The FDA Approval of Eteplirsen – Necessary Flexibility or a Worrying Precedent?

Abstract

In November 2016, eteplirsen received FDA-accelerated approval for the treatment of Duchenne muscular dystrophy (DMD). This was controversial; a small, non-comparative dataset demonstrated what FDA reviewers considered to be minor benefits in a surrogate marker (dystrophin). The FDA advisory panel voted against approval but their advice wasn’t followed. This research will evaluate eteplirsen’s FDA-approval in the context of its two main competitors: drisapersen (FDA-rejected), and ataluren (not accepted for FDA-review, but EMA-approved). Publically-available FDA Summary Review documentation on the DMD appraisals were analysed and compared. Drisapersen was FDA-rejected primarily due to lack of efficacy in phase 3, despite significantly improving 6-minute walk distance (6MWD) versus placebo in phase 2. Ataluren claimed positive phase 2b data based on increasing dystrophin versus baseline, but a follow-on placebo-controlled phase 3 trial did not meet its primary endpoint of significantly improving 6MWD. The FDA judged the company’s filing incomplete, not warranting review. Eteplirsen was FDA-approved on the basis of a statistically significant improvement in dystrophin levels from a non-comparative dataset versus baseline and compared with historical controls, however the analysis methodology and its clinical significance were questioned. The FDA-approval of eteplirsen is arguably problematic given that other putative DMD treatments showed benefits in Phase 2 that was not confirmed in Phase 3. But how strong should the level of evidence be for a positive benefit–risk profile? With eteplirsen’s benign toxicity profile and the severe unmet need, arguably this could be set quite low. Additionally, by receiving FDA-accelerated approval, market withdrawal may follow if phase 3 data is not confirmatory. Nevertheless, approvals based on non-comparative datasets with claimed improvements in surrogate endpoints and where the link to clinical benefit has not been shown may set a worrying precedent that could undermine the FDA’s credibility, reflected in the denials/restrictions eteplirsen’s coverage by some payers.