FDA Rejects Duchenne Muscular Dystrophy Drug Golodirsen, Citing Safety Concerns


The regulatory agency cited 2 concerns in the complete response letter: the risk of infections related to intravenous infusion ports and renal toxicity.

Dr Doug Ingram,

Doug Ingram, Sarepta Therapeutics

Doug Ingram

The FDA has issued a complete response letter to Sarepta Therapeutics for its new drug application (NDA) for golodirsen, previously known as SRP-4053, to treat Duchenne muscular dystrophy in patients with a confirmed mutation amenable to exon 53 skipping.

The agency cited 2 concerns: the risk of infections related to intravenous infusion ports and renal toxicity seen in preclinical models and observed following administration of other antisense oligonucleotides. Sarepta is immediately requesting a meeting with the FDA to determine next steps.

“We are very surprised to have received the complete response letter this afternoon,” Doug Ingram, president and chief executive officer, Sarpeta, said in a statement. “Over the entire course of its review, the Agency did not raise any issues suggesting the non-approvability of golodirsen, including the issues that formed the basis of the complete response letter. We will work with the Division to address the issues raised in this letter and, to the fullest extent possible, find an expeditious pathway forward for the approval of golodirsen. We know that the patient community is waiting.”

The FDA accepted the NDA in February 2019, which was backed by data from the 4053-101 (NCT02310906) phase 1/2 study that assessed the safety, tolerability, pharmacokinetics, and dystrophin expression of SRP-4053. In the 4053-101 study, renal toxicity was not observed. The NDA was completed at the end of 2018 as part of a rolling submission of which the FDA had granted priority review.

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 golodirsen, while part 2 was an open-label evaluation of golodirsen 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.

The trial results demonstrated statistically significant results in favor of the therapy on all biological endpoints. Patients treated with golodirsen 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.

Golodirsen is currently being studied in the phase 3 ESSENCE study (4045-301; NCT02500381), a global, randomized, double-blind, placebo-controlled study assessing the efficacy and safety of golodirsen and casimersen, Sarepta’s exon 45 skipping agent, in approximately 220 patients.


Sarepta Therapeutics (SRPT) Receives CRL from FDA Related to Golodirsen NDA [news release]. Cambridge, Mass.: Sarpeta Therapeutics; Aug. 19, 2019. https://www.globenewswire.com/news-release/2019/08/19/1903797/0/en/Sarepta-Therapeutics-Receives-Complete-Response-Letter-from-the-US-Food-and-Drug-Administration-for-Golodirsen-New-Drug-Application.html. Accessed Aug. 20, 2019.

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