Sarepta Therapeutics Inc. has received a complete response letter (CRL) from the FDA as the agency declined to issue a sought-after accelerated approval for the company's Duchenne muscular dystrophy (DMD) follow-on therapy, Vyondys 53 (golodirsen).

The candidate is designed for the treatment of people with DMD who have genetic mutations amenable to skipping exon 53 of the dystrophin gene. They account for about 8% of patients, a group not reached by Sarepta's first commercial product, Exondys 51 (eteplirsen). (See BioWorld, Sept. 20, 2016.)

The CRL generally cites two concerns, Sarepta said: the risk of infections related to I.V. infusion ports and renal toxicity seen in preclinical models of golodirsen and observed following administration of other antisense oligonucleotides.

Renal toxicity with golodirsen was observed in preclinical models at doses that were 10-fold higher than the dose used in clinical studies, but not in Study 4053-101, on which the application for golodirsen was based, Sarepta said.

Sarepta President and CEO Doug Ingram said his team was "very surprised" to receive the CRL in light of the agency not having raised any issues suggesting the non-approvability for golodirsen, including those raised in the letter. Sarepta's team will immediately request a meeting with the FDA to determine next steps, the company said.

Phase III trial underway

Duchenne is a rare but fatal X-linked degenerative neuromuscular disorder. It affects an estimated one in every 3,500 to 5,000 males born worldwide. It is caused by genetic changes that stand in the way of functional dystrophin, a protein crucial in strengthening and protecting muscle fibers.

A rolling NDA submission was completed for the drug in December that included data from Study 4053-101 assessing the safety, tolerability, pharmacokinetics and dystrophin expression of golodirsen in 25 boys with confirmed deletions of the DMD gene amenable to exon 53 skipping. Sarepta reported that results of that trial illustrated statistically significant results in favor of golodirsen on all biological endpoints, including properly exon-skipped RNA transcript using reverse transcription polymerase chain reaction, increase in quantity of dystrophin expression from baseline using Western blot and increase in dystrophin intensity as measured by immunohistochemistry.

The Essence study, a randomized double-blind, placebo-controlled phase III trial evaluating golodirsen and another exon-skipper, casimersen, in patients amenable to skipping exons 53 or 45 remains underway. Before now, that trial had been cast as an intended postmarketing confirmatory study to support full approval for golodirsen. It's unclear whether it will produce data that could sway FDA reviewers.

Vyondys 53 uses Sarepta's phosphorodiamidate morpholino oligomer chemistry and exon-skipping technology to skip exon 53 of the DMD gene. It's designed to bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion of the exon during mRNA processing to allow for production of an internally truncated but functional dystrophin protein.

Based on interim results from an analysis of muscle biopsy endpoints comparing casimersen treatment to placebo in Essence, Sarepta is working to file an NDA for casimersen this year. It's unclear what impact, if any, the golodirsen CRL will have on those plans.

News of the CRL came after market close Monday. Shares of Sarepta (NASDAQ:SRPT) fell 15.2% on Tuesday to $102.07. But what Sarepta's news might mean for others with DMD drugs in development wasn't clear.

SVB Leerink's Mani Foroohar opined that the FDA's response to Sarepta "could reflect a broadly higher bar for approval in DMD, especially given the lack of disease-modifying treatments for patients with exon 53-skipping amenable disease and the relatively minor (compared to the severity of DMD in these patients) safety concerns cited in the CRL."

That led to some concern that Wave Life Sciences Ltd.'s suvodirsen might face a tougher time with reviewers, though views on how true-to-reality the agency's concerns about oligonucleotides might be were mixed. "In our view, it's atypical for the FDA to use all-inclusive language like 'other antisense oligonucleotides' in a CRL. Is it possible? Sure, but we believe this is atypical," Mizuho Securities analyst Salim Syed said. "The cynical view here is that Sarepta may be trying at this point to direct attention now away from all oligos toward its gene therapy," he added. Mizuho holds a buy rating on Wave's shares (NASDAQ:WVE), with a price target of $65, about triple their value at Tuesday's close of $21.29.

Shares of another DMD player, Solid Biosciences Inc. (NASDAQ:SLDB), by contrast, rose 5.6% to $9.30 on Monday, ticking up just slightly to $9.32 on Tuesday. By and large, company observers seemed to attribute the rise to optimism about amendments made to the trial protocol for testing of its potential gene therapy for DMD, SGT-001, updates the company said on Aug. 14 would "expedite the path" to obtaining results from its phase I/II Ignite trial as the broader development of the SGT-001 program. (See BioWorld, May 15, 2019.)

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