Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy

Abstract

Background: Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years.

Objective: Evaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls.

Methods: Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change.

Results: FVC% p annual change was greater for CINRG DNHS Exon 51 controls (- 6.00) versus patients in studies 201/202, study 204, and study 301 (- 2.19, P < 0.001; - 3.66, P 0.004; and - 3.79, P 0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (- 5.67) and All CINRG DNHS (- 5.56) cohorts (P < 0.05, all comparisons).

Conclusions: Significant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls.

Keywords: Dystrophin; Exondys 51; forced expiratory volume; vital capacity.

Figures

Fig.1

Study design for eteplirsen studies 201/202. Study 201 was a 24-week, double-blind, placebo-controlled study that randomized 12 patients to receive placebo or eteplirsen (30 or 50 mg/kg/wk). At week 25, patients originally randomized to eteplirsen treatment continued with the same dosage in study 202, an open-label extension study; patients originally randomized to receive placebo were randomized to eteplirsen 30 or 50 mg/kg. All patients were followed for 4 years. Respiratory function assessments included FVC% p as an exploratory endpoint. FVC% p, percent predicated forced vital capacity; OL, open-label; PTP, primary treatment period; R, randomized.

Fig.2

Study design for eteplirsen study 204. In this 2-year (96-week), open-label study, patients with advanced-stage DMD (minimally ambulatory to non-ambulatory patients; N = 24) received weekly infusions of eteplirsen 30 mg/kg. Respiratory function assessments included FVC% p as an exploratory endpoint. AEs, adverse events; ECG, electrocardiogram; FVC% p, percent predicated forced vital capacity; ECHO, echocardiogram; LVEF, left ventricular ejection fraction.

Fig.3

Study design for eteplirsen study 301. In this open-label study, patients with DMD (N = 71) received weekly IV infusions of eteplirsen 30 mg/kg and had both baseline and post-baseline FVC% p. An interim analysis was conducted at year 2 (96 weeks) for all patients who reached that time point. Respiratory function assessments included FVC% p as an exploratory endpoint. BL, baseline; FVC% p, percent predicted forced vital capacity.

Fig.4

Derivation of CINRG DNHS cohorts for comparison of eteplirsen studies. The CINRG DNHS database contains data from 440 patients with DMD across all ages. The All CINRG DNHS cohort (n = 172) comprised glucocorticoid-treated patients with FVC% p assessments obtained between the ages of 10 and 18 years, and excluded any known exon 44 skip–amenable patients. The Genotyped CINRG DNHS cohort (n = 148) comprised glucocorticoid-treated, genetically confirmed patients with FVC% p assessments between the ages of 10 and 18 years and excluded exon 44 skip-amenable patients. The Exon 51 CINRG DNHS cohort (n = 20) comprised glucocorticoid-treated patients between the ages of 10 and 18 years with mutations amenable to exon 51 skipping. CINRG DNHS, Cooperative International Neuromuscular Research Group Duchenne Natural History Study; FVC% p, percent predicted forced vital capacity; GC, glucocorticoid. Dashed box represents pre-specified comparator.