FDA Accepts NDA for SRP-4053 as Potential Therapy for Duchenne Amenable to Skipping Exon 53


The therapy, which has a PDFUA date of Aug. 19, 2019, is being studied in an ongoing phase 3 study.


The FDA has accepted Sarepta Therapeutics’ new drug application (NDA) seeking accelerated approval of SRP-4053 (golodirsen) for treatment of patients who have Duchenne muscular dystrophy (DMD) with genetic mutations subject to skipping exon 53 of the dystrophin gene.

The NDA is backed by data from the 4053-101 (NCT02310906) phase 1/2 study that assessed the safety, tolerability, pharmacokinetics, and dystrophin expression of SRP-4053. Sarepta completed the NDA at the end of 2018 as part of a rolling submission and requested priority review, which the FDA granted. The therapy currently has a Prescription Drug User Fee (PDUFA) action date of Aug. 19, 2019.

“If approved, golodirsen will serve up to another 8% of the Duchenne community, bringing us closer to helping as many Duchenne patients as possible,” Doug Ingram, president and chief executive officer, Sarpeta, said in a statement.1 “We look forward to working with the FDA toward advancing this important therapy and rapidly bringing it to individuals with Duchenne who are amenable to exon 53 skipping.”

Study 4053-101 was the first-in-human, multiple-dose 2-part study that assessed SRP-4053 in 25 boys with confirmed deletions of dystrophin gene amenable to exon 53 skipping over a total of 144 weeks. The first part of the trial was randomized, placebo-controlled and dose-titrated to assess safety, tolerability, and pharmacokinetics of 4 dose levels of SRP-4053; while part 2 was an open-label evaluation of SRP-4053 in patients from part 1, along with newly enrolled participants with DMD with deletions amenable to exon 53 skipping, and an untreated group of participants with DMD with deletions not amenable to exon 53 skipping.

Escalating doses of SRP-4053 were tested against placebo to evaluate the safety for the trial’s first 12 weeks. Participants then amendable to exon 53 skipping received weekly treatment infusions at 30 mg/kg. The efficacy of the therapy was measured against an untreated group of patients with Duchenne whose disease-causing mutation is not amenable to exon 53 skipping.

The primary outcomes of the study included the incidence of adverse and serious adverse effects; the change in the total distance walked during the 6-minute walk test; and the change in the dystrophin protein levels determined by the Western Blot.

Trial results demonstrated statistically significant results in favor of the therapy on all biological endpoints. Patients treated with SRP-4053 had significantly increased dystrophin production from .095% at baseline to 1.019% at week 48 (range: 0.09%&shy;—4.30%), a significant mean change of .924% (P <.001). The data also confirmed that SRP-4053 effectively skipped exon 53, which enabled the production of functional dystrophin.

SRP-4053 is being studied in the ongoing global, randomized ESSENCE phase 3 study (4045-301) (NCT02500381) in approximately 220 patients to assess the safety and efficacy of SRP-4053 and SRP-4045 (casimersen), Sarepta’s exon 45 skipping agent. The Division previously confirmed that ESSENCE could serve as a post-marketing confirmatory study.

Eligible patients with out-of-frame deletion mutations amenable to exon 45 or 53 skipping will be randomized to receive once weekly intravenous infusions of 30 mg/kg SRP-4045 or 30 mg/kg SRP-4053 respectively or placebo for up to 96 weeks. The primary outcome is the change in the total distance walked during the 6-minute walk test at week 96. This period will be followed up by an open-label extension period (NCT03532542) where all patients will receive open-label active treatment for 48 weeks, where the primary outcome measure is the number of participants with serious adverse effects up to 30 days after the last infusion of the study drug. The estimated primary completion date is May 2022.


1. Sarepta Announces FDA Acceptance of Golodirsen (SRP-4053) New Drug Application for Patients with Duchenne Muscular Dystrophy Amenable to Skipping Exon 53 [news release]. Cambridge, Mass.: Sarepta Therapeutics; Feb. 14, 2019.


-4053-new-drug. Accessed Feb. 15, 2019.

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