Duchenne muscular dystrophy is an inherited disorder that results in progressive muscle weakness and loss of muscle mass, primarily affecting males. Duchenne muscular dystrophy results from non-sense or frame-shifting variant(s) in the Duchenne muscular dystrophy gene, which is responsible for producing dystrophin, a cohesive protein essential for maintaining muscle support and strength. Antisense oligonucleotides (ASOs) are short, synthetic, single-stranded oligodeoxynucleotides that selectively bind to specific exons of the dystrophin pre-messenger RNA, causing the exon to be skipped and thereby repairing the mutated reading frame, resulting in production of an internally truncated, yet functional, dystrophin protein. Four antisense oligonucleotides—eteplirsen, golodirsen, viltolarsen, and casimersen—have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of Duchenne muscular dystrophy. Each targets a specific exon. For example, eteplirsen targets skipping of exon 51, golodirsen and viltolarsen target skipping of exon 53, and casimersen targets skipping of exon 45. Clinical benefit of these ASOs have not been established. Continued approval for these ASOs for their respective indications may be contingent upon verification of a clinical benefit in confirmatory trials​.

Eteplirsen

In September 2016, eteplirsen (Exondys 51™; Sarepta Therapeutics) was approved by the U.S. Food and Drug Administration (FDA) for treatment of Duchenne muscular dystrophy patients who have a confirmed variant of the Duchenne muscular dystrophy gene that is amenable to exon 51 skipping. This indication was approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with eteplirsen.

The FDA, under the accelerated approval regulations (21 CFR 314.510), requires that Sarepta conduct a confirmatory trial to demonstrate the clinical benefit of eteplirsen. In the preceding 3 years after the FDA approval, there has still been no publication of a trial confirming or refuting a clinical benefit of eteplirsen. Th​e European Medicines Agency rejected marketing approval for eteplirsen in September 2018.

Golodirsen

In December 2019, golodirsen (Vyondys 53™; Sarepta Therapeutics) was approved by the FDA for treatment of Duchenne muscular dystrophy patients who have a confirmed variant of the Duchenne muscular dystrophy gene that is amenable to exon 53 skipping. This indication was approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with golodirsen.

The FDA, under the accelerated approval regulations (21 CFR 314.510), requires that Sarepta conduct a randomized double-blind, placebo-controlled trial of 96 weeks with an open-label extension to 144 weeks to verify the clinical benefit of golodirsen with the primary endpoint of a 6-minute walk test. The expected date of trial completion is October 2025 and final report submission to the FDA by October 2025.

Viltolarsen

In August 2020, viltolarsen (Viltepso™; Nippon Shinyaku Co.) was approved by the FDA for the treatment of Duchenne muscular dystrophy patients who have a confirmed mutation of the Duchenne muscular dystrophy gene that is amenable to exon 53 skipping. This indication was approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with viltolarsen.

The FDA, under the accelerated approval regulations (21 CFR 314.510), requires that Nippon Shinyaku Co. conduct a randomized, double-blind, placebo-controlled trial over 48 weeks to verify the clinical benefit of viltolarsen with the primary endpoint "time to stand". The expected date of trial completion is July 2024 and final report submission to the FDA by Dec 2024.

Casimersen

In February 2021, casimersen (Amondys ​45™; Sarepta Therapeutics​) was approved by the FDA for the treatment of Duchenne muscular dystrophy patients who have a confirmed mutation of the Duchenne muscular dystrophy gene that is amenable to exon 45 skipping. This indication was approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with casimersen.

The FDA, under the accelerated approval regulations (21 CFR 314.510), requires that Sarepta verify the clinical benefit of casimersen by completing Study 4045­-301 (Essence), A Double-Blind, Placebo-Controlled, Multicenter Study with an Open-Label Extension to Evaluate the Efficacy and Safety of SRP-4045 and SRP-4053 in Patients with Duchenne Muscular Dystrophy. The study includes a randomized, double-blind, placebo-controlled period of 96 weeks and concludes after an open label extension period to 144 weeks. The primary endpoint will be the 6-minute walk test. The expected date of trial completion is April 2024 and final report submission to the FDA by October 2024.​

​