P.53 - Effects of long-term treatment with eteplirsen on cardiac function

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked, recessive genetic disease characterized by dystrophin deficiency or absence. Eteplirsen, a phosphorodiamidate morpholino oligomer, targets DMD pre-mRNA to trigger skipping of exon 51 in order to restore the reading frame, thereby enabling production of internally truncated dystrophin protein. Herein we report effects of long-term treatment with eteplirsen on cardiac function in patients with DMD in comparison to reports from disease natural history and a clinical study of perindopril. Eteplirsen patients were treated in two consecutive studies. Study 201 was a randomized, double-blind, 28-week trial. Patients aged 7–13 years with DMD amenable to exon 51 skipping were randomized to receive 1 of 2 once-weekly intravenous (IV) eteplirsen infusions (30 mg/kg, n = 4; 50 mg/kg, n = 4) or placebo (n = 4). At week 25, all patients received open-label eteplirsen through week 28. Study 202 was an open-label extension of study 201; all patients received once-weekly eteplirsen at the same dose (30 mg/kg or 50 mg/kg) for up to 240 weeks. Both trials included longitudinal evaluation of cardiac function using echocardiographic left ventricular ejection fraction (LVEF). We found that the mean annual rate of decline in ejection fraction for eteplirsen-treated patients over the 240-week trial was 0.18%. A study of perindopril (N = 57; mean age at baseline, 10.6 years) reported a 1.28% annual decline in perindopril-treated patients (n = 28) and a 1.88% annual decline in placebo-to-perindopril patients (n = 29; placebo treatment, 3 years; perindopril treatment, 2 years) over the 5-year study period, as measured by radionuclide ventriculography. A disease natural history study of 98 DMD patients aged 7–29 years reported a 0.58% annual decline in LVEF, as measured by magnetic resonance. In conclusion, safety monitoring showed gross LVEF stability in eteplirsen-treated patients over the 240-week study period.