Exon-Skipping Shows Promise in Duchenne Muscular Dystrophy

October 5, 2012

Results from a Phase IIb extension trial of the drug eteplirsen show an increased ability to walk in boys with Duchenne muscular dystrophy  Eteplirsen, a drug that skips exon 51 of the dystrophin gene, may improve quality of life for patients with Duchenne muscular dystrophy and slow disease progress.  These are the findings from a Phase IIb extension trial that is taking place at Nationwide Children’s Hospital.  

The first-of-its-kind Phase II trial of eteplirsen as potential treatment for Duchenne muscular dystrophy began at Nationwide Children’s in August 2011.  Only boys with certain out-of-frame dystrophin gene deletions that may be corrected by skipping exon 51 were included in the study, a mutation that represents about 13 to 15 percent of Duchenne patients.   The drug is designed to address the underlying cause of Duchenne muscular dystrophy by allowing a functional dystrophin protein to be produced.  By skipping exon 51, eteplirsen may restore the gene’s ability to make a shorter, but still functional, form of dystrophin from messenger RNA.  

During the trial, 12 boys received IV infusions of placebo, 30 mg/kg of eteplirsen or 50 mg/kg of eteplirsen once weekly for 48 weeks.  Muscle biopsies were performed at baseline,  12 weeks for participants receiving 50/mg/kg, 24 weeks for those in the 30 mg/kg cohort, and then again at 48 weeks for both dose cohorts.  The four placebo patients were rolled over to an open-label eteplirsen of either 30 or 50 mg/kg at week 24.  

Results showed that the boys who received the highest dose of eteplirsen for the full 48 weeks had a slightly improved ability to complete the six-minute walk test used to measure functional ability in the disease.  These boys walked an average of 21 meters farther after 48 weeks of treatment than at the beginning of the trial while the placebo group walked 68 meters fewer after 48 weeks than at its beginning. No treatment-associated adverse events occurred. 

“These data represent a significant milestone and a defining moment of progress and hope for patients with Duchenne muscular dystrophy and their families, as well as those of us in the scientific community who have been pursuing potential treatments for this devastating and deadly disease for decades,” says Jerry Mendell, MD  director of the Center for Gene Therapy of The Research Institute at Nationwide Children’s Hospital and principal investigator of the Phase IIb study. “By addressing the underlying cause of Duchenne muscular dystrophy, eteplirsen has demonstrated unparalleled effects on enabling dystrophin production and slowing the progression of the disease as measured by the 6-minute walk test.  While eteplirsen is targeted to Duchenne muscular dystrophy patients with a specific genetic mutation, I think the implication for all Duchenne muscular dystrophy patients with related genetic mutations are clearly evident.”

Dr. Mendell, also director of Neuromuscular Disorders at Nationwide Children’s, will present his findings at the World Muscle Society Congress’ Late-Breaking Science program in Perth, Australia during October 9 through October 13, 2012. 

Despite these findings, Dr. Mendell explains that caution should still be taken.  The trial only included 12 patients, with only four receiving the high dose and four receiving the placebo.  It is unclear how long the effects of the drugs would last or if safety issues would arise with longer treatment.  Also, two of the boys on a lower dose of the drug rapidly lost the ability to walk, even though the level of dystrophin in their muscles increased substantially. 

About Nationwide Children's Hospital

Named to the Top 10 Honor Roll on U.S. News & World Report’s 2019-20 list of “Best Children’s Hospitals,” Nationwide Children’s Hospital is one of America’s largest not-for-profit freestanding pediatric health care systems providing wellness, preventive, diagnostic, treatment and rehabilitative care for infants, children and adolescents, as well as adult patients with congenital disease. Nationwide Children’s has a staff of more than 13,000 providing state-of-the-art pediatric care during more than 1.5 million patient visits annually. As home to the Department of Pediatrics of The Ohio State University College of Medicine, Nationwide Children’s physicians train the next generation of pediatricians and pediatric specialists. The Abigail Wexner Research Institute at Nationwide Children’s Hospital is one of the Top 10 National Institutes of Health-funded freestanding pediatric research facilities. More information is available at NationwideChildrens.org.