Duchenne Lessons: Advocates For Rare Spinal Disease Have Eyes on FDA

Xconomy National — 

[Updated, 1:09 pm ET, see below] Heather and Jessica Tomko will tell you that they’re nothing alike. They’ve got different interests, different tastes in movies, television, and music. If Jessica hates a gift, Heather probably loves it. Heather just scored tickets to see the Broadway show Hamilton and can’t wait. Jessica sighs.

“You can’t get a bigger fad than Hamilton,” Jessica says. “We go to very few concerts together. Heather refuses to go to anything I enjoy going to.”

But the sisters also have things in common, including the rare disease spinal muscular atrophy. They have spent their lives—Jessica is 26, Heather is 27—in wheelchairs. Neither has ever walked. They need help getting out of bed and getting dressed in the morning. Heather had a feeding tube implanted a few years back. They can no longer lift their arms over their head the way they could five or 10 years ago.

“It’s just little things like that where it’s a gradual loss of strength,” Heather says.

There is no approved treatment for SMA. Left untreated, Heather and Jessica, who have a slower-developing form of the disease, might expect to continue to get weaker as time goes on.

Jessica and Heather Tomko

Jessica and Heather Tomko

Their story has undeniable emotional appeal. But that appeal also underscores an important issue in healthcare these days: The growing power and sophistication of patient advocacy groups for rare diseases, the complex roles they play in the development and regulation of new drugs, and the big business opportunities those drugs provide to pharmaceutical companies.

According to a 2015 report from EvaluatePharma, the market for drugs for rare, or “orphan” diseases, as they’re known, has been growing by 12 percent every year and is expected to reach $178 billion worldwide by 2020. The small populations of patients with those diseases, combined with a lack of alternative treatments, means the drugs typically command very high prices—on average, an estimated $111,820 per patient, per year between 2010 and 2014, according to the report. Twenty-one orphan drugs were approved in 2015, a record for the second straight year.

The first-ever treatment for SMA could soon gain approval, too. In the next few months, Biogen (NASDAQ: BIIB) and Ionis Pharmaceuticals (NASDAQ: IONS) are expected to ask the FDA for approval of nusinersen, which is meant to help improve the motor function in SMA patients.

Nusinersen would become the first in an advancing pipeline of SMA drugs—at least six in clinical trials now, according to the nonprofit group Cure SMA—to make it that far.

Once the application is filed, the FDA typically makes an approval decision in up to 10 months. That review period gives patient advocates a chance to impact a typically bureaucratic process. For Duchenne muscular dystrophy, also a rare disease without treatments, public hearings to discuss drugs under review have featured throngs of patients and patient advocates pleading with regulators to approve experimental drugs despite flawed data. Two drugs have been rejected, nonetheless. A third, eteplirsen, from Cambridge, MA-based Sarepta Therapeutics (NASDAQ: SRPT) was under review with what seemed like a bare minimum of data. FDA officials made unusually pointed comments about the effect of advocates’ appeals, and the agency has since delayed a final decision and asked for more data.

Patient groups played a critical role in the advancements of therapies for AIDS, multiple myeloma, and cystic fibrosis, now approved and used by people every day. Cure SMA backed early research that helped scientists understand the underlying cause of SMA. The ALS Foundation announced recently that money raised from the Ice Bucket Challenge—in which people shared videos of themselves dumping buckets of ice water on their heads to promote ALS awareness—helped scientists uncover a gene implicated in the disease.

Some rare diseases have become profitable targets for drug makers. Alexion Pharmaceuticals (NASDAQ: ALXN) has turned eculizumab (Soliris), a treatment for the blood disorder paroxysmal nocturnal hemoglobinuria, into a $2 billion-a-year cash cow. But many other diseases remain underfunded or completely neglected. Patient groups help raise money for basic research and, if a drug emerges that seems promising, help recruit patients for trials. The stories from within their communities—like that of Heather and Jessica Tomko, who agreed through Cure SMA to speak with the media—can lead to awareness and help their cause. (Other SMA patient groups did not respond to inquiries from Xconomy.)

“These groups have now taken it upon themselves to drive research, to raise money, and to really stimulate scientists working on their diseases,” says Voyager Therapeutics (NASDAQ: VYGR) CEO and former Eli Lilly R&D chief Steve Paul. “It’s just remarkable how effective [patient groups] have been.”

They’re increasingly involved in the regulatory process as well. According to Cure SMA CEO Kenneth Hobby, his organization has been in contact with the FDA for some time about the disease and its impact on families and patients. Hobby says he hopes a more thorough, “patient-led” meeting will take place within the next year. This meeting, he says, would be to convey information that Cure SMA believes “should be taken into account” both for nusinersen’s coming application and “for all potential future drug applications for SMA.”

People with SMA can share the same malfunctioning SMN1 gene but exhibit a broad range of different outcomes, classified as types 1 through 4. Type 1, for example, is diagnosed in infants and the impact—many die within two years without help from a ventilator—is much more significant than the other types.

Hobby says a drug focused on that genetic problem, like the Biogen-Ionis drug and others in development, should be applicable to more than just a fraction of patients. Cure SMA doesn’t know how the FDA will stand on that issue, however, so through the meeting, Hobby hopes to “ensure this perspective is taken into account.”

“Rather than just presenting stories and anecdotes, we’ll provide data and statistics to the FDA that they can use,” he says.

But industry watchdogs say pressure from advocacy groups can lead to approval of ineffective or unsafe therapies. And funding from drug makers creates a potential conflict of interest when the two campaign for a drug’s approval.

Sharon Batt, a bioethics professor at Dalhousie University in Nova Scotia, points to the case of bevacizumab (Avastin). Already approved for several other cancers, bevacizumab got the FDA’s conditional nod for metastatic breast cancer in 2008 based on a thinner body of evidence than usual. At the time, as this New York Times article points out, “oncologists and patients advocates were divided, in part because of the drug’s sometimes severe side effects.” The FDA’s compromise was to approve the drug on a conditional basis, subject to further testing that could pave the way for a wider approval.

The data from additional studies didn’t support that claim, however. The agency revoked the approval three years later after more conclusive results showed bevacizumab wasn’t helping patients live longer, and worse, was leading to serious health risks like hemorrhages.

Batt says some patient advocates supported the FDA’s decision, but the majority “pleaded and protested” for the drug to keep its breast cancer approval; as the Washington Post wrote in 2011, some patients “likened the FDA’s rejection to a death sentence.” The situation, the Post wrote, “sparked one of the more emotional and acrimonious debates in years over a medical treatment among patients, oncologists, women’s health advocates, health-care policymakers, politicians and the pharmaceutical industry.”

The calculus isn’t all that different with rare devastating diseases. SMA is the leading genetic cause of infant deaths. Duchenne muscular dystrophy puts most patients in wheelchairs by their teens and kills them—typically from heart or lung complications—by their mid-20s. Rare disease advocates acknowledge the danger of pressing too hard, but they say the stakes are higher.

“If we end up with a dozen really bad [approval] decisions, that’s going to throw everything backwards,” says Durhane Wong-Rieger, the president and CEO of the Canadian Organization for Rare Disorders (CORD), which advises several patient advocacy organizations. “But a patient group might say, ‘We’re willing to take that risk because we don’t have any other options.’ Can I ask those parents to wait, knowing that by the time [a safe, effective drug] gets there it may be too late?”

This scenario is currently playing out publicly with Duchenne muscular dystrophy. The patient community has rallied around a group of drugs that, one by one, have come up for FDA review over the past year with significantly flawed data. The FDA has rejected two of them, from BioMarin Pharmaceutical (NASDAQ: BMRN) and PTC Therapeutics (NASDAQ: PTCT). A decision on Sarepta’s eteplirsen could come at any moment. As with the other two, the FDA can either approve a drug it normally wouldn’t because the need is so significant, or deny a drug for sick and dying children.

“Whenever the pressure succeeds, it creates a model that patient groups and drug companies see as worth repeating,” says bioethicist Batt. “I know it’s really hard for the scientists or the people on the FDA committee to take a strong stance and to sort of be held up as heartless, but they really have to do it. That’s their responsibility.”

Batt says it’s important to hear from patient groups about their needs. But it’s also important to know where their funding comes from. Patient groups that take money from drug makers, she says, are less likely to challenge the high cost of drugs or talk about serious problems like side effects. The nonprofit group Public Citizen recently published a report showing that the majority of patient groups publicly opposing a Medicare B proposal to reduce drug costs—110 out of 147 total—received Big Pharma funding.

“You don’t have very many critical voices within the patient community,” Batt says.  “They’re now kind of in a box, because they realize that if they do speak critically they risk losing funding that they’re now dependent on.”

Funding levels vary. Cure SMA, for instance, drew $228,675, or just 4 percent, of its roughly $5.4 million in funding in fiscal 2015 from “national corporate supporters,” some but not all of whom are drug makers, says the nonprofit.

CORD receives about half its funding from corporate entities, according to Wong-Rieger.

Cure SMA CEO Hobby says his organization manages potential conflicts that could arise from industry funding in a few ways. It controls the content for all of its events. It assists with drug development by providing clinical trial recruitment, patient perspective, and helps develop outcome measures and biomarkers—but this help comes regardless of whether Cure SMA has a relationship or gets funding from a drug’s developer, and only after its advisors and board of directors review the request. There are no “exclusive” deals with anyone, Hobby says.

Hobby adds that there are important benefits to working with industry: The patient’s voice is better heard, and Cure SMA can promote collaborations and joint research efforts between companies, which can speed development.

[Updated to include more of Hobby’s comments on pricing] Hobby says Cure SMA has had a longstanding view on orphan drug pricing, which is that “the ability and freedom to price drugs to match the smaller market size is a key incentive to encourage companies to invest their own resources to develop new therapies. And so we make sure that we are not putting up any barriers that would actually reduce this incentive though pushing for lower prices.” Cure SMA will fight for broader access to drugs, though, as it plans to do with the patient-led meeting with the FDA it wants to schedule.

“It is of minimal impact if we get an approval with a drug label that would cover just 5 percent of our patients, no matter what the price,” he says.

The FDA’s internal struggle, and the pressure it faces from advocates, have never been more clear than with eteplirsen. In April, hundreds of patients and their advocates showed up at a meeting of outside medical experts who advise the agency. More than 50 spoke. All but one pleaded for approval of eteplirsen, the scientific case for which revolves largely around one small, 12-patient study that the FDA has had a hard time drawing conclusions from.

At the hearing, William Dunn, director of the agency’s division of neurology products, said that regardless of how urgently a Duchenne drug is needed, and though “emotions [would] run high,” the FDA would not lower its approval standards.

At the end of the meeting, the advisory panel voted against approval of eteplirsen, which typically—though not always—means the FDA will follow suit. Yet Janet Woodcock, the FDA’s top drug evaluator, showed up during the hearing—an uncommon occurrence. She spoke of regulatory “flexibility” and expressed fear that an unwarranted rejection would have “consequences” on Duchenne patients.

The FDA has since delayed a final decision and asked Sarepta for more data— specifically, information from muscle biopsies taken from 13 more patients on eteplirsen.

With an SMA drug likely to enter FDA review soon, advocates have been watching the Duchenne situation closely. “We’re paying a lot of attention to it,” says Cure SMA CEO Hobby. Cure SMA has “active discussions and dialogue” with the Duchenne community and its patient groups, and some of Cure SMA’s board members are involved with Duchenne foundations.

What Hobby is watching for: Will the FDA approve eteplirsen on an “accelerated” basis, or make Sarepta complete an additional trial? Will the agency fall somewhere in the middle and approve eteplirsen for a narrower group of patients?

“Whatever they do there is going to set a precedent for other orphan therapeutics coming through,” Hobby says. “It’s going to have to be the benchmark for other diseases, like SMA.”

It appears the task will be easier for SMA groups than their Duchenne counterparts. Biogen and Ionis stopped a randomized, placebo-controlled Phase 3 trial of nusinersen in type 1 SMA patients early because they said the drug was clearly improving infants’ motor function—the ability to roll, crawl, or control their head.

“We feel like this is a very clinically meaningful result,” says Wildon Farwell, a senior medical director of clinical development at Biogen. “These are motor milestones that a parent, physician, or patient would appreciate.”

But a number of questions remain. How long do the improvements in motor function last, and what happens if they wear off? Do patients continue to improve as they take the drug, which Farwell says would likely be a chronic therapy? Will any safety problems crop up over time? And how much would it cost?

“We still have a lot to learn about the disease,” Farwell says. “And we’ll only understand as we continue to follow these patients over time.”

If Cure SMA is going to fight for a broader label on nusinersen, ongoing studies will be crucial. A Phase 3 trial of nusinersen in childhood-onset SMA, which includes the less common type 2 and 3, should wrap up in the first half of 2017. That study is particularly important for folks like the Tomko sisters, who have type 2. If nusinersen doesn’t produce positive results, they might not be eligible for it.

Both Jessica and Heather Tomko admit that they haven’t paid close attention to nusinersen’s development, since it’s unclear whether it’ll ever impact them personally. But Heather has started to work with Cure SMA on some fundraising, even if it’s hard given the impact her disease has had on her. She says she knows more about SMA and how it affects people than the doctors she sees. She knows what works, what her body needs, when she’s getting sick, and what to do about it.

Perhaps, if nusinersen shows even a slight benefit for type 2 SMA patients, that’s a story she’ll tell at an FDA hearing some day.