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reliably used as a measure of kidney function or as a basis for adjusting the medication dose. With no established way of monitoring kidney function in Duchenne patients, clinicians could be blind to kidney problems, the FDA letter says.
Eteplirsen was approved on an accelerated basis, which means the decision was made using less evidence than is typically required for a drug decision, but with the understanding that the drug maker will conduct additional studies to confirm the medicine’s benefit to patients. The FDA rejection of golodirsen came nearly three years after eteplirsen’s approval. But the agency notes in its letter that Sarepta had not yet started the required confirmatory study of eteplirsen that could have informed the drug reviewers about risks and benefits of golodirsen.
“Please understand that your failure to initiate eteplirsen’s confirmatory study with due diligence is very concerning to FDA and is of concern to the public,” the letter says.
Sarepta disputes that conclusion. Sorrentino, the company’s spokeswoman, said that the timeline for further evaluating eteplirsen was extended by an FDA request that the company evaluate the drug at a higher dose—which called for an additional study in healthy volunteers. With that study done, the company was able to proceed with the main post-marketing study. Clinical trial records filed with the National Institutes of Health show that the first record of the study was June 20, 2019.
Sarepta had filed for approval of golodirsen based on data from a 25-patient study. The FDA letter stated that in order to secure approval of the drug, Sarepta needed to provide more evidence of the drug’s benefit by completing a placebo-controlled study. The agency asked the company to develop a way to monitor kidney function in Duchenne patients who are given the drug. Finally, the FDA letter said that finding a way to give patients the drug without an implanted infusion port would reduce the risks of the therapy.
Peter Stein, director of the FDA’s Office of New Drugs, granted Sarepta’s appeal of the golodirsen rejection. In Nov. 22 correspondence also posted to the FDA’s website, Stein disagreed with Unger’s conclusion that the likely clinical benefit of the drug would be “at most, very small.” Though large changes in muscle strength are unlikely with golodirsen, Stein wrote, more modest improvements “would be meaningful to patients.”
“Patients with [Duchenne] are looking for improvement in muscle strength, even if only a modest increase in handgrip or arm strength, or respiratory muscle strength that might allow them some improvement in their ability to perform daily tasks, such as dressing or typing, or even reduce their time on mechanical ventilation,” he wrote.
Stein disagreed with the safety conclusions stated in the August rejection letters. While acknowledging the risk of kidney injury, he noted that alternatives markers can be measured to monitor kidney function. He also acknowledged the infection risk posed by the ports used to administer the drug, but suggested a peripheral intravenous line, which doses medication through a small plastic catheter, as an alternative to an implanted port. The kidney risks and monitoring recommendations are part of the drug’s label.
Like eteplirsen, Sarepta submitted golodirsen to the FDA for review on an accelerated basis. That means that keeping that approval is subject to another clinical trial to confirm that drug’s benefit. Sarepta says that the study is underway and expected to be complete in 2023.