FDA Rejects Sarepta’s Second Duchenne Drug, Citing Safety Concerns

Xconomy Boston — 

[Updated, 8/20/19, see below] Sarepta Therapeutics won one of the most dramatic and controversial drug approvals in the history of the FDA a few years ago. It didn’t have the same luck the second time around.

The FDA late Monday rejected golodirsen (Vyondys 53), which was widely expected to become the second approved Duchenne muscular dystrophy drug from Sarepta (NASDAQ: SRPT), following the agency’s 2016 approval of eteplirsen (Exondys 51).

In a statement, Cambridge, MA-based Sarepta said that the agency has two concerns with golodirsen. One is the risk of infections from the “ports” used to infuse golodirsen into patients. The second is kidney problems seen in animal tests of golodirsen and in studies of other drugs like it, a class of RNA-based medicines known as antisense oligonucleotides.

Sarepta countered that the problems seen in animal tests occurred at doses “ten-fold higher” than those used in clinical tests. What’s more, no such problems have been seen in human patients on golodirsen thus far.

“We are very surprised,” CEO Doug Ingram said in the company’s statement. Ingram added that the agency “did not raise any issues suggesting the non-approvability of golodirsen” during its review. Sarepta will work with the FDA to “address the issues raised” and “find an expeditious pathway forward for the approval of golodirsen.”

The company will seek a meeting with the FDA immediately to determine the next steps forward.

Sarepta shares fell about 13 percent following the announcement in post-market trading Monday.

The news marks a stunning outcome for Sarepta, which had been following a similar strategy to the one that helped it land FDA approval of Exondys in 2016. There were no FDA-approved treatments for Duchenne until the nod for Exondys, which treats a subset of roughly 13 percent of patients and is meant to slow the progression of the disease. A steroid sold by PTC Therapeutics (NASDAQ: PTCT), deflazacort (Emflaza), has since been approved for Duchenne patients as well. But there still is no cure.

The primary data the FDA had on Exondys before approval came from a tiny, 12-patient clinical trial that compared patients on the drug to a “historical control”—previous data from patients deemed to have similar characteristics to those who took the drug. The main evidence supporting Exondys was its ability to help patients produce around 1 percent of normal levels of dystrophin, known as a “surrogate” marker because studies did not conclusively show that patients were getting better. With Exondys, that evidence still doesn’t exist. A STAT report last week indicated that data may not be available until 2024.

When Exondys was under FDA review in 2016, patient advocates argued at a dramatic advisory meeting that the drug was making a difference, but Sarepta’s studies weren’t showing it. The case caused a highly publicized rift within the FDA. Nonetheless, top drug evaluator Janet Woodcock ultimately supported the drug, and Exondys was approved. (As Xconomy reported here, a few advocates started a company, Casimir Trials, to try to better measure the effects of Duchenne drugs in the wake of the Exondys saga.)

That decision provided a roadmap for Sarepta. It has been aiming for accelerated approvals of golodirsen and, possibly next year, another drug—casimersen—for different subgroups of Duchenne patients based on the medicines’ ability to help patients produce dystrophin.

As with Exondys, there isn’t evidence yet that golodirsen is improving outcomes. But there were important differences this time around that appeared to portend good news for golodirsen. The 25 patients enrolled in the main human study of golodirsen have produced more dystrophin, on average, than those in Exondys trials. The FDA didn’t schedule an advisory meeting this time, typically a bullish sign for its prospects. And Sarepta already began its confirmatory study, Essence, before the FDA made its decision. (That study tests the effects of casimersen, as well.) Wall Street analysts widely expected the FDA to clear the drug. Recently, for instance, SVB Leerink analyst Joseph Schwartz put golodirsen’s approval odds at 90 percent.

[Updated with analyst comments] Multiple analysts were shocked by the FDA’s decision and argued that Sarepta is now paying the price for the polarizing approval of Exondys. The drug’s rejection “seemed to come out of nowhere,” wrote Brian Abrahams of RBC Capital Markets. FDA leadership could be using golodirsen to “send a message that the agency’s bar for safety will be exceptionally high in cases where an unproven surrogate is used to support accelerated approval of the drug.”

SVB Leerink analyst Schwartz added, after speaking with Sarepta management, that the company had even reviewed an approval press release with the FDA before getting the news. The rejection letter was signed by an FDA director who wasn’t involved in the drug’s review, according to Schwartz. Sarepta “is being slapped on the wrist for the prior questionable accelerated approval of Exondys,” he wrote. “We believe that the rejection of golodirsen…may be less about safety and toxicity and more about making a point.”

The implication, going forward, is that Sarepta may need to show the FDA more than just an increase in dystrophin expression to win approval of other Duchenne drugs and that the agency prefers data from a randomized trial, Abrahams wrote. Casimersen, which could be under FDA review next year, “would seem to have the greatest read-through risk” if that is the case, he wrote.

Golodirsen is one of several drugs the FDA has ruled on over the past week. Just this afternoon, the agency cleared lefamulin (Xenleta), a Nabriva Therapeutics (NASDAQ: NBRV) antibiotic for community-acquired bacterial pneumonia. Xconomy previewed that drug and other new medicines—among them therapies for rheumatoid arthritis and cancer—here.