Drisapersen treatment for Duchenne muscular dystrophy (DMD): results of a randomized, double-blind, placebo-controlled clinical trial of two doses for 24 weeks, followed by a 24-week post-treatment period

● AEs of special interest included those resulting from any of the laboratory safety parameter stopping criteria for hepatic or renal toxicity, thrombocyte counts, inflammation and coagulation abnormalities, and any AEs resulting from injection-site reactions. ■ Change from baseline in the primary efficacy endpoint, and CK were analyzed using mixed models for repeated measures, including fixed terms for treatment, visit, treatment by visit interaction, center group, baseline 6MWD, and baseline 6MWD by visit. ■ Other continuous secondary endpoints were analyzed for the observed case dataset using analysis of covariance, including fixed terms for treatment, center group, and baseline score. ■ CGI-I was dichotomized (responders were considered to be those subjects with a response of much or very much improved), and analyzed using logistic regression, including fixed terms for treatment and center group. ● Treatment benefit was maintained at Week 48 (mean 27.9 m vs placebo; p=0.177), with an overall mean increase from baseline of 14.7 m (Table 2; Figure 2). ■ The drisapersen 3 mg/kg group showed no clinically relevant difference versus placebo at Weeks 24 or 48 (mean treatment differences of -8.9 and -24.8 m, respectively) in 6MWD, with an overall mean decrease from baseline of -37.9 m at Week 48 (Table 2; Figure 2). ● The analysis at Week 48 included one outlier in the drisapersen 3 mg/kg arm who lost 200 m after treatment was discontinued. ■ Greater percentages of subjects receiving drisapersen 6 mg/kg once weekly showed stability (0 m change; 72%) or clinically meaningful improvement from baseline (30 m change; 44%) in 6MWD at Week 24 versus placebo (56 and 13%, respectively), as shown in Table 3. ● Similarly, at Week 48, greater percentages of subjects in the drisapersen 6 mg/kg group showed stability (0 m change; 56%) or clinically meaningful improvement from baseline (30 m change; 44%) in 6MWD versus the placebo group (27 and 13%, respectively), as shown in Table 3. ■ In the drisapersen 6 mg/kg group, an improvement was seen in the percent-predicted 6MWD (5.2% (p=0.051) and 4.8% (p=0.154) mean increase from placebo at Weeks 24 and 48 (Table 2; Figure 3)). In contrast, subjects in the drisapersen 3 mg/kg group experienced a mean worsening compared with placebo in the percent-predicted 6MWD (-1.5% (p=0.584) and -4.1% (p=0.240) at Weeks 24 and 48 (Table 2; Figure 3)). ■ During the treatment phase, renal AEs were observed in 5 (31%), 2 (12%), and 5 (28%) subjects in the placebo, and drisapersen 3 and 6 mg/kg groups, respectively. ● During the treatment phase, the renal AEs reported most frequently in the drisapersen 6 and 3 mg/kg groups were proteinuria and chromaturia, with the highest incidence of proteinuria (3 subjects (17%)) occurring in the drisapersen 6 mg/kg group, and that of chromaturia (2 subjects (13%)) in the placebo group. ● By the end of the post-treatment phase at Week 48, renal AEs were observed in none of the subjects receiving placebo or 3 mg/kg of drisapersen and in 1 subject (6%) receiving 6 mg/kg drisapersen. ■ No deaths occurred during both the treatment and the post-treatment phases; the only serious AE during treatment was a staphylococcal wound infection in a subject receiving placebo.