A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy

Abstract

This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.

Magnetic resonance imaging in facioscapulohumeral muscular dystrophy

“…The limitations of currently available outcome measures have been made apparent by our collective experience in DMD, where multiple therapeutic trials have already taken place and are ongoing. Several publications on these trials have reported that the variability of the primary outcome measure (the 6‐minute walk distance) within the study population was larger than anticipated . Unanticipated high variability can greatly impact the interpretability of trial results, and we may not discover until the end of the trial that we are unable to agree upon whether the absence of a statistically significant effect is due to underpowering or true ineffectiveness of the intervention.…”

“…Several publications on these trials have reported that the variability of the primary outcome measure (the 6-minute walk distance) within the study population was larger than anticipated. 8,9 Unanticipated high variability can greatly impact the interpretability of trial results, and we may not discover until the end of the trial that we are unable to agree upon whether the absence of a statistically significant effect is due to underpowering or true ineffectiveness of the intervention. The inability of a trial to answer its prospective scientific question carries multiple costs, including loss of participant time, consumption of limited investigator resources, and potential divisiveness within a rare disease field where collaboration is instrumental to success.…”

Early phase 2 trial of TAS‐205 in patients with Duchenne muscular dystrophy

“…The DMD care consideration guidelines have been updated due to recent advances in the diagnosis of DMD and the emergence of novel treatments, including genetic and molecular therapies. [3][4][5][6][7][8][9][10] Currently, DMD is treated with orally administered steroids, which suppress the infiltration of inflammatory cells into the muscle. 11,12 However, there are several problems with steroidal treatments, particularly with their safety profile in paediatrics.…”

Placebo‐controlled Phase 2 Trial of Drisapersen for Duchenne Muscular Dystrophy

“…These results are consistent with those of the DMD114117 and DMD114044 studies. 19,31 Data from natural history studies demonstrated that it can be difficult to observe significant treatment effects on the measures that were used as secondary outcome in this study after a period of only 48 weeks, 22,30,32,33 while the current study only had a 24 week treatment period. In addition, the 24 week treatment period was not sufficient to reach steady state drisapersen tissue levels.…”

“…However, in the phase 3 study, 16% of the injection site reactions remained unresolved upon study close. 31 The progressing injection site reactions were one of the reasons that drisapersen did not reach approval.…”