Editor's note: This story was updated on April 27, 2012, and revised April 3, 2012.
Weekly intravenous administrations of the experimental exon-skipping agenteteplirsen (AVI-4658) in a U.S. trial have resulted in significant increases in production of the needed dystrophin protein in the muscles of boys with Duchenne muscular dystrophy (DMD) who have specific mutations in the dystrophin gene.
Eteplirsen is designed to cause cells to construct a shorter-than-normal, but still functional, version of the muscle protein dystrophin by skipping over a section of dystrophin genetic instructions called exon 51.
The trial was conducted at Nationwide Children's Hospital in Columbus, Ohio, and was the first U.S.-based study of this drug.
The company explained the lack of change in muscle function, despite an increase in dystrophin protein, by noting that performances on a standard "six-minute walk test" and other outcome measures were generally stable for most trial participants, including those receiving a placebo.
It said this finding suggests that "a longer period of observation will be required to demonstrate clinical effects of eteplirsen versus a placebo control." (The muscles of pre-adolescent children with DMD, despite their nearly complete lack of dystrophin, generally have enough regenerative capacity to provide functional stability over relatively short periods of time.)
MDA provided supplemental funding for this trial, which was conducted at Nationwide Children's Hospital in Columbus, Ohio.
Neurologist Jerry Mendell, a current and longtime MDA research grantee at Nationwide, where he also co-directs the MDA neuromuscular disease clinic, was the study's principal investigator.
Twelve boys with DMD who were between 7 and 13 years old and had dystrophin gene mutations potentially treatable by skipping exon 51 participated in this phase 2b trial.
Four participants received 30 milligrams per kilogram of body weight of intravenous eteplirsen once weekly for 24 weeks; four received 50 milligrams per kilogram of body weight for 24 weeks; and four received placebo (without eteplirsen) infusions.
The trial was "double-blinded," meaning neither the participants nor the investigators knew who was receiving which treatment until after the study was completed.
Muscle biopsies were taken before treatment from all participants. Those in the 50-milligram-per-kilogram dosage group and two placebo participants then underwent another muscle biopsy after 12 weeks of treatment. Those in the 30-milligram-per kilogram group and two placebo participants underwent a biopsy after 24 weeks of treatment. (Both dosage groups received 24 weeks of treatment, but only one group had a biopsy at 24 weeks.)
Those in the 30-milligram-per-kilogram group, whose biopsies were taken at 24 weeks, experienced an increase in dystrophin protein production, so that an average of 22.5 percent of their sampled muscle fibers were dystrophin-positive. (Pretreatment dystrophin-positive fibers were not reported, but boys with DMD generally have very little or no dystrophin.)
Those in the 50-milligram-per-kilogram group, whose biopsies were taken at 12 weeks, did not show a significant increase in dystrophin production, despite the higher dosage level.
Those treated with a placebo experienced no increase in dystrophin production.
These findings suggest that longer duration of treatment may be more effective, even at a lower dose, than shorter treatment duration.
In July 2011, AVI announced that a trial of eteplirsen conducted in the United Kingdom in boys with DMD also showed dystrophin protein production in some of the participants.
In that trial, conducted in 19 boys ages 6-13, eteplirsen was administered intravenously once a week for 12 weeks at six different dosage levels. Dystrophin production was roughly correlated with the level of eteplirsen administered. As in the U.S. trial, no changes in function were seen.
In the U.K. trial, eteplirsen was well-tolerated and apparently safe. The investigators noted that, in their study, the immune system appeared to tolerate the newly produced dystrophin protein. (AVI has not yet commented on this aspect of eteplirsen treatment for the U.S. trial.)
AVI said the results of the phase 2b trial in the United States "support advancing eteplirsen into a pivotal study," meaning a trial that the U.S. Food and Drug Administration can use to decide whether or not to approve a drug.
Update 4/27/12: Additional details about the eteplirsen study were provided at the American Academy of Neurology held April 21-28, 2012, in New Orleans. The investigators said the drug was apparently safe; that the percentage of dystrophin-producing fibers seen in the biopsies would probably provide a functional benefit if it were sustained for a longer period of time; and that there was a trend toward functional benefits in the current trial if the two lowest-performing trial participants were removed from the analysis. See Details provided on eteplirsen trial.
Revision 4/3/12: This story was revised to reflect that an average of 22.5 percent of sampled muscle fibers were producing dystrophin protein after 24 weeks in those who received 30 milligrams per kilogram of body weight of eteplirsen. An earlier version of this story expressed those numbers differently.