Three years ago, the FDA made one of the most polarizing decisions in its history. It approved a drug for the rare genetic disease Duchenne muscular dystrophy on the slimmest of evidence, a watershed moment that caused a highly publicized rift within the agency.
In the midst of it all were parents who pushed hard and advocated like never before, even making public presentations to the FDA, under the agency’s new willingness to hear public and patient input.
Some of that patient input included data, gathered through videos and interviews with caregivers, that seemed to show kids in the trial improving after taking the drug, known as eteplirsen (Exondys 51). These detailed personal accounts were compiled independently; neither eteplirsen’s developer, Sarepta Therapeutics (NASDAQ: SRPT), nor the FDA had them.
Top FDA officials said those data didn’t influence their decision. After the approval, head drug evaluator Janet Woodcock spoke at a conference with one of the Duchenne parents, Christine McSherry, and said that her data, collected from her son and other patients in the eteplirsen trial, weren’t rigorous enough.
But then Woodcock said something surprising: If they could better quantify the results and have their methodologies validated by a federal Institutional Review Board, the data could be extremely useful.
So McSherry and Mindy Leffler, another Duchenne advocate who helped gather the data, decided to start a company. Their startup, Casimir Trials, is working with a dozen drug makers, among them Sarepta, to compile data that show the impact rare-disease medicines might be having on patients.
Casimir’s goal is to address a frustrating gap. Patient experience seems to demonstrate that an medicine might be working, but the “hard” clinical data, approved as part of the study’s design, might show no effect whatsoever.
“We are tired of hearing parents saying, ‘Oh my gosh, I swear that drug was working, I swear he was walking better or he ran better,’ and then the drug gets put on the shelf because it didn’t meet its primary endpoint,” McSherry tells Xconomy.
Ten years ago, maybe even five, the idea of a patient advocate supplying important data to the world’s most powerful drug agency would have been ludicrous. But Casimir’s progress illustrates so much about big changes in the way biomedical science and its regulators have recently evolved.
In the past, “people have tended to consider these [types of data] to be ‘soft’ outcomes,” says Harlan Krumholz, the director of the Center for Outcomes Research and Evaluation at Yale-New Haven Hospital. But “what is ‘hard’ data anyway, except that it is reproducible and it triangulates with other information that we know about people in ways that make us believe it’s valid?”
Casimir’s efforts are worth watching as more and more rare-disease drugs come to market—including, potentially, a group of gene therapies for Duchenne that are in human testing. One method Casimir and its tech partner, iTakeControl, have developed to study patients’ ability to move over time is under FDA review, McSherry says. If approved, the measure could be used as a study goal in future clinical trials. McSherry and Leffler mentioned that goal at a meeting held Thursday (pictured above) by the Institute for Clinical and Economic Review (ICER), the nonprofit drug pricing watchdog.
In a research note following the meeting, RBC Capital Markets analyst Brian Abrahams noted that this “type of endpoint could potentially be explored by Sarepta” in its Duchenne gene therapy trials to “further support approval and eventual reimbursement.” Sarepta isn’t currently working with Casimir in its gene therapy trials, says spokesperson Tracy Sorrentino. But McSherry says the two are “in discussions” about the possibility. (They are already working together in at least one other trial, she says.)
The FDA doesn’t comment on discussions it has with companies, says spokesperson Sandy Walsh. But Walsh did confirm that conversations took place between McSherry and Woodcock, and that “the FDA is very much in favor of seeking to measure, in a reliable way, outcomes of interest and value to patients.”
Filling the Gap
Duchenne is a deadly genetic disease that afflicts some 300,000 kids worldwide who can’t produce a shock-absorbing protein known as dystrophin. Without dystrophin, their muscles gradually waste away, beginning with their legs. They often can’t walk by their teenage years and die at a young age because of heart or lung problems.
Before eteplirsen, which treats a small subset of patients and is meant to slow the progression of the disease, there were no FDA-approved treatments for Duchenne. A steroid sold by PTC Therapeutics (NASDAQ: PTCT), deflazacort (Emflaza), has since been approved for Duchenne patients as well. But there still is no cure.
McSherry’s son Jett—one of her five children—was diagnosed with Duchenne at the age of five. As McSherry explained in this 2018 podcast, the pain of hearing the diagnosis was so severe that “you could think of nothing else but wanting to die.” But she turned those emotions into relentless advocacy. A registered nurse, she started the nonprofit Jett Foundation in 2001 in an effort to save Jett’s life.
“Every parent who has a child with a deadly disease, they really do think they can conquer the world,” McSherry says on the podcast.
Jett lost the ability to walk around the age of 15. As his condition worsened, McSherry’s foundation got stronger. She raised some $20 million to fund research and promote awareness, and she worked her way to the forefront of a movement for patient and advocate empowerment. Jett was enrolled in a clinical trial of eteplirsen, and McSherry lobbied for the FDA to review the drug.
That was a controversial quest. Sarepta had an unusually contentious relationship with the FDA as it tried for years to get the agency to approve the drug on an “accelerated” basis, based on the amount of dystrophin patients taking its drug were producing. The only data the FDA had on eteplirsen before approval came from a tiny, 12-patient clinical trial.
Those scant data compared patients on eteplirsen to a “historical control”—previous data from patients deemed to have similar characteristics to those who took the drug. The study did not compare its patients to those receiving a placebo, which the FDA usually prefers. This clinical scenario typically wouldn’t even get a look from the FDA, but a number of factors changed the equation—among them, arguably, pressure from a very mobilized patient group.
The decision was so contentious that it caused infighting at the FDA. Opponents were worried of setting a precedent that “pressure and even intimidation—not science—guides FDA decisions,” according to an agency document released following the eteplirsen decision. Some staffers were critical of Woodcock, who championed eteplirsen and was backed by then-FDA commissioner Rob Califf.
The story was a litmus test for the increasing power of patient advocates and their impact on drug approvals, a complex and controversial topic given that many groups receive funding from drug makers. (Here’s more on pharma/patient group relationships from a 2018 Kaiser Health News report.)
Sarepta priced its drug at an average of $300,000 per year, based on a patient’s weight. Convincing payers to cover the drug “has been difficult, there’s no question about it,” says Parent Project Muscular Dystrophy founding president and CEO Pat Furlong. That’s in part because Sarepta still doesn’t have clinical data proving, definitively, that eteplirsen benefits patients.
Drug-price watchdog ICER argued in a draft report earlier this month that “no persuasive evidence yet exists” to demonstrate eteplirsen’s clinical effectiveness. “Eteplirsen has been on the market for three years, and yet we still found notably inadequate data on patient outcomes,” said ICER chief medical officer David Rind in a prepared statement at the time.
Thursday’s meeting convened to elicit a variety of perspectives, including that of patient advocates, before ICER issues its final report about eteplirsen’s price relative to its perceived effectiveness. The report could have consequences. The patient community is concerned that a negative ICER review—which insurers have increasingly valued—will make it even harder for them to get access to the drug, McSherry says.
Yet McSherry swears by eteplirsen. Jett has been taking the drug for years. He can smile fully now, she says. He opened a beer bottle on his own for the first time. (He’s 22 years old now.) He stopped snoring because he’s breathing better at night. These are improvements that as a young man with Duchenne, Jett wasn’t likely to achieve on his own, she says. Yet they weren’t reflected in Sarepta’s data. And that disconnect was reflected at the ICER meeting Thursday, she says.
“The biggest takeaway was the lack of outcome measures that are relevant and meaningful to patients with Duchenne,” McSherry said after the meeting.
Casimir aims to fill this gap by using video to catch changes, over time, in the quality of patients’ movements, rather than, say, how fast they can walk in six minutes or how long it takes for them to get up off the floor. Are they no longer using two hands to grab a bannister and pull themselves up the stairs, for instance? Are they compensating for their weakness in other ways, like swinging one of their legs out to climb a step? The goal is to pick up subtle changes that wouldn’t be detected on timed tests. “It’s not how fast you move, but how well you move that is the difference, especially in Duchenne,” McSherry says.
The information-gathering process the FDA is reviewing from Casimir involves shooting videos of activities in patients’ homes then uploading the information to cloud-based databases. Physical therapists would review the video and issue scores based on whether patients are using compensatory factors—like using one’s arms to make up for weak leg muscles.
Sarepta spokesperson Sorrentino confirmed that the company is working with Casimir on a study called LEAP. Casimir’s videos are being used alongside standardized clinical tests, as Sarepta outlined in this poster. The LEAP trial is evaluating both eteplirsen and an experimental drug called golodirsen that is currently under FDA review.
McSherry says Casimir has contracts with others in the Duchenne space but declined to name them. McSherry and Leffler—who wasn’t available to comment for this story—want to go beyond Duchenne and apply their methods to evaluate drugs for Huntington’s disease, rare forms of epilepsy, and other conditions, in ways that standardized tests may not capture.
“We want to get to the truth of what’s happening when we give these kids with rare diseases drugs,” McSherry says, “and the benefit that patients and caregivers find meaningful.”