Reviewers Question Sarepta NDA Data for Duchenne Drug
FDA reviewers are raising concerns that data are not sufficient to allow approval of a Sarepta Therapeutics NDA for eteplirsen, indicated for treating Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. In briefing materials released in advance of a 1/22 Peripheral and Central Nervous System Drugs Advisory Committee meeting to review the submission, the reviewers said “data overall did not provide statistical evidence to support the efficacy in subjects who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping.
“The only randomized controlled study submitted by the applicant, Study 201, can only be considered as exploratory because of study design and statistical analysis issues,” according to the reviewers. “The comparison of eteplirsen with historical controls, as proposed by the applicant in the open label extension of Study 201 (called Study 202 by the applicant), is statistically uninterpretable, as this open-label extension did not have a prespecified statisitical analysis plan, and had an inadequate control for bias. Among the potential sources of bias in the open-label extension of Study 201 are possible differences in various factors between eteplirsen-treated patients and the selected historical control cohort unaddressed by the applicant’s attempt to match patients, the potential selection bias due to the post-hoc identification of the control cohort by the applicant, and other known sources of bias with the use of a historical control.”
FDA has been under pressure by patient advocates and Congress after it reversed course in 2013 and told Sarepta that an NDA for eteplirsen would be premature for treating DMD (see story). At the time, the agency cited recent developments that caused some alarm, including a failed study with a competitive product and recent natural history data in DMD, according to the company. The agency said the new data raise “considerable doubt” about “both the dystrophin biomarker and the supportive clinical efficacy assessed on the six-minute walk test (6MWT) in the Phase 2b clinical study of eteplirsen,” according to the company.
In 2014, CDER director Janet Woodcock said the agency was willing to explore the use of all potential pathways for approving drugs for DMD, including accelerated approval, as appropriate. That is the response she gave to a petition on the White House’s Web site that has garnered over 100,000 signatures in support of the agency’s accelerated approval pathway for such products.
Woodcock’s response said the agency’s “ongoing analyses of eteplirsen and other drugs for the treatment of Duchenne muscular dystrophy are based on rigorous assessments by a large multi-disciplinary team of scientists. Although our assessments are rigorous and extensive, we recognize the urgency of the needs of patients with Duchenne muscular dystrophy, and we carry out our analyses expeditiously.”