Eteplirsen, an exon-skipping drug in development by Sarepta Therapeutics to treat Duchenne muscular dystrophy (DMD) caused by specific mutations in the dystrophin gene, continues to show benefit at 62 weeks with respect to the distance walked in six minutes.
Sarepta announced the 62-week results in a Dec. 7, 2012, press release. "We are excited to see continued stability on the six-minute walk test with more than a year of follow-up, where we would otherwise predict a significant decline," said Sarepta CEO Chris Garabedian.
Results at 62 weeks show sustained benefit
Neurologist Jerry Mendell, who conducted the eteplirsen trial at Nationwide Children's Hospital in Columbus, Ohio, with the help of supplemental support from MDA, reported the trial results Dec. 7, 2012, at the European Neuromuscular Centre Workshop in Naarden, Netherlands. His presentation is available on the Sarepta website.
At 62 weeks, the six ambulatory trial participants who received either of two dosage levels of eteplirsen for the entire trial period walked 203.4 feet farther than those who received a placebo for the first 24 weeks and then received eteplirsen for 38 weeks (known as the "placebo/delayed-treatment" group).
Four participants received weekly intravenous infusions of eteplirsen at 50 milligrams per kilogram of body weight for 62 weeks; and two received the drug at 30 milligrams per kilogram of body weight. Four people were in the placebo/delayed-treatment group.
Two other trial participants could not be tested for walking distance because they had stopped walking by week 24.
The six boys treated with eteplirsen for 62 weeks continued to show stabilization of their disease, with an average of less than 5 percent decline in walking distance on the six-minute walk test, compared to their baseline measurements.
The placebo/delayed-treatment group also showed stability in walking ability over their last 26 weeks of eteplirsen treatment — from week 36 through week 62 — "the period in which we would expect to see dystrophin levels translate to clinical benefit," said Garabedian.
The 48-week trial results reported in October showed that trial participants who received eteplirsen at the higher dose for all 48 weeks increased the distance they could walk in six minutes by 68.9 feet, compared to their baseline distance. Although that increase in walking distance was not seen at 62 weeks, walking ability appeared to have stabilized.
Muscle biopsies at 48 weeks showed that all trial participants, including those who initially received a placebo, had a significant increase in production of the needed dystrophin protein. (See A Closer Look at the 48-Week Eteplirsen Trial Results.)
Sarepta reported no dystrophin data at 62 weeks. However, the company said there was evidence of continued stabilization on pulmonary function tests, echocardiograms, muscle strength and clinical laboratory tests over the 62 weeks in the treatment and placebo/delayed treatment groups.
Eteplirsen's safety profile continued to be positive.
Eteplirsen targets exon 51 of the gene for the dystrophin protein, coaxing muscle fibers to leave exon (section) 51 out of the genetic instructions for this protein and create a functional, though shortened, version of this protein. (Dystrophin's absence in muscles is the underlying cause of DMD.)
Eteplirsen is designed to treat patients with deletions of dystrophin exons 45-50; 47-50; 48-50; 49-50; 50; 52; and 52-63.
Sarepta says it will discuss next steps toward approval of eteplirsen with the U.S. Food and Drug Administration (FDA) during the first quarter of 2013.
Garabedian said that the 62-week data "support our belief that the dystrophin levels we observed at 48 weeks are potentially an important surrogate marker [a measurement that can stand in for accepted measurements] in assessing disease progression in Duchenne and renews our commitment to advance this program forward as we prepare our primary 48-week dataset for discussion with the FDA."
Under the FDA’s accelerated approval pathway for drugs designed to treat rare diseases, an approved surrogate marker, or surrogate endpoint, can be used to show the drug is effective, which can shorten the time necessary for approval.
If the FDA gives accelerated approval to eteplirsen, the drug would become available to individuals with DMD caused by specific mutations, and Sarepta would continue to study the drug in a set of patients enrolled in a confirmatory trial.
For more information, read What's Next for Eteplirsen? in which Sarepta CEO Chris Garabedian responds to questions from MDA, and discusses Sarepta's pursuit of FDA approval and future trials for additional exon-skipping compounds for DMD.