Cover story
After eteplirsen A rare disease community contemplates what comes next following approval of a controversial drug LISA M. JARVIS, C&EN CHICAGO
O
n 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. 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,
36
C&EN | CEN.ACS.ORG | NOVEMBER 14, 2016
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
Families from all over the country attended FDA’s advisory board meeting for 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.
CREDIT: DAVID STALLING
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. 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 NOVEMBER 14, 2016 | CEN.ACS.ORG | C&EN
37
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.
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.
Jenn McNary, shown with her sons Max (left) and Austin, was a fierce advocate for the approval of eteplirsen. 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.
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
Full deck
As the Duchenne drug pipeline expands, companies are designing clinical trials in new ways.
PF-06252616 SRP-4045/SRP-4053
DEVELOPER
MODE OF ACTION
Pfizer
Myostatin inhibitor
Sarepta
Skips exon 45 or 53
ezutromid
Summit Therapeutics
Utrophin promoter
CAT-1004
Catabasis
NF-KB inhibition
idebenone
Santhera
Unknown
BMS-986089
III
266
yes
Bristol-Myers Squibb
Myostatin inhibitor
II
40
yes
Nippon Sankyo
Skips exon 53
I/II
14
yes
Ohio State University
Aldosterone antagonist
III
52
noa
Nationwide Children's Hospital
Gene therapy
I
6
yes
ReveraGen BioPharma
Glucocorticoid analog
II
48
no
DS-5141b
Daiichi Sankyo
Skips exon 45
I/II
6
no
TAS-205
Taiho Pharmaceuticals
HPGDS inhibitor
Iia
33
yes
NS-065 eplerenone Micro-dystrophin gene therapy vamorolone
a Eplerenone was compared to spironolactone. Source: clinicaltrials.gov; companies
38
NUMBER PLACEBO PHASE ENROLLED TRIAL AGES males, age 6-15 II 105 yes years old males, age 7-13 III 99 yes years old males, age 5-10 II 40 no years old males, age 4-7 I/II 30 yes years old
C&EN | CEN.ACS.ORG | NOVEMBER 14, 2016
males, all ages males, age 5-10 years old males, age 4-9 years old males, age 10 and older non-ambulant males, age 7 and older males, age 4-6 years old males, age 5-10 years old males, age 5 and older
ENDPOINT four-stair climb six-minute walk test muscle health as measured by MRI muscle health as measured by MRI lung strength as measured by forced vital capacity safety, four-stair climb dystrophin production heart function as measured by cardiac MRI safety safety safety, pharmacokinetics six-minute walk test
CREDIT: CAROLINE CLAFLIN
DRUG
Afer the approval
The news cycle has churned with controversy afer FDA gave eteplirsen the green light. Sept. 28, 2016
Insurers weigh in
Sept. 9, 2016
Exondys gets FDA nod Sarpeta’s eteplirsen, now known as Exondys, is conditionally approved to treat people whose Duchenne muscular dystrophy is caused by a mutation in exon 51. Later that day, the biotech firm says the drug will cost on average $300,000 per year.
Cigna says it will provide broad coverage of Exondys. Oct. 4, 2016 Oct. 6, 2016
First patient dosed A boy at University of Florida Health Shands Children’s Hospital receives the first commerciallyavailable dose of Exondys.
Combination therapy sought Sarepta pays $40 million for the European rights to Summit Therapeutics’ utrophin modulators. The deal follows a smaller agreement to conduct preclinical studies of exon-skipping drugs in combination with Catabasis Pharmaceuticals’ NF-kB inhibitors.
Oct. 14, 2016 Oct. 7, 2016
Anthem controversy Anthem, one of the country’s largest insurers, says it will not cover Exondys. The company later reportedly agrees to cover the drug for a child whose family challenged the policy.
Oct. 20, 2016
JAMA judgment In an editorial in the Journal of the American Medical Association, two Harvard professors, one of whom was on the eteplirsen advisory committee panel, call out eteplirsen’s problematic data, question how patient voices should be integrated into the review process, and caution that the eteplirsen approval could have wider implications at FDA.
“The drug 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.”—Aaron Kesselheim and
CREDIT: U OF FLORIDA
Jerry Avon of Harvard Medical School
Oct. 26, 2016
Conditional coverage Insurer Humana says it will cover Exondys, but with narrow parameters. Most notably, it says boys must be able to walk to receive the drug.
Sarepta’s golden ticket FDA issues Sarepta a priority review voucher, which can be used to shorten the agency’s review of a new drug application by four months. PRVs are transferrable and have been sold for as much as $350 million.
Oct. 19, 2016
FDA hubbub John Jenkins, director of FDA’s Ofce of New Drugs, tells the audience at rare disease summit that the path taken by Sarepta is “not a good model for other development programs.” He devotes several slides to its deficiencies.
Nov. 4, 2016
Surrogate endpoints questioned More documents related to FDA’s review of eteplirsen are released, including emails between ofcials debating the reliability of the limited data on the drug.
“Perhaps granting accelerated approval to drugs that show a mere scintilla of an effect on a surrogate endpoint represents a stroke of brilliance—one that will stimulate investment in the development of drugs for these disorders. But in my opinion, this approach should receive broader public (and FDA) input before being implemented.”—CDER director Ellis Unger in memo to FDA commissioner Robert Califf
Sources: companies, FDA, JAMA NOVEMBER 14, 2016 | CEN.ACS.ORG | C&EN
39
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 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 di-
“The controversy over the approval of eteplirsen, I think, was a little bit of a tempest in a teapot.”
vided 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.” Miles Barnett (standing) is keeping up with his younger brother Pfizer does not after two years on eteplirsen. 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
40
C&EN | CEN.ACS.ORG | NOVEMBER 14, 2016
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 pro-
—Ed Kaye, CEO, Sarepta gresses 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
CREDIT: BARNETT FAMILY
rate 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
CREDIT: DAVID STALLING
The placebo question
addition to dystrophin production, the early letions, “it would be very difficult to do a Duchenne trials relied upon the six-minute Although companies developing placebo-controlled trial” for future drugs, walk test, a measure that regulators critiDuchenne drugs do not think FDA is relaxKaye says, because even fewer boys carry cized during their review of the exon-skiping its expectations for scientific rigor, they the mutations addressed by the next wave ping drugs as potentially unreliable. are well aware that families and advocacy of exon-skipping drugs. “By necessity, Indeed, the next wave of trials incorpogroups might think the barriers to approval we’re going to have a different pathway,” rates new tools and different endpoints that, have been lowered. Now that a drug has he says. together, could provide a better picture of a been approved based on a trial without a Families are well aware of the need to drug’s efficacy. For example, Pfizer and Brisplacebo arm, the families of children with follow the science but argue that flexibility tol-Myers Squibb have each elected to use Duchenne might push back against placein studies will become even more urgent a four-stair climb, which seems to yield less bo-controlled trials in the future. as the pipeline grows. “The number of variable performance, as the primary outThe majority of the clinical trials in the available patients is getting smaller with all come measurement in the Phase II studies past two years have included a placebo the choices, making it more difficult to run of their myostatin inhibitors. Other firms are arm. But now, families have seen a drug trials,” McNary says. “You shouldn’t have to looking at a combination of measurements. approved based on trial in which every boy be penalized for having a rare disease verCatabasis Pharmaceuticals is using musgot the drug. sus a common one.” cle health as measured by MRI imaging as Bolno notes that Wave, which plans to Advocates would like to see creative the primary endpoint of a Phase II study of ask for permission to start clinical trials of solutions—ideally studies that would its inhibitor of NF-κB, a protein complex its DMD drugs in the second half of 2017, allow data to be collected while patients involved in inflammation and muscle degen- wants to design a study that balances the have access to treatments. They are quick eration. Duchenne experts have in recent needs of regulators and families. “A lot of to remind researchers that they are runyears explored whether MRI can acning against an unforgiving clock: curately assess muscle composition, While waiting for effective drugs, and the company’s CEO, Jill Milne, kids will lose the ability to walk. argues that it now can. She notes that Some will die. Catabasis will still use a performance Emily Pritchard has been followmeasurement as the primary ending the eteplirsen story for years. point when it runs a Phase III study. Although her son Jake would not Summit is also incorporating MRI benefit from eteplirsen, his muinto its Phase II study of ezutromid, tation, exon 53, has for years been a small molecule that turns on the eyed by drug firms developing other production of utrophin, a protein exon-skipping therapies. that functions similarly to dystroIn August, Pritchard’s family phin during fetal and early muscle flew to Los Angeles for Jake to be development. An MRI of the muscle screened for Sarepta’s Phase III in healthy boys reveals high water study of its exon 53 and 45 treatand low fat, a balance that reverses ments. To qualify, Jake needed to in boys with Duchenne. Summit’s be able to walk a certain distance in hope is that MRIs taken periodsix minutes, a measure of mobility FDA’s advisory board meeting for eteplirsen was packed that will be the primary endpoint ically during its study will show with young men hoping for the drug’s approval. the drug is stopping or slowing fat for the trial. development. At a check-up in February, Jake Companies developing Duchenne drugs work we’re doing right now is not on the had been able to walk far enough to make say watching two treatments go through the drug discovery side, but rather in making the trial cut-off. But he’s at an age where the review process also has been critical to unsure we work with communities and agendisease causes a precipitous decline in musderstanding the agency’s thinking about the cies to have a study that delivers on what cle function. In August, “unfortunately, he level of improvement it considers necessary everyone expects,” he says. was like 20 meters short on the six-minute for approval. On the heels of the eteplirsen approvwalk test,” Pritchard says. The review process was particularly al, “one of the things we’re evaluating is The family was deeply disappointed. The instructive for Wave Life Sciences, which what does a placebo-controlled trial look two-year exon 53 study is one of the few is one of several firms working on novel like in this space,” Bolno adds. Instead of options left for Jake, who at 12 is too old for exon-skipping drugs. comparing its drug for exon 51 to a placebo, many of other clinical trials underway. If A major takeaway for Wave was that Wave could compare it to eteplirsen—an the drug turns out to work, he will still have regulators wanted exon-skipping drugs to approach that would make it easier to conspent several more years waiting—and losproduce enough dystrophin for boys with vince families to enroll their kids in a trial. ing function. Duchenne to look like people with Becker Complicating the matter is eteplirsen’s As companies, advocates, and regulators muscular dystrophy, a milder disease in conditional approval. Sarepta has agreed pause to reach consensus on how best to which people have a typical or close-to-norto conduct a follow-up “confirmatory” design clinical trials and approve drugs, mal life span. From the line of questioning trial, although the design has yet to be stories like Jake’s remind them of the urin the advisory panels for drisapersen and decided. gency. Parent Project’s Furlong says it is eteplirsen, “what became kind of clear is Sarepta itself will be faced with the platime for everyone involved to regroup and FDA had this 10% dystrophin number in cebo question in the near future. Although approach the challenge with less drama. their head,” CEO Paul Bolno says. That num- it has included a placebo arm in a two-year “We have a lot to do,” she says, “and our ber “was our pole in the ground,” he says. study of drugs addressing other exon dechildren deserve us to do it better.” ◾ NOVEMBER 14, 2016 | CEN.ACS.ORG | C&EN
41
