PHILADELPHIA — Combined results from two extension trials of the investigational drug drisapersen for Duchenne muscular dystrophy (DMD) showed a suggestion of benefit, but only for a subset of patients.
Among 69 boys 5 to 16 years old followed for 96 weeks while taking drisapersen continuously or intermittently, mean 6-minute walking distance (6MWD) declined by more than 60 meters, according to Nathalie Goemans, MD, of University Hospitals in Leuven, Belgium, and colleagues.
Although the drug was obviously not a cure for DMD, that result was better than the 100-meter decline in mean 6MWD in 44 boys who took placebo for 48 weeks and then took drisapersen for 48 weeks, Goemans and colleagues reported at the American Academy of Neurology’s annual meeting here.
The investigators called the difference “clinically significant” but it did not meet the normal P<0.05 standard for statistical significant.
Complicating the interpretation was that, when the results were stratified according to the “feeder trial” that led into the combined extension, participants in one appeared to fare much better than the others.
Boys first enrolled in a phase II trial conducted primarily in western Europe who were assigned to the active-drug arm and who stayed on the drug for 96 weeks in total showed no decline in mean 6MWD. The primary outcome analysis at 25 weeks had found a clear benefit for the drug versus placebo.
But those initially assigned to drisapersen in a larger phase III trial, which included participants from Canada, South America, and Asia as well as eastern and western Europe, and which failed to meet its primary efficacy endpoint during the placebo-controlled phase, lost a mean of 87 meters in 6MWD after 96 weeks.
Goemans and colleagues, in their poster presentation, suggested that one explanation for the discordant results could lie in the feeder studies’ differing demographics.
Not only did the phase III trial have more geographic diversity, but it also included a broader age range — 5 to 16, versus 5 to 11 in the phase II study.
An age-stratified analysis of the combined samples in the extension phase showed that mean 6MWD remained at or near baseline in the 52 boys who were 7 or younger, irrespective of whether they were on drisapersen throughout or only for the last 48 weeks.
In contrast, participants older than 7 showed marked declines in 6MWD — by a mean of 128 meters in those taking drisapersen continuously and by 140 meters in those on placebo for the first 48 weeks. Even during the initial 48-week placebo-controlled, double-blind phase, there was only a weak trend toward benefit for drisapersen.
Because age and disability are closely correlated in DMD, the age-stratified analysis probably reflects a greater effect for drisapersen in patients with less disability at baseline, Goemans and colleagues suggested.
Overall, they concluded, the analysis “suggests maintenance of benefit in a subpopulation of boys with less severe disease, and a clinically meaningful benefit slower to emerge in a subpopulation that is, on average, more severely affected.”
The effect of age and/or baseline disability “may help direct what’s going on here,” said Thomas Vidic, MD, a neurologist at the Elkhart Clinic and medical director of Indiana Medical Research in Elkhart, Ind.
“This is one of the things we’re finding out with a lot of the research in degenerative diseases — maybe what we’re doing is we’re attacking disease at the wrong stage. The earlier we can attack it, perhaps the more effective we can be.”
Vidic, who was not involved with the trials, told MedPage Today that the analysis should be regarded as “early proof-of-concept,” despite the phase III designation, and needs confirmation in a prospective study.
Drisapersen is a so-called exon skipping drug, targeting the approximately 13% of DMD patients with deletions in or near exon 51 in the dystrophin gene. Normally, transcription of the dystrophin gene is halted when these deletions are present, but exon-skipping drugs such as drisapersen or eteplirsen force transcription to continue past the deletions to allow a functional dystrophin protein to be expressed.
Eteplirsen has shown benefit in its clinical trials but with big question marks. However, because there is currently no disease-modifying treatment for DMD, its sponsor, Sarepta Therapeutics, believes the FDA will look favorably on the results if supplemented with some additional data. Sarepta said it planned to file a marketing application later this year.
Drisapersen’s developers, Netherlands-based Prosensa Therapeutics and GlaxoSmithKline, also believe they can eventually win approval for their drug.
Vidic added that the drisapersen results so far do indicate that the drug is safe. Moreover, to the extent that it did benefit some participants, “it did not appear to stop working” during the extension phase.
By John Gever