Sarepta’s ENDEAVOR Cohort 8 Targets Safer Gene Therapy for Non-Ambulant Duchenne Patients—FDA Approval Sets Stage for Enhanced Immunosuppression Study
FDA Greenlights Innovative Safety Strategy for Non-Ambulant Duchenne Population
Sarepta Therapeutics has just received FDA approval to initiate Cohort 8 of its ENDEAVOR study, marking a significant advance for gene therapy access in Duchenne muscular dystrophy (DMD) patients who have lost the ability to walk. This new cohort aims to assess whether an enhanced immunosuppression regimen—including the drug sirolimus—can reduce the risk of serious liver complications associated with the ELEVIDYS gene therapy. Sarepta expects to begin enrolling approximately 25 U.S. participants before the end of the year.
Addressing Acute Liver Injury: The Need for Enhanced Immunosuppression
ELEVIDYS is the first and only gene therapy currently approved for Duchenne, having been administered to over 1,100 patients globally. However, a known risk of AAV-based gene therapies like ELEVIDYS is acute liver injury (ALI) and, in rare cases, acute liver failure (ALF). The enhanced protocol for Cohort 8 will add sirolimus to standard corticosteroid use, starting 14 days before gene therapy infusion and continuing for 12 weeks after. Primary endpoints are incidence of ALI and the degree of ELEVIDYS-induced dystrophin expression at 12 weeks post-treatment. Sarepta aims to complete initial data collection in the second half of 2026.
| Key Cohort 8 Features | Details |
|---|---|
| Study Name | ENDEAVOR (SRP-9001-103) Cohort 8 |
| Participants | ~25 non-ambulant DMD individuals in U.S. |
| Immunosuppression Regimen | Sirolimus + corticosteroids, starting 14 days before and continuing 12 weeks after ELEVIDYS infusion |
| Primary Endpoints | Incidence of ALI and ELEVIDYS-dystrophin expression at 12 weeks |
| Expected Study Initiation | Before end of 2024 |
| Data Collection Completion | Second half of 2026 |
Balancing Promise with Risk: A Closer Look at ELEVIDYS
The hope behind this approach is to broaden treatment options for non-ambulant Duchenne patients—currently an underserved population—while mitigating safety risks. ELEVIDYS remains available to ambulatory individuals age 4 and older per recent FDA labeling, but the ability to treat those who have lost mobility depends on resolving the liver injury concern. Importantly, acute liver failure, including fatal cases, has occurred in this non-ambulant population both in trials and post-marketing. Other significant risks include serious infections (due to increased immunosuppression), myocarditis, and infusion-related reactions.
| ELEVIDYS Not Recommended For | Reason |
|---|---|
| Preexisting liver impairment or active hepatic viral infection | Increased risk of serious or fatal liver injury |
| Recent vaccination or infection (within 4 weeks) | Potential for safety concerns with immunosuppression |
| Genetic deletions in exon 8 and/or 9 | Contraindicated due to observed adverse outcomes |
| Elevated anti-AAVrh74 antibody titers (≥1:400) | Reduced gene transfer effectiveness |
Why This Matters: Access, Data, and Long-Term Outcomes Remain in Focus
This regulatory step signals ongoing efforts to refine the safety of gene therapies for DMD—an irreversibly progressive and ultimately fatal condition. By piloting enhanced immunosuppression, Sarepta aims not just to minimize liver complications but also to potentially restore commercial access to gene therapy for a broader set of patients, pending FDA review of trial outcomes.
As data emerge from ENDEAVOR Cohort 8, both clinicians and investors will watch closely to see whether this protocol delivers a meaningful safety improvement without undermining efficacy. With enrollment targeted to start by year’s end and topline data expected in 2026, Sarepta’s next moves could reshape the landscape for non-ambulant Duchenne care—and raise important questions about how gene therapies evolve for high-risk populations.
Key Takeaway
Sarepta’s FDA-approved ENDEAVOR Cohort 8 could pave the way for safer, more accessible gene therapy for non-ambulant Duchenne patients, but the road ahead depends on clinical results and regulatory outcomes over the next two years. The focus remains on delivering benefits while rigorously managing risks, with liver safety front and center in the next phase of innovation for Duchenne treatment.
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