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After eteplirsen: Duchenne stakeholders contemplate what comes next

After a controversial drug approval, biotech firms and patient advocacy groups look for a consensus on the design of trials for future drugs

by Lisa M. Jarvis
November 14, 2016 | A version of this story appeared in Volume 94, Issue 45


Photo of eteplirsen advisory meeting attendees.
Credit: David Stalling
Families from all over the country attended FDA’s advisory board meeting for eteplirsen.

On Sept. 19, the Food & Drug Administration announced it had granted “accelerated approval,” a conditional stamp based on limited data, to Sarepta Therapeutics’ Duchenne muscular dystrophy treatment eteplirsen.

In brief

FDA’s approval of Exondys, Sarepta’s treatment for Duchenne muscular dystrophy, was the agency’s most contentious decision in recent history. By granting its green light based on tenuous data from just 12 patients, critics say, FDA caved to pressure from advocacy groups to let an expensive, ineffective drug on the market. Now, as debate continues about whether FDA has lowered its standards of scientific rigor, the Duchenne community is grappling with how to move the next wave of treatments forward. Read on to find out how companies and patient groups are negotiating trial designs that combine science and humanity. The process is being watched by advocates for patients with many other rare diseases.

Jump to "After the approval" timeline

The agency’s decision closed a tumultuous chapter for a rare disease community and opened a new one about how drugs should be tested and reviewed. Eteplirsen, the first drug for a deadly disease that affects children, was one of the most closely watched treatments in the pharmaceutical industry. It had also become one of the most contentious.

Critics suggested the agency had bowed to pressure from advocacy groups and, in a potentially precedent-setting decision, gave a pass to a drug that didn’t work. Eteplirsen, now sold under the brand name Exondys, was approved based on a trial of just 12 boys. The study lacked a placebo arm and yielded little evidence—some would argue no evidence—that the drug is effective. Industry watchers were left wondering if FDA had lowered its scientific standards.

Adding to the controversy were documents, released alongside the approval, that laid bare a deep rift within FDA over the drug’s merits. Janet Woodcock, director of the agency’s Center for Drug Evaluation & Research, had lobbied for the drug’s approval despite a negative vote from the agency’s advisory committee, an inconsistency that prompted vehement protests from others within FDA.

Moreover, Sarepta said Exondys would cost on average $300,000 per year. Sticker shock is common in the rare disease space, but given the scant evidence that the drug works, the price was particularly galling. Policy experts argue it sets a disturbing precedent for other so-called precision medicines, potentially burdening the health care system. One insurer, Anthem, initially declined to cover the drug. Another, Humana, put narrow parameters on eligibility.

While debate over the regulatory implications of the eteplirsen approval continues, the Duchenne community is quietly regrouping. Getting a single disease-modifying drug to market has been a years-long ordeal for advocacy groups. As much as families are relieved to see eteplirsen approved, they know they have not finished the race, just completed the first leg.

Sarepta’s drug treats only a small fraction of the people with Duchenne, and it’s not a cure. Dramatically changing the course of the disease will likely require a cocktail of medicines, and in the time that eteplirsen was in the clinic, the pipeline has filled with many other kinds of treatments.

To get the next wave of treatments to market, the Duchenne community—companies, families, regulators, insurers—knows the process needs to get easier. And in fact, this is already happening. Better insight about how the muscle-wasting disease progresses and better ways to measure whether drugs are having an effect on Duchenne are together setting the stage for stronger studies.

But in the aftermath of the eteplirsen approval, all the players acknowledge that a consensus needs to be reached about how to design studies that balance good science with humanity for patients and their families.

“This is a time for a new social contract,” says Pat Furlong, chief executive officer of Parent Project Muscular Dystrophy, a nonprofit she founded in 1994—a decade after her two sons were diagnosed with Duchenne—to push forward treatments for the disease. “All stakeholders should come together and figure out what we’ll accept and what’s going to be best practice.”

The stakes are high: streamlining the drug development process isn’t just critical for Duchenne patients. It matters for people with the thousands of other rare diseases that don’t have cures.

The trek

The genetic driver of Duchenne was discovered in 1986. A year later, researchers figured out that the gene encoded a protein, dystrophin, that is essential for maintaining strong skeletal and heart muscles.

Credit: Caroline Claflin
Jenn McNary, shown with her sons Max (left) and Austin, was a fierce advocate for the approval of eteplirsen.
Photo of Jenn McNary and her sons Max and Austin.
Credit: Caroline Claflin
Jenn McNary, shown with her sons Max (left) and Austin, was a fierce advocate for the approval of eteplirsen.

Like the springs that connect a trampoline to its frame, dystrophin helps cushion the stress our daily activities have on our muscles. Without it, muscles slowly break down. By their early to mid-teens, most people—they are almost always boys—with Duchenne are wheelchair-bound. By their late teens to early 20s, many are unable to perform basic life functions, such as eating or using the bathroom, without assistance. By their late 20s to early 30s, they are dead. Roughly 20,000 new cases are diagnosed around the world each year.

Dystrophin turns out to be the largest-known human gene, carrying the recipe for a giant protein. That size leaves a lot of room for error, and the lion’s share of cases of Duchenne are caused by mutations that delete exons, or chunks of genetic code, from the gene, thereby preventing cells from building the protein.

In the past decade, two companies, Sarepta and Prosensa, developed drugs targeting boys with a deletion in exon 51, a mutation that affects about 13% of the Duchenne population. Both companies used oligonucleotides—albeit with differing backbone chemistry—to allow protein synthesis machinery to skip over the missing stretch of code and make the rest of the protein.

The two exon-skipping drugs were put on divergent pathways to approval. Prosensa, which initially partnered with GlaxoSmithKline and later was acquired by BioMarin Pharmaceutical, tested drisapersen in hundreds of kids, including a large Phase III study with a placebo arm. In January, FDA rejected the drug on the basis of shaky evidence of its efficacy and side effects that many worried would be magnified if the drug were given to the larger patient population.

Sarepta, meanwhile, put its exon-skipping drug into a study of just 12 boys, all of whom received the drug, and asked for “accelerated approval.” That route allows FDA to weigh the efficacy of a drug on the basis of a surrogate endpoint, in this case dystrophin production, rather than a functional endpoint, such as how far a boy can walk in a six-minute test or whether he lives longer.

Anecdotes from families, highlighted in mainstream media outlets throughout the course of the study, suggested Sarepta’s drug was slowing the disease’s progression. Some boys seemed to be walking farther and were stronger than expected.

But the anecdotes aren’t supported by the dystrophin data extracted from muscle biopsies taken during the trial. The small data sample showed the drug increases dystrophin production on average by just 0.9% of the level seen in a person without Duchenne. Moreover, panelists had doubts about the reliability of the method used to measure that tiny amount of dystrophin in muscle fiber.

At a heart-wrenching advisory committee meeting—one closely watched by other rare disease groups—families and advocacy groups argued that the balance of evidence suggested the drug works and is safe. They implored FDA to allow access in the near term and pull eteplirsen from the market if it later turned out to be unsafe or ineffective.

The advisory committee looked at the scientific evidence and did not agree, recommending FDA reject Sarepta’s new drug application.

For months after, families were on edge. “It was terrifying. I really thought they weren’t going to approve it,” recalls Erin Barnett, whose son, Miles, had participated in a six-month study of drisapersen and later was one of the first kids enrolled in a larger study of eteplirsen.

Barnett knows eteplirsen isn’t a cure. Because she hasn’t seen data from her son’s trial, she can’t even be sure it is working. But after two years of watching Miles, who is now 9, on the drug, she thinks that it’s helping. “He’s not falling, he’s not tired, he’s walking through Costa Rica and Europe by himself,” she says.

The fear she felt wasn’t just about losing access to eteplirsen. She worried that, without the approval, the entire field would be set back, and she is counting on combination therapies to emerge while her son is young enough to benefit from them. “We really felt like the sooner this gets pushed through … the sooner we can move on and the community can concentrate our efforts on other drugs,” Barnett says.

Mixed emotions

Given the hard-fought battle to get eteplirsen on the market, one would expect to find families still celebrating their victory. But the news is bittersweet. The same advocates who for years had enjoyed a deep well of sympathy in the press are now stung by the constant stream of criticism of the eteplirsen approval.

The negative reaction began on social media the moment the approval was announced. That feedback machine continues to churn today, as everyone from insurers to policy-makers to investors weighs in on the broader impact of the decision and the appropriate way to incorporate patient voices into drug development.

“As a community, it feels to me like we’re learning to fly a plane while we’re 35,000 feet up and in a storm,” PPMD’s Furlong says.

Speaking a month after the eteplirsen decision, Furlong sounds weary. The previous week had brought two separate public critiques of the drug. John Jenkins, director of FDA’s Office of New Drugs, told an audience at a rare disease conference that it never should have been approved. And two Harvard physicians penned a tough editorial in the Journal of the American Medical Association calling eteplirsen “a worrisome model for the next generation of molecularly targeted therapies” (2016, DOI: 10.1001/jama.2016.1643).

In response to those criticisms, Furlong ticks off a litany of reasons it can be difficult to get a clear readout from Duchenne trials. The message underlying all of them is that the Duchenne population is highly heterogenous, making it hard to predict the disease course for any one boy. That difficulty is exacerbated by the different drugs—steroids, heart drugs, growth hormones—that doctors use to care for kids.

Advocates are frustrated at the hubbub over eteplirsen. The goal in pushing for accelerated approval was always to find “ethical ways to get reliable data” while also providing access to the drug, says Jenn McNary, who has two sons with Duchenne. “I think that’s lost in the mix. Now we’re talking about personalities and conflict and comments at conferences.”

McNary has been a fierce advocate for early approval of eteplirsen. Her younger son, Max, had a spot in the early trial, while her older son, Austin, had to wait until a new trial years later.

At 15, Max is still walking—even wowing his physical therapist by running down the hall at a visit last month. McNary is sure the drug is helping him, but she also acknowledges that not all kids seem to get the same benefit. “The bottom line is maybe these drugs work really well in some kids and less well in other kids,” she says. “We are going to find that out, but we need access while you negotiate and debate the science.”

Moving on

Photo of Miles Barnett.
Credit: Barnett family
Miles Barnett (standing) is keeping up with his younger brother after two years on eteplirsen.

While the patient community takes stock, companies are watching to see whether regulators shift their approach to reviewing other drugs for rare diseases.

“The controversy over the approval of eteplirsen, I think, was a little bit of a tempest in a teapot,” says Ed Kaye, Sarepta’s CEO. “I think what happened is that FDA used all of their legal approaches to get the drug approved because it is a huge unmet medical need.”

The documents released after the approval show that FDA managers were deeply divided over the decision, leaving many agency watchers to wonder whether FDA will take that approach for a rare disease again.

“This is the only example right now where FDA has given an accelerated approval on a study with a few patients and no placebo,” says Greg LaRosa, chief scientific officer of Pfizer’s rare disease unit. “Whether that’s really going to become the more mainstream process the agency will look toward with some of these rare diseases, we just don’t know yet.”

Pfizer does not anticipate changing its clinical strategy for PF-06252616, an antibody that inhibits myostatin, a protein that prevents muscle cell growth—currently in a two-year Phase II trial in Duchenne—or for a recently acquired gene therapy that has yet to be tested in humans.

Although FDA leaders have, in the past month, made public comments at conferences about the decision, the agency turned down an interview request, saying it will not be doing any media interviews related to eteplirsen. “In this era of precision medicine, the agency expects that the issues associated with developing therapies for rare diseases will be magnified,” an FDA spokesperson said in a statement to C&EN.


The angst over the FDA decision, drug company executives say, has diverted attention from just how far the Duchenne field has come in recent years. Companies now know far more about the basic biology and pathogenesis of Duchenne than they did when the two exon-skipping drugs went into the clinic. As a consequence, they are now better equipped to run good studies.

“I think the Sarepta decision is an outlier,” says Glyn Edwards, CEO of Summit Therapeutics. “There’s a very clear picture emerging of what you need to do to get an approval.”

Two key developments are helping shape the template for future drug programs: Much better data on how the disease progresses in boys with Duchenne and clearer direction from FDA, both through formal guidance and from the questions asked during its panels, about what it considers to be acceptable measurements for approval.

The first development—better natural history data for Duchenne—has been critical to designing trials that quickly yield clear results. By understanding the natural course of the disease, companies can put the appropriate people into their trials, a step that vexed earlier studies. Indeed, Sarepta and BioMarin have argued that the results from their exon-skipping studies were muddied by including boys who never had a chance of markedly benefiting from their drugs.

When Sarepta’s study of eteplirsen began in 2011, “we did not understand the natural history of DMD,” Kaye says. The field lacked good information about how kids performed over time on tests that were being used to determine the efficacy of drugs. Part of the problem was the dearth of data and part was the impact of steroids, which have become a routine part of Duchenne care because they help boys walk longer.

The second development was FDA’s release last year of a lengthy guidance document—crafted with input from advocacy groups—outlining its thinking about acceptable trial design.

Companies say the document has provided much-needed clarity about endpoints. In addition to dystrophin production, the early Duchenne trials relied upon the six-minute walk test, a measure that regulators criticized during their review of the exon-skipping drugs as potentially unreliable.

Indeed, the next wave of trials incorporates new tools and different endpoints that, together, could provide a better picture of a drug’s efficacy. For example, Pfizer and Bristol-Myers Squibb have each elected to use a four-stair climb, which seems to yield less variable performance, as the primary outcome measurement in the Phase II studies of their myostatin inhibitors. Other firms are looking at a combination of measurements.

Catabasis Pharmaceuticals is using muscle health as measured by MRI imaging as the primary endpoint of a Phase II study of its inhibitor of NF-κB, a protein complex involved in inflammation and muscle degeneration. Duchenne experts have in recent years explored whether MRI can accurately assess muscle composition, and the company’s CEO, Jill Milne, argues that it now can. She notes that Catabasis will still use a performance measurement as the primary endpoint when it runs a Phase III study.

Summit is also incorporating MRI into its Phase II study of ezutromid, a small molecule that turns on the production of utrophin, a protein that functions similarly to dystrophin during fetal and early muscle development. An MRI of the muscle in healthy boys reveals high water and low fat, a balance that reverses in boys with Duchenne. Summit’s hope is that MRIs taken periodically during its study will show the drug is stopping or slowing fat development.

Companies developing Duchenne drugs say watching two treatments go through the review process also has been critical to understanding the agency’s thinking about the level of improvement it considers necessary for approval.

The review process was particularly instructive for Wave Life Sciences, which is one of several firms working on novel exon-skipping drugs.

A major takeaway for Wave was that regulators wanted exon-skipping drugs to produce enough dystrophin for boys with Duchenne to look like people with Becker muscular dystrophy, a milder disease in which people have a typical or close-to-normal life span. From the line of questioning in the advisory panels for drisapersen and eteplirsen, “what became kind of clear is FDA had this 10% dystrophin number in their head,” CEO Paul Bolno says. That number “was our pole in the ground,” he says.

Full deck

As the Duchenne drug pipeline expands, companies are designing clinical trials in new ways.

Drug Developer Mode of Action Phase Number Enrolled Placebo Trial Ages Endpoint
PF-06252616 Pfizer Myostatin inhibitor II 105 yes males, age 6-15 years old four-stair climb
SRP-4045/SRP-4053 Sarepta Skips exon 45 or 53 III 99 yes males, age 7-13 years old six-minute walk test
ezutromid Summit Therapeutics Utrophin promoter II 40 no males, age 5-10 years old muscle health as measured by MRI
CAT-1004 Catabasis NF-kB inhibition I/II 30 yes males, age 4-7 years old muscle health as measured by MRI
idebenone Santhera Unknown III 266 yes males, all ages lung strength as measured by forced vital capacity
BMS-986089 Bristol-Myers Squibb Myostatin inhibitor II 40 yes males, age 5-10 years old safety, four-stair climb
NS-065 Nippon Sankyo Skips exon 53 I/II 14 yes males, age 4-9 years old dystrophin production
eplerenone Ohio State University Aldosterone antagonist III 52 noa males, age 10 and older heart function as measured by cardiac MRI
Micro-dystrophin gene therapy Nationwide Children's Hospital Gene therapy I 6 yes non-ambulant males, age 7 and older safety
vamorolone ReveraGen BioPharma Glucocorticoid analog II 48 no males, age 4-6 years old safety
DS-5141b Daiichi Sankyo Skips exon 45 I/II 6 no males, age 5-10 years old safety, pharmacokinetics
TAS-205 Taiho Pharmaceuticals HPGDS inhibitor Iia 33 yes males, age 5 and older six-minute walk test

Drug: PF-06252616
Developer: Pfizer
Mode of action: Myostatin inhibitor
Phase: II
Number enrolled: 105
Placebo trial: yes
Ages: males, age 6-15 years old
Endpoint: four-stair climb

Drug: SRP-4045/SRP-4053
Developer: Sarepta
Mode of action: Skips exon 45 or 53
Phase: III
Number enrolled: 99
Placebo trial: yes
Ages: males, age 7-13 years old
Endpoint: six-minute walk test

Drug: ezutromid
Developer: Summit Therapeutics
Mode of action: Utrophin promoter
Phase: II
Number enrolled: 40
Placebo trial: no
Ages: males, age 5-10 years old
Endpoint: muscle health as measured by MRI

Drug: CAT-1004
Developer: Catabasis
Mode of action: NF-kB inhibition
Phase: I/II
Number enrolled: 30
Placebo trial: yes
Ages: males, age 4-7 years old
Endpoint: muscle health as measured by MRI

Drug: idebenone
Developer: Santhera
Mode of action: Unknown
Phase: III
Number enrolled: 266
Placebo trial: yes
Ages: males, all ages
Endpoint: lung strength as measured by forced vital capacity

Drug: BMS-986089
Developer: Bristol-Myers Squibb
Mode of action: Myostatin inhibitor
Phase: II
Number enrolled: 40
Placebo trial: yes
Ages: males, age 5-10 years old
Endpoint: safety, four-stair climb

Drug: NS-065
Developer: Nippon Sankyo
Mode of action: Skips exon 53
Phase: I/II
Number enrolled: 14
Placebo trial: yes
Ages: males, age 4-9 years old
Endpoint: dystrophin production

Drug: eplerenone
Developer: Ohio State University
Mode of action: Aldosterone antagonist
Phase: III
Number enrolled: 52
Placebo trial: noa
Ages: males, age 10 and older
Endpoint: heart function as measured by cardiac MRI

Drug: Micro-dystrophin gene therapy
Developer: Nationwide Children’s Hospital
Mode of action: Gene therapy
Phase: I
Number enrolled: 6
Placebo trial: yes
Ages: non-ambulant males, age 7 and older
Endpoint: safety

Drug: vamorolone
Developer: ReveraGen BioPharma
Mode of action: Glucocorticoid analog
Phase: II
Number enrolled: 48
Placebo trial: no
Ages: males, age 4-6 years old
Endpoint: safety

Drug: DS-5141b
Developer: Daiichi Sankyo
Mode of action: Skips exon 45
Phase: I/II
Number enrolled: 6
Placebo trial: no
Ages: males, age 5-10 years old
Endpoint: safety, pharmacokinetics

Drug: TAS-205
Developer: Taiho Pharmaceuticals
Mode of action: HPGDS inhibitor
Phase: Iia
Number enrolled: 33
Placebo trial: yes
Ages: males, age 5 and older
Endpoint: six-minute walk test

Source:; companies
a Eplerenone was compared to spironolactone.

The placebo question

Photo of eteplirsen advisory meeting attendees.
Credit: David Stalling
FDA’s advisory board meeting for eteplirsen was packed with young men hoping for the drug’s approval.

Although companies developing Duchenne drugs do not think FDA is relaxing its expectations for scientific rigor, they are well aware that families and advocacy groups might think the barriers to approval have been lowered. Now that a drug has been approved based on a trial without a placebo arm, the families of children with Duchenne might push back against placebo-controlled trials in the future.

The majority of the clinical trials in the past two years have included a placebo arm. But now, families have seen a drug approved based on trial in which every boy got the drug.

Bolno notes that Wave, which plans to ask for permission to start clinical trials of its DMD drugs in the second half of 2017, wants to design a study that balances the needs of regulators and families. “A lot of work we’re doing right now is not on the drug discovery side, but rather in making sure we work with communities and agencies to have a study that delivers on what everyone expects,” he says.

On the heels of the eteplirsen approval, “one of the things we’re evaluating is what does a placebo-controlled trial look like in this space,” Bolno adds. Instead of comparing its drug for exon 51 to a placebo, Wave could compare it to eteplirsen—an approach that would make it easier to convince families to enroll their kids in a trial.

Complicating the matter is eteplirsen’s conditional approval. Sarepta has agreed to conduct a follow-up “confirmatory” trial, although the design has yet to be decided.

Sarepta itself will be faced with the placebo question in the near future. Although it has included a placebo arm in a two-year study of drugs addressing other exon deletions, “it would be very difficult to do a placebo-controlled trial” for future drugs, Kaye says, because even fewer boys carry the mutations addressed by the next wave of exon-skipping drugs. “By necessity, we’re going to have a different pathway,” he says.

Families are well aware of the need to follow the science but argue that flexibility in studies will become even more urgent as the pipeline grows. “The number of available patients is getting smaller with all the choices, making it more difficult to run trials,” McNary says. “You shouldn’t have to be penalized for having a rare disease versus a common one.”

Advocates would like to see creative solutions—ideally studies that would allow data to be collected while patients have access to treatments. They are quick to remind researchers that they are running against an unforgiving clock: While waiting for effective drugs, kids will lose the ability to walk. Some will die.

Emily Pritchard has been following the eteplirsen story for years. Although her son Jake would not benefit from eteplirsen, his mutation, exon 53, has for years been eyed by drug firms developing other exon-skipping therapies.

In August, Pritchard’s family flew to Los Angeles for Jake to be screened for Sarepta’s Phase III study of its exon 53 and 45 treatments. To qualify, Jake needed to be able to walk a certain distance in six minutes, a measure of mobility that will be the primary endpoint for the trial.

At a check-up in February, Jake had been able to walk far enough to make the trial cut-off. But he’s at an age where the disease causes a precipitous decline in muscle function. In August, “unfortunately, he was like 20 meters short on the six-minute walk test,” Pritchard says.

The family was deeply disappointed. The two-year exon 53 study is one of the few options left for Jake, who at 12 is too old for many of other clinical trials underway. If the drug turns out to work, he will still have spent several more years waiting—and losing function.

As companies, advocates, and regulators pause to reach consensus on how best to design clinical trials and approve drugs, stories like Jake’s remind them of the urgency. Parent Project’s Furlong says it is time for everyone involved to regroup and approach the challenge with less drama. “We have a lot to do,” she says, “and our children deserve us to do it better.” 

After the approval

The news cycle has churned with controversy after FDA gave eteplirsen the green light.
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