How casimersen works
DMD is a rare genetic disease in which muscles lose strength and degenerate over time. It is caused by mutations in the DMD gene. The largest in the human genome, the DMD gene is made of 79 exons (portions of a gene that code for protein). As a result of the mutations, the protein encoded by the gene is either truncated (not fully made) or made with errors because the exons after the mutation are not aligned in a proper sequence. Dystrophin, the protein encoded by the DMD gene, plays an essential role in maintaining muscle health. So its absence causes the muscle cells to weaken and degenerate over time and be replaced with scar and fat tissue.
Casimersen works by using Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology, which directs the muscle cells to skip exon 45 when processing the messenger molecule used to make dystrophin protein. When exon 45 is skipped, the remaining exons can “fit together” in the right sequence, allowing the production of a shorter but still functional dystrophin protein, and potentially slowing the decline in muscle wasting.
Casimersen in clinical trials
A randomized, placebo-controlled dose-adjustment Phase 1 study (NCT02530905) evaluated the safety, tolerability, and pharmacokinetics (movement in the body) of casimersen in 12 patients with advanced-stage DMD with mutations amenable to exon 45 skipping. The study is completed but the results have not been published yet.
A Phase 3, double-blind, placebo-controlled clinical trial called ESSENCE (NCT02500381) is currently underway to evaluate the efficacy and safety of casimersen and golodirsen (SRP-4053), another exon-skipping treatment.
The trial aims to recruit 222 boys, ages 7 to 13, with DMD amenable to exon 45 or exon 53 skipping at clinical sites in the U.S., Europe, Canada, and Israel. Participants will be randomized to receive either active treatment (casimersen or golodirsen) or a placebo as a once-weekly infusion into the bloodstream for up to 96 weeks. This will be followed by an open-label extension phase, in which all patients will receive active treatment for up to 48 weeks.
The primary outcome will be changes in muscle strength from study start (baseline) as measured by changes in the six-minute walk test. The secondary outcomes include changes in dystrophin protein production and respiratory strength (measured by forced vital capacity, or the amount of air that can be expelled in one forced breath).
Sarepta Therapeutics announced positive results from an interim analysis of experiments conducted on muscle biopsies obtained from the patients’ bicep muscles at baseline and after treatment with casimersen or a placebo for 48 weeks. The key findings were:
- Mean dystrophin protein levels in the casimersen treatment group increased by a statistically significant 1.736% compared with 0.925% in the placebo group.
- When a sample of 22 DMD patients who were treated with casimersen was tested, all showed an increase in the levels of mRNA in which exon 45 was skipped compared with their baseline levels. This represented a 100% response rate. Moreover, there was a statistically significant positive correlation between exon 45 skipping and dystrophin protein production.
Based on these results, Sarepta Therapeutics plans to submit a new drug application for casimersen to the U.S. Food and Drug Administration in the middle of 2019.
Additionally, the company is enrolling 260 DMD male participants, ages 7 to 23, by invitation for a Phase 3, open-label, extension study (NCT03532542) to evaluate the long-term effects of casimersen or golodirsen. This study is expected to be completed by June 2026.
Last updated: 07/15/2019
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