Analysis: Exondys 51 Works to Delay Respiratory Decline in DMD Boys

Approved therapy may improve lifespan, quality of life for boys 10–17

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Exondys 51 trial data analysis | Muscular Dystrophy News | clinical trial graphs illustration

Treatment with Exondys 51 (eteplirsen) outperformed standard of care therapy at delaying respiratory decline in boys with Duchenne muscular dystrophy (DMD), an analysis of data from several clinical trials found.

Compared with boys on other therapies, those treated with Exondys 51 in trials had “a delay of 5.72 years in time to needing continuous ventilation, 3.31 years in time to needing nighttime ventilation, and 2.11 years in time to needing a cough assist device,” according to researchers.

Overall, Exondys 51 was found to slow the decline of key pulmonary parameters by two to six years among boys ages 10 to 17 — an age range in which respiratory health typically declines steadily among DMD patients.

“Our study has shown clinically meaningful delays in time to multiple pulmonary milestones indicating a slowing of overall disease progression that could potentially lead to improvement of quality of life and lifespan of patients with DMD,” the team wrote.

The study, “Delays in pulmonary decline in eteplirsen-treated patients with Duchenne muscular dystrophy,” was published in the journal Muscle & Nerve.

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The hallmark of Duchenne is muscle wasting due to mutations in the DMD gene. These mutations lead to a lack of dystrophin, a protein important in the maintenance of healthy muscle.

Along with loss of mobility, boys with Duchenne typically experience a progressive decline in pulmonary function.

Evaluating the effects of Exondys 51

Exondys 51, developed by Sarepta Therapeutics, was the first DMD-specific therapy approved by the U.S. Food and Drug Administration (FDA), in September 2016. It works by increasing the amount of functional dystrophin protein in patients with mutations amenable to exon 51 skipping.

Notably, however, only about 13% of all DMD cases involve patients for whom exon 51 skipping works.

Prior clinical evidence has shown that Exondys 51 was effective at slowing respiratory decline in boys with DMD, including those with more advanced disease.

In this study, researchers at Sarepta and the University of California Davis Medical Center, together with colleagues at Analysis Group, conducted a post hoc analysis — that is, an analysis designed and carried out after a study’s data already has been collected — to evaluate the effectiveness of Exondys 51 in lessening pulmonary decline.

They evaluated the outcomes of 72 boys, ages 10 to 17, treated with Exondys 51. The majority of the boys — 52 — had participated in a Phase 3 study known as 301 (NCT02255552). The other 20 were involved in a Phase 2 study called 204 (NCT02286947.

All of these Exondys 51-treated patients were taking glucocorticoids before enrolling in their respective trials.

Now, the respiratory function of these boys was compared with that of 20 boys on standard of care therapy (glucocorticoids) in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS; NCT00468832). These boys also had genetic mutations amenable to exon 51 skipping.

Results showed that Exondys 51-treated patients had a significantly slower decline in respiratory function compared with boys given glucocorticoid therapy in the CINRG-DNHS group. Respiratory function had been measured by mean predicted forced vital capacity (FVC%p), a commonly used measure of respiratory health that reflects the maximum amount of air exhaled after a deep breath.

Compared with a mean FVC%p annual decline of 5.95% in the standard glucocorticoid group, those given Exondys 51 experienced a decline of 3.47% — a statistically significant 42% difference favoring Exondys 51.

This corresponded to a delay in decline by nearly two to six years in key parameters of respiratory function with Exondys 51.

These findings were generally maintained when the researchers included data from boys given a placebo in the DEMAND III Phase 3 trial (NCT01254019).

Overall, “the findings from this post hoc pooled analysis suggest that eteplirsen [Exondys 51] treatment was associated with statistically significant and clinically meaningful attenuation in FVC%p decline that corresponded to an estimated delay of approximately 2 to 6 years to critical pulmonary milestones compared with [standard of care] patients,” the scientists concluded.