Casimersen Shows Promising Phase 3 Results for DMD, May Open Door for FDA New Drug Application

Sarepta Therapeutics‘ casimersen (SRP-4045), one of the company’s investigational exon-skipping therapies for Duchenne muscular dystrophy (DMD), showed promising results in an interim analysis of an ongoing Phase 3 clinical trial.

These positive data are expected to support the submission of a new drug application (NDA) with the U.S. Food and Drug Administration later this year, the company announced in a press release.

The trial (NCT02500381) is currently recruiting participants. More information on contacts and locations is available here.

DMD, the most common type of muscular dystrophy, is caused by mutations in the DMD gene that provides instructions for the production of a protein called dystrophin. In some cases, these mutations result in the loss of entire exons — the coding sequence of a gene that provides instructions to make proteins — leading to the production of a dysfunctional dystrophin protein.

Exon-skipping therapies, such as casimersen and golodirsen (SRP-4053), work by binding to specific exons using molecules called antisense oligonucleotides. With this approach, the DMD coding sequence is partially “patched,” meaning that a functional, but still abnormally short, dystrophin can then be produced.

Despite sharing the same mode of action, casimersen and golodirsen bind to different exons (exon 45 and 53, respectively), meaning that only patients carrying mutation defects amenable to “hiding” either exon can benefit from these therapies.

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The Phase 3 ESSENCE trial (NCT02500381), also known as 4045-301, is a global, randomized, double-blind, placebo-controlled study, designed to assess the safety and efficacy of casimersen and golodirsen therapies in DMD patients whose mutations are amenable to exon 45 or 53 skipping.

Based on feedback from the FDA, the company performed an interim analysis to determine the levels of dystrophin produced by patients who were amenable to exon 45 skipping and had been treated with casimersen. These preliminary data could help to determine if this experimental therapy shows enough potential for an NDA submission to the federal agency.

In the trial, 43 DMD patients were randomly assigned to receive either a once-weekly intravenous (into-the-vein) infusion of casimersen at a dose of 30 mg/kg (27 patients), or a placebo (16 patients), for 96 weeks. The interim analysis was based on data from muscle biopsies performed at the start and at week 48.

Results showed that, after 48 weeks of treatment, patients receiving casimersen had significantly higher levels of dystrophin compared with those on the placebo. Casimersen-treated patients showed an increase of 0.811% in normal protein levels compared with before receiving the treatment.

“We are pleased to see that the anticipated exon skipping after treatment resulted in a statistically significant mean increase of dystrophin protein,” said Francesco Muntoni, MD, a professor at the University College London. “This is the third exon-skipping agent to have shown a statistically significant increase in dystrophin production, and reinforces our confidence in the exon-skipping approach for treating Duchenne patients with amenable mutations.”

In addition, quantitative real-time polymerase chain reaction (qPCR; a technique that allows researchers to measure the expression levels of genes) analysis showed that all the patients who had been treated with casimersen and analyzed by qPCR were effectively skipping exon 45, confirming the effectiveness of the therapy with a response rate of 100%.

Data showed a positive correlation between improvements of protein production and casimersen efficacy to induce exon 45 skipping.

“Casimersen results and submission of our application for golodirsen earlier this year further validate our RNA research engine,” said Doug Ingram, president and CEO of Sarepta Therapeutics. “If golodirsen and casimersen are approved, nearly a third of the boys and young men living with DMD in the United States could benefit from our RNA therapies.

“We continue to advance toward our ultimate goal of profoundly improving the lives of as many patients around the world with DMD as possible.”