FDA Raises Concerns About Golodirsen as Potential Exon 53 Skipping Duchenne Therapy

The U.S Food and Drug Administration (FDA) has rejected Sarepta Therapeutic’s application seeking accelerated approval of golodirsen (SRP-4053) for Duchenne muscular dystrophy (DMD) patients amenable to exon 53 skipping.

Golodirsen (SRP-4053) was placed under priority review by the FDA in February 2019.

The FDA’s complete response letter to the new drug application raises two concerns regarding golodirsen: the risk of infections upon injection of the therapy, and the possibility of toxicity to the kidneys.

Toxicity to the kidneys was detected in pre-clinical studies (using animal models) where the dose of golodirsen was 10 times higher than the dose used in clinical trials.

Sarepta’s application for priority review was based on clinical data from a Phase 1/2 clinical trial (NCT02310906) that evaluated the safety, tolerability, and effectiveness of golodirsen in 25 DMD patients with a genetic mutation amenable to exon 53 skipping.

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Patients received escalating doses of golodirsen or a placebo to evaluate safety for the trial’s first 12 weeks, followed by weekly treatment infusions at 30 mg/kg of weight. Treatment effectiveness was measured against an untreated group, or Duchenne patients whose disease-causing mutation is not amenable to exon 53 skipping.

The trial results showed that treated patients had significantly increased levels of functional dystrophin compared to patients who did not have exon 53 mutations. Specifically, dystrophin production increased significantly — by 0.924% —  in all patients at week 48, rising to 1.019% normal dystrophin levels from 0.095% at baseline or the study’s start (initial biopsy).

No renal toxicity was detected in that trial.

“We are very surprised to have received the complete response letter … . 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,” Doug Ingram, president and CEO of Sarepta, said in a press release.

Sarepta said it will request a meeting immediately with the FDA to determine the next steps for its application.

“We will work with the [the FDA] to address the issues raised in the 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,” said Ingram.

Golodirsen is an exon-skipping therapy for patients with mutations amenable to skipping exon 53 of the DMD gene, the largest gene in the human genome.

Exondys 51 (eteplirsen), also by Sarepta, was the first disease-modifying treatment for DMD. It was approved by the FDA in 2016 for patients amenable to exon 51 skipping, which represents about 13% of all DMD patients.

A Phase 3 clinical trial, called ESSENCE  (NCT02500381), is evaluating the safety and effectiveness of golodirsen and casimersen (SRP-4045) — another exon-skipping treatment — in DMD patients with a genetic mutation amenable to exon 53 (golodirsen) or exon 45 skipping (casimersen). The study is still recruiting participants.