Abstract
DRIS is a 2′-O-methyl-phosphorothioate antisense oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA of boys with DMD. In a Ph 3 study (DMD114044), a 10 m treatment difference (NS) on 6-min walking distance (6MWD) in favour of DRIS was seen in the overall study population but there was a treatment benefit of 21 m in a pre-specified subset of boys aged ⩽7y (n = 79), suggesting that younger, less progressed boys could benefit more from DRIS in terms of ambulatory endpoints vs older boys in whom DMD is more advanced. In an open-label extension (OLE; DMD114349) of two 48-wk placebo (PBO)-controlled trials (DMD114117, DMD114044), 96 wks’ DRIS resulted in a clinically meaningful difference from 48 wks’ PBO (feeder study) followed by DRIS (OLE) in 6MWD of 46 m (n = 113; completed 48 wks’, DMD114349). By feeder study, the treatment effect was 52 m (n = 30) for DMD114117 and 49 m for DMD114044 (n = 83), for those on DRIS for 96 wks vs PBO/delayed treatment. Data suggest that treatment benefits that manifest early in less severe DMD are maintained, while in more advanced DMD, benefits may emerge only after prolonged exposure. In a pooled analysis of two comparable Ph 2 trials (DMD114117, DMD114876), a subset of boys with similar BL demographic and functional characteristics who received DRIS 6 mg/kg/wk (n = 36) was compared with PBO-treated boys (n = 34; Mixed-Effect Model Repeated Measure model including Treatment, Visit, Treatment by Visit, Country/Study, BL 6MWD, BL 6MWD by Visit). At Wk 24, there was a clinically meaningful and statistically significant difference in 6MWD between DRIS- and PBO-treated boys of 31 m (n = 70; 95% confidence interval: 11, 51; p = 0.003), based on an adjusted mean (standard error) difference of −11(7) m for placebo and + 20(7) m for DRIS. DMD114044 enrolled boys aged ⩽16y, whereas in the pooled dataset, the oldest boys were only 13y, supporting the premise that treatment at a younger age is more immediately beneficial for preserving ambulatory capacity.
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