Déjà vu: Marks Overrides Reviewers on Duchenne Drug Again
CBER director Peter Marks has again overridden his Center’s review teams in expanding the limited approval of Sarepta Therapeutics’ Duchenne muscular dystrophy (DMD) gene therapy Elevidys to full approval. On 6/20, Marks signed off on the supplemental BLA and dismissed reviewers’ objections to broaden Elevidys’ use to about 80% of people in the U.S. with DMD. Previously, the gene therapy was approved for only a specific group of boys aged four and five years.
In granting accelerated approval in 2023, Marks had written a decisional memo saying: “Although I agree with the review team’s conclusions regarding product quality and safety, I disagree with certain interpretations of the efficacy data and come to a different conclusion regarding individuals aged four through five years.”
In the recent action, a similar decisional memo from Marks says: “I come to a different conclusion regarding the overall interpretation of the data... Substantial evidence of effectiveness of clinical benefit has been demonstrated for the original population of ambulatory four- and five-year-old individuals with DMD for whom the product previously received accelerated approval, as well as for the larger population of ambulatory individuals with DMD; I therefore determine that the demonstration of effectiveness supports traditional approval in ambulatory individuals at least four years of age with DMD.”
Reviewers in their 6/20 summary memo objected to the expanded approval and the full approval, pointing to Sarepta’s Study SRP-9001-301 Part 1 that “did not meet the success criterion for the primary clinical endpoint of a statistically significant greater improvement in [North Star Ambulatory Assessment] NSAA total score from baseline to Week 52 in the SRP-9001 group compared with placebo group. This study therefore did not satisfy the accelerated approval letter requirement, that the study ‘describe and verify clinical benefit of SRP-9001 in ambulatory patients with DMD…evidenced by effects such as improved North Star Ambulatory Assessment (NSAA) Total Score from baseline to Week 52.’”
Additionally, the reviewers said that “post-hoc subgroup analyses by age group did not demonstrate that clinical benefit in the primary and key secondary efficacy endpoints were substantial and consistent across age subgroups. The results from the two randomized studies include only ambulatory subjects, so there is no evidence of effectiveness in non-ambulatory subjects with DMD. These results do not suggest there is substantial evidence to support the effectiveness of SRP-9001 for the expanded indication to all DMD patients and do not support the conversion of accelerated to traditional approval.”
Marks’ action is reminiscent of a review override (see story) almost eight years ago by then-CDER director Janet Woodcock on a Sarepta NDA for DMD drug Exondys 51 (eteplirsen). Both cases add up to top-level FDA responsiveness to activists for a U.S. patient population estimated at about 870,000, mostly males under 25 who die of the disease by about that age. At the time, Woodcock’s interference sparked controversy and internal dissent when Office of Drug Evaluation 1 director Ellis Unger challenged Woodcock’s override and brought an appeal before the FDA Scientific Dispute Process Review Board chair and then-acting chief scientist Luciana Borio, who sided with Unger in his argument that the NDA’s data had not met the standard for accelerated approval. The board subsequently asked FDA commissioner Robert Califf, who was serving under his first term as the agency’s head, to review the scientific merits of the case, and he ruled in favor of Woodcock and the drug's approval.