In an unexpected move, the FDA has declined to approve Sarepta’s marketing application for Vyondys 53 (golodirsen).
Vyondys was expected to become the second approved product from Sarapta’s extensive pipeline of therapies for the treatment of DMD. The antisense drug aims to restore functional protein (dystrophin) production in DMD sufferers by skipping the missing exon 53, in the same way that Sarepeta’s first approved drug, Exondys 51 (eteplirsen) skips the missing exon 51.
Sarepta said that the FDA had cited two main concerns: the risk of infections related to IV infusion ports and renal toxicity seen in preclinical models of golodirsen and following administration of other antisense oligonucleotides.
In its defence, Sarepta stated that renal toxicity with golodirsen was only observed in preclinical models at doses that were ten-fold higher than the dose used in clinical studies and that renal toxicity wasn’t observed in the 25-patient trial on which the application for golodirsen was based.
Efficacy outcomes weren’t mentioned by Sarepta in its statement to the market. After 48 weeks of treatment, golodirsen demonstrated a mean dystrophin protein increase to 1.019% of normal, compared with 0.095% at baseline. While the trial was also supposed to collect outcomes-related data in the form of a six-minute walk test, those have not been reported yet.
Biotech commentator, Adam Feuerstein, questioned whether Sarepta’s explanation told the full story and speculated that the FDA may no longer be willing to grant accelerated approval to Duchenne drugs based on a very small increase in dystrophin production, particularly when there are safety concerns and no data to confirm clinical benefit.
The Vyondys 53 rejection is likely to put a spotlight on the need for solutions that can address the challenge posed by the inverse correlation between efficacy and toxicity in antisense therapies.
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