Data presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference revealed that Sarepta Therapeutics' investigational gene therapy for limb-girdle muscular dystrophy (LGMD) maintained a favorable safety profile over a 4-to-5-year follow-up period.
The phase 1/2 trial (NCT03652259) evaluated bidridistrogene xeboparvovec (SRP-9003) in six pediatric patients with LGMD2E/R4, also known as beta-sarcoglycanopathy. Patients received a one-time intravenous infusion of the gene therapy at either a low dose (1.85×10¹³ vg/kg) or high dose (7.41×10¹³ vg/kg), with three patients in each cohort.
Long-Term Safety Data Demonstrates Favorable Profile
Over the 5-year observation period, researchers documented 25 treatment-related treatment-emergent adverse events (TR-TEAEs), with the majority occurring within the first 90 days after infusion. Most adverse events were classified as mild (13) or moderate (10) in severity.
Early post-infusion TR-TEAEs included vomiting and increased gamma-glutamyltransferase levels. Only two severe TR-TEAEs were reported: one case of acute liver injury in the low-dose cohort, which resolved with hospitalization, and one case of dehydration in the high-dose cohort, which resolved with appropriate care and medication.
The study, led by neuromuscular expert Dr. Jerry Mendell, advisor to the Jerry R. Mendell Center for Gene Therapy, enrolled patients aged 4 to 15 years with mutations in both alleles of the beta-sarcoglycan gene and who tested negative for antibodies against adeno-associated virus serotype rh74 (rAAVrh74).
Mechanism of Action and Clinical Significance
Bidridistrogene xeboparvovec utilizes an AAVrh74 vector designed to deliver a full-length beta-sarcoglycan (SGCB) transgene throughout the body, targeting skeletal, diaphragm, and cardiac muscles. The therapy employs the MHCK7 promoter, specifically selected for its strong expression in cardiac tissue.
This cardiac focus is particularly important for LGMD2E/R4 patients, as many ultimately succumb to pulmonary or cardiac complications. The disease is characterized by progressive muscle weakness affecting the hip, shoulder, and proximal limb muscles, with varying rates of progression.
"The sustained safety profile over nearly five years is encouraging for this patient population that currently has no approved disease-modifying treatments," said Dr. Mendell in the presentation. "The data continue to support further clinical development of this promising therapy."
Efficacy Signals and Functional Improvements
Interim efficacy data from the trial, previously published in Nature Medicine earlier this year, demonstrated robust SGCB protein expression at 60 days post-treatment: 36.2% in the low-dose cohort and 62.1% in the high-dose cohort.
All treated patients showed substantial reductions in serum creatine kinase (CK) levels, a biomarker of muscle damage, with decreases of 92.4% in the low-dose cohort and 94.9% in the high-dose cohort at 60 days. These reductions were maintained through two years of follow-up.
Post-hoc exploratory analyses revealed preliminary improvements in motor function as measured by the North Star Ambulatory Assessment for Limb-girdle Type Muscular Dystrophies (NSAD). Over two years, patients treated with bidridistrogene xeboparvovec showed greater improvements in NSAD scores compared to natural history cohorts, with a least-squares mean difference of 7.3 points (95% CI, 0.7–13.9).
Timed function tests also showed improvements, with treated patients demonstrating better performance in both 100-meter and 10-meter walk tests compared to natural history controls.
Advancing to Phase 3 and Regulatory Pathway
Based on these promising results, Sarepta Therapeutics is currently conducting EMERGENE (NCT0624613), a phase 3 multinational, open-label study that completed enrollment in December 2024. This pivotal trial includes both ambulatory and non-ambulatory LGMD2E/R4 patients aged 4 and older.
The primary endpoint is change in SGCB expression at 60 days post-treatment, with multiple secondary functional measures and safety objectives being tracked through 60 months. Sarepta intends to use data from this trial to support a future Biologics License Application (BLA) submission for accelerated approval.
The EMERGENE trial has specific inclusion criteria: ambulatory participants must walk unaided, complete a 10-meter walk test in under 30 seconds, and have an NSAD score of at least 25. Non-ambulatory participants must complete the walk test in 30 seconds or more (or be unable to perform it) and have a PUL 2.0 score of at least 3.
All participants must have confirmed pathogenic beta-sarcoglycan gene mutations, low AAVrh74 antibody titers (<1:400), and be able to cooperate with muscle testing. Patients with severe cardiac or respiratory issues, active autoimmune disease, or other significant medical conditions are excluded.
Treatment Landscape and Unmet Need
LGMD2E/R4 is a rare, autosomal recessive form of limb-girdle muscular dystrophy caused by mutations in the SGCB gene, which encodes the beta-sarcoglycan protein. This protein is a critical component of the sarcoglycan complex that helps stabilize muscle fibers.
Currently, there are no approved disease-modifying treatments for LGMD2E/R4, with management focused on supportive care, physical therapy, and addressing complications. The progressive nature of the disease often leads to loss of ambulation in adolescence or early adulthood, with cardiac and respiratory complications being major contributors to morbidity and mortality.
If approved, bidridistrogene xeboparvovec would represent a significant advancement in treatment options for patients with this devastating condition, potentially altering the disease course by addressing the underlying genetic cause rather than just managing symptoms.
