Sarepta Receives FDA Approval for Enhanced ELEVIDYS Gene Therapy Trial in Non-Ambulatory Duchenne Patients
Key Insights
Sarepta Therapeutics received FDA approval to begin ENDEAVOR Cohort 8, evaluating an enhanced immunosuppression regimen with sirolimus for ELEVIDYS gene therapy in non-ambulatory Duchenne muscular dystrophy (search) patients.
The study will enroll approximately 25 non-ambulatory participants and aims to mitigate acute liver injury (search) risks associated with AAV gene therapy through 14 days of peri-infusion sirolimus dosing plus 12 weeks post-treatment.
Primary endpoints include incidence of acute liver injury (search) and ELEVIDYS-dystrophin expression at 12 weeks, with data collection expected to complete in the second half of 2026.
Sarepta Therapeutics has received U.S. Food and Drug Administration approval to initiate Cohort 8 of its ENDEAVOR study, marking a significant step toward addressing safety concerns that have limited access to ELEVIDYS gene therapy for non-ambulatory patients with Duchenne muscular dystrophy (search). The new cohort will evaluate whether an enhanced immunosuppression regimen incorporating sirolimus can reduce the risk of acute liver injury (search) associated with AAV-based gene therapy.
Enhanced Immunosuppression Protocol
The ENDEAVOR Cohort 8 study will enroll approximately 25 non-ambulatory participants in the United States, with enrollment expected to begin before the end of 2025. The enhanced immunosuppression regimen includes 14 days of peri-infusion sirolimus dosing prior to ELEVIDYS administration, continuing for 12 weeks after treatment. This approach represents a significant modification from previous protocols and is designed specifically to mitigate acute liver injury (search) (ALI) and acute liver failure (search) (ALF) risks.
"We remain deeply committed to serving all individuals living with Duchenne, including those who have lost the ability to walk," said Louise Rodino-Klapac, Ph.D., president of research & development and technical operations at Sarepta. "Guided by real-world experience, external clinician expertise, and FDA input, Cohort 8 of the ENDEAVOR study will evaluate integrating sirolimus into our immunosuppression approach, with the goals of mitigating the risk of acute liver injury (search) and restoring access for non-ambulant individuals living with Duchenne."
Study Design and Endpoints
The primary endpoints for Cohort 8 include the incidence of acute liver injury (search) and ELEVIDYS-dystrophin expression at 12 weeks. The approach is based on preclinical data and shaped by real-world clinical experience, including guidance from independent specialists in Duchenne and liver health. Pending enrollment, the company expects to complete primary endpoint data collection in the second half of 2026.
The ENDEAVOR study (Study SRP-9001-103) is an open-label, Phase 1b study that has enrolled 55 participants across seven previous cohorts, dosing younger ambulatory individuals aged 2-7 at time of treatment, older ambulant individuals, and non-ambulant individuals. The primary endpoint across the study is the change from baseline in the quantity of ELEVIDYS micro-dystrophin protein (search) expression measured by western blot at 12 weeks.
Safety Considerations and Current Status
ELEVIDYS carries a boxed warning for acute serious liver injury and acute liver failure (search), with onset typically beginning within 8 weeks of administration. In non-ambulatory patients treated with ELEVIDYS, acute liver failure with fatal outcomes has occurred in both clinical and post-marketing settings. Life-threatening mesenteric vein thrombosis, complicated by bowel ischemia and necrosis, and portal hypertension have been reported following acute liver injury (search) in a non-ambulatory patient.
The therapy is currently indicated for ambulatory patients 4 years of age and older with Duchenne muscular dystrophy (search) who have a confirmed mutation in the DMD gene (search). ELEVIDYS is the only approved gene therapy for Duchenne and has been administered to over 1,100 patients globally in clinical and real-world settings.
Regulatory Path Forward
Decisions regarding resuming commercial dosing for the non-ambulatory population will be made in collaboration with the FDA after reviewing study data from Cohort 8. The company continues to work closely with the FDA to ensure that all regulatory decisions are grounded in science and the best interests of patients facing this rare, irreversibly progressive and ultimately fatal disease.
ELEVIDYS (delandistrogene moxeparvovec-rokl (search)) is a single-dose, adeno-associated virus (AAV)-based gene transfer therapy designed to address the underlying genetic cause of Duchenne muscular dystrophy (search) through delivery of a transgene that codes for targeted production of ELEVIDYS micro-dystrophin in skeletal muscle. The therapy addresses mutations or changes in the DMD gene (search) that result in the lack of dystrophin protein (search).