FDA Advisors Issue Harsh Opinion of Muscular Dystrophy Drug Eteplirsen

FDA staff reviewers have issued a negative assessment of eteplirsen (Sarepta Therapeutics), a potential treatment for certain patients with Duchenne muscular dystrophy (DMD), ahead of an April 25 meeting that will consider the drug’s suitability for accelerated approval. The reviewers expressed their discomfort with the design of pivotal studies, the small number of patients tested, the statistical analyses employed, and the drug’s overall effectiveness.

FDA staff members had highlighted similar concerns in a statement issued on January 15. At that time, Sarepta submitted additional information and pointed toward “key inaccuracies” in the reviewers’ analysis.

In their new announcement, the FDA staff refuted Sarepta’s “characterization of inaccuracies” and said the new information presented by the company further increased concerns about the reliability of its trial data. The reviewers added that any potential beneficial effects of eteplirsen are unlikely to be large enough to be detectable outside of a large placebo-controlled trial.

The reviewers pointed out that while the FDA is flexible with respect to diseases that have no treatment options, such as DMD, “we cannot approve drugs for which substantial evidence of effectiveness has not been established.”

During the clinical development of eteplirsen, Sarepta conducted three small studies in DMD patients: two exploratory trials to assess the drug’s potential to increase dystrophin expression, and a clinical study (Study 201) to further assess the extent to which eteplirsen increased the expression of dystrophin proteins, and to explore the drug’s potential clinical benefits.

Study 201 was a 24-week, single-center, controlled trial in 12 patients assigned to receive eteplirsen 30 mg/kg, eteplirsen 50 mg/kg, or placebo. According to the FDA reviewers’ new statement, the clinical endpoints of this study “were essentially uniformly negative, without trends supportive of efficacy.”

Study 201 was continued as an open-label extension trial, which has been ongoing for more than three years. Shortly after this study passed one year’s duration, Sarepta proposed a post hoc analysis with a number of changes from the original analysis: 1) data for two out of eight patients treated with eteplirsen (patients who quickly lost ambulation) were dropped; 2) the prespecified comparison of each dose arm to placebo was changed to a comparison of the six remaining treated patients to the four placebo-treated patients; and 3) the endpoint was extended to week 36 instead of week 24. In March 2013, the FDA explained in detail to Sarepta why this proposed analysis was “unreasonable even for hypothesis generation,” according to the reviewers’ new announcement.

Sources: Reuters; April 21, 2016; and FDA Briefing Memo; April 9, 2016.