WASHINGTON — A wheelchair by age 12, maybe 15 if he were one of the lucky ones. A ventilator would be next and then would come the casket, probably before he turned 30.
That was what Terri and Bill Ellsworth expected for their son when doctors confirmed his diagnosis of Duchenne muscular dystrophy, a debilitating and fatal disease striking one in 3,500 boys.
Instead, Billy has become an active, happy teenager who likes to dance to Beatles songs, walk around at classic car shows, hike on local trails and jog in his living room along with avatars of Michael Jackson and Elton John he created for his Wii video game.
He's like a lot of other 13-year-olds but for an awkward gait and the Wednesday afternoons he spends at Children's Hospital of Pittsburgh of UPMC for an infusion of an experimental drug that's keeping his disease at bay -- and without any side effects.
Billy, of Coraopolis, is one of a dozen Duchenne patients who are receiving eteplirsen as part of a clinical trial. The drug was expected only to slow the progression of the disease, but Billy and others in the trial are finding their symptoms are improving. Testing confirms that their lungs are getting stronger and their bodies are producing dystrophin, an essential protein that wasn't present in muscles biopsied two and a half years ago when the trial began.
Results astounded researchers.
"I've done many, many clinical trials and never encountered one that was so clean, effective and very well tolerated," said principal investigator Jerry Mandell, Ohio State University professor of medicine and director of gene therapy at Nationwide Children's Hospital in Columbus, where testing was initially conducted.
For the 12 boys and their families, it's a miracle drug, but other Duchenne patients can't access it because the Food and Drug Administration hasn't yet approved it. Mrs. Ellsworth and other mothers are lobbying regulators to expedite approval under a 2012 law that encourages faster reviews of breakthrough therapies that address unmet medical needs for rare and life-threatening diseases.
They spent the past month collecting signatures on a petition they sent to the White House urging the administration to expedite approvals of drugs that treat Duchenne muscular dystrophy. The White House has promised to respond publicly in writing to petitions with at least 100,000 signatures. The Duchenne petition reached that threshold Tuesday. Supporters can still sign by going to TheRaceToYes.org.
Duchenne parents believe eteplirsen meets all the requirements for expedited approval, and they're urging action now because their children are running out of time.
They were hopeful last July when the FDA expressed interest in eteplirsen, but were disappointed when the agency came back three months later and paused the process, saying government scientists needed more data from drug developer Sarepta Therapeutics. The Massachusetts-based company is awaiting more direction from the agency.
"FDA's drug approval process requires well-controlled clinical trials that provide the necessary scientific data," agency spokeswoman Sandy Walsh said in an email message, noting she could not discuss specific cases under review. "If a drug product is to be marketed, well-controlled clinical trials are needed to ensure that the drug is safe and effective when used as indicated."
Small trial, but clear results
The issue seems to be the size of the sample, not the quality of the research, Dr. Mandell said.
He knows his trial was small, but its results were clear. All 12 boys showed increased dystrophin production and clinical improvement or stabilization well beyond expectations for patients whose muscles normally degenerate rapidly.
"We didn't breach any acceptable protocol. Everything was done according to the way it should be done," Dr. Mandell said.
The delay is astounding to Steve Wilton, a neurologist at Murdoch University in Australia who developed the science behind eteplirsen while working at the University of Western Australia.
"There is no doubt that more trials will give more information, but from what I have seen, the data is very compelling that eteplirsen is working as anticipated," he said. "It's obvious that it's working."
More trials would cost money and, worse, time -- at least four years.
"The FDA may have the time but our boys don't have time," Mrs. Ellsworth said. "I'm watching my friends' boys losing ambulation daily, weekly."
Her son is sure that without eteplirsen he would be like them.
"I would probably not be walking," said Billy, who has been helping his mom advocate for FDA approval so others can access the drug. "I want to help them because I want them to do the things I can do."
The delay has been devastating to parents who had hoped the drug would be on the market early next year.
In a form letter, the FDA has been telling parents and others who inquire that the scientists who are reviewing eteplirsen have not yet reached any conclusions.
"We are prevented by legal regulations from divulging this information or our assessment of this information, making it hard to understand FDA's evolving position," wrote Catherine Chew, acting director of the Division of Drug Information at the FDA's Center for Drug Evaluation and Research.
"Please know that we hear your frustration, and fully understand the dire urgency of the situation," she wrote. "We understand that you feel that eteplirsen is highly effective. FDA's ongoing analyses of eteplirsen and other drugs for the treatment of Duchenne muscular dystrophy are based on thorough and extensive assessment of all data and information by a large multi-disciplinary team of FDA scientists."
Parents believe the FDA is conflating eteplirsen with drisapersen, another Duchenne treatment that competitors GlaxoSmithKline and Prosensa were jointly developing. Prosensa is planning more trials, but GlaxoSmithKline ended its involvement after a clinical trial failed to show statistically significant results on a key measurement of the distance trial subjects could walk in six minutes.
The FDA "isn't comparing apples to apples. That study has nothing to do with ours," Mrs. Ellsworth said.
Scientists around the world had high hopes for both drugs and were as disappointed that the drisapersen trial showed only small increases in dystrophin and inconsistent changes in subjects' walking ability.
"I desperately wanted drisapersen to work. The bad news is that [the drisapersen trial results] cast a specter over the entire field," Dr. Wilton said. "To me, this is the same as saying one early-generation antibiotic did not clear up a bacterial infection, hence all antibiotics do not work."
Dr. Mendell said the FDA seems to want data that doesn't exist yet.
"I don't think we know in Duchenne dystrophy whether replacing dystrophin alone would be adequate to improve function. And we just don't know how much dystrophin we need to improve clinical function. There are no measures for that because it's never been done before now," he said.
Sarepta is prepared to conduct additional trials of its drug. Chris Garabedian, Sarepta's president and CEO, was hoping the FDA would give preliminary approval to take the drug to market even as trials are conducted to confirm eteplirsen's effectiveness, but that appears less likely now.
Still, he is continuing to press for fast action.
"We continue to believe that the currently available data for eteplirsen could be sufficient to qualify for consideration of an early approval with the understanding that we'll conduct a larger study to confirm the findings," he said. "We are working with the FDA to address their concerns and get their agreement that an application for eteplirsen is worthy of a formal review."
Mr. Garabedian is confident that approval will come eventually. The key is whether it happens soon enough for the thousands of Duchenne boys whose muscles are rapidly weakening.
Parents know that side effects could emerge years down the road, but that's a risk they are willing to take to save their dying boys.
"Parents are willing to take the risk because we have no alternative," Mrs. Ellsworth said. "The alternative is death."
How eteplirsen works
Duchenne muscular dystrophy is caused by a mutation, or error, in the gene responsible for production of dystrophin, a protein that stabilizes muscle cells. Without dystrophin, normal activity causes excessive damage to muscles -- first limb muscles and later other muscles including the heart. Over time, the progressive damage causes muscle cells to die, and they are replaced by fibrotic tissue and fat.
Eteplirsen works by directing the cellular machinery to skip exon 51, a small part of the dystrophin gene, to correct genetic mutations. That allows enough dystrophin production to transform Duchenne muscular dystrophy into Becker, a less severe form of the disease. About 13 percent of patients with the disease have genetic mutations that could be corrected with eteplirsen.
If approved, it would be the first drug on the market to treat muscular dystrophy. Approval would encourage Sarepta and other pharmaceutical companies to develop more exon-skipping genes that address the larger number of Duchenne patients with other genetic mutations in the dystrophin gene.
"The longer it takes to get eteplirsen approved, the longer it will take to get started on [approving] these other compounds," including several that are nearly ready for clinical trials, Dr. Wilton said.
That's a big concern for Amy Aikins of Seneca in Venango County. Her 9-year-old son Elijah has a form of Duchenne muscular dystrophy characterized by a different genetic mutation. Eteplirsen won't help him, but another exon-skipping compound might.
Dr. Mendell hopes approval of exon-skipping drugs like eteplirsen would lead to routine muscular-dystrophy tests for newborns so children can be treated before symptoms appear. Such tests already are available but are not done routinely because there are no approved treatments.
Meanwhile, Duchenne parents are growing increasingly frustrated -- and increasingly vocal.
"I know this drug works. It more than works. It's reversing symptoms in Billy. He's doing things he couldn't do before," Mrs. Ellsworth said. "You would not know this kid has Duchenne. He has coordination and stamina."
Billy is hiking, jogging, kicking a ball around his yard and dreaming of dancing on television with Ellen DeGeneres. As a boy who imagined himself in a wheelchair by now, he appreciates even simpler things.
"I can climb into my bed without help. I can open water bottles and Jell-o cups. I can climb uphill without help," Billy said.
It's a different story for Elijah, whose physical decline is apparent from one month to the next. He used to walk more easily up stairs but now uses his arms on the railing to drag himself up, his mother said.
Elijah knows he will be in a wheelchair before long, and he is starting to have questions about death that no 9-year-old should have.
"There's a chance to give my son a better life," Mrs. Aikins said. "If we do nothing, we know what's going to happen. We know."
Mrs. Aikin has seen it up close. Her brother died of Duchenne when he was 18 and she was 22. A few years earlier, a cousin had succumbed to it, also at age 18. And she grew up hearing about twin uncles who died of the hereditary disease before she was born.
"It's time to put an end to this terrible disease. For our family, it's time to put an end to it," she said.
An estimated 20,000 boys across the country have Duchenne muscular dystrophy. Mrs. Ellsworth has gotten to know many of them through her advocacy work, through online forums for parents of Duchenne patients and at conferences of the Parents Project for Muscular Dystrophy, where she has been invited to speak.
Those speaking engagements are difficult.
"I have to think 'How can I do this?' How dare I talk about what my son is doing when a lot of boys -- some of my friends' boys -- are deteriorating quickly, taking their last steps," she said. "How can I get up and say, 'My name is Terri and my son is in a clinical trial and he's doing great,' when I know their boys can't get the drug that's helping him? It breaks my heart."
Washington Bureau Chief Tracie Mauriello: tmauriello@post-gazette.com, 703-996-9292 or on Twitter @pgPoliTweets.
First Published: March 30, 2014, 4:05 a.m.
