FDA Approves Golodirsen for DMD Amenable to Exon 53 Skipping


After receiving expedited review after receiving a Complete Response Letter in August, the therapy was approved based on data showing a statistically significant increase in dystrophin production in skeletal muscle.

Dr Doug Ingram

Doug Ingram, Sarepta's president and chief executive officer

Doug Ingram

The FDA has approved Sarepta Therapeutics’ antisense oligonucleotide golodirsen (Vyondys 53) injection, previously known as SRP-4053, for the treatment of Duchenne muscular dystrophy (DMD) with genetic mutations subject to skipping exon 53 of the dystrophin gene.1

It is estimated that about 8% of patients with DMD have this mutation. The regulatory go-ahead was granted based on data showing a statistically significant increase in dystrophin production in skeletal muscle observed in patients treated with golodirsen, enough so to indicate benefit for those who are amenable to exon 53 skipping. A post-marketing, placebo-controlled confirmatory trial, dubbed ESSENCE, is expected to be completed in 2024.

“Today is monumental for Sarepta and, more importantly, for the DMD community,” said Doug Ingram, president, and chief executive officer, Sarepta, in a statement. “VYONDYS 53, our second approved exon-skipping RNA therapy for DMD, may treat up to 8% of the DMD community, representing those patients who have a confirmed exon 53 amenable mutation. Along with EXONDYS 51 (eteplirsen), we now offer treatment options for approximately 20% of those with DMD in the US.”

In August, the FDA issued a Complete Response Letter (CRL) to Sarepta following its new drug application (NDA) for the therapy, to which Sarepta replied with a formal dispute resolution request. The matters raised in the letter were “rapidly evaluated and resolved” according to Sarepta, and its appeal and re-submission were accepted for expeditious review.

READ MORE: FDA Authorizes First Duchenne Muscular Dystrophy Newborn Screening Test

“In the span of 4 months, we commenced and completed the formal dispute resolution process culminating in the grant of our appeal, resubmitted our NDA and obtained an approval—a great benefit to DMD patients awaiting treatment,” Ingram said. “This unprecedented timing could not have been achieved without the commitment of the Review Division under the leadership of Dr. Billy Dunn, and the Office of New Drugs, which expeditiously heard and granted our appeal. Along with the DMD community, we owe our gratitude to both the Review Division and the OND for their objective, evidence-based approach to this review, for their fairness, and for the sense of urgency with which they addressed and resolved the CRL and granted this approval.”

The NDA was supported by Study 4053-101, the first-in-human, multiple-dose, 2-part study that assessed golodirsen 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 golodirsen 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.2

Escalating doses of golodirsen were tested against placebo to evaluate 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.

Results revealed statistically significant findings in favor of the therapy on all biological end points. Patients treated with golodirsen had significantly increased dystrophin production, from .095% at baseline to 1.019% at week 48 (range, 0.09—4.30), a significant mean change of .924% (P <.001). The data also confirmed that golodirsen effectively skipped exon 53, which enabled the production of functional dystrophin.

“With the approval of VYONDYS 53, up to another 8% of Duchenne families will have a therapy to treat this devastating disease,” said Pat Furlong, founding president, and chief executive officer, Parent Project Muscular Dystrophy (PPMD), in a statement. “For 25 years, PPMD has been working with researchers, clinicians, industry, and the Duchenne community to find treatments for all people living with Duchenne. And while we need to ensure that these approved therapies are accessible for patients, today we celebrate this approval and thank Sarepta for their continued leadership in the fight to end Duchenne.”

Although it was not observed in the clinical studies, renal toxicity, including potentially fatal glomerulonephritis, has been observed after the administration of some antisense oligonucleotides, Sarepta noted. The most common adverse reactions that occurred in ≥20% of golodirsen-treated patients and more frequently than in placebo-treated patients were headache (41%), pyrexia (41%), falls (29%), abdominal pain (27%), nasopharyngitis (27%), cough (27%), vomiting (27%), and nausea (20%).

“The FDA recognizes the urgent need for new medical treatments for serious neurological disorders and we have a long-standing commitment to working with researchers, drug companies and patients to facilitate the development and approval of treatments for rare diseases. With today’s accelerated approval, patients with Duchenne—a rare and devastating disease&mdash;who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” said Billy Dunn, MD, acting director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, in a statement.3 “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”


1. Sarepta Therapeutics Announces FDA Approval of VYONDYS 53™ (golodirsen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 53 [press release]. Cambridge, MA: Sarepta Therapeutics; Published 12, 2019. sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-vyondys-53tm. Accessed December 12, 2019.

2. 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. investorrelations.sarepta.com/news-releases/news-release-details/sarepta-announces-fda-acceptance-golodirsen-srp-4053-new-drug. Accessed December 12, 2019.

3. FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular dystrophy mutation [press release]. Silver Spring, MD: FDA; Published December 12, 2019. fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation. Accessed December 12, 2019.

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