Golodirsen (SRP-4053) is an exon-skipping therapy being developed by Sarepta Therapeutics to treat Duchenne muscular dystrophy (DMD) patients whose disease is amenable to skipping exon 53.

Exon skipping addresses the underlying cause of DMD by promoting the production of a shorter, but still functional, dystrophin protein to stabilize or slow disease progression.

How golodirsen works

The primary cause of DMD is a mutation or error in the gene that encodes for dystrophin, an essential protein involved in muscle cell integrity. Without dystrophin, normal activity damages muscle cells.

Exons are the section of a DNA or RNA molecule that contains coding information for a set of amino acids, the building blocks of proteins. Some cases of DMD are caused by the deletion of exons, which leads to the remaining exons being “out-of-frame,” causing no dystrophin protein being produced by the cell.

Golodirsen is designed to skip exon 53 in the pre-mRNA of the DMD gene in order to enable the remaining exons to come back into frame and be read into a protein. Approximately 8 percent of boys with DMD may be amenable to exon 53 skipping.

 

Golodirsen research

A Phase 1/2 study (NCT02310906) is assessing the safety, tolerability, efficacy, and pharmacokinetics of golodirsen in 25 DMD boys with deletions amenable to exon 53 skipping.

Results to date show that golodirsen enhances dystrophin protein production. Participants received a 30mg/kg intravenous infusion of the drug once weekly for at least 48 weeks. Muscle biopsies then taken from patients confirmed that all boys had responded to treatment, and a 10.7-fold increase in the levels of dystrophin protein was seen.

A Phase 3 study (NCT02500381), called ESSENCE, is currently recruiting about 99 DMD patients to evaluate the efficacy of golodirsen and SRP-4045, another exon skipping therapy, compared to placebo. Boys, ages 7 to 13, with mutations amenable to exon 53 and exon 45 skipping are now being enrolled at 46 test sites across the U.S. and Europe, and in Canada and Israel.

ESSENCE is expected to conclude in June 2021.

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