Sarepta Therapeutics (NASDAQ:SRPT) has become accustomed to success. The biotech won approval in 2016 for Exondys 51 (eteplirsen), its Duchenne muscular dystrophy (DMD) drug targeting patients with a mutation of the DMD gene amenable to exon 51 skipping. Since then, Sarepta's revenue has soared, with the company reporting sales of $94.7 million in the second quarter -- up 29% year over year.

The biotech appeared to be headed for a second approval with golodirsen, a DMD drug for patients with a DMD gene mutation amenable to exon 53 skipping. CEO Doug Ingram noted in the company's Q2 conference call that there would be no Food and Drug Administration advisory-committee review of golodirsen (as there was for Exondys 51). He stated that Sarepta would be "ready to launch by August immediately after approval."

But that approval didn't happen. On Monday, Sarepta announced that it had received a complete response letter (CRL) from the FDA rejecting its application for golodirsen. What's next for Sarepta after this surprising FDA decision?

Hand holding a jigsaw puzzle piece with a question mark on it

Image source: Getty Images.

Why the FDA gave a thumbs-down

Sarepta stated in its press release announcing the FDA decision that the agency expressed concern about the risk of infections related to intravenous infusion ports. The CRL also cited a concern about renal toxicity found in pre-clinical testing of golodirsen and with the administration of other antisense oligonucleotides (drugs that, like golodirsen, work by blocking the production of a protein).

The more worrisome concern cited by the FDA related to potential renal toxicity -- damage to kidneys caused by a drug or toxin. Renal toxicity wasn't observed in the 25 patients who participated in Study 4053-101, the clinical study on which the regulatory filing for golodirsen was based. In pre-clinical testing, renal toxicity was observed in animals. But this toxicity was seen at doses of golodirsen that were 10 times higher than the dose used in clinical studies.

It was interesting that the FDA referenced renal toxicity in other antisense oligonucleotides as part of its rationale for rejecting golodirsen. The FDA has approved several antisense oligonucleotides in recent years, including Sarepta's Exondys 51, Biogen's spinal muscular atrophy drug Spinraza, and Jazz Pharmaceuticals' hepatic veno-occlusive disease drug Defitelio.

This thumbs-down from the FDA blindsided Sarepta's management. Ingram said that the company was "very surprised" by the CRL, adding, "Over the entire course of its review, the agency did not raise any issues suggesting the non-approvability of goldodirsen, including the issues that formed the basis of the complete response letter."

Sarepta's next moves

Sarepta's press release stated that the biotech "will immediately request a meeting with the FDA to determine next steps." Ingram said the company will work with the FDA's Division of Neurology Products to address the specific issues identified in the CRL. He noted that Sarepta wanted to "find an expeditious pathway forward for the approval of golodirsen."

While Sarepta will immediately request the meeting with the FDA, though, it won't happen immediately. It could be several months before the company has a plan for how it will proceed in its effort to secure approval for golodirsen.

It's likely that at minimum, the FDA will require additional data. What isn't known at this point, though, is whether Sarepta will have to conduct additional clinical studies. If so, any potential FDA approval for golodirsen could be delayed longer than Sarepta would like.

Another DMD drug waiting in the wings

Sarepta continues to move forward with its Essence late-stage clinical study evaluating casimersen and golodirsen in treating patients with mutations of the DMD gene amenable to exon 45 or exon 53 skipping. The company didn't state whether or not anything would change with this study.

Ingram said in the Q2 conference call that the company intended to submit casimersen for FDA approval later this year. The Essence study includes two separate arms of patients taking casimersen and other patients taking golodirsen. But it's possible that the FDA's concerns about golodirsen could carry over to casimersen. If so, Sarepta might become as accustomed to failure as it has been to success.