Drisapersen: An Overview of the Exon-51 Skipping Antisense Oligonucleotide Clinical Program to Date in Duchenne Muscular Dystrophy (DMD) (P2.230)

OBJECTIVE: To assess the safety and efficacy of drisapersen in DMD. BACKGROUND: DMD is caused by DMD gene mutations leading to disruption of the open-reading frame and dystrophin absence/defects. Approximately 13[percnt] of boys with DMD have exon-51 mutations. Drisapersen is a 2′-O-methyl-phosphorothioate antisense oligonucleotide that induces exon-51 skipping in pre-mRNA to allow some dystrophin synthesis. DESIGN/METHODS: The drisapersen clinical program comprises two Phase II, one Phase III placebo-controlled (total N=290), and two open-label extension (OLE; N=245) studies. RESULTS: The Phase II studies enrolled similar populations with mean baseline 6-minute walking distance (6MWD) ~400m. At Week 25, study DMD114117 (N=53) showed a statistically significant and clinically meaningful treatment difference of 35m (p=0.014) in 6MWD for drisapersen 6mg/kg/week versus placebo (maintained at Week 49 [36m; p=0.051]). After 24 weeks’ drisapersen 6mg/kg/week in study DMD114876 (N=51), a clinically meaningful treatment difference was seen in 6MWD (27m; p=0.069). The Phase III study, DMD114044 (N=186), enrolled a more severe population (mean baseline 6MWD <350m). After 48 weeks, there was a non-statistically significant 10m difference in favor of drisapersen 6mg/kg/week versus placebo. At Week 48 of OLE DMD114349, the 6MWD difference (n=113) was 46m for subjects receiving 96 weeks’ drisapersen versus those receiving delayed treatment (placebo in feeder studies/48 weeks’ drisapersen). In OLE DMD114673 (n=10; average age: 12.9y), mean change in 6MWD at Week 177 was -24.5m (median 8m) from OLE baseline. Most common drisapersen adverse events were injection-site reactions and sub-clinical proteinuria. Infrequent moderate-to-severe thrombocytopenia was also seen. CONCLUSIONS: Overall the results are promising, as deterioration of muscle function is associated with the natural history of DMD in young boys. Observed 6MWD improvements/reductions in decline over 24-177 weeks at this stage of DMD are indicative of an encouraging effect of drisapersen in reducing disease progression. Study Supported by: GlaxoSmithKline; Prosensa Therapeutics BV additionally supported DMD114673. Disclosure: Dr. McDonald has received personal compensation for activities with PTC Therapeutics and Sarepta Therapeutics as an advisory board participant and/or consultant. Dr. Goemans has nothing to disclose. Dr. Voit has received personal compensation for activities with Prosensa. Dr. Wilson has received personal compensation for activities with Prosensa as a consultant. Dr. Wardell has nothing to disclose. Dr. Campion has received personal compensation for activities with Prosensa Therapeutics as an employee.