WASHINGTON — Marissa Penrod knew something was wrong with her son early on.
Marissa Penrod founded the nonprofit Team Joseph in 2009 after her son, Joseph, was diagnosed with the deadly genetic disease Duchenne muscular dystrophy.
Photo courtesy of Marissa Penrod.
At 4 years old, Joseph couldn’t run or walk up a flight of stairs normally. He had never ridden a bike.
After multiple pediatric consultations, she was referred to a neurologist in Ann Arbor, Mich., where Joseph underwent blood and laboratory tests focusing on creatine kinase, a liver enzyme that regenerates muscle tissue. Normal CK levels average around 300. Joseph’s levels topped 20,000 — levels akin to marathon runners — indicating extreme muscle breakdown.
Genetic tests confirmed a diagnosis of Duchenne muscular dystrophy, a deadly childhood disease few survive past their early 20s. The most common form of childhood muscular dystrophy, Duchenne affects about 1 in 3,500 young boys, the primary demographic affected by the disease. About 20,000 new cases of Duchenne are diagnosed annually.
There is no approved cure or treatment to halt or slow Duchenne’s progression.
After extensive discussions with experts who said more money is needed to move faster on treatment and prevention research, Penrod founded the nonprofit Team Joseph in 2009. It is one of several Duchenne organizations working with the Food and Drug Administration and members of Congress to try to accelerate research for the disease. But it is a slow process fraught with disagreements over pending treatments — too slow for a disease with such rapid progression, Duchenne groups argue.
‘Worse than cancer’
Duchenne muscular dystrophy is a debilitating genetic condition that causes muscle fibers to deteriorate rapidly, leading to extreme muscle loss. It results from an error in the dystrophin gene, which provides coding for a protein that determines muscle tissue structure.
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With symptoms generally manifesting before age 6, most Duchenne patients lose the ability to walk by 11 — Joseph’s current age. Motor skills and skeletal and muscle formation deteriorate over time, and by 21 many are essentially paralyzed from the neck down. Most die from heart attacks or respiratory failure.
“Duchenne’s worse than cancer,” said Eric Hoffman, a longtime Duchenne researcher and director of the Research Center for Genetic Medicine at George Washington University. “With Duchenne you just relentlessly fade away over 20 years. As a parent, to watch that with your child is just devastating.”
Everyday life isn’t easy for Joseph. He can still walk but cannot participate in team sports, sometimes struggles to keep up with friends and must be carried up stairs.
Joseph’s experience coping with the disease can serve a greater purpose, his mother said.
“I wanted to make sure that Joseph’s life and his journey — whatever it would entail — that it would have some kind of meaning and that we would use it for something really good,” Penrod said.
Searching for a cure
Duchenne patients face a sparse treatment landscape.
Duchenne is treated primarily with steroids and artificial ventilation machines, which both have serious drawbacks. Even though steroids allow children to walk two to four years longer, they stunt growth and make bones very brittle. Ventilation machines detract from quality of life and make patients completely reliant on caregivers, Hoffman said.
But although no FDA-approved cure or treatment for Duchenne exists, researchers and drug developers say they now know enough about the disease’s origins to work toward treatments to halt and potentially reverse its progression.
Potential treatments fall under four categories: drugs that trick cells into ignoring dystrophin gene mutations, muscle stem cells, direct gene therapy and drugs that slow down muscle inflammation and regenerate tissue, said Jeff Chamberlain, a neurologist at the University of Washington working on several muscular dystrophy projects.
“We’re at the point now where things can be done,” Chamberlain said. “And 20 years ago there weren’t things that could be done.”
Researchers are also looking at using hormone-based drugs like Relaxin, which has been used to improve blood flow in pregnant women. In initial studies, the drug increased blood flow to muscles, which could possibly reverse muscle damage in Duchenne patients, said Ron Berenson, a researcher working with Chamberlain at UW’s Center for Commercialization.
Ultimately, Berenson said, the definitive cure for Duchenne will be gene therapy that replaces the defective dystrophin gene, but experts say it will be years before it’s available.
“These things take time and I think it will take a few decades before that happens,” he said. “I wish it would go faster, too.”
Strife over treatments
Despite research advancements, experts and advocacy groups differ on how to best tackle Duchenne and whether the FDA and Congress are prioritizing the disease.
Eteplirsen, one of the drugs that tricks cells into skipping sections of genes, has been a sticking point between Duchenne advocacy groups and FDA representatives, who have yet to place the drug on a track for accelerated approval. The slow progress has been source of frustration for parents, legislators and nonprofits like Team Joseph.
Although experts say the drug shows promise, it’s tailored to specific gene mutations and only would help 13 percent of Duchenne cases.
Publicly, the FDA has not shared its conclusions on accelerated approval for Eteplirsen, citing its “evolving position” on the drug and the ongoing analysis of Duchenne treatments based on “extensive assessments and discussion of all available data and information by a large multi-disciplinary team of FDA scientists.”
“We recognize 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,” according to an FDA statement.
Multiple scientific experts on Duchenne say drugs like Eteplirsen are encouraging and have yielded compelling results. However, its delay for accelerated approval may result from a lack of sound clinical trials, which need to be double-blinded to combat the placebo effect, Hoffman said.
Duchenne’s severity makes additional clinical trials especially problematic, Penrod said. Placebo trials prevent some boys from receiving drugs and involve muscle biopsies under general anesthesia — especially dangerous for boys with Duchenne, she said.
“Parents are desperately looking for anything that can improve the quality of life of Duchenne kids. Everybody’s desperate,” said Hoffman, who is working on alternative Duchenne therapies. “To think that the regulators are somehow purposely keeping a drug from patients couldn’t be further from the truth.”
Others are not as optimistic about the FDA’s approach. Berenson called the agency “extremely difficult” to work with and unwilling to modify a mindset focused on safety, one that does not readily apply to rare diseases like Duchenne.
Seven other Duchenne experts met with the FDA last month to discuss the evidence supporting Eteplirsen.
At a briefing in early February attended by staffers from more than 80 congressional offices, several leading Duchenne experts touted the drug’s promising results and lack of negative side effects.
“This drug works,” Jerry Mendell, Eteplirsen’s lead investigator, said at the briefing. “It has minimal side effects. I say minimal — we haven’t seen a single one, which is incredibly remarkable.”
Louis Kunkel, a Harvard Medical School professor and discoverer of Duchenne’s link to the dystrophin gene, also praised the new therapy.
“They are stabilized,” Kunkel said of the boys who have received the drug. “They are making dystrophin. This is really quite an amazing feat.”
Parents who feel time is running out for their children may be more amenable to riskier treatments, said Pat Furlong, president of Parent Project Muscular Dystrophy. The group is expanding a survey in which parents of children with Duchenne said they would be willing to participate in risky therapies due to Duchenne’s serious nature.
A report based on the survey recommended the FDA grant accelerated approval for Duchenne therapies, improve flexibility in approval processes for deadly disease treatments and “amplify the patient voice in drug evaluations.”
Racing against the clock
Like many diseases, Duchenne research requires enormous amounts of time, energy and money.
Team Joseph, Parent Project Muscular Dystrophy and other Duchenne organizations are working together and with legislators to accelerate research and boost funding, in part by seeking reauthorization of the 2001 Muscular Dystrophy Community Assistance, Research, and Education Act.
The bill, which expires every five years, requires the National Institutes of Health to prioritize muscular dystrophy, establishing programs and funneling funds into research. The bill has generated nearly $500 million worth of research and programs benefiting muscular dystrophy, Furlong said.
“That legislation has touched in one way or another every single scientific strategy and every single trial that we see today,” she said.
Up for reauthorization this year, the MD-CARE Act has the support of 78 members of Congress so far. Additionally, Team Joseph and other groups are working with the FDA to accelerate Duchenne research under provisions of the 2012 Food and Drug Administration Safety and Innovation Act, which created new approval routes for drugs treating deadly diseases.
In July, Rep. Spencer Bachus,R-Ala., a co-sponsor of the MD-CARE Act, spoke on the House floor to advocate for the approval of Eteplirsen and increased Duchenne research. Bachus has also signed letters urging the FDA to expedite access to treatments like Eteplirsen.
“I am concerned that the FDA has not adequately taken into account the views of the Duchenne community and the unmet need of medication to treat Duchenne,” Bachus wrote to Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, in December. “The families and even young Duchenne patients tell me that, due to the debilitating nature of Duchenne, they are desperate for a solution and willing to assume all risks because time is unfortunately not on their side.”
Confronting the criticism, the FDA solicited feedback from the Duchenne community. In December, it held a policy forum with Duchenne stakeholders, where Penrod testified against delaying potential treatments to sick children. Officials said they recognize the “dire urgency of the situation.”
“We will continue to work relentlessly with the community to make safe and effective treatments for Duchenne muscular dystrophy available to patients,” the FDA said in a statement.
Even in the face of research setbacks, Penrod is still optimistic about finding a cure.
“I don’t think we’re on a race against the science,” Penrod said. “It’s like we’re on a race against the clock. It’s how quickly we do it.”
