Teen left in limbo by FDA inaction on muscular dystrophy treatment
By now, Billy Ellsworth shouldn't be walking, but he is.
The 15-year-old Coraopolis boy has Duchenne muscular dystrophy, a rare genetic disorder that starves muscles of needed protein and confines most of its sufferers to wheelchairs by the time they reach their teenage years.
On a recent weeknight, he ambled from a PlayStation 3 to an electronic drum set to the kitchen in his home. He swims, swings at baseballs and plays group games at Camp AIM, a YMCA summer program for young people with physical and cognitive challenges.
His mother, his doctor and some of the world's Duchenne experts credit his mobility to weekly doses of an experimental drug called eteplirsen. Billy and at least 11 other boys enrolled in the drug's first clinical trial are waiting to find out whether the Food and Drug Administration — after a review marked by confusion and delays — will approve the drug.
Billy's parents worry that, without the drug, his health will deteriorate. His mother, Terri Ellsworth, fears Cambridge, Mass.-based Sarepta Therapeutics could stop making eteplirsen.
“That will be a whole other nightmare for us to deal with if he loses the drug,” she said.
A Sarepta spokeswoman declined to answer questions, including what would become of the drug if it is not approved.
There are no approved treatments for Duchenne, which affects one in 3,500 to 6,000 newborn boys and almost no girls, according to the Centers for Disease Control and Prevention. It kills most people who have it in their teens or 20s.
The FDA planned to announce May 26 whether it would grant eteplirsen accelerated approval, but the agency has delayed the decision indefinitely despite an emotional campaign by patients, families and advocates.
Accelerated approval requires less evidence of clinical benefits than full approval.
For Billy, time could be running out.
He can still walk, but he is losing strength. He stands on the balls of his feet and has started crawling up stairs that he once walked. He limits his trips to other floors in his house because the exertion wears down his muscles, Terri Ellsworth said.
Sarepta, meanwhile, is conducting more extensive testing in a larger group of patients.
On April 25, an FDA advisory committee voted against approving the drug, citing shortcomings in Sarepta's methods for testing it and ambiguity in the FDA's directions to the committee.
The FDA is not required to follow the recommendation. Sarepta announced June 6 that the agency had requested more information to help it make a decision.
An FDA spokeswoman wrote in an email that the agency cannot discuss pending drug applications.
“The FDA recognizes the huge unmet medical need in Duchenne muscular dystrophy, the devastating nature of the disease for patients and their families and the great urgency to make new treatments available,” the spokeswoman wrote in a statement. “As a result, we are working diligently with drug companies on the development and approval of safe and effective drugs for patients who are suffering with this rare and devastating condition.”
A 2014 study in the Journal of Neuromuscular Diseases showed that boys with the form of Duchenne Billy has became wheelchair-dependent at a mean age of 11.
Boys in the eteplirsen trial started treatment five years ago when they were between 7 and 13 years old. Ten boys in the trial could still walk after four years of treatment. Researchers compared the treated boys' mobility at four years with the mobility of 13 boys of similar age and condition at two European centers. After five years, none of those boys could walk, according to information included in an FDA document. That result, combined with experience with other patients, convinced Billy's doctor of the drug's effectiveness.
“From what we see with other patients, there's definitely a difference,” said Dr. Hoda Abdel Hamid, a Duchenne expert at Children's Hospital of Pittsburgh of UPMC. Abdel Hamid receives money from Sarepta to consult on experiment protocols, but not for things such as promotional speaking.
She said the money does not affect her research.
The FDA urged the advisory committee to be cautious when comparing the boys who received eteplirsen with those who didn't. The comparison group served as what is known as a historical control group, which produces lower-quality evidence in a study than a randomly selected control arm receiving a placebo. For example, two of the boys in the control group who reportedly couldn't walk were found to be able to walk by a different test, according to the briefing document.
Duchenne inhibits the body's ability to make dystrophin, a protein that gives strength and stability to muscle fibers. One of the FDA's questions is whether eteplirsen helps people with a specific type of Duchenne — the most common mutation, which Billy and the other boys in the trial have — make the protein.
After initial tests showed dramatic increases in the protein, the agency sent investigators to inspect Sarepta's labs and found “significant methodological concerns,” according to the briefing document. Subsequent tests showed much smaller increases.
Steve Wilton, one of the scientists who discovered the mechanism by which eteplirsen works, said a little dystrophin can make a big difference.
“There's not a great deal of protein there, but there's definitely much more,” said Wilton, who collaborates with Sarepta and is director of the West Australian Neuroscience Research Institute.
“The drug is working,” he said. “It would be nice if it was making more protein, but there will be ways to improve it.”
The kind of high-quality evidence the FDA prefers often is unavailable for drugs treating rare diseases, said Paul Melmeyer, associate director of public policy for the National Organization for Rare Disorders.
“Oftentimes, it's unethical to ask patients — especially children — to go on a placebo,” Melmeyer said. “Particularly in life-threatening situations, you're not going to ask a patient to go off a potentially life-saving therapy.”
Several members of the advisory committee that voted on eteplirsen said they were confused about what evidence they could take into account.
Their votes followed a meeting that lasted more than 10 hours as muscular dystrophy patients, their families, advocates and experts testified about the drug. Seven voted no, three voted yes and three abstained.
The committee had to answer the question, “Do the clinical results of the single historically-controlled study provide substantial evidence that eteplirsen is effective for the treatment of (Duchenne)?”
Dr. Mark Green, a professor of neurology, anesthesiology and rehabilitation medicine at New York's Icahn School of Medicine at Mt. Sinai, abstained.
“I'm uncomfortable by the language of the question. … I'm still quite sympathetic to and persuaded by the public's presentation,” Green said at the meeting.
Billy spoke about six hours into the meeting.
“I see other boys my age and younger that cannot do what I can do, and it makes me mad that they also cannot have the drug,” he said. “I hardly ever have to ask my parents to help me with anything because I can do most everything in my daily life by myself. I'm going to beat this bloody disease, but I need your help. So please help me and my friends and do the right thing. FDA, please don't let me die early.”
The drug has so far shown no cause for safety concerns, which makes some observers question why approval has not been easier.
Billy was diagnosed with Duchenne when he was 4 years old. In addition to the eteplirsen trial, he is participating in two others. He takes steroids that stunt his growth, along with three heart medications, calcium and vitamin D.
He said he tries not to think about his illness.
“I just deal with it; that's what I do,” he said. “It's hard to fight. I just forget about it and just continue on with my normal life.”
Wes Venteicher is a Tribune-Review staff writer. Reach him at 412-380-5676 or firstname.lastname@example.org.