FDA staff reviewing Sarepta Therapeutics Inc.'s eteplirsen (Exondys 51) expressed "considerable doubt" regarding how much the drug improves dystrophin production for patients with Duchenne muscular dystrophy (DMD) and about whether improvements seen in small trials could be reliably attributed to the drug. The negative comments followed closely on the agency's rejection of Biomarin Pharmaceutical Inc.'s DMD drug, Kyndrisa (drisapersen), and suggest that chances for eteplirsen's approval are low.

FDA action on the drug is expected by Feb. 26.

Following the document's release on Friday, ahead of the committee's planned Jan. 22 meeting, Sarepta shares (NASDAQ:SRPT) fell 54.9 percent to close at $14.28. Shares of PTC Therapeutics Inc. (NASDAQ:PTCT), the next contender in line to face FDA scrutiny of its DMD drug, Translarna (ataluren), lost 72 cents to close at $23.11.

Sarepta is seeking accelerated approval to market eteplirsen for patients with DMD who have a mutation of the dystrophin gene amenable to exon 51 skipping, a group that accounts for about 13 percent of boys with the condition. Skipping of exon 51, scientists believe, might restore the reading frame of dystrophin, increasing the production of a truncated dystrophin protein that, while not restored to normal, would nevertheless be partially functional, thus slowing or preventing the progression of DMD. To support its application, Sarepta ran two small exploratory studies, study 28 and study 33, to assess eteplirsen's potential to increase dystrophin expression, and a single controlled 12-patient study, study 201/202, to assess whether the therapy increased expression of dystrophin protein.

While reviewers told members of the Peripheral and Central Nervous Systems Drugs advisory committee that they found no significant safety signals for eteplirsen in the studies, they took issue with trial design, efficacy, dystrophin measurement methods and statistical analysis approaches, a litany of issues that bodes ill for the drug's chance of obtaining FDA approval.

Among the reviewers' complaints were that the company's dataset was too small and that differences in DMD progression between eteplirsen patients and Sarepta's natural history controls were "too small and variable, in the context of a poorly controlled trial, to be reliably attributed to drug treatment." They also cast doubt of the reliability of biomarker assessments from three of the four biopsies done to measure dystrophin protein production in the muscles of boys included in study 201/202.

A statistical review and evaluation concluded that "the data, overall, did not provide statistical evidence to support the efficacy of eteplirsen in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping."

Even on safety, the one bright spot for Sarepta, reviewers noted that the clinical safety database for the drug is small, with only 12 patients exposed to it for one year or longer and with only 36 patients exposed for 24 weeks or longer. "As a consequence," reviewers wrote, "the one-year database only has adequate power to assess the frequencies of the more common adverse events. Less frequent events, possibly serious, may have been missed because of the small database." Long-term safety is important since boys taking the drug would take it for their entire lives.

Given the reviewers' contention that any beneficial effects of eteplirsen are unlikely to be large enough to be detectable outside of a placebo-controlled trial, Jefferies analyst Gena Wang observed that it was unclear if an ongoing open-label confirmatory phase III trial (study 4658-301) would meet the agency's criteria without modification of its design.

Sarepta declined to speak with BioWorld Today regarding the briefing document, but it did file an addendum with the agency seeking to provide reviewers and adcom members with updated efficacy data and clarification on what it views as inaccuracies in some of the agency's interpretations. It also sought to convince the agency of its authority to use "scientifically driven flexibility" in making approval decisions, in particular through the accelerated approval pathway for serious or life-threatening diseases, such as DMD.

Beyond the immediate ripple in shares of PTC following the eteplirsen briefing release, it's unclear whether there will be any deeper takeaways for that company, which completed a rolling submission of its new drug application for Translarna to the FDA last year. It expects a decision midyear. (See BioWorld Today, Jan. 14, 2016, and Jan. 15, 2016.)