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Sarepta seeks full approval for exon-skipping DMD drugs after failed confirmatory trial, testing FDA flexibility on surrogate endpoint evidence
Sarepta Therapeutics has disclosed plans to request full FDA approval for two exon-skipping Duchenne muscular dystrophy therapies despite a failed confirmatory clinical study, after the agency indicated it would be open to receiving such a filing, according to Endpoints News. The two drugs are casimersen (AMONDYS 45, exon 45) and golodirsen (VYONDYS 53, exon 53), both of which received accelerated approval based on dystrophin expression as a surrogate endpoint, with full approval contingent on demonstrating clinical benefit in the Phase 3 ESSENCE confirmatory trial. That study, which completed in Q3 2025, did not reach statistical significance on its primary endpoint (4-stair ascend velocity at 96 weeks, p=0.309), as reported by Endpoints News. FDA openness to a full approval filing despite this result suggests the agency may be weighing the totality of real-world evidence and the limited treatment alternatives available to this patient population. The FDA faces institutional pressure to enforce confirmatory study requirements more rigorously under FDORA (enacted December 29, 2022), making Sarepta's situation a closely watched test case. If the agency accepts the filing and ultimately grants full approval, it could influence how other sponsors of accelerated approvals in ultra-rare settings structure their confirmatory evidence packages and engage with regulators when primary endpoints are not met.
Pipeline Watch
A National Human Genome Research Institute study focused on diagnosis and treatment of inborn errors of metabolism is actively recruiting, with arterial calcification due to CD73 deficiency among listed conditions, per ClinicalTrials.gov. CD73 deficiency is an ultra-rare autosomal recessive disorder with limited published natural history data. NHGRI participation signals ongoing federal investment in characterizing and potentially treating conditions that may eventually become gene therapy targets as delivery platforms mature.
An NCI-sponsored anti-CD22 chimeric antigen receptor T-cell study targeting recurrent or refractory CD22-expressing B-cell malignancies in pediatric and young adult patients has reached completed status, according to ClinicalTrials.gov. CD22-directed CAR-T remains an area of interest given CD19 antigen escape as a resistance mechanism. Completed NCI data, once published, could inform commercial CAR-T developers assessing dual-targeting or sequential antigen strategies for pediatric hematologic malignancies.
A Phase 1/2a open-label trial sponsored by 4D Molecular Therapeutics is actively recruiting adults with Fabry disease and cardiac involvement to evaluate the AAV-based gene therapy 4D-310, per ClinicalTrials.gov. The trial (NCT05629559) is enrolling up to 18 participants across four sites, with a primary completion date of June 2026. Fabry disease is an X-linked lysosomal storage disorder affecting an estimated 1 in 40,000 to 60,000 males, and current standard of care relies on chronic enzyme replacement therapy. A successful gene therapy could offer a one-time alternative, positioning 4D Molecular against Sanofi's established ERT franchise and uniQure's competing AAV5-GLA program (AMT-191), which entered Phase 1/2 in mid-2024.
Competitive Landscape
If exon-skipping drugs casimersen and golodirsen receive full approval, payers and clinicians will face a more complex DMD sequencing question alongside ELEVIDYS. Full approval would strengthen reimbursement positioning for exon-skipping therapies in the exon 45 and exon 53 populations, potentially affecting patient flow toward the one-time gene therapy option priced at approximately $3.2 million (Sarepta WAC).
| Therapy | Modality | Approval Status | Approx Annual or One-Time Cost |
|---|---|---|---|
| Casimersen (AMONDYS 45) | Exon 45-skipping ASO | Accelerated (sNDA for full pending) | ~$300K/yr (Sarepta WAC) |
| Golodirsen (VYONDYS 53) | Exon 53-skipping ASO | Accelerated (sNDA for full pending) | ~$300K/yr (Sarepta WAC) |
| ELEVIDYS (delandistrogene moxeparvovec) | Gene therapy (AAV) | Traditional approval, ambulatory only (Jun 2024); non-ambulatory indication withdrawn | ~$3.2M one-time (Sarepta WAC) |
The FDA's willingness to accept a full approval filing from Sarepta despite the ESSENCE trial's failure to meet its primary endpoint raises questions about how the agency is applying enforcement provisions mandated by FDORA (enacted December 29, 2022). Sponsors across rare neuromuscular and metabolic disease programs with accelerated approvals will be watching whether clinical context and treatment scarcity can substitute for missing confirmatory efficacy data.
Federal natural history and diagnostic programs for conditions such as CD73 deficiency arterial calcification tend to precede commercial therapeutic development by a decade or more. Academic data generated through NHGRI studies often seeds investigator-initiated gene therapy programs that later attract industry licensing interest, particularly as AAV and mRNA delivery platforms expand to metabolic targets.
With the NCI anti-CD22 CAR-T study completed, published data could inform commercial developers including those with bispecific CD19/CD22 programs. Pediatric B-cell malignancies represent a rare disease segment where antigen escape drives clinical unmet need, and CD22 data from an academic setting may accelerate IND discussions for next-generation constructs.
Forward Looking
- Sarepta indicated it intends to submit sNDAs for casimersen and golodirsen by end of April 2026; watch for FDA filing acceptance decision and review division commentary, which will signal how broadly the agency applies FDORA confirmatory study flexibility to other rare disease accelerated approvals.
- Publication of NCI anti-CD22 CAR-T pediatric trial (NCT02315612) data, expected in 2026, is a catalyst for commercial developers assessing dual-antigen or sequential targeting strategies in relapsed or refractory pediatric B-cell malignancies where CD19 escape limits current options.
- NHGRI inborn errors of metabolism recruitment progress for CD73 deficiency and related conditions warrants monitoring by gene therapy developers building metabolic disease pipelines, as natural history data is a prerequisite for IND-enabling work.
- 4D Molecular Therapeutics' Fabry disease gene therapy trial (NCT05629559) has a primary completion date of June 2026; initial safety and efficacy readouts could reshape the competitive landscape against established enzyme replacement therapies.
- Payer response to potential full approval of Sarepta exon-skipping drugs remains an open question; outcomes-based contract structures already in place for ELEVIDYS may extend to antisense oligonucleotide therapies if approval is granted.