Casimersen, Exon 45 Skipping Duchenne Therapy, Under FDA Priority Review

An application requesting the approval of casimersen (SRP-4045) to treat Duchenne muscular dystrophy (DMD) amenable to exon 45 skipping has been accepted and placed under priority review by the U.S. Food and Drug Administration (FDA), Sarepta Therapeutics announced.

A regulatory decision is expected no later than Feb. 25, 2021. The FDA also conditionally approved Amondys 45 as the possible brand name for casimersen, and indicated that no advisory committee meetings are planned regarding the application.

“The FDA’s acceptance of our NDA [new drug application] for casimersen is an important step toward our goal of rapidly bringing therapies to patients living with Duchenne muscular dystrophy,” Doug Ingram, Sarepta’s president and CEO, said in a press release.

Duchenne, the most common type of muscular dystrophy, is caused by mutations in the gene DMD, which codes for a protein called dystrophin.

Genes are divided into protein-coding segments called exons, which are often separated by non-coding DNA segments called introns. During transcription and translation — when DNA is “read” to produce a protein — the exon sequences are stitched together to form the full protein.

Casimersen is an exon-skipping therapy. As the name implies, this type of therapy allows the cellular machinery to skip over a specific exon, producing a protein that will be functional although shorter than the normal version.

Specifically, casimersen is intended to skip over exon 45 of the DMD gene, the largest known human gene with 79 exons in total.

“If it is approved, casimersen, our third exon-skipping medicine in our PMO RNA-based platform, will offer treatment to the 8% of Duchenne patients who are amenable to exon 45 skipping,” Ingram said. Sarepta already markets Vyondys 53 (golodirsen) for patients with mutations amenable to exon 53 skipping, and Exondys 51 (eteplirsen) for those with mutations amenable to exon 51 skipping.

The application for casimersen is supported by data from the Sarepta-sponsored Phase 3 clinical trial called ESSENCE (NCT02500381). This global trial, which opened in September 2016, is evaluating the safety and efficacy of casimersen in boys with DMD amenable to exon 45 skipping, and of Vyondys 53.

ESSENCE aims to enroll about 222 patients, ages 7 to 13, and recruitment is ongoing across Europe, and in Canada, Australia, and Israel. U.S. sites are fully enrolled, except for one possible New York site. Information is available here.

Participants will be randomly assigned to treatment or a matching placebo for a total of 96 weeks. A 48-week open-label extension period, in which all will be treated, will then follow.

Preliminary trial data showed that, after 48 weeks, boys given once-weekly intravenous infusions of casimersen at a dose of 30 mg/kg experienced a significant increase in dystrophin levels in muscle biopsies, compared both with measures taken at the study’s start and the placebo group.

Sarepta previously stated that, should the FDA approve casimersen, the remainder of the ESSENCE trial will serve as a post-marketing confirmatory study. The study is due to fully end in May 2023.