Families of boys suffering from Duchenne muscular dystrophy push for approval of a new medicine
Austin Leclaire steered his electric wheelchair into the hotel ballroom and prepared for what he would later describe as the proudest moment of his life. Upon taking the microphone, the 17-year-old pleaded with US regulators to approve an experimental drug for the deadly wasting disease he suffers from. “It lets me feed myself, it gives us a chance,” he told the assembled scientists and doctors. “It’s time to listen to the real experts.”
Austin has Duchenne muscular dystrophy, a rare genetic disorder that sends its victims — almost all of them boys — to an early grave, usually before they are 25. He was one of more than 150 sick children to attend a meeting organised by the US Food and Drug Administration last month, where it discussed whether to give the green light to Eteplirsen, the first medicine for the disease.
The parents of Duchenne sufferers and their doctors are united in calling for the medicine to go on to the market, most likely with a price of several hundred thousand dollars a year per patient. But there is deep scepticism among the FDA’s scientists and others in the medical establishment, who say there is scant evidence the drug works.
“If this drug is approved — on the skimpiest, most pathetic data I’ve ever seen — then it is going to set a precedent that is very uncomfortable,” says Diana Zuckerman, president of the National Center for Health Research.
Sarepta, the Boston biotech group that makes Eteplirsen, is trying to secure a positive verdict from the FDA using a clinical trial in which the drug was tested on 12 boys, a tiny sample of patients even for a rare disease. When the company started the trial in 2011, it said it could not afford to make enough of the medicine to do a larger study.
Duchenne sufferers, who number between 9,000 and 12,000 in the US, do not produce dystrophin, a protein that works as a shock absorber to stop muscles from wasting away. The disease progresses in a way that is all but unbearable for the patients and their parents. When young, the children fall over more than their peers and struggle to climb stairs or run. By the time they are 12, most are confined to a wheelchair. The cause of death is usually respiratory or heart failure.
In theory, Eteplirsen makes the body produce a type of dystrophin by altering a faulty piece of genetic code. It is intended for 13 per cent of patients who have a specific genetic defect, but if the drug works then Sarepta thinks it could use the technology to help many more boys. No one argues that the medicine will stop or reverse the disease but proponents claim it can slow its progression so patients live fuller, longer lives.
Whether one believes that Eteplirsen works depends on who is best placed to judge — regulators or the patients who have taken the medicine. Who, as Austin puts it, are the “real experts”? Although Sarepta is seeking approval based on data from 12 boys, the drug has been given to at least 100 more, and all their parents have reported a significant improvement.
Such a level of support for a new drug is rarely seen, let alone in a disease where there are so few sufferers. The FDA had to move last month’s meeting from its campus in a suburb of Washington DC to a nearby hotel so it could accommodate the more than 1,000 advocates who turned up to press for approval. Over nearly three hours, more than 50 of them took the microphone to lobby the FDA.
Jenn McNary, Austin’s mother, has two sons on Eteplirsen. Her youngest, Max, 14, was part of the “Columbus 12”, the trial that Sarepta is using as the basis for approval; the nickname comes from the Ohio state capital where the study was conducted.
She says she has seen an “incredible amount of benefits in both boys”. Max is still walking, while Austin, who was in a wheelchair before he started taking the drug, can grasp objects and raise his hand above his head.
If the improvements in Ms McNary’s children and other Duchenne sufferers are being brought about by the drug, then it would be reasonable to assume their muscles are wasting more slowly than before, and that they might ultimately live longer.
The six-minute test
Yet the contrast between the experiences reported by the parents and the opinion of FDA scientists could not be starker. Staffers from the agency’s neurology division, charged with reviewing Sarepta’s application, have spent much of the past four years pushing the company to do bigger and better clinical studies, without success. Now the FDA must base its decision on the “Columbus 12” trial.
The trial was not only tiny but badly flawed, according to the FDA reviewers. Initially, four boys were given a placebo instead of Eteplirsen but the company started giving them the drug 12 weeks later — before it had established whether it was working in the other patients.
The actions flouted one of the tenets of drug testing: that some patients should be given a placebo to ensure the others are in fact responding to treatment, rather than other factors, like hope or family pressure.
To determine whether the drug was working, researchers measured how far the boys could walk in six minutes. In the absence of placebo data, they had to compare their findings with the histories of Italian and Belgian Duchenne sufferers who purportedly had similar characteristics — a technique fraught with statistical imperfection.
Worse still, Sarepta said two boys who stopped walking shortly after taking the drug should be discounted from the results.
Researchers working on the Sarepta trial also completed muscle biopsies and reported that the boys were producing very high levels of dystrophin. But following an FDA inspection, regulators discovered that imperfect methods had produced results that were highly misleading: the levels were much lower — just 0.9 per cent of what a healthy child would produce, versus the 50 per cent the company had claimed.
Over time, relations between the FDA and Sarepta soured, so much so that in April the company replaced its chief executive in an attempt to restore trust. “The FDA felt tricked,” says Brad Loncar, an independent biotech investor who does not hold shares in Sarepta. “They felt they were led along in an unfair way and there’s some resentment about that.”
At the end of last month’s meeting, a group of external advisers to the FDA voted seven to three, with three abstentions, against giving approval to Eteplirsen. Despite deciding that the drug is safe, they concluded that the results from the “Columbus 12” trial did not prove that it works.
However, another ballot on whether the medicine should be granted a form of conditional or “accelerated” approval was much closer — seven against, six in favour. The FDA does not have to heed the advisory vote, and the close result coupled with the strength of feeling in the Duchenne community has led some parents to hope they will soon be able to access the drug. Some investors agree: Sarepta’s shares have jumped by almost 15 per cent since the meeting.
An executive decision
Ever since the start of the Aids crisis in the 1980s, when campaigners successfully lobbied for dying patients to be given unproven experimental drugs, the FDA has been under pressure to become faster and, to some extent, looser. Legislative changes have allowed the agency to approve some drugs on an accelerated basis, normally in cases where patients are dying but there is still little clinical data. A law passed in 2012 also ordered regulators to take much greater account of the wishes of patients and their families.
Parents like Ms McNary hope that FDA directors will overrule agency scientists and advisers and give the drug accelerated approval. They have taken solace from comments made by Dr Janet Woodcock, head of the agency’s drug evaluation unit, who took the unusual step of attending last month’s meeting to make some opening remarks.
Dr Woodcock told the meeting that the agency spends much of its time trying not to approve ineffective drugs, but warned there was “little consideration of another error, which is failing to approve a drug that actually works”. Accelerated approval, by its very nature, required the FDA to say yes to medicines with “more uncertainty”, she added.
“If this was up to the FDA scientists, then it would be 100 per cent rejected,” says Mr Loncar. “This is definitely a situation where Dr Woodcock is going to have to make an executive decision.”
Such terrain is unusual for the FDA but not uncharted. In an era of social media, it has become easier for patients to organise themselves and exert pressure. Last year, regulators approved Flibanserin, a sexual dysfunction drug for women dubbed “female Viagra”, following a high-profile campaign that sought to portray the FDA as sexist.
Patient campaigns have few restrictions on the funding they can take. Many of the Duchenne groups have received cash from Sarepta and other pharma companies developing drugs for the disease, just as the supporters of Flibanserin were part-funded by the company behind the medicine.
Sceptical doctors and scientists warn that patient power has gone too far. They argue that if the FDA approves Eteplirsen it would herald a dangerous era in medicine, where well-
organised groups of sick people and their families can trump scientific
A handful involved in the case of Eteplirsen even say they were intimidated by the Duchenne community. Laura Gottschalk, a scientist at the National Center for Health Research, spoke against approval at last month’s meeting. She says that she was subsequently followed to her car by a man shouting abuse who then threatened to punch her colleague in the face.
A doctor advising the FDA says that he received an abusive email after the meeting. Many others declined to speak on the record for fear of sparking similar repercussions.
Such heightened emotions are perhaps best understood in the context of what is at stake: if the FDA turns down Eteplirsen, Sarepta will probably abandon the drug, meaning the patients being treated will be left with nothing. The biotech group would become the third company to have had a Duchenne medicine knocked back by regulators in the past year, which could have a chilling effect on investment in research into the disease.
“If there is not a path forward for Sarepta and it ceases to exist, then we will not only lose access to a drug that is keeping the boys moving,” says Ms McNary. “We’ll also lose hope that other Duchenne companies will press ahead.”
Tragic though such an outcome might be, others argue that hard data, not emotion, should govern whether drugs are approved.
“If this gets through, I’m not sure what you have the FDA for,” says a doctor advising the agency. “Is this about science or is it all about the court of public opinion?”
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