Rare Daily Staff

The U.S. Food and Drug Administration notified Sarepta Therapeutics that it would not approve its experimental exon-skipping drug golodirsen for certain patients with the rare and fatal neuromuscular disease Duchenne muscular dystrophy because of safety concerns.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration and weakness that primarily affects boys with symptoms beginning as early as three years of age. It is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. Progressive muscle weakness in the lower limbs spreads to the arms, neck and other areas of the body. The condition is universally fatal, and death usually occurs before the age of 30 generally due to respiratory or cardiac failure.

DMD is associated with specific errors in the gene that codes for dystrophin, a protein that plays a key structural role in muscle fiber function. Golodirsen is designed to bind to exon 53 of dystrophin pre-mRNA, resulting in “skipping” of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon skipping is intended to allow for production of an internally truncated but functional dystrophin protein.

According to the company, the complete response letter from the FDA cited two concerns: the risk of infections related to intravenous infusion ports and renal toxicity seen in pre-clinical models of golodirsen and observed following administration of other antisense oligonucleotides. 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 company said.

“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 CEO of Sarepta. “We will work with the Division to address the issues raised in the letter and, to the fullest extent possible, find an expeditious pathway forward for the approval of golodirsen. We know that the patient community is waiting.”  

Sarepta said it will immediately request a meeting with the FDA to determine next steps.

Photo: Doug Ingram, president and CEO of Sarepta

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