In a Surprise Decision, FDA Rejects Sarepta's Second Duchenne Drug

In a highly anticipated decision, the FDA on Monday rejected accelerated approval for Sarepta Therapeutics’ second Duchenne drug, handing the drug maker a surprising blow that has some questioning the motivation behind the decision.

Golodirsen, or Vyondys 53, is an investigational injection for the treatment of Duchenne muscular dystrophy (DMD)—a rare muscle-wasting disease typically seen in boys—in those with a confirmed mutation amenable to exon 53 skipping.

In a statement released by Sarepta, the company said the FDA’s complete response letter cites concerns over risks of infections related to intravenous infusion ports, as well as renal toxicity seen in preclinical models of the drug and observed following administration of other antisense oligonucleotides.

According to the company, these preclinical models used doses of golodirsen that were 10-fold higher than the dose used in clinical studies; additionally, renal toxicity was not observed in Study 4053-101, which the drug application was based on.

“We are very surprised to have received the complete response letter this afternoon. 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 Doug Ingram, president and chief executive officer of Sarepta, in a statement.

He added that the company will meet with the FDA to address the concerns raised in the letter and work to determine next steps. The FDA has not issued its own statement on the decision.

According to STAT News, the data that Sarepta submitted to the FDA demonstrated that golodirsen offered a small increase in the muscle protein dystrophin, which is normally missing in children with DMD. However, Sarepta did not submit data on the drug’s ability to improve muscle function in patients or slow progression of disease.

In 2016, the FDA granted a controversial approval to Sarepta’s first DMD treatment, eteplirsen (Exondys 51), overruling medical staffers and even some advisors within the agency who argued that there was not enough evidence that the drug was effective. Prior to the drug’s approval, FDA staff raised concerns over “life-threatening” adverse effects, such as low blood platelet counts and severe kidney damage.

The company was supposed to conduct a 2-year trial to verify the clinical benefit of eteplirsen, which would allow the FDA to withdraw approval if results came back negative. However, the company has yet to do so, which has some questioning if this has anything to do with Monday’s decision on golodirsen.

Alethia Young, head of healthcare research at Cantor Fitzgerald and RBC Capital Market, expressed belief that the FDA’s rejection “could be political.” In a letter to investors, SVB Leerink analyst Joseph Schwartz wrote that, “In our view, [Sarepta] is being slapped on the wrist for the prior questionable accelerated approval of Exondys 51.”

Following Monday night’s decision, those in the DMD community reacted and expressed their disappointment. Parent Project Muscular Dystrophy released a statement saying, “Today has been marked on many of our calendars and like you, we were hopeful that an approval was imminent. 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.”