Rare Disease Report

Sarepta Prepares to Submit NDA for Duchenne Therapy

MARCH 12, 2018
Mathew Shanley
A February 2018 Type C meeting between Sarepta Therapeutics, Inc. and the Division of Neurology Products of the U.S. Food and Drug Administration (FDA) was held to solicit the Division’s guidance on the development pathway for Sarepta’s golodirsen (SRP-4053).

The therapeutic candidate, a hosphordiamidate morpholino oligomer, is being developed to treat patients with Duchenne muscular dystrophy (DMD) who have genetic mutations subject to skipping exon 53 of the DMD gene.

Based on the results of Study 4053-101 and informed now by feedback from the FDA, Sarepta plans to complete and submit a rolling submission of a golodirsen new drug application (NDA) by year-end 2018, seeking accelerated approval of the drug based on an increase in dystrophin protein as a surrogate endpoint.

"Sarepta is thankful for the FDA Neurology Division’s thoughtful and direct guidance regarding golodirsen," said Doug Ingram, Sarepta's president and chief executive officer in a press release. "Obviously, whether golodirsen will obtain accelerated approval is a review decision that will come after the submission and review of our NDA. But we greatly appreciate the willingness of the Neurology Division to engage and provide clear direction to us on the steps necessary to support an NDA submission for accelerated approval."

SRP-4053 is intended to bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion – or “skipping” – of the exon during mRNA processing in patients with genetic mutations that are amenable to it.

Top-line results from the company’s Phase 1/2 muscle biopsy study of the gene therapy in DMD were originally released in September, but additional data were provided in a poster presentation at the Annual Congress of the World Muscle Society in France in October. The results, authored by Francesco Muntani, M.D. of University College London, denibstrated statistically significant results in favor of SRP-4053 on all biological endpoints, and confirmed the boost in overall production of dystrophin provided by the drug in patients with DMD, and that the increase was seen in the sarcolemma – the area of muscle necessary for clinical benefit.

In the study, golodirsen demonstrated 100% response rate in the 25 subjects enrolled, all of whom experienced exon 53-skipping activity.

Among the other guidance provided by the FDA at the meeting, the Division reported that truncated dystrophin protein in Study 4053-101 may serve as a basis for accelerated approval of golodirsen for the treatment of DMD. The Division also indicated that it is willing to accept a rolling submission of the NDA, but that the complete submission must include data from long-term animal toxicology studies.

SRP-4053 is currently being evaluated in the ESSENCE study; a global, randomized double-blind, placebo-controlled study evaluating safety and efficacy in patients amenable to skipping exons 45 or 53. The Division confirmed that the study could serve as a confirmatory study if the drug is granted accelerated approval. This is, however, with the understanding that it is incumbent upon Sarepta to describe how it will successfully enroll and complete the study considering an accelerated approval.

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