Moms, Regulators, Biotech Startups, and the Battle Over a Potentially Life-Saving Drug

Moms, regulators, biotech startups, and the battle over a potentially life-saving drug

Leffler's son Aidan was diagnosed with Duchenne in 2006
Photograph by Ryan Pfluger

The 2014 World Cup elevated soccer to the top of Aidan Leffler’s roster of obsessions, rivaled only by endangered big cats—especially jaguars, “the coolest”—and Star Wars spaceships. In recognition of his new interest, he’s set up a miniature soccer field with 4-foot-wide goals in his backyard in suburban Bellevue, Wash. “Watch this!” he shouts, preparing to fire a penalty kick.

Small for his age, Aidan, 11, moves awkwardly, shoulders high and hunched. He uses a lightweight plastic beach ball, not a regulation leather soccer ball. He begins his approach, pulls back his right foot, and … collapses to the grass.

Mitch Leffler, the sole spectator, moves toward his son. “I’m OK,” Aidan says. “I can do it.” He struggles onto his hands and knees, raises his butt, places his hands one at a time on his thighs, and slowly pushes himself into an upright position. “My leg just wasn’t there,” he says matter-of-factly. His father nods, and the game resumes.

Aidan has Duchenne, the deadliest strain of muscular dystrophy. It’s inherited maternally on the X chromosome and mostly afflicts boys. Parents typically sense something is wrong when their sons at 3 or 4 don’t run around or they start falling for no obvious reason. Beginning in the legs, Duchenne destroys muscle, which is replaced by fat and scar tissue. Victims lose the ability to walk by adolescence. Eventually the disease causes cardiac and/or respiratory complications that lead to death by the mid-20s. One in 3,500 newborns has Duchenne, which translates to around 15,000 cases in the U.S. There’s no cure.

“Aidan doesn’t really understand yet,” his mother, Mindy, says, “but it’s basically a slow-motion death sentence.”

There’s reason to hope—not for a miracle, but for a reprieve. Three small biotech companies are competing to develop drugs designed to address the cellular defects that cause some cases of Duchenne. If proven safe and effective, the drugs would turn Duchenne into a less devastating form of muscular dystrophy. Clinical trials, however, have yielded uneven results, and the U.S. Food and Drug Administration has made equivocal pronouncements about which of the drugs, if any, have a shot at approval. Even a marginally effective drug would likely command an astronomical price, making the winning company a billion-dollar sensation.

The hunt for a Duchenne treatment has generated a collision of commerce, cutting-edge science, and Wall Street speculation. The FDA, though, seems flummoxed over how to evaluate the experimental drugs, especially given a lack of large, clearly successful randomized studies. That’s left the Lefflers confused and increasingly desperate.

McSherry with her son, Jett, who began college this fall
Photograph by Ryan Pfluger

Mindy believes that one experimental treatment—eteplirsen, made by a company called Sarepta Therapeutics—has shown sufficient promise in a tiny trial to warrant wider availability. If approved, eteplirsen might help 13 percent of Duchenne boys who have certain genetic flaws. Mindy’s son is among the 13 percent. “I want Aidan on that drug,” she says, “and I want it to happen before he’s in a wheelchair or worse.”

She and a group of similarly minded moms are pressuring the FDA to give provisional approval to eteplirsen while Sarepta proceeds with confirmatory studies. Taking to Twitter, Facebook, YouTube, and Instagram, they’ve got the attention of top FDA officials. They’ve also encountered resistance from career FDA staff members and some rare-disease advocates alarmed by their assertiveness.

“What’s hard to understand,” says Mindy’s friend Jennifer McNary, “is why the whole Duchenne community and the FDA aren’t pulling together behind eteplirsen.” McNary, who lives south of Boston, has two sons with the disease. Maternal genetic predisposition sometimes results in such sibling pairs. Max McNary, 12, gets eteplirsen in the small Sarepta trial; over the past two-and-a-half years, his symptoms have eased remarkably. Max’s older brother, Austin, 15, didn’t qualify for the study because he was already in a wheelchair when it started. He’s declining physically, losing the use of his arms and having trouble feeding himself.

“Why doesn’t the government let me have eteplirsen?” Austin asks when we meet. He waits for an answer, which I don’t have. His mother joins the conversation: “The FDA’s inaction,” she says, “is killing my son.”

Mindy agrees with Jennifer and Austin. “Aidan doesn’t have time to wait for a perfect placebo-controlled trial with hundreds of subjects,” she says. “The benefits outweigh any risks.”
In 1986 researchers at Harvard isolated the gene responsible for making the protein dystrophin, a “shock absorber” that surrounds muscle cells. Boys with Duchenne have one of several genetic defects that inhibit production of dystrophin. Without it, ordinary physical exertion causes progressive muscle breakdown. The disease is named for Guillaume Duchenne, a French neurological pioneer who described the symptoms in the 1860s.

For generations, physicians reacted passively to Duchenne. Patricia Furlong’s sons, Christopher and Patrick, were diagnosed in 1984. Her doctor told her to “take them home and love them, because there was nothing medicine could do.” A former nurse with a stubborn streak, she began traveling the country from her home in central Ohio, pleading with researchers to look for a cure. “She was at NIH [National Institutes of Health]. She was on Capitol Hill. She was in my office,” recalls Eric Hoffman, a genetic researcher at Children’s National Medical Center in Washington. “Pat would not be denied.” She couldn’t save her sons, however, who died in the mid-1990s.

Angered by what she describes as the fatalism she encountered at the Muscular Dystrophy Association—sponsor of the long-running Labor Day telethon hosted by actor Jerry Lewis—Furlong formed a breakaway nonprofit: Parents Project Muscular Dystrophy, dedicated strictly to Duchenne. In 2001, largely because of her agitation, Congress passed the Muscular Dystrophy CARE Act, which over the following decade provided more than $400 million in funding, much of it for Duchenne research. The federal backing, says Hoffman, “got the biotech companies thinking maybe there’s money to be made with a Duchenne drug.”

A startup in New Jersey called PTC Therapeutics focuses on mutations that block dystrophin production. These “nonsense mutations” are akin to a period mistakenly placed in the middle of a sentence, which makes the genetic code incomprehensible. In 2008, Genzyme, a much larger biotech, gave credibility to PTC’s research by paying the tiny company $100 million upfront to secure future marketing rights to its drug outside North America.

Prosensa, a Dutch biotech, targets a different type of flaw in the exons, or segments, of the dystrophin gene. By “skipping” a defective exon, Prosensa’s compound is supposed to allow the formation of a truncated version of dystrophin. In 2009 the pharmaceutical giant GlaxoSmithKline added momentum to exon-skipping research by paying Prosensa $25 million upfront for development and marketing rights and promising hundreds of millions more in future compensation.

In the U.S., Sarepta was also angling to get into the Duchenne chase. Choosing to work without a larger corporate partner, it began testing eteplirsen, an exon-skipping compound that relies on a different biochemical recipe from Prosensa’s drug.

The proliferation of potential treatments gave the Lefflers reason for optimism after years of mounting apprehension. Aidan had first been diagnosed in 2006, at the age of almost 3, after breaking his leg while playing on a slide. As he lost strength, his parents installed an elevator at home so he could avoid stairs, but for the most part he remained ambulatory.

Mindy dug into the science of Duchenne, finding solace in genetics and chemistry, subjects she’d avoided as an English major in college. She works part-time developing software for a tech company and time-and-a-half seeking care for Aidan. Mitch—she met her husband in the early 1990s when they were Seattle-area high school track stars—teaches gym and takes a lot of responsibility for Aidan’s two younger siblings. In 2010, the Lefflers felt inspired when the New Yorker published an article titled “Mother Courage” that described how the death of Furlong’s sons propelled her campaign against Duchenne. “I thought, wow, Pat really got a lot done,” says Mindy, “and now we’re going to take the next step and actually find a treatment for Aidan, so he doesn’t end up like Pat’s boys.”

In 2011, Mitch took Aidan to a hospital in Columbus, Ohio, where Sarepta was beginning a trial for eteplirsen. Then 7, Aidan was showing such ominous symptoms as knotty, seemingly overdeveloped calves—evidence of scar tissue swiftly replacing muscle. He performed well on a baseline walking test. Too well, it turned out: He was rejected for the study because he was much healthier than most other subjects whose disease was more advanced.

As a fallback, Mindy hustled to get Aidan enrolled in a 180-person Prosensa-GlaxoSmithKline trial at a test site in Vancouver. The trial proved to be an ordeal. Multiple muscle biopsies to check dystrophin levels required Aidan to undergo surgery with general anesthesia. And almost immediately, Leffler suspected he was receiving a saline-solution placebo, rather than injections of Prosensa’s drug. She figured this out when he didn’t have the swelling and pain other moms said their sons experienced.

For 48 weeks, Aidan’s parents took him by plane or car to Vancouver every week for stays ranging from a few hours to several days, depending on the protocol, all the while suspecting he wasn’t actually receiving medication. “This may be good for science,” Leffler says she thought at the time, “but how’s it good for my son?”

McNary with her sons, Max (left), who is receiving treatment, and Austin, who isn't
Photograph by Ryan Pfluger

In late 2012, researchers switched all of the subjects on placebo over to treatment with Prosensa’s compound, drisapersen. Aidan began to suffer the side effects from getting the drug, but Leffler couldn’t tell whether his Duchenne symptoms were easing. “He fluctuated: sometimes better, sometimes worse,” she says.

Over time, Leffler became jealous of moms with sons in the Sarepta study—the one from which Aidan had been rejected—because the company was reporting solid results. In October 2012, Sarepta announced that, after 48 weeks, boys receiving eteplirsen had stabilized, with statistically significant improvement in a standardized six-minute walking test. Moreover, unlike the Prosensa drug, which at higher doses creates risks that could lead to kidney damage, the Sarepta study didn’t show any dangerous side effects.

The weakness of the Sarepta trial was that it had enrolled only 12 boys. Started in 1980 at the dawn of the biotech era, the company had gone public in 1997 but never put a drug on the market. After a series of management shake-ups, a newly hired chief executive officer, Chris Garabedian, decided in 2011 to bet Sarepta’s few remaining chips on eteplirsen. The company simply couldn’t afford a larger trial. “We had a limited amount of drug and no capacity to make more,” Garabedian says. “So we took what we had and did the best small trial we could design.” Sarepta’s shortage of eteplirsen also precluded providing the drug to individual applicants under the FDA’s “compassionate use” program.

Despite the skimpy sample size, Sarepta’s results ignited a stock market frenzy. The company’s shares rose threefold on Oct. 3, 2012, to $45. CNBC stockpicker Jim Cramer raved about Sarepta on his Mad Money show and interviewed Garabedian on camera. In June 2013, PTC announced an initial public offering that raised $144 million. In their enthusiasm, investors were willing to overlook that PTC’s drug, ataluren, had failed to show statistically significant improvement in subjects’ walking ability in a clinical trial three years earlier. Prosensa soon followed with its own IPO, raising $90 million, even though it hadn’t yet reported results from its main ongoing clinical study. In July, Sarepta added to the bullishness by announcing that the FDA had provided guidance that it was open to considering eteplirsen for regulatory approval. (The agency routinely communicates with companies as they move toward a “new drug application.”)

“It felt like a lot of good stuff was coming together,” Leffler recalls.

Then the bubble burst. In September 2013, only three months after its IPO, the Prosensa-GSK trial in which Aidan was enrolled failed to show meaningful improvement on the six-minute walk test. The study was shut down, and Prosensa’s stock plummeted 70 percent in a day. “No one called us,” says Leffler. “We learned that the trial was over from a GSK investor conference call. … There’s no safety net. You just crash.” London-based GSK and Prosensa later terminated their partnership.

More bad news followed in November: After encouraging Sarepta to apply for approval of eteplirsen, the FDA reversed itself and called such a move “premature.” Explaining its turnaround, the agency cited Prosensa’s and PTC’s trial failures. The FDA expressed “considerable doubt” that dystrophin production—the goal set out by all three companies—could be linked to meaningful clinical benefits. Sarepta’s stock fell 64 percent that day.

The Lefflers received word about the FDA about-face on Sarepta while at Walt Disney World on a vacation with Aidan and his younger brother and sister. After the Prosensa-GSK trial failure, “it was a double blow,” Mindy says. “I felt like I couldn’t breathe.”
After collecting herself, Leffler decided to fight. She’d already been communicating with two other moms she’d met via Facebook and at Duchenne conferences: McNary, who had the exquisitely painful situation of one son doing well in the Sarepta trial while his older brother, denied the drug, declined, and Christine McSherry, whose son, Jett, then a wheelchair-bound high school senior, struggled to sit up straight.

“The three of us, the ‘Three Musketeers,’ had a lot of the same questions,” McSherry says. Why had Prosensa’s and PTC’s setbacks influenced the FDA to shun Sarepta? After all, the companies used different types of chemistry. The moms also didn’t understand why the incipient scientific consensus on the importance of dystrophin production had suddenly become clouded. “We began to realize that the FDA was confused,” says McSherry, a former nurse who is now 49. “Eteplirsen, a drug that appeared to work, was in danger of becoming a victim to the shortcomings of other drugs and other trials.”

The moms had begun in 2012 demanding personal attention from FDA officials. Remarkably, they got a meeting—then another, and another. In a law enacted that year, Congress instructed the FDA to entertain more flexible paths to provisional approval of rare-disease drugs. Under the aegis of that statute, the trio became self-appointed consultants at FDA headquarters in Silver Spring, Md.

McNary organized an online petition demanding “accelerated approval” of eteplirsen. The 2012 FDA reform statute encouraged the agency to grant accelerated approval based on relatively small trials that achieve a “surrogate” goal—such as dystrophin production—with the burden left on the manufacturer to conduct broader research. The FDA can rescind accelerated approval if follow-up studies don’t demonstrate efficacy. McNary swiftly gathered 180,000 signatures for her petition, and she and other moms bombarded the FDA with tweets, Instagrams, and YouTube videos showing boys in Sarepta’s 12-person trial climbing rocks, dancing, and diving into swimming pools.

McNary’s heart-rending tale became a centerpiece of the lobbying campaign. “I could possibly be the mother of the last child to die from Duchenne and first child to survive it,” she said in a video that zinged around the Internet.

Following its standard policy, the FDA didn’t respond publicly to the lobbying drive. But the agency’s ambivalent reactions could be discerned from private communication with the three moms, who used blogs and websites to report on the back-and-forth. According to the moms, senior FDA leaders sought to reassure the Duchenne parents, while rank-and-file staff members tended to express more skepticism.

In July 2013, McSherry recounted on her blog a conference call with Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research. “As always, Dr. Woodcock was warm, compassionate, and extraordinarily supportive of our position,” McSherry wrote. “We are one step closer to getting this drug [eteplirsen] to our boys.”

Four months later, though, evaluators working under Woodcock’s supervision told Sarepta not to bother applying for approval. Asked for comment, Sandy Walsh, an FDA spokeswoman, says: “Under the law, we are not able to discuss any investigational new drug or any drug application.” She adds that the agency “has been working with Sarepta to provide guidance on various clinical and regulatory issues related to eteplirsen.”

In February 2014, the three moms joined forces with a fourth, Tracy Seckler, to ratchet up the pressure on the FDA by organizing a two-day summit in Washington that included a visit to the agency by several leading Duchenne researchers. The next day, a bipartisan briefing on Capitol Hill sponsored by Representatives William Keating (D-Mass.) and Spencer Bachus (R-Ala.) drew an audience of dozens of congressional staff members.

Louis Kunkel, the Harvard Medical School professor who headed the team that isolated the dystrophin gene in 1986, told the gathering that boys receiving eteplirsen were making dystrophin and called this success “amazing.” Steve Wilton, a leading neuromuscular researcher from Australia, was even more emphatic about eteplirsen’s promise. “In Australia,” he told attendees, “we’d say it’s bleeding obvious.”

Leffler added the moms’ sense of impatience: “The FDA,” she said, “is standing in the way.” Not so, says the agency’s Walsh: “The FDA is fully committed to make safe and effective drugs available for patients with Duchenne as soon as possible and is actively engaged with all drug companies developing new drugs for Duchenne.”

Notably absent from the Washington event was Furlong. She’d held her own Washington round table two months earlier, one that was far more deferential to the FDA’s authority.

In an interview, Furlong, 68, says she was traveling on business in Europe at the time of the February summit and sent a representative from her organization. She decries what she describes as a splintering of “the Duchenne community” she has spent two decades building. Now a stateswoman rather than a firebrand, she criticizes younger mothers such as McNary, 34, who publicly describe their sons as dying. “What must those boys think?” she asks. More broadly, she adds, “It’s just not smart strategy to chain yourself to the gates of the FDA in protest,” an allusion to a tactic once used by AIDS activists.

While the more aggressive Duchenne moms haven’t actually chained themselves to anything, their tone at times is abrasive. In March 2014, McNary appeared on John Stossel’s government-bashing Fox Business News television show. A subscript running across the screen morphed from “Government Medicine Bullies” to “FDA Regulations Can Kill.” Stossel asked McNary whether her son Austin is “angry” because he couldn’t get eteplirsen.

“Fifteen-year-olds in general are angry,” McNary responded. “Fifteen-year-olds who are being betrayed by their government are even angrier.” Stossel’s other guest, Darcy Olsen of the libertarian Goldwater Institute, added: “What the FDA is doing here is an abomination.”
In April, without public explanation, the FDA once again reversed its position on eteplirsen, saying Sarepta could move ahead toward regulatory approval. Given the absence of new data, the only plausible reason for the switch was escalating pressure from the three moms and their backers. Five months after rebuffing Sarepta, the FDA laid out a detailed “path forward” for eteplirsen to receive accelerated approval.

The agency’s revised guidance—conveyed privately to Sarepta, then disclosed by the company—stressed government evaluators’ continuing uneasiness regarding the data on eteplirsen. The company would have to conduct larger placebo-controlled studies before provisional approval would become permanent. Still, a closed door had cracked open.

Sarepta immediately said it would seek accelerated authorization by the end of 2014 and launch confirmatory studies. From April 17 to April 22, the company’s stock rose 59 percent.

In June, the regulatory door opened further. Prosensa announced that the FDA would entertain an accelerated-approval application for drisapersen, even though the Dutch company’s drug had failed its main clinical trial in 2013. Regulators’ sudden receptivity struck some observers as peculiar, given the lack of fresh evidence of effectiveness. “It sure looks like the FDA wants to give itself cover and say, ‘See, we’re giving everyone a chance to apply, so parents, stop attacking us,’ ” says Steve Brozak, president of WBB Securities and a longtime analyst of the biotech industry.

Prosensa’s CEO, Hans Schikan, disagrees with Brozak. The unsuccessful 2013 study was devised and run by GSK, he says. “Based on our reanalysis of our data, we strongly believe it was the trial that failed the drug, not the drug that failed the trial.” Flaws in GSK’s study design, he claims, muddied the results.

Adding yet another level of ambiguity to the situation, PTC, which had seemed out of the running for a Duchenne treatment, has reentered the race. “We shot ourselves in the foot” by conceding defeat after the failed 2010 ataluren trial, says Stuart Peltz, PTC’s co-founder and chief executive. After reanalysis of its data, PTC concluded its drug actually works. “In biotech, you’re building the airplane while you’re trying to fly it at the same time,” Peltz continues. “It took us a while to realize that when you focus on the boys with the most severe symptoms, ataluren does show a robust efficacy.” In August the European Union’s equivalent to the FDA granted conditional approval to ataluren, and PTC is beginning to sell the drug in Europe. After completing more clinical trials, Peltz says, his company will apply for full approval in Europe, the U.S., and elsewhere.

Furlong has faith the FDA will sort out which Duchenne drugs are effective. “Ideally,” she says, “we’d like to see all of the drug candidates move forward in the regulatory process.”

The three moms, in contrast, say the FDA’s one-step-back, one-step-forward routine has them feeling unnerved, not reassured. “The boys on eteplirsen are walking when the natural history of the disease says that they should be in wheelchairs,” says Leffler. Why, she wants to know, don’t industry and government cooperate to get as many boys on eteplirsen as quickly as possible?

“That’s not the way medical science works,” says Hoffman, the Duchenne researcher at Children’s National Medical Center. The FDA, Hoffman continues, “is doing the best it can, moving cautiously and looking skeptically at Sarepta’s data, and all of the data from all of the companies.” On Oct. 27, Sarepta announced that as a result of a new round of FDA data requests, the company would have to postpone its application for approval of eteplirsen until mid-2015. Hoffman, who for years has had a close working relationship with Furlong and her organization, expresses sympathy for moms like Leffler, McNary, and McSherry who are impatient for faster action. “They must mean well—their boys are sick,” he says, “but their pressure tactics on the FDA seem like bullying more than anything else.”

Leffler, 42, doesn’t care anymore what anyone calls her tactics. Her determination to get Aidan on eteplirsen became more urgent in August when he fell and fractured the femur in his left leg while kicking a ball in the backyard. Doctors told Aidan’s parents he had a 50-50 chance of ever getting back on his feet. He had surgery the next day to have a steel rod placed in his leg. Two weeks later, to his doctors’ surprise, but not his parents’, he started hobbling around with a walker. With some effort, he can even get in and out of the family minivan more or less on his own. “He’s an amazing kid,” Leffler says.

Soccer, even in modified form, is probably over forever. Aidan, now in sixth grade, has redoubled his attention to big cats. He’s writing fundraising letters and passing along the money to a conservation group called Panthera.

He’s not oblivious to his medical predicament. If anything, he’s growing more worried. The other day, Leffler found a piece of paper in her bathroom with a question written in Aidan’s neat block letters: “Does muscular dystrophy make you die sooner?”

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