General Information

Exondys 51 (eteplirsen) is an antisense oligonucleotid designed to bind to exon 51 of dystrophin pre-mRNA. This results in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.

Exondys 51 is specifically indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping.

Exondys 51 is supplied as an injection for intravenous administration. The recommended dose of Exondys 51 is 30 milligrams per kilogram administered once weekly as a 35 to 60 minute intravenous infusion. If a dose is missed, it may be administered as soon as possible after the scheduled time.

Mechanism of Action

Clinical Results

Exondys 51 was granted accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with Exondys 51. A clinical benefit of Exondys 51 has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trial. Exondys 51 was evaluated in three clinical studies in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping.

In Study 1, patients were randomized to receive weekly infusions of Exondys 51 (30 mg/kg, n=4); Exondys 51 (50 mg/kg, n=4), or placebo (n=4) for 24 weeks. The primary endpoint was dystrophin production; a clinical outcome measure, the 6-minute walk test (6MWT), was also assessed. Patients had a mean age of 9.4 years, a mean 6-minute walk distance (6MWD) at baseline of 363 meters, and were on a stable dose of corticosteroids for at least 6 months. There was no significant difference in change in 6MWD between patients treated with Exondys 51 and those treated with placebo.

All 12 patients who participated in Study 1 continued treatment with open-label Exondys 51 weekly for an additional 4 years in Study 2. The 4 patients who had been randomized to placebo were re-randomized 1:1 to Exondys 30 or 50 mg/kg/week such that there were 6 patients on each dose. Patients who participated in Study 2 were compared to an external control group. The primary clinical efficacy outcome measure was the 6MWT. Eleven patients in Study 2 had a muscle biopsy after 180 weeks of treatment with Exondys 51, which was analyzed for dystrophin protein level by Western blot. Study 2 failed to provide evidence of a clinical benefit of Exondys51 compared to the external control group. The average dystrophin protein level after 180 weeks of treatment with Exondys 51 was 0.93% of the dystrophin level in healthy subjects. Because of insufficient information on dystrophin protein levels before treatment with Exondys 51 in Study 1, it was not possible to estimate dystrophin production in response to Exondys 51 in Study 1.

In Study 3, 13 patients were treated with open-label Exondys 51 (30 mg/kg) weekly for 48 weeks and had a muscle biopsy at baseline and after 48 weeks of treatment. Patients had a mean age of 8.9 years and were on a stable dose of corticosteroids for at least 6 months. Dystrophin levels in muscle tissue were assessed by Western blot. In the 12 patients with evaluable results, the pre-treatment dystrophin level was 0.16% ± 0.12% (mean ± standard deviation) of the dystrophin level in a healthy subject and 0.44% ± 0.43% after 48 weeks of treatment with Exondys 51 (p < 0.05). The median increase after 48 weeks was 0.1%.