FDA Accepts Sarepta's sNDAs for Casimersen and Golodirsen for Duchenne Muscular Dystrophy

The FDA has accepted Sarepta Therapeutics’ supplemental new drug applications (sNDAs) for casimersen (Amondys 45) and golodirsen (Vyondys 53), 2 exon-skipping therapies indicated for Duchenne muscular dystrophy (DMD), and has assigned a PDUFA target action date of February 28, 2027. The submissions seek conversion of the existing accelerated approvals for both agents to traditional approvals, which will require the FDA to weigh confirmatory phase 3 data that narrowly missed its primary end point alongside an extensive body of real-world evidence.¹

“The FDA’s acceptance of these applications for review is an important step for the Duchenne community. The submissions draw on the ESSENCE study and years of published real-world evidence, which together offer a fuller understanding of how these therapies benefit patients and change the progression of disease,” Louise Rodino‑Klapac, PhD, president of research & development and technical operations at Sarepta, said in a statement.¹ “We look forward to working with the FDA throughout the review.”

ESSENCE Trial Overview

The sNDAs are anchored to data from ESSENCE (NCT02500381), a global, randomized, double-blind, placebo-controlled phase 3 confirmatory study enrolling 228 ambulatory boys with DMD amenable to exon 45 or exon 53 skipping, aged 6 to 13 years. Participants were randomized 2:1 to combined phosphorodiamidate morpholino oligomer (PMO) treatment (casimersen 30 mg/kg or golodirsen 30 mg/kg intravenously once weekly) or placebo over a 96-week double-blind period, followed by a 48-week open-label extension.

The primary end point, the change from baseline in 4-step ascend velocity at week 96, was not met; the observed least-squares mean difference of 0.06 steps per second versus placebo did not reach statistical significance (P = .309). Secondary functional measures, including 6-minute walk test distance and 10-meter walk/run velocity, also did not achieve significance at 96 weeks. However, dystrophin expression by western blot showed a statistically significant mean difference from baseline of 0.69 (unadjusted; P <.001) and 1.25 (muscle-content adjusted; P = .020) at week 96, and dystrophin fiber intensity by immunohistochemistry demonstrated a significant mean difference of 0.023 (P <.001). Through week 144, no new safety signals were reported, and most treatment-emergent adverse events were mild or moderate and resolved without intervention.²

READ MORE: FDA Advisory Committee Schedules Meeting to Review Deramiocel's BLA in Duchenne Muscular Dystrophy

An updated analysis excluding approximately 23 participants (~10% of the intent-to-treat population) whose baseline assessments occurred during the COVID-19 pandemic period, during which Sarepta reported that 43% of affected participants missed consecutive doses, suggested a potentially clinically meaningful slowing of disease progression. A prognostically relevant subgroup analysis further identified a meaningful improvement in 4-step ascend velocity among patients at higher baseline risk of decline.

Clinical Context and Disease Burden

DMD is an X-linked recessive disorder caused by pathogenic variants in the dystrophin gene, occurring in approximately 1 in 3,500 to 5,000 live male births.³ In the absence of functional dystrophin, repeated muscle contraction leads to progressive myonecrosis, with most affected individuals losing ambulation by the early teenage years, followed by respiratory and cardiac decline. The exon 45–53 deletion hotspot accounts for a substantial proportion of DMD mutations; targeted skipping of specific exons, including 45 and 53, is predicted to benefit approximately 47% of all individuals affected by DMD. In that broader group, however, each individual exon-skipping target defines an ultra-rare subpopulation, complicating both trial design and statistical powering.

Drug and Drug-Class Background

Casimersen and golodirsen are PMO antisense oligonucleotides that bind to exon 45 and exon 53 of dystrophin premRNA, respectively, inducing exon exclusion during splicing and enabling production of an internally truncated but partially functional dystrophin protein. Golodirsen received FDA accelerated approval in 2019, and casimersen followed in 2021, both based on demonstrated increases in dystrophin production in skeletal muscle as a surrogate end point. Eteplirsen (Exondys 51), targeting exon 51 skipping, preceded both agents with an accelerated approval in September 2016. Collectively, Sarepta reports that more than 1800 patients worldwide have been treated across its exon-skipping portfolio.⁴

“We appreciate the FDA’s continued willingness to apply regulatory adaptability in addressing the unique challenges of rare disease drug development. The acceptance of these supplemental applications for review reflects both the progress the Duchenne community has made over the past several years and the needs that remain, while maintaining a commitment to evaluating therapies with rigor,” Pat Furlong, president and founder at Parent Project Muscular Dystrophy, said in a statement.¹ “We are grateful for the FDA’s engagement with the Duchenne community and the Agency’s dedication to advancing therapeutic options through pathways adaptable to rare disease.”

REFERENCES
1. Sarepta Announces FDA Acceptance of sNDAs for AMONDYS 45® and VYONDYS 53®. News release. Sarepta Therapeutics. June 30, 2026. Accessed June 30, 2026. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-announces-fda-acceptance-sndas-amondys-45r-and-vyondys
2. Efficacy and Safety of Golodirsen and Casimersen Compared With Placebo in Duchenne Muscular Dystrophy (ESSENCE): Phase 3 Topline Results. Presented at: MDA Clinical & Scientific Conference 2026. Accessed June 30, 2026. https://www.mdaconference.org/abstract-library/efficacy-and-safety-of-golodirsen-and-casimersen-compared-with-placebo-in-duchenne-muscular-dystrophy-essence-phase-3-topline-results/
3. Wang RT, Barthelemy F, Martin AS, et al. DMD genotype correlations from the Duchenne Registry: Endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype. Hum Mutat. 2018;39(9):1193-1202. doi:10.1002/humu.23561
4. Sarepta Therapeutics Announces Third Quarter 2025 Financial Results and Recent Corporate Developments, Including Completion of Its Confirmatory Study, ESSENCE. News release. Sarepta Therapeutics. November 3, 2025. Accessed June 30, 2026. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-third-quarter-2025-financial