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.

Keywords: Exondys 51; dystrophin; maximal expiratory pressure; maximal inspiratory pressure; vital capacity.

Figures

Fig.1

Study design for eteplirsen studies 201/202. Twelve patients with DMD were randomly assigned to 1 of 3 cohorts receiving weekly infusions in a 24-week, double-blind, placebo-controlled study: eteplirsen 30 mg/kg or 50 mg/kg (purple lines), or placebo (blue line). At week 25, eteplirsen-treated patients continued the same weekly dose as open-label, while placebo patients were randomized to open-label treatment with eteplirsen 30 mg/kg or 50 mg/kg weekly IV (study 202). Pulmonary function tests were assessed in compliance with American Thoracic Society guidelines at least every 24 weeks. The 5-year data represent time on drug, beginning at week 0 for patients in treatment arms and at week 24 for those in the placebo arm of study 201. DMD, Duchenne muscular dystrophy; IV, intravenous.

Fig.2

(A) FVC in liters by weeks on treatment, and (B) FVC in liters versus age (rounded to nearest 0.5 year for mean line). Only assessments performed every 24 weeks are represented graphically, although additional time points were assessed during the first 96 weeks. In Figures 2 through 7, the thick black line represents the mean while individual patients are represented by the same colored line throughout. FVC, forced vital capacity.

Fig.3

(A) FVC% p by weeks on treatment, and (B) FVC% p versus age (rounded to nearest 0.5 year for mean line). Only assessments performed every 24 weeks are represented graphically although additional time points were assessed during the first 96 weeks. FVC% p, percent predicted forced vital capacity.

Fig.4

FVC% p: Natural history controls compared with eteplirsen-treated patients. (A) Natural history controls (ages 7–15.5 years), with an annual decline of 4.1%, and (B) eteplirsen-treated patients (30 or 50 mg/kg/wk IV) from studies 201/202, all available on-treatment data plotted versus age, with an annual decline of 2.3%. FVC% p, percent predicted forced vital capacity.

Fig.5

MEP% p in eteplirsen-treated patients (A) by weeks on treatment, and (B) by average age in years (rounded to the nearest 0.5 years for mean line). Only assessments performed every 24 weeks are represented graphically, although additional time points were assessed during the first 96 weeks. MEP% p, percent predicted maximum expiratory pressure.

Fig.6

MIP% p in eteplirsen-treated patients (A) by weeks on treatment, and (B) by average age in years (rounded to the nearest 0.5 years for mean line). Only assessments performed every 24 weeks are represented graphically, although additional time points were assessed during the first 96 weeks. % pMIP, percent predicted maximum inspiratory pressure.