A Real-World Target Trial Emulation of Eteplirsen, Casimersen, and Golodirsen to Evaluate Survival Among Patients with Duchenne Muscular Dystrophy

Introduction: Real-world data are needed to understand the treatment effect of eteplirsen, casimersen, and golodirsen (phosphorodiamidate morpholino oligomers [PMOs]) on all-cause mortality in patients with DMD. Methods: The study objectives were to describe the unadjusted time to death from treatment start and from birth, assess PMO treatment's impact on survival, and describe the frequency of comorbidities prior to death. Sequential target trial emulation with inverse probability of treatment and censoring weighting were used to compare survival between patients who received glucocorticoids (GCs) and eteplirsen, casimersen, or golodirsen (PMO + GCs) or GCs alone (GCs-only). Inovalon closed claims data (January 2016-September 2024) were tokenized and linked with Datavant mortality data. Results: In the PMO + GCs group, 208/372 (56%) received eteplirsen, 123/372 (33%) casimersen, and 41/372 (11%) golodirsen. Twelve of 372 patients (3%) died after treatment initiation with PMO + GCs versus 114/2656 (4%) for GCs-only without adjustment for confounding or length of follow-up. In the adjusted target trial emulation analysis, 112 patients initiated PMOs and 2916 initiated GCs-only treatment in the first trial; median follow-up time was 4.6 and 4.8 years, respectively. In sequential trials, 260/2916 patients originally in the GCs-only group initiated treatment with PMOs. While the mortality rate in both groups was low, data from 48 sequentially emulated trials estimated PMO + GCs reduced mortality risk versus GCs-only (hazard ratio 0.303; 95% confidence interval 0.119-0.769; P = 0.012). In patients from either group with claims in the 3 months preceding death (n = 84), more than 75% had circulatory/respiratory claims. Conclusion: The relative risk reduction in mortality suggests a promising treatment effect of PMO + GCs versus GCs-only, which should be confirmed in future studies with longer follow-up.