FDA says no to Sarepta's golodirsen, blocking bid to expand its Duchenne stable

The FDA has rejected Sarepta Therapeutics’ new Duchenne muscular dystrophy (DMD) Vyondys 53 due to concerns about potential side effects.

The setback prompted a 13% drop in Sarepta’s shares in after-hours trading as investors tried to work out how long the company’s second DMD drug might be kept from the market.

In a statement, Sarepta said that the US regulator refused to approve Vyondys 53 (golodirsen) due to a risk of infections related to intravenous infusion ports used to deliver the drug, as well as kidney toxicity that was observed in animal testing. It has requested a meeting with the FDA to “determine next steps.”

Sarepta already sells Exondys 51 (eteplirsen) for DMD after the FDA granted the drug a conditional approval back in 2016, and recorded sales of $182 million from that product in the first six months of the year.

The approval of the first exon-skipping therapy for DMD was controversial, however, coming after the FDA’s own expert advisers recommended rejecting it because of concerns that its clinical trials did not clearly demonstrate efficacy.

Exondys 51 was also rejected by the EMA, although the EU agency did give a green light to a rival exon-skipping therapy from PTC Therapeutics called Translarna (ataluren), which failed to win a green light from the FDA.

Exondys 51 is an exon-skipping therapy suitable for treating around 13% of DMD patients. Vyondys 53 works in a similar way but targets a different DMD mutation and would have expanded the eligible patient population by another 8%.

One of the most common fatal genetic disorders, DMD affects approximately one in every 3,500-5,000 male births worldwide.

Sarepta had been hoping to win approval based on data showing that Vyondys 53 was able to improve levels of dystrophin – the protein that is deficient in DMD – rather than showing whether the drug could actually slow the progressive muscle wasting that characterises the disease.

It used the same approach to secure approval for Exondys 51, and the FDA drew a lot of flak for that earlier approval with critics suggesting the agency had caved in to pressure from DMD patient groups.

Sarepta CEO Doug Ingram expressed surprise about the rejection, saying that “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.”

The company maintains that infusion site infections have been seen with other antisense oligonucleotide drugs, and that the kidney toxicity seen in animal studies involved a dose 10 times that used in clinical trials of the drug.

Parent Project Muscular Dystrophy (PPMD) said in a statement that “one of our toughest challenges in the fight to end Duchenne is time because it is so precious for each of our loved ones affected by this disease.”

The charity added: “We are hopeful that these outstanding concerns can be rectified quickly as Sarepta and the FDA work to bring our community a safe, effective therapy.”

Sarepta has another trial of golodirsen ongoing which is testing the drug alongside casimersen, another exon-skipping therapy that is due to be filed with the FDA shortly.

The company is also adding to its exon-skipping approach in DMD with a foray into gene therapy, in the hope of developing a one-shot therapy for the disorder, with phase 1 results reported earlier this year.