Long-Term Pulmonary Function in Duchenne Muscular Dystrophy: Comparison of Eteplirsen-Treated Patients to Natural History

Abstract

Background: Duchenne muscular dystrophy (DMD) is a rare, degenerative, X-linked genetic disease that results in progressive muscle loss and premature death, most commonly from respiratory or cardiac failure. DMD is primarily caused by whole exon deletions, resulting in a shift of the dystrophin mRNA reading frame that prevents production of functional dystrophin protein. Eteplirsen, a phosphorodiamidate morpholino oligomer (PMO), is designed to skip exon 51, restore the reading frame, and induce production of internally shortened dystrophin in patients with mutations amenable to such treatment. Objective: Describe lung function assessed throughout eteplirsen studies 201/202. Methods: Studies 201/202 included 12 patients treated with eteplirsen over 5 years. Pulmonary function tests included forced vital capacity (FVC), maximum expiratory pressure (MEP), and maximum inspiratory pressure (MIP). With no long-term placebo control, FVC results were compared with data from the United Dystrophinopathy Project (UDP). MIP and MEP were compared to published natural history. Results: Age-adjusted mixed-model repeated-measures analysis showed decreases of 2.3% and 2.6% annually for FVC% p and MEP% p, and an annual increase of 0.6% for MIP% p for the eteplirsen-treated cohort. Data from the UDP demonstrated a 4.1% decline in FVC% p. The published natural history reports annual declines of at least 2.7% and 3.8% for MEP% p and MIP% p, respectively, in patients with DMD. Conclusions: With eteplirsen treatment, deterioration of respiratory muscle function based on FVC% p was half of that seen in the UDP; MEP% p and MIP% p compared favorably with natural history.