel Splits on Second DMD Drug

To find out what has happened since this story was originally published on April 26, click here.

Weighing hard data against patient testimonials, an FDA advisory panel voted 7-6 that a new Duchenne muscular dystrophy (DMD) failed to meet the minimum standards for accelerated approval on Monday.

The Peripheral and Central Nervous System Drugs Advisory Committee’s vote signaled a lack of “substantial evidence from adequate and well-controlled studies” to trigger dystrophin production at a level considered “reasonably likely to predict clinical benefit.”

In other words, the chosen surrogate endpoint was inadequate to promote any claim that the drug would actually help DMD patients — at least in the majority’s view.

The panel also voted 7-3, with three abstentions, that a single historically-controlled study also did not offer substantial evidence of the drug’s efficacy.

In November, the same panel determined in more lopsided votes that the evidence in support of a similar agent, Biomarin’s drisapersen, was also weak.

Benjamin Dupree, a 23-year-old with DMD from Dallas, who was the panel’s patient representative, voted that the drug met the “substantial evidence” standard in both questions.

However, the Duchenne patient was deeply conflicted. “The study doesn’t provide what I think is adequate evidence to support all of this testimony that I’m seeing in here,” he said, referring to extensive public testimony, before breaking down in tears.

Eteplirsen (tentatively branded Exondys 51), a product of Cambridge, Mass.-based Sarepta Therapeutics, has been proposed for treating DMD in patients with a specific verified mutation of the dystrophin gene. The disease is thought to occur when a genetic mutation in exon 51 causes a shortage or lack of dystrophin protein. Eteplirsen is intended to prevent exon 51 from being translated, enabling muscle cells to produce a shortened but still functional form of dystrophin.

The panel’s first vote reflected the committee’s views regarding the drug’s suitability for approval under an accelerated approval pathway — using dystrophin levels as a surrogate endpoint. The second vote viewed potential approval based on clinical efficacy.

Chiadi Onyike, MD, associate professor of psychiatry and behavioral sciences at John Hopkins University School of Medicine in Baltimore, voted against approval in either an accelerated or conventional approach.

While eteplirsen may have caused the production of some dystrophin, “it’s very small … too small to go from dystrophin production to clinical effect,” he said.

Moreover, the question implies that dystrophin is responsible for clinical benefit, and “I’m not entirely sure that one should lock the clinical effect to the dystrophin production,” he said.

Onyike, echoing Dupree, said, “What I would consider meaningful evidence of testimony from the families is not properly measured in the study.”

William Dunn, MD, director of the FDA’s Office of Drug Evaluation I for the Division of Neurology Products, told the committee in opening remarks, “We come to you with sincere concerns, not because we take some perverse delight in keeping new medicines from those who urgently need them … but because it is our — we the FDA, and you, our advisory committee — collectively, it is our fundamental responsibility to ensure, as required by law, that the treatments we approve are effective.”

Dunn urged the panel to focus on “whether we can truly conclude that what these few eteplirsen patients are experiencing is clearly outside the natural variability of the disease.”

During an unusually long public comment period, many parents pleaded with the committee to speed the drug’s approval.

Mindy Leffler, from Seattle, described how her son regained the ability to pull himself into a car after taking eteplirsen. Leffler noted that “regaining definitively lost milestones” was not part of the natural progression for any Duchenne patient.

“Medical students are often told when they hear hoof-beats to think of horses not zebras,” she urged the panel, “Look to the obvious conclusion, rather than searching for the unlikely. It is now time to stop hunting zebras.”

When, at the end of a long day, Onyike called for an adequate controlled trial, as other panelists and FDA staff had before him, the audience erupted into jeers, shouting “biopsies hurt.”

One wheelchair-bound teen, cursing angrily, ran his vehicle through a couple rows of empty chairs before rolling out of the room.

For this application, Sarepta submitted two exploratory studies and a single clinical trial in two phases — a randomized placebo-controlled study and an open-label extension trial that used data from Italy and Belgium for comparison.

FDA’s technical experts noted shortcomings in the sponsor’s bioassay methods leading to possible “overestimation” of the percent of dystrophin-positive muscle fibers. The experts also pointed out the inability to distinguish drug-induced dystrophin from naturally-occurring dystrophin in immunofluorescence.

Sarepta’s re-analysis of the biopsied tissue by three independent experts found a mean percent of dystrophin positive fibers of 17% [± 10%] at 180 weeks, which was about one-quarter to one-third of Sarepta’s initial estimates at 48 weeks.

Similarly, using a Western blot assay, a fourth biopsy from patients at 180 weeks of treatment found dystrophin levels at 0.93% [± 0.84%] of normal muscle. The sub-1% increase was markedly different from the 10- to 20-fold increase with eteplirsen the sponsor initially reported at 12 weeks of treatment.

In the single clinical trial comparing three groups of four patients each at different doses — eteplirsen 30 mg/kg or 50 mg/kg versus placebo, the drug failed its prespecified endpoints.

But the technical experts were more concerned with the way endpoints were defined. For example two participants who completed the 10-meter walk-run (10MWR) also reported a score of zero on the 6-minute walk test (6MWT). This finding suggested possible subjectivity in decision-making regarding loss of ambulation.

The agency’s technical experts also considered whether less capable or less motivated patients might more frequently be relegated to natural history studies, and whether this could have confounded study results.

Lastly, the sponsor’s results showed no correlation between the amount of dystrophin patients had and their outcomes on the 6MWT.

Based on the clinical trial, the agency’s experts ultimately concluded, “[T]here does not appear to be any evidence of efficacy for eteplirsen.”

The FDA is not required to follow the advice of its advisory committees, but it often does.

Eteplirsen Approval Seen as Marking New Direction at FDA

On April 26, an FDA advisory committee voted 7-6 that the exon-skipping drug eteplirsen for Duchenne muscular dystrophy (DMD) failed to meet the standards needed for accelerated approval. It was widely assumed that the FDA would tell the drug’s developer, Sarepta Therapeutics, to try again with better data. That, of course, did not happen. In this follow-up, we report on how it eventually did turn out for the drug and for the DMD community.

To the surprise of many, the FDA approved eteplirsen in September with the trade name Exondys 51.

While patients and families applauded the decision, believing their efforts in collaborating with industry and the agency had paid off, critics in the medical and research community questioned whether the drug really worked, and whether the FDA had made the right call. Documents later revealed internal FDA friction, and even though the agency’s boss backed the approval, he also called for a key study supporting the drug to be retracted.

In addition, two recent events — passage of the 21st Century Cures Act, a major health bill meant to spur innovation and speed the delivery of new drugs, and the surprise election of Donald Trump as president — have sparked concerns that the FDA might inch closer to deregulation for the sake of innovation under the new administration.

Perhaps more than in previous White House transitions, confusion and uncertainty cloud the FDA’s future.

Yet while consumer groups express alarm, some clinicians and policy experts believe a dramatic reversal in the FDA’s core mission is unlikely. MedPage Today spoke with key stakeholders to gauge the importance of eteplirsen’s approval: what it means for patients and the future of the FDA’s review process.

Flash Point

In approving eteplirsen, the FDA had overruled its own advisory committee. The seven members voting against approval did not believe Sarepta had shown adequate evidence that eteplirsen triggered production of the protein dystrophin at a level that was “reasonably likely to predict clinical benefit.” (DMD is caused by a genetic deficiency in dystrophin.)

Moreover, several of the FDA’s senior staff members also saw evidence that patient benefit was inadequate, as documents detailing a months-long dispute between those staff members and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research (CDER), showed. She overruled their conclusions and FDA Commissioner Robert Califf, MD, ultimately sided with Woodcock. Curiously, however, Califf also called for the retraction of a 2013 study that aimed to demonstrate that eteplirsen produces adequate levels of dystrophin, which he called “misleading.”

Insurers also appear to need more convincing that the drug is effective. The investment firm Jefferies found that three of five national payers and eight of 15 regional managed care organizations “denied or restricted coverage for the drug,” according to Gena Wang, PhD, CFA, an analyst for Jefferies. Wang told Endpoints News, a biopharma newsletter, the response was “in line with our expectation of pushback from private payers.”

Unlike private insurers, public payers such as Medicaid do not have the option to omit FDA approved drugs from their formularies.

The ripple effect of the eteplirsen decision could prove damaging to the healthcare system, Diana Zuckerman, PhD, president of the National Center for Health Research, told MedPage Today.“Many drug companies will be submitting applications that they wouldn’t have dreamed of submitting [before].”

Zuckerman said Woodcock’s decision stemmed from sympathy for the patients.

“She approved a drug not realizing that by approving the drug based on evidence that was so obviously inadequate many health insurance companies would just refuse to pay for it.”

Without insurance coverage, families have to pay $300,000 a year for the drug. “The company failed in its responsibility, the FDA failed in its responsibilities, and the patients are paying the price,” Zuckerman said.

If the agency continues to move in this direction, insurers will spend more money to perform their own analyses of product data. Money that could have been better spent on coverage, she added.

On the issue of coverage determinations, Annie Kennedy, senior vice president of legislation and public policy at the Parent Project Muscular Dystrophy (PPMD), said some insurers’ refusals stemmed from a misunderstanding about the burden of the disease. Only about 2,000 U.S. patients have the specific genetic mutation making them potentially eligible for treatment.

PPMD has also pressed insurers offering narrow coverage determinations, arguing that even non-ambulatory patients can benefit from the drug. Kennedy and others have been sharing additional pulmonary data demonstrating “stability” on functional tests in treated participants compared to “a steady decline observed in the DMD natural history,” according to Sarepta documents.


Kennedy anticipates that some insurers will revise their coverage determinations based on engagement with the community.

Looking Ahead

One of the FDA’s advisory committee members who voted against approving eteplirsen, Aaron Kesselheim, MD, JD, of Harvard Medical School/Brigham and Women’s Hospital in Boston, told MedPage Today that one of the challenges of that meeting was balancing the inconsistencies in the testimony he heard from patients and families with the data.

“How do we make sure that the patient voice is taken seriously, but at the same time also take the science seriously and come to an adequate final decision?” he said.

The newly passed “Cures Act” also has provisions that could affect the FDA’s review process. It allows the agency to use “real world evidence” in deciding whether to approve expanded indications for already marketed drugs.

If Cures is given “maximum flexibility” and FDA leadership has a deregulatory agenda, said Kesselheim,”I think the future will hold a lot more products like eteplirsen that are approved on the basis of a marginal effect on a surrogate measure that does not have a clear connection to clinical endpoints.”

“That’s going to put a lot of pressure on physicians trying to make the decisions whether or not to use the product [and] patients deciding whether or not to take the risk … in this context of insufficient information,” he added.

Trump’s election also brings the likelihood of new leadership at the FDA. Although he has made no announcement about replacing Califf as commissioner, most of his other appointees have been staunchly anti-regulation and many are coming from industry.

The possible change in agency leadership and the Cures Act together could allow the FDA to reconsider the balance between innovation and ensuring appropriate levels of safety and efficacy, said Caleb Alexander, MD, of the Johns Hopkins Bloomberg School of Public Health in a phone interview. Alexander chaired the FDA committee that voted on eteplirsen.

However, given the massive size of the FDA, whatever change does occur will be gradual, he said. “I’ll be surprised if it’s a total sea change.”

“While cases such as Addyi (flibanserin) and eteplirsen have been quite controversial, those represent a small fraction of the reviews that FDA has performed … I don’t think that those cases are reflective of wholesale change or any deliberate decisions … regarding a change in the evidentiary threshold for market access.”

As for the worry that the “Cures Act” could encourage the use of more real world evidence, Alexander saw no conflict between leveraging patient reported outcomes, for example, and high quality science.

He added, “There’s a reason the FDA has evolved toward the use of randomized controlled trials, and frankly I don’t see that reliance diminishing substantially anytime soon.”

Advocates Respond

In response to the backlash against the FDA’s decisions and scorching criticism of Sarepta’s own clinical trial, Kennedy explained that the community was “flying the plane as we were building it.” For example, meetings focused on developing guidance for a protocol regarding how best to measure dystrophin happened as Sarepta’s own research was already underway.

“I know there’s been a lot of blame cast at this cast of characters or that cast of characters and a 152-page document released about disagreements,” said Kennedy referencing the FDA’s summary review.

But, she noted, “What we think happened was exactly what accelerated approval was designed for … All of these policies and tools that so many people have pushed for, for so long … were applied by everyone collaboratively and now we’ll get to see how this plays out going forward.”

“Now the onus is on Sarepta to conduct further studies to show [clinically meaningful benefit], that continues to happen in the broader subset of the community. If we don’t, then the product will get pulled,” she said.

Still the Watchdog

The FDA, in an emailed statement, underscored that its commitment to holding drug manufacturers, including Sarepta, accountable for confirmatory studies to determine clinical benefit will continue.

“The required study is designed to assess whether eteplirsen improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval,” wrote Sandy Walsh, a press officer for the FDA in an email.

As for the future direction of agency, Walsh noted, “In appropriate situations, the agency exercises flexibility when evaluating treatments for serious and life-threatening conditions. However, as each situation is unique, we cannot speculate on potential decisions on other product applications.”

FDA Officials, Advisors Split Over New DMD Therapy

WASHINGTON — The FDA approved the first-ever drug for Duchenne muscular dystrophy (DMD), despite internal disagreements over the drug’s efficacy.

Eteplirsen (Exondys 51), a product of Sarepta Therapeutics of Cambridge, Mass., won approval from the agency — despite a split vote from its own advisory committee — to treat DMD patients who have a “confirmed mutation of the dystrophin gene amenable to exon 51 skipping” on Monday.

The FDA said it granted accelerated approval of the drug based on the surrogate endpoint of an increase in dystrophin production. However, its press statement failed to acknowledge the breadth of internal discord over this very point.

Following a conference call with investors Monday, Sarepta said that it anticipates charging $300,000 per patient per year for the new drug, according to Forbes.

‘The Principal Question’

The agency’s summary review chronicles a months-long dispute among senior staff and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research (CDER) over what FDA Commissioner Robert Califf, MD, dubbed the “principal question — whether the quantity of dystrophin produced by eteplirsen is an effect that is reasonably likely to predict clinical benefit,” as required by FDA statute and regulation.

Woodcock said she believes that clinical benefit is predicted, but Ellis Unger, MD, office director of the CDER’s Office of New Drugs (OND) disagreed. Back in April, seven of 13 members of the Peripheral and Central Nervous System Drugs Advisory Committee also said they felt eteplirsen failed to meet the minimum standards for accelerated approval.

In a 27-page July appeal letter to the Office of Scientific Integrity, Unger noted that members of the review team for Division of Neurology Products unanimously concluded that the new drug application should receive a “complete response action” (i.e. a rejection) and that OND director John Jenkins, MD, also verbally supported that decision (Ronald Farkas, MD, PhD, a lead reviewer in the neurology products division who was highly critical of eteplirsen data has already left the agency, according to STAT).

In his appeal letter, Unger argued that the small increase in dystrophin shown in the trials was not “reasonably likely” to predict clinical benefit, and that the effect size of dystrophin levels was “inadequate on its face.”

He noted that methods for quantifying dystrophin in the field are not standardized. Nevertheless, it was not valid to compare an increase in”Becker-type dystrophin” with dystrophin levels cited in other mutation or patient populations measured at other laboratories. Becker muscular dystrophy is a milder form of muscular dystrophy in which a truncated version of dystrophin is produced by muscle cells.

That said, if such a comparison were possible, Unger continued, “the largest change reliably demonstrated in Study 301 [a study comparing pre and post-treatment values of dystrophin after 48 weeks] of 1.3% is an order of magnitude less that the minimum dystrophin levels cited to be important in affecting the course of patients with Becker muscular dystrophy (at least 10%).”

Califf Defers

After Unger’s appeal, Califf was called on by the Scientific Dispute Process Review board to either conduct his own scientific review of the data, or to direct a panel of experts to make a recommendation on the current data, and if it meets the standard for accelerated approval.

Califf chose to conduct his own review and ultimately deferred to Woodcock’s “judgment and authority.”

“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 judgment of the Center Director to approve eteplirsen under accelerated approval,” he stated in a letter.

He also responded to a series of concerns over Woodcock’s actions, with regard to the drug:

  • Her “intense involvement”at the early stages of the review process for the drug
  • Her “extensive involvement” in planning and engaging in the April 25, 2016 advisory committee meeting
  • Her “initial decision” to approval eteplirsen on May 4, 2016, before the reviewers had even established a decision-making process
  • Her completion of a final decisional memorandum before Unger completed his own

At the core of such complaints was an underlying assumption of bias towards Sarepta, and the patient community, which Califf said he acknowledged.

“Overall, while I recognize the strain created by political and public pressures, given Dr. Woodcock’s well documented history of not bowing to such influences and a record in this case showing her close consideration of all relevant scientific evidence, I do not find that this deviated from her responsibility as Center Director, nor do I find that she succumbed to pressure from the patient community, the public, the press, or others.”

Califf defended Woodcock saying her “hands-on” management style has been a characteristic of her career thus far, and was not related to eteplirsen specifically. He said he acknowledged that her “general pattern of discourse and involvement” was not “typical,” but affirmed that he did not “find that her conduct was in conflict with the job requirements for Center Directors at the FDA.”

A Complex Process

MedPage Today spoke with two members of the advisory committee about the FDA’s final decision, which went against their recommendation.

The process of approving a drug is very complex, said Aaron Kesselheim, MD, JD, MPH, of Brigham and Women’s Hospital in Boston, and a temporary advisory committee member who voted against approving eteplirsen. “As an advisory committee member, you are only involved in one small slice of the decision-making process.”

Kesselheim said that he could not say whether the FDA’s ultimate decision was a surprise. He added that he knew that the agency received additional data on eteplirsen prior to its decision, but that he had not been able to review that data in depth.

“I’m hopeful that the effectiveness of the drug ends up being validated in additional trials,” he said, referring to the agency’s approval requirement of post-market research. “It’s a terrible disease, and the current treatment options, there aren’t a lot of them. So if this drug does turn out to work in helping extend people’s lives and making them better, that would be a great thing.”

Richard Kryscio, PhD, of the Sanders-Brown Center on Aging at the University of Kentucky in Lexington also voted against recommending the accelerated approval of eteplirsen. He called the data presented at the April review as only “borderline.”

However, he pointed out that “this is a rare disease, and the more we learn about the therapy that’s being suggested here, I think the better off we’ll be.” He noted that the FDA has asked Sarepta for additional data, including dose-response data, as a stipulation of approval.

Kryscio said he encourages parents in DMD activist groups to stay involved in the postmarketing research by getting patients to enroll in postapproval studies, “so we can get the kinds of data that we need.”

FDA Ruffles Feathers by Delaying DMD Tx Review

WASHINGTON — Two drugs are competing for FDA approval as treatment for Duchenne muscular dystrophy (DMD), and the agency upset DMD advocates by delaying review of one of the drugs.

On Tuesday, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee discussed the safety and efficacy of BioMarin’s drisapersen (Kyndrisa), which is thought to slow the progression of DMD.

They had been set to discuss Sarepta’s eteplirsen this week, but that review was pushed to late January, and DMD advocates were frustrated by the agency’s decision.

In an Oct. 19 letter to Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research (CDER), they explained that the consequences of postponing eteplirsen’s review could affect providers’ prescribing habits and payer decisions.

“Families have been expressing concerns around potential approvals and the impact such decisions have on provider prescribing recommendation and the ability of providers to have adequate information on both compounds in order to recommend the most appropriate therapy for each patient,” they wrote. “These families also will need to navigate a complex payer environment and are concerned about being locked into an initial drug even if another therapy becomes available.”

The letter was signed by the Duchenne Alliance, Parent Project Muscular Dystrophy, The Race to Yes, and the “Be Reasonable” campaign from the Center for Duchenne Muscular Dystrophy at the University of California Los Angeles.

The representatives of the DMD community asked Woodcock to explain the reason for delaying the review and urged her to reconsider the change. A representative of Parent Project Muscular Dystrophy told MedPage Today that they had not received a response from Woodcock as of Tuesday.

DMD is a rare genetic disorder found only in boys, The disease causes severe deterioration of the muscles, leaving most boys too weak to walk in their teenage years. Most DMD patients live only until their mid-20s or early 30s. There is no cure for this disease.

The muscular degeneration seen in DMD is caused by an aberration in a gene that produces the protein dystrophin, without which muscles can’t function.

Both of the proposed drugs proposed are exon-skipping therapies that target the genetic aberration responsible for producing dystrophin. Drisapersen forces the mechanism that produces dystrophin to skip over the aberrant portion of the gene, exon 51, and then allows a “truncated” and “partially functional” form of dystrophin to be produced, according to FDA briefing documents.

While both drug targets the most common mutation in DMD, that mutation accounts for only 13 to 15% of DMD cases. The approval of either drisapersen or eteplirsen would be a boon for other exon-skipping therapies that have been modified to treat forms of DMD with different mutations.

Some patient advocates who support eteplirsen were said they were puzzled by the FDA’s decision to allow the drisapersen meeting to occur before eteplirsen’s review, especially when it appeared that BioMarin did not meet the agency’s request for confirmatory trials, according to The Street.

An FDA representative would not comment to MedPage Today on the completeness of BioMarin’s application. “Under the law, that is confidential information between the FDA and the company and we are not permitted to discuss specifics or release any non-public documents,” the spokesperson told MedPage Today.

In response to questions regarding why the eteplirsen review was delayed until January, the spokesperson told MedPage Today that advisory committee meeting dates are listed as “tentative” and aren’t considered final until posted in the Federal Register.

The spokesperson also wrote that the “FDA recognizes the unmet medical need in Duchenne muscular dystrophy (DMD), the devastating nature of the disease for patients and their families, and the urgency to make new treatments available.”

However, the FDA’s technical review of the research for drisapersen was not yielding positive results.

Drisapersen is administered to only a subset of patients with Duchenne muscular dystrophy, following a genetic test, and given via subcutaneous injection.

In briefing documents, technical reviewers described drisapersen’s safety profile as “concerning.” Regarding the effectiveness of the drug, they wrote “while there may be some evidence suggestive of efficacy of drisapersen, the evidence is inconsistent and in some cases contradictory.”

Terri Ellsworth of Pittsburgh whose son Billy, 14, has DMD, watched Tuesday’s proceedings and told MedPage Today, “it’s a very nervous time for our community.”

Billy has been taking eteplirsen since 2011, when he enrolled in a clinical trial. Eleven other boys received treatment in the same trial. Billy is still able to walk, feed himself, dress himself, activities unthinkable to many of his friends with DMD, she said.

Ellsworth commented that the review of drisapersin did not seem to be going well. Asked whether she was relieved that eteplirsen’s review had been delayed, she said, “I don’t know that I’m relieved. It’s just 2 more months of anxiety, but maybe this delay can be seen as a watch and learn experience.”