• In an unexpected decision, the Food and Drug Administration rejected Sarepta Therapeutics’ experimental drug for Duchenne muscular dystrophy, issuing on Monday a Complete Response Letter to the rare disease biotech. 
• According to Sarepta, the agency cited in its refusal infection risk tied to the drug’s delivery as well as preclinical signs of kidney toxicity. Called Vyondys 53, the medicine is designed for roughly 8% of Duchenne patients with a specific genetic mutation. 

Approval of Vyondys 53 (golodirsen) looked like a safe bet given its similarities to Sarepta’s marketed drug, Exondys 51 (eteplirsen), which is cleared for use in another subset of Duchenne patients. 

Instead, Sarepta will now need to work through safety data with FDA officials as it tries to persuade the agency that the issues flagged do not present an excessive risk.

“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” said company CEO Doug Ingram in a statement. 

Neither Exondys nor Vyondys has results from a traditional placebo-controlled trial, but that didn’t stop the FDA from controversially approving the former in 2016, overruling the recommendation of its own advisory panel in the process. 

The two treatments work by a process known as exon-skipping, altering genetic expression to help patients produce a key-muscle building protein called dystrophin.

Missing exons in the code for the dystrophin gene prevent the related protein from being assembled correctly, a chain reaction that leads to progressive muscular weakening. Sarepta’s products aim to restore functional protein production by skipping the missing exon 51 in the case of Exondys and the missing exon 53 in the case of Vyondys.

A third drug, called casimersen and now about to face 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 the drugs could generate sales of $1.7 billion by 2024, a lofty sum reflecting the lack of other treatment options for DMD patients currently.

That forecast will obviously need to be reviewed, as well as assumptions that casimersen would receive the same treatment as Exondys.

According to Sarepta, the FDA’s complete response letter outlining the reasons for rejection cited two safety issues: The risk of infection at intravenous infusion ports, and kidney toxicity seen in pre-clinical studies of Vyondys as well as other antisense oligonucleotides, the class of drugs that includes Exondys and casimersen.

If so, casimersen’s review could entail a closer look at kidney toxicity issues as well. 

In Vyondys’ defense, Sarepta said: “Renal toxicity with golodirsen was observed in pre-clinical models at doses that were ten-fold higher than the dose used in clinical studies. Renal toxicity was not observed in Study 4053-101, on which the application for golodirsen was based.”

The FDA apparently did not raise a separate issue that has dogged Exondys and now Vyondys — that of limited data on its effectiveness. In the case of Exondys, questions on the therapy’s benefit so divided FDA officials that then agency head Robert Califf was called on to mediate the scientific dispute between staff. 

For Vyondys, the company submitted to FDA results from a trial of 25 boys, all of whom showed signs of exon 53 skipping. Mean dystrophin protein increased to 1.019% of normal, compared with 0.095% at baseline, after 48 weeks of treatment, a 10.7-fold increase.

Sarepta’s trial was planned to collect outcomes-related data in the form of the six-minute walk test, but those 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 (deflazacort), found there was little evidence to suggest that the exon-skipping agents were superior to treatment with corticosteroids and supportive care. The increases in dystrophin production “are of uncertain clinical significance,” the report said.

Sarepta said Monday that it would immediately request a meeting with FDA to determine its next steps for Vyondys. A study testing the drug alongside casimersen remains ongoing.