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 exon 53 skipping.

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.

Sarepta Therapeutics applied to the U.S. Food and Drug Administration (FDA) for the approval of golodirsen, and the treatment is currently under priority review. A decision is expected by August 2019. 

How golodirsen works

DMD is caused by is a mutation or error in the DMD gene, which encodes for dystrophin, an essential protein involved in muscle cell integrity. Without dystrophin, the muscles integrity is lost, and muscles become easily damaged during normal activity.

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. The exons are decoded sequentially to synthesize a protein. Some cases of DMD are caused by the deletion of certain exons, disturbing the alignment of the neighboring exons and interfering with the genetic code. The interruption in the code hinders protein production, resulting in no dystrophin protein being produced by the cells. 

Golodirsen is designed to mask exon 53 in the mRNA (a temporary copy of a gene used to make a protein) of the DMD gene so the protein synthesis machinery can skip this exon and piece together the remaining exons to make a smaller, but functional, dystrophin protein.

Approximately 8% of boys with DMD may be amenable to exon 53 skipping.

Golodirsen in clinical trials

A Phase 1/2 clinical trial (NCT02310906) assessed the safety, tolerability, efficacy, and pharmacokinetics (movement in the body) of golodirsen in 25 DMD boys with deletions amenable to exon 53 skipping. Participants received weekly infusions of 30 mg per kg of bodyweight of golodirsen for at least 48 weeks. Muscle biopsies were performed before and after 48 weeks of treatment. Results showed a marked increase in functional dystrophin following golodirsen treatment. Sarepta Therapeutics’ application to the FDA to review golodirsen for approval is supported by these findings.

A Phase 3 study called ESSENCE (NCT02500381) initiate3d in 2016 is still recruiting DMD patients to evaluate the effectiveness of golodirsen and Casimersen (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 being enrolled at multiple sites across several countries, including the U.S., Canada, Australia, Israel, and Europe. Interim results showed a significant mean increase in dystrophin protein in the Casimersen-treated group. Results about golodirsen-treated patients are not yet available. The trial is expected to conclude in May 2023.

A Phase 3 extension study (NCT03532542) is underway to evaluate the long-term safety and tolerability of golodirsen and Casimersen in DMD patients who have been treated previously with these exon-skipping treatments in a clinical trial setting. A total of 260 DMD boys, ages 7 to 13 will be invited to participate in this study. Boys with mutations amenable to exon 53 skipping will be included in the golodirsen treatment group, while those with mutations that can benefit from exon 45 skipping will be treated with Casimersen. Patients will receive weekly intravenous infusions of treatment for up to 144 weeks, and the number of severe adverse events (side effects) will be assessed.


Last updated: 07/11/2019


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