|Editor's note (July 30, 2012): This story was revised to include information about the specific mutations being targeted by eteplirsen.|
Eteplirsen, an experimental drug designed to cause skipping of exon 51 of the dystrophin gene in boys with Duchenne muscular dystrophy (DMD), provided "significant clinical benefit" with no indications of safety concerns in a 36-week study, its developer has announced.
These new results are from a 12-week, open-label extension of a 24-week, phase 2b clinical trial of eteplirsen.
The clinical benefit was measured by the distance participants were able to walk in six minutes — the six-minute walk test. Sarepta Therapeutics— formerly AVI BioPharma — announced the findings July 24, 2012.
"This is a very encouraging result for a trial of a drug specifically designed to treat Duchenne muscular dystrophy," said Sanjay Bidichandani, MDA's vice president for research. “These results also exemplify the hopeful stage we are at in terms of being able to ameliorate the deleterious effects of specific types of genetic mutations.”
Exon skipping for DMD involves using antisense oligonucleotides to block error-containing instructions in the gene for dystrophin, the muscle protein missing in this disease. The goal of exon-skipping compounds is to cause cells to make a shorter-than-normal, but still functional, dystrophin protein.
Eteplirsen targets "out-of-frame" deletions in the dystrophin gene in exons 45-50; 47-50; 48-50; 49-50; 50; 52; and 52-63. The negative effects of these mutations, estimated to affect about 13 percent of the Duchenne MD population, potentially can be lessened by skipping exon 51.
Sarepta (formerly AVI BioPharma) announced results for a phase 2b trial of eteplirsen in DMD in April 2012. That 24-week trial included 12 boys ages 7 to 13 with dystrophin mutations potentially treatable by skipping exon 51. There were two eteplirsen dosage groups of four people each and one placebo group of four.
After 24 weeks, the company reported that trial participants who received weekly intravenous administrations of eteplirsen produced dystrophin protein in their muscle fibers, as shown by analysis of muscle biopsy samples. However, at that time, there was no difference in the distance walked in six minutes in treated participants compared to participants receiving a placebo.
Dystrophin measurements from muscle biopsies taken at 12 weeks did not show a significant increase in dystrophin production, leading investigators to conclude that duration of treatment is probably a factor in eteplirsen's effectiveness.
These new results are from an open-label extension study that ran an additional 12 weeks after the phase 2b trial. In the extension study, all participants received weekly infusions of eteplirsen at 50 milligrams per kilogram of body weight for 12 weeks, regardless of what treatment they received during the 24-week phase 2b trial.
All participants showed a decline in walking distance over the 36 weeks of the study. However, in the extension study, the four participants who received the 50-milligram-per-kilogram weekly infusion throughout all 36 weeks showed a small decline — 8.7 meters (28.5 feet) — between the initial and final measurements taken for the 6-minute walk test.
By contrast, the four participants who received a placebo for the first 24 weeks and then the 50-milligram dose for the next 12 weeks showed a substantial decline — 78 meters (255.9 feet) — between the first and last walk tests.
Those who received a 30-milligram-per-kilogram weekly dose of eteplirsen for the first 24 weeks and then the higher dose for 12 weeks performed about the same as the placebo group.
The difference in decline between those who received the highest dose of eteplirsen for the longest time and the other two groups was highly significant — 69.4 meters (227.7 feet).
"The magnitude [of effect] is unprecedented for a disease-modifying drug in Duchenne muscular dystrophy," said Chris Garabedian, president and CEO of Sarepta Therapeutics, on a July 24, 2012, conference call.
On the call, Garabedian said the company was "simply thrilled by these results" and that it believes it has "a drug that represents a major advance to treat the underlying cause of Duchenne muscular dystrophy."
Garabedian noted that Sarepta plans to release results for 48 weeks of eteplirsen treatment — an additional 12 weeks — in October. It plans to present additional clinical data and dystrophin data from muscle biopsy samples at that time.
By the end of 2012, Garabedian said, Sarepta plans to meet with the U.S. Food and Drug Administration (FDA) to clarify its path toward approval of eteplirsen for treating patients with DMD who have specific dystrophin gene mutations.
MDA has been supporting the development of exon skipping as a strategy to treat DMD through its basic research program.
The trial’s principal investigator, neurologist Jerry Mendell at Nationwide Children's Hospital in Columbus, Ohio, received supplemental MDA funding for the trial.
An audio replay of the July 24, 2012, conference call is available through July 31 by dialing (888) 286-8010 or (617) 801-6888 and entering access code 44234182. The call and an accompanying slideshow will be archived for 90 days at Events & Presentations on Sarepta's website.