FDA's approval of Duchenne muscular dystrophy drug under scrutiny: Clearance based on limited study, plus it can cost $1M yearly

By Lisa Marie Basile | Fact-checked by Davi Sherman
Published August 25, 2023

Key Takeaways

  • The 2016 accelerated approval of eteplirsen (Exondys 51) for Duchenne muscular dystrophy has been called into question in a commentary published this week in the Annals of Internal Medicine.

  • The drug’s manufacturer will not complete a post-approval clinical trial to determine the drug’s benefit until 2024 or later. The authors say that the drug was approved without fully understanding its efficacy and that delays in mandated post-approval testing can be problematic. 

  • Experts say that whether or not to use a drug like eteplirsen comes down to a shared decision-making process between a patient’s family and their care team

In 2016, the US Food and Drug Administration (FDA) approved eteplirsen (Exondys 51) for the treatment of Duchenne muscular dystrophy (DMD), a neuromuscular disease caused by mutations to the dystrophin gene. This week, commentary published in the Annals of Internal Medicine says that the greenlight, which was granted as part of the FDA’s accelerated approval program, calls into question the approval process as well as the drug’s efficacy.[] 

DMD typically affects young boys, leading to progressive muscle weakness and degeneration. Most patients die in their 20s or 30s. 

Peter Morelli, MD, Duchenne Care Center program director at Stony Brook Children's Hospital in Stony Brook, NY, tells MDLinx, “Eteplirsen is a class of exon-skipping medications. It works at the level of the gene that makes the dystrophin, and it requires a regular infusion every few weeks.”

Dr. Morelli explains that the mutation precludes the body’s DNA from being transcribed into RNA, which is responsible for making the protein the body needs for normal muscle health. 

“The drug looks at the area and tries to jump over it to avoid the abnormal part of the gene. With this, you can make a truncated transcription—which can make a smaller amount of the protein. It still isn’t normal, but it’s closer,” Morelli explains. 

The authors note that the disease has “long had no disease-modifying treatments available” and that eteplirsen met a need for treatment. “Eteplirsen’s approval and market entry were celebrated by many DMD advocates and clinicians,” the authors wrote.

The drug’s accelerated approval was based on a study of 12 boys, with the FDA saying the drug resulted in small increases in patients’ dystrophin levels. This, they said, signaled clinical benefit. However, as the authors note, after 24 weeks, the study changed from a randomized, double-blind trial to an open-label (but blinded to the dose), uncontrolled study. The authors say no “convincing benefit was shown in patients’ mobility or functional status.” 

At this point, an external FDA advisory committee voted seven to three (there were also three abstentions) that the drug had not demonstrated substantial evidence of efficacy. Despite this, this review was overruled. 

The FDA then set a November 2020 deadline for the drug’s manufacturer, Sarepta Therapeutics, to finalize a clinical trial to determine the drug’s benefit. However, the manufacturer will not complete the trial until 2024 or later, the authors state. The authors note that there are still questions regarding the relationship “between levels of truncated dystrophin, the muscle protein studied in eteplirsen’s pivotal trial, and clinical outcomes.” 

The FDA’s decision to fast-track the drug (which isn’t a cure and requires ongoing infusions) led to criticisms of the small study’s lack of long-term data and questions around its efficacy. The approval also spotlighted the drug’s price tag in the US—$300,000 per year, with estimates reaching as high as $1 million. 

“Extremely high prices for such drugs do not correspond to the value of these products or the level of evidence supporting their use, and approving a drug on the basis of flimsy surrogate measure data can create a disincentive for developing truly innovative treatments,” the authors write.

Additionally, the authors state that approvals of other drugs in the same class via the same pathways followed the eteplirsen approval and that the evidence for these is questionable. For example, the authors site delandistrogene moxeparvovec (Elevidys)—also a DMD gene therapy drug sponsored by the same manufacturer as eteplirsen, which was fast-track approved in June this year, “on the basis of a similar unvalidated surrogate measure,” the authors state. Because of this, they say, delays in mandated postapproval testing must be examined.

More so, the authors say that additional reforms are needed to “better balance evidence generation with patient safety and access to promising medications,” calling for limitations around spending funds on unproven therapies and making sure that drug sponsors are running confirmatory trials within a timely fashion, especially after being greenlit by accelerated approval.

Dr. Morelli says he’s not surprised that the drug’s accelerated approval led to such controversy. On the other hand, he says it can be challenging to do large, placebo-controlled studies on treatments for rare diseases like DMD. “It can take years to clinically know if a drug will have an impact…especially if you give [the drug] earlier in life,” he says. 

But for many patients and their families, drugs like eteplirsen provide hope since “time is of the essence,” he says. “We are using these therapies for boys that get very sick. We know the natural course of the disease without treatment. Even with treatment, we know we can’t cure it. So, these measures of gene manipulation are looking at ways to at least salvage some protein production that can help the muscle stay stronger,” Dr. Morelli explains. 

He also says he has seen reason to be optimistic about the amount of protein being made after the use of the drug that he prescribes.  

Dr. Morelli says it’s key that families are part of the shared decision-making process around whether or not to turn to a drug like eteplirsen. “It’s not a simple answer. It’s a family decision along with their neurologist and neuromuscular team of doctors. Talk to the family about short and long-term side effects, talk about the natural course of disease. And if we see a complication, we need to stop the therapy,” he says. “The story is still being written.”

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