Phase II Exon-Skipping Trial in Duchenne Dystrophy Raises More Questions Than It Answers

John T. Kissel, MD, Michael Benatar, MD, MS, PhD

The results of a recently completed phase II trial of drisapersen are difficult to interpret.

Duchenne muscular dystrophy (DMD) results from a heterogeneous group of mutations in the dystrophin gene that disrupt the transcriptional reading frame and lead to dystrophin protein deficiency. Antisense oligonucleotides (ASOs) may be used to induce “exon skipping,” thereby restoring the open reading frame and resulting in a truncated but functional dystrophin protein intended to yield a milder phenotype. Researchers conducted a phase II, randomized, placebo-controlled, manufacturer-sponsored study of drisapersen, which targets skipping of exon 51, a therapeutic strategy relevant to about 13% of DMD patients. Fifty-three patients were randomized to 48 weeks of placebo, drisapersen 6 mg/kg administered subcutaneously either continuously (once weekly), or intermittent drisapersen (on a set schedule for 9 doses every 10 weeks).

The continuous-treatment group, but not the intermittent-treatment group, had improved walking distance (by 31.5 meters, vs. a 3.6-meter decrease with placebo) on the 6-minute walking test at week 25, the prespecified primary outcome measure, but no effect at week 49. Measurement of pharmacodynamic markers of dystrophin expression showed minimal increases in half the active-treatment recipients (and no placebo recipients). Mild to moderate injection-site reactions were the most common treatment-related adverse event.

Citation(s):

Voit T et al. Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): An exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol 2014 Oct; 13:987.