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

https://doi.org/10.1016/j.nmd.2017.10.004Get rights and content
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Highlights

  • 48-week phase 3 RCT evaluating efficacy and safety of drisapersen 6 mg/kg/week.

  • The pre-specified analyses did not meet statistical significance.

  • Due to increased data variation, statistical power for 6MWD was reduced to 53%.

  • Evidence for a greater treatment benefit was seen in a selected population post-hoc.

  • Most common adverse events were injection-site reactions and subclinical proteinuria.

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.

Keywords

Duchenne muscular dystrophy
Drisapersen
Dystrophin
Antisense oligonucleotide
Exon skipping
six-minute walking distance

Cited by (0)

1

Member of the DEMAND III study team 2.