Longitudinal effect of eteplirsen vs. historical control on ambulation in DMD

Objectives: To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy. Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC). Methods: Ambulatory DMD patients ≥7 years amenable to exon 51 skipping were randomized to eteplirsen (30/50 mg/kg) or placebo for 24-weeks. Thereafter, all received eteplirsen open-label. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and Months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use and genotype. Results: At 36 months, eteplirsen-treated patients (N=12) demonstrated a statistically significant advantage of 151 meters (p<0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (N=13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well-tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The sub-set of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping. Interpretation: Over three years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT over three years compared to untreated matched HC.