FDA Publishes Initial Rejection Letter of Sarepta's Vyondys 53 for DMD


In August 2019, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to Sarepta Therapeutics over its golodirsen for Duchenne muscular dystrophy (DMD) with a confirmed mutation amenable to exon 53 skipping. In December, the FDA approved the drug, now named Vyondys 53.

After receiving the CRL, Sarepta’s chief executive officer, Doug Ingram, told investors and DMD families that the FDA’s rejection was related to concerns about the risk of infection and possible kidney toxicity. When asked to release the actual CRL, he declined, saying that “might not look like we’re being as respectful as we’d like to be.” Then he assured the audience that he hadn’t misrepresented the FDA’s CRL.

Only now, the FDA, in a surprise move, posted the CRL on the agency’s website. The CRL was written by Ellis Unger, director of the FDA’s CDER’s Office of Drug Evaluation I. The CRL not only brings up the potential toxicities of the drug but raises questions about the drug’s efficacy.

For example, the CRL notes, “The 6-minute walk data from Study 4053-101 are not discussed herein, but they show progressive loss of physical function in essentially all boys. Moreover, there is no correlation between maintenance of physical performance and the magnitude of truncated dystrophin production, further suggesting that if there is indeed a clinical effect of golodirsen, the effect size is small.”

The letter then goes on to discuss the infections and renal toxicity, saying, “Both are potentially life-threatening, and the latter (renal toxicity) is difficult or impossible to monitor.”

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The publication of the letter not only raises the question of why the agency decided to approve it several months later, but why the company has failed to run a confirmatory trial over the company’s Exondys 5, for DMD, which was approved after considerable drama and controversy in 2016. Exondys 51 is approved for DMD patients with a confirmed mutation amenable to exon 51 skipping.

DMD is a muscle wasting disease caused by mutations in the dystrophin gene. It is a progressive disease that usually causes death in early adulthood, with serious complications that include heart or respiratory-related problems. It mostly affects boys, about 1 in every 3,500 or 5,000 male children.

After the CRL, Sarepta made a formal dispute resolution request to the FDA. Sarepta indicated that the agency’s Review Division quickly evaluated and resolved the issue and granted the appeal. Sarepta re-submitted its NDA to the Review Division, which approved the drug.

The agency is requiring Sarepta to conduct a confirmatory trial for Vyondys 53, which Sarepta says it will wrap by 2024. This echoes the company’s plans to run a confirmatory trial as required by the FDA for Exondys 51, but which four years later has not been performed.

Exondys 51 costs about $300,000 per year, based on the patient’s weight, but can run up to $1 million annually. Vyondys 53 has a similar pricing structure.

In the CRL, Unger also ties in safety concerns to Exondys 51. At the time of that approval in 2016, the concerns over infections was theoretical. Unger wrote, “Three years later, with 469 patients exposed to commercial eteplirsen, we have incontrovertible evidence of a significant likelihood of serious infections, including sepsis, septic shock, and possibly death. Thus, the risk of serious and life-threatening infections is no longer theoretical.”

And he goes on to make the connection between risk of infection and Vyondys 53 because the “the infection risk is a function of the patient population and the delivery system—not the drug.”

He also said that based on the animal research data, the risk of renal toxicity was worse in Vyondys 53 than it was for Exondys 51. And there’s still no particular way to monitor patients for early signs of renal toxicity.

Meanwhile, the FDA is still waiting for Sarepta to launch its confirmatory trial for Exondys 51, which was required as part of the drug’s 2016 approval.

Unger wrote, “Given that you have established a standard paradigm and design for these types of studies, given that you have relationships with a number of DMD referral centers, and given that some 469 patients have received commercial eteplirsen, it is necessary to ask why you have not initiated your required confirmatory study with due diligence.”

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