In stunning reversal, FDA clears Sarepta DMD drug it rejected 4 months ago

The FDA’s attitude toward Sarepta Therapeutics’ Duchenne muscular dystrophy (DMD) therapies is nothing short of dramatic. In just four months, the agency shocked industry watchers twice, first with a rejection and now a reversal for the biotech’s Exondys 51 follow-on.

Out of nowhere, the agency Thursday granted accelerated approval to Sarepta’s Vyondys 53 (golodirsen), a drug it turned down in August for safety reasons. The go-ahead covers about 8% Duchenne patients whose dystrophin gene bears a certain mutation amenable to exon 53 skipping.

While the FDA didn’t elaborate on the sudden change of course, Sarepta said it had launched a formal dispute resolution request after receiving the agency's complete response letter (CRL) detailing its reasons for the rejection. Sarepta worked with Peter Stein, director of the FDA's Office of New Drugs, to resolve the concerns raised in that CRL.

In August, a stunned Sarepta said the FDA had rejected Vyondys 53 for the risk of infection linked to intravenous infusion ports and for kidney toxicity seen only in animal studies. Analysts suspected at the time that the agency had changed its standards on using dystrophin as a surrogate marker for approval. DMD patients lack dystrophin, a protein that helps maintain the structure of skeletal muscle fibers, due to missing exons in the DMD gene.

Controversy erupted in 2016 when Sarepta’s Exondys 51 won an FDA thumbs-up based on dystrophin data without showing actual clinical benefits such as improvement on disease progression. Opinions were split even within the FDA; in fact, two officials who'd opposed the green light decided to retire. In contrast, European regulators shot down Exondys 51 last September—for the second time.

Like Exondys 51, Vyondys 53 was approved based only on dystrophin production “that is reasonably likely to predict clinical benefit” in DMD patients, the FDA said in a statement—not on proven clinical improvements. In a small clinical trial, 25 patients on Vyondys 53 saw 1.02% of normal dystrophin production after 48 weeks of treatment, up from 0.1% at baseline.

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The win confirmed “that dystrophin is an adequate surrogate for accelerated approval, and FDA’s continuing flexibility in areas of high unmet need like DMD,” RBC Capital Markets analyst Brian Abrahams wrote in a Thursday note to clients. It also showed that Sarepta “still has a productive and collaborative relationship with the agency, which should help them navigate the paths for the gene therapies,” he added.

Even though renal toxicity didn’t show up in clinical studies, the FDA noted that such safety problems had been observed with other antisense oligonucleotides. Therefore, it’s asking patients taking Vyondys 53 to be monitored for renal function.

Sarepta said it’s pricing the new antisense therapy “at parity” with Exondys 51, which the company has claimed costs about $300,000 on average per patient a year, though others estimated it could reach as much as nearly $1 million.

RELATED: Want bang for your buck? Don't look to Sarepta's pricey DMD therapy Exondys, ICER says

Part of the criticism around Exondys 51 still lingering today is that, despite a conditional approval, the company has not presented any post-approval data to confirm the drug’s benefit, while still being able to collect expected sales of between $370 million to $380 million from it in 2019.

For Vyondys 53, its approval is again conditional upon Sarepta running a confirmatory trial. The company is already conducting one, called Essence, which is designed to assess whether the drug improves motor function in its indicated patient population. Data aren't expected for almost five years, however.

“If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug,” the agency said Thursday. Nevertheless, RBC’s Abrahams said his team reviewed “it unlikely that the results of Essence fail to show functional benefits to the level that would support continued marketing of Vyondys” after it reads out around 2024.

Abrahams pegged Vyondys 53’s peak worldwide sales at about $220 million.