Treatment with Exondys 51 (eteplirsen) significantly slows respiratory decline in boys with Duchenne muscular dystrophy (DMD), including those with more advanced disease, compared to standard glucocorticoid therapy, an analysis of clinical trials shows.
Low levels of the dystrophin protein due to genetic mutations affecting the DMD gene, in various locations, cause Duchenne MD and its hallmark wasting of muscles throughout the body.
Respiratory function starts to decline between the ages of 7 and 10 in untreated patients, but glucocorticoids — currently the standard DMD therapy — can somewhat delay onset. As boys approach adolescence and up to the age of 18, however, respiratory function typically declines even with glucocorticoids at a significant rate of 5% per year, as measured by the mean predictive forced vital capacity (FVC%p), a commonly used measure of respiratory health.
Exondys 51, developed by Sarepta Therapeutics, was the first therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of DMD. It restores dystrophin levels in patients with mutations amenable to exon 51 skipping, which represents about 13% of all DMD cases.
Previous clinical trials comparing patients taking Exondys 51 with DMD’s natural history showed that treated patients experienced a statistically significant and clinically meaningful reduction in pulmonary function decline as measured by the mean FVC%p.
As glucocorticoids are the standard DMD treatment, it is important to evaluate Exondys 51 effects on respiration to patients using glucocorticoids, especially during the period — between 10 and 18 years old — where respiratory function declines rapidly.
Researchers evaluated respiratory function in Exondys 51-treated patients from three of four open-label clinical trials — the Phase 2 trials 201 (NCT01396239) with its follow-up 202 (NCT01540409) study, the Phase 2 study known as 204 (NCT02286947), and the Phase 3 301 study (NCT02255552).
Patients were followed between two and four years. All the Exondys 51-treated patients (74 patients) analyzed were taking glucocorticoids before enrolling in their respective trials. The 201/202 studies and the 301 study included ambulatory DMD patients; the 204 study enrolled primarily non-ambulatory patients (those unable to walk without assistance).
Respiratory function of the Exondys 51-treated patients was compared to that of patients using only glucocorticoids using the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) global database.
That database, one of the largest natural history studies of DMD, allowed researchers to analyze three groups of glucocorticoid-treated patients (340 in total). These three DMD cohorts were: patients amenable to exon 51 skipping (20 boys); all CINRG patients, regardless of genotype confirming DMD (172 boys); and all with disease confirmed genetically (148 patients).
Patients were matched for glucocorticoid use, age, and amenability to exon skipping within each group.
Results showed that all the Exondys 51-treated patients had a significantly slower decline in respiratory function compared to matched controls in the CINRG DNHS group.
The decline in FVC%p in Exondys 51-treated patients varied between –2.19 to –3.79 compared to –6.00 in the control group, a statistically meaningful difference that “will likely impact both the quality of life and the duration of life in patients with DMD,” the researchers wrote.
Moreover, the slower decline of respiratory function with Exondys 51 was seen in both ambulatory (54 boys) and primarily non-ambulatory (20) patients, “highlighting treatment benefit in all patients between the ages of 10 and 18, including more advanced patients who had lost ambulation,” they added.
Since better respiratory function is linked with better use of the arms in non- ambulatory patients, these data also suggest that “slowing the decline in respiratory function in non-ambulatory patients may indicate a general slowing of overall disease progression,” researchers said.
Overall, the slowing of respiratory decline seen with Exondys 51 “may translate to prolonged time to required mechanical airway clearance, noninvasive ventilation, reduced risk of hospitalization due to respiratory illnesses, improved quality of life, and improved survival,” the study concluded.