FDA Panel Split Vote Not Encouraging for Duchenne Drug
FDA’s Peripheral and Central Nervous System Drugs Advisory Committee has voted 7 to 6 that a Sarepta Therapeutics NDA did not provide substantial evidence from adequate and well controlled studies that eteplirsen induces production of dystrophin to a level that is reasonably likely to predict clinical benefit in patients with Duchenne muscular dystrophy (DMD). The vote is seen as a setback for the company’s bid to gain accelerated approval for the drug. A separate 7 to 3 vote by the panel recommended that data were not sufficient to meet traditional approval standards.
The voting followed an assessment by FDA medical reviewers who found the submission’s data “overall did not provide statistical evidence to support the efficacy” of the drug. The assessment is part of a briefing document released in advance of the 4/25 advisory committee meeting.
Sarepta is seeking accelerated approval for eteplirsen in patients with DMD who have mutations amenable to exon 51 skipping. The advisory committee meeting had been slated for 1/22 but was rescheduled due to a weather emergency. The briefing document notes that the materials released in advance of 1/22 contained a negative view of the drug and since then the company submitted additional information about clinical outcomes and its responses to what Sarepta said were “inaccuracies” in the FDA document. The latest briefing document incorporates the additional company information and rejects Sarepta’s allegation of FDA inaccuracies in the earlier document.
The reviewers said that the new information submitted by the company actually increased concerns about the reliability of its clinical trial data. One issue deals with the three small studies the company submitted to support its NDA. The reviewers said that while FDA is flexible in looking at treatments for diseases that have no current treatment options, “we cannot approve drugs for which substantial evidence of effectiveness has not been established.” The reviewers criticized Sarepta’s clinical study design and statistical analysis, arguing that the company over-estimated how much dystrophin was produced by the drug the extent of its role in meeting a clinical endpoint.
FDA’s review has been a politically charged issue, leading to an early appearance by CDER director Janet Woodcock to set the tone for the meeting. Woodcock said Sarepta’s data are difficult to interpret, and the small increase in dystrophin may or may not confer a benefit. She said the agency is always concerned about approving a drug that does not work. “There often is little consideration of another error — which is failing to approve a drug that actually works,” she told the panel. “But most of this consequence is borne by patients who have little say.”
Over 50 public speakers addressed the panel, with most urging accelerated approval. But earlier in the day, CDER Neurology Drug Products division director William Dunn told the panel that the agency has a responsibility to approve drugs based on scientific proof of their safety and effectiveness. “Anecdote and emotions don’t change the data,” he said.