After August Rejection, FDA Approves Sarepta’s Vyondys 53 for Muscular Dystrophy

The agency is requiring Sarepta to conduct a confirmatory trial, which Sarepta says will conclude by 2024.

The U.S. Food and Drug Administration (FDA) approved Sarepta’s Vyondys 53 (golodirsen) for Duchenne muscular dystrophy (DMD) patients amenable to skipping exon 53. In August 2019, the agency issued a Complete Response Letter (CRL) to the company over the drug related to the risk of infections at intravenous infusion ports and renal toxicity observed in preclinical models.

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.

Sarepta is the only company to have an approved treatment for DMD on the market, Exondys 51, which was approved in 2016 after a contentious and year-long public process. Exondys 51, as the name suggests, is for DMD patients with a confirmed mutation amenable to exon 51 skipping.

After the CRL, Sarepta made a formal dispute resolution request to the agency. The company indicates that the agency’s Review Division were quickly evaluated and resolved by Peter Stein, director of the Office of New Drugs (OND), which granted the appeal. Sarepta re-submitted its New Drug Application (NDA) to the Review Division, which approved the drug.

Otherwise, Vyondys 53 was studied in a two-part clinical trial. The first included 12 DMD patients. Eight patients received Vyondys 53 and four received placebo. The second part of the trial was open-label and included the 12 patients from part one and 13 additional patients who had not received the treatment yet. The drug increased dystrophin levels on average from 0.10% of normal baseline to 1.02% of normal after 48 weeks or longer treatment.

The renal toxicity was observed in laboratory animals, but not in the human patients. The most common side effects were headache, fever, cough, vomiting, abdominal pain, cold symptoms and nausea. There were also hypersensitivity reactions such as fever, rash and skin irritation.

“Today is monumental for Sarepta and, more importantly, for the DMD community,” said Doug Ingram, president and chief executive officer of Sarepta. “Vyondys 53, our second approved exon-skipping RNA therapy for DMD, may treat up to 8% of the DMD community, representing those patients who have a confirmed exon 53 amenable mutation. Along with Exondys 51 (eteplirsen), we now offer treatment options for approximately 20% of those with DMD in the U.S.”

The agency is requiring Sarepta to conduct a confirmatory trial, which Sarepta says will conclude by 2024. The trial is called ESSENCE and is currently enrolling patients. This is an echo of the FDA’s approval of Exondys in 2016, which was both dramatic and controversial, with public hearings, the involvement of Congress, and internal conflict in the FDA over the drug’s efficacy and safety.

Although Vyondys 53 has shown in a clinical trial to slightly increase the muscle protein dystrophin, which is typically missing in Duchenne children, the trials haven’t yet shown the drug improves muscle function or slows disease progression. This, too, is similar to the Exondys 51 treatment and clinical trials. The company has said it will run a confirmatory trial for Exondys 51, but apparently has fallen behind schedule.

Meanwhile, the company indicates Vyondys 53 will be priced similarly to Exondys 51. The drug is based on a patient’s weight, is about $300,000 per year, but can run up to $1 million per year.

“The FDA recognizes the urgent need for new medical treatments for serious neurological disorders and we have a longstanding commitment to working with researchers, drug companies and patients to facilitate the development and approval of treatment for rare diseases,” said Billy Dunn, acting director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “With today’s accelerated approvals, patients with Duchenne muscular dystrophy—a rare and devastating disease—who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype.”