- In an unexpected decision, the Food and Drug Administration rejected Sarepta Therapeutics' experimental drug for Duchenne muscular dystrophy, and on Monday issued a complete response letter to the rare disease biotechnology.
- According to Sarepta, the agency cited infection risk associated with drug delivery as well as preclinical evidence of renal toxicity. The medicine is called Vyondys 53, and is designed for about 8% of Duchenne patients with a specific genetic mutation.
- Stocks in Cambridge, Mass-based Sarepta fell sharply in trading after the market. Approval of the drug was widely expected, which turned the refusal into Sarepta's ambition to treat a wider pool of Duchenne patients.
Approval of Vyondys 53 (golodirsen) looked like a safe bet given its similarities to Sarepta's marketed drug, Exondys 51
Instead, Sarepta will now have to work through security data with FDA officials as it tries to persuade the agency that flagged cases do not pose an excessive risk.
"During the review, the agency did not raise any questions suggesting that the golodirsen could not be approved, including the issues underlying the complete response letter," company CEO Doug Ingram said in a statement.
Neither Exondys nor Vyondys have the results of a traditional placebo-controlled study, but that did not prevent the FDA from controversially approving the former in 2016, and violated the recommendation of its own advisory panel in the process.
The two treatments work on a process called exon jumping, and modify genetic expression to help patients produce a key muscle-building protein called dystrophin.
Missing exons in the dystrophin gene code to prevent the related protein from being properly assembled, a chain reaction that leads to progressive muscle weakness. Sareptâ & # x20AC; & # x2122; s products aim to restore functional protein production by skipping the missing exon 51 for Exondys and the missing exon 53 for Vyondys.
A third drug, called casimersen and now in the process of meeting FDA review, skips exon 45, and if all three reach the market, Sarepta should cover about 30% of DMD patients. SVB Leerink analysts had estimated that the drugs could generate sales for $ 1.7 billion by 2024, a high sum reflecting the lack of other treatment options for DMD patients currently.
This prognosis would obviously have to be reviewed, as well as assumptions that the casimers would receive the same treatment as Exondy's.
According to Sarepta, the FDA's complete response letter describing the reasons for rejection identified two safety concerns: the risk of infection in intravenous infusion ports, and renal toxicity seen in pre-clinical studies of Vyondys as well as other antisense oligonucleotides, including the class of drugs and drugs. casimersen.
In that case, the casimer's review may also involve a closer look at renal toxicity problems.
In Vyondys & # 39; s defense, Sarepta said: “Renal toxicity with golodirsen was observed in pre-clinical models at doses that were ten times higher than the dose used in clinical trials. Renal toxicity was not observed in study 4053-101, on which the application for golodirsen was based. "
The FDA apparently did not raise its own question that has dogged Exondys and now Vyondys – the one with limited data on its effectiveness. The case of Exondys, questions about the benefit of therapy, then divided FDA officials that the then agency chief Robert Califf was asked to mediate The scientific dispute between employees.
For Vyondys, the company passed FDA results from a 25-boys trial, all of which showed signs of exon 53. Average dystrophin protein increased to 1,019% from normal, compared to 0.095% at baseline, after 48 weeks of treatment, a 10.7-fold increase.
Sarepta's study was scheduled to gather results-related data in the form of a six-minute walk test, but they have not been reported yet.  An analysis of DMD drugs done by the Institute for Clinical and Economic Review, which included Exondys, Vyondys and Emflaza (deflazacor t), found that there was little evidence that exon jumps were better than treatment with corticosteroids and supportive care. The increase in dystrophin production "is of uncertain clinical significance," the report states.
Sarepta said Monday that it would immediately request a meeting with the FDA to determine the next steps for Vyondys. A study testing the drug with casimersen is still ongoing.