Association between exon-skipping therapy with eteplirsen and cardiac outcomes in Duchenne muscular dystrophy

Background Duchenne muscular dystrophy (DMD) leads to dilated cardiomyopathy and heart failure during teenage years or young adulthood. Eteplirsen promotes dystrophin production through skipping of exon 51 of the DMD gene. Objective This analysis compared LVEF decline between eteplirsen-treated and control patients with exon 51 skip-amenable DMD. Methods Eteplirsen-treated patients from clinical trials were matched with control patients from natural history studies in a propensity score analysis. Risk of reaching LVEF thresholds (50%, 55%, and 60%) was evaluated using Cox proportional hazard models. Annual rate of LVEF decline was characterised using linear mixed effects models. Results Among 141 eteplirsen-treated and 103 control patients available for matching, the analysis included 122 eteplirsen-treated patients matched with 122 control patients (64 unique control patients). No eteplirsen-treated and 27 controls (22.1%) reached LVEF <50%; eteplirsen-treated patients had a lower risk of reaching <55% and <60% thresholds versus controls (hazard ratio = 0.22; 95% CI = 0.07–0.66; P < 0.01 and hazard ratio = 0.40; 95% CI = 0.22–0.76; P < 0.01, respectively). Annual rate of LVEF decline for eteplirsen-treated and controls was −0.66% (95% CI = –0.96 to −0.36, P < 0.01) and −1.38% (95% CI = –1.60 to −1.16; P < 0.01), respectively. Results were consistent with a sensitivity analysis matching each eteplirsen-treated patient once with a unique control patient and with several tests for potential bias. Conclusions In this retrospective study, eteplirsen-treated patients were observed to have a significantly lower risk of reaching LVEF thresholds indicative of cardiac function decline and attenuation of LVEF decline compared with matched controls.