FDA Approves Golodirsen Injection for DMD with Genetic Mutations

An original version of this article was published on sister publication NeurologyLive.

The US Food and Drug Administration (FDA) has approved antisense oligonucleotide golodirsen injection (Vyondys 53) for the treatment of Duchenne muscular dystrophy (DMD) with genetic mutations subject to skipping exon 43 of the dystrophin gene.

The injection therapy from Sarepta Therapeutics, previously known as SRP-4053, is anticipated to benefit the 8% of patients with DMD who also have this mutation. The approval was based on data from a clinical trial showing statistically significant increases in dystrophin production in skeletal muscle among treated patients.

Clinical findings were so significant for this outcome, in fact, that investigators indicated a benefit for patients with DMD who are amenable to exon 53 skipping. A post-marketing, placebo-controlled confirmatory trial (ESSENCE) is expected to be completed in 2024.

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.

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.

The indication was monumental for both the therapeutic company and the DMD community, Doug Ingram, Sarepta president and chief executive officer, said 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,” Ingram said in a statement. “Along with EXONDYS 51 (eteplirsen), we now offer treatment options for approximately 20% of those with DMD in the US.”

Billy Dunn, MD, acting director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, added the FDA’s recognition of an urgent need for new therapies indicated for serious neurological disorders includes that of DMD.

“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,” Dunn said in a statement.