Limb-Girdle Gene Therapy Bididistrogene Xeboparvovec Demonstrates 5-Year Safety in Early-Stage Trial

Author(s):

Over the 5-year period, treatment-related adverse events with the gene therapy were mild or moderate, with most occurring within the first 90 days after infusion.

Jerry Mendell, MD

New data from a phase 1/2 trial (NCT03652259) studying bidridistrogene xeboparvovec (Sarepta Therapeutics), an investigational gene therapy for limb-girdle muscular dystrophy 2E/R4 (LGMD2E/R4), showed that the agent was safe for patients, with a profile that was sustained over a 4-to-5-year follow-up. Although it was a small-scale study, most treatment-related treatment-emergent adverse events (TR-TEAEs) occurred within the first 90 days post infusion.¹

Presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19 in Dallas, Texas, the findings comprised 6 patients across 2 cohorts who received a one-time intravenous dose of either 1.85x1013 vg/kg (cohort 1; n = 3) or 7.41x1013 vg/kg (cohort 2; n = 3) of bidridistrogene xeboparvovec. Over the 5-year period, there were 25 TR-TEAEs, most of which were either mild (n = 13) or moderate (n = 10) in severity. TR-TEAEs observed within the first 90 days included vomiting and increased gamma-glutamyltransferase.

Led by neuromuscular expert Jerry Mendell, MD, an advisor to the Jerry R. Mendell Center for Gene Therapy, the study featured patients aged 4 to 15 years with mutations at both alleles and who were negative for antibodies against adeno-associated virus serotype rh74 (rAAVrh74). In the study, the 2 remaining TR-TEAEs that were considered severe were both resolved with clinical care. They included acute liver injury (cohort 1) which was resolved with hospitalization, and dehydration (cohort 2), which was resolved with appropriate care and medication.

Also known as SRP-9003, the gene therapy uses AAVrh74 vector, which is designed to systemically and robustly delivered to skeletal, diaphragm, and cardiac muscles. The agent is designed to deliver a full-length beta-sarcoglycan (SGCB) transgene using the MHCK7 promoter, selected for its strong expression in cardiac tissue. This is particularly significant for individuals with limb-girdle muscular dystrophy Type 2E (LGMD2E), also referred to as beta-sarcoglycanopathy or LGMDR4, as many patients succumb to pulmonary or cardiac complications.

Bidridistrogene xeboparvovec is also currently being evaluated in a phase 3 study, dubbed EMERGENE (NCT0624613), that the company hopes to use for a future biologics license application (BLA) submission for accelerated approval. This multinational, open-label study comprises ambulatory and non-ambulatory patients with LGMD2E/R4, aged 4 and older, using change in the expression of SGCB at 60 days as the primary end point. The trial, which completed enrollment in December 2024, includes several other functional measures and safety objectives through 60 months of dosing.²

To be included in the study, 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 pathogenic beta-sarcoglycan gene mutations, low AAVrh74 antibody titers (<1:400), and be able to cooperate with muscle testing. Exclusions include severe cardiac or respiratory issues, active autoimmune disease, or other significant medical conditions.

Interim data from the phase 1/2 trial was previously published in Nature Medicine in early 2024, with results that showed robust SGCB expression of 36.2% in cohort 1 and 62.1% in cohort 2 at 60 days. Post-hoc exploratory analyses revealed preliminary improvements in motor function, as assessed through the North Star Ambulatory Assessment for Limb-girdle Type Muscular Dystrophies, through year 2. In addition, at 60 days post-treatment serum creatine kinase (CK) levels were reduced in all patients (cohort 1: –92.4%; cohort 2: –94.9%). At 2 years post-treatment, all patients in cohorts 1 and 2 maintained reductions in serum CK levels.³

Over 2 years of follow-up, patients treated with bidridistrogene xeboparvovec showed greater improvements in NSAD scores compared to the natural history cohort. The least-squares mean difference in NSAD score change at Year 2 was 7.3 (95% CI, 0.7–13.9), with an unadjusted mean difference of 8.9 (95% CI, 3.5–14.4). Timed function tests also improved, with least-squares mean differences of −6.2 s (95% CI, −19.6 to 7.1) for the 100-m test and −0.8 s (95% CI, −2.2 to 0.6) for the 10-m test. Unadjusted differences were −8.1 s (95% CI, −22.3 to 6.2) for the 100-m test and −0.1 s (95% CI, −1.2 to 1.0) for the 10-m test.

Click here for more MDA 2025 coverage.

REFERENCES
1. Mendell J, Connolly AM, Sahenk Z, et al. Long-Term Safety of Bidridistrogene Xeboparvovec After 5-Year Follow-up From a Phase 1/2 Trial. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. ABSTRACT P223
2. Sarepta Therapeutics Completes Enrollment in EMERGENE, a Phase 3 Clinical Study of SRP-9003 for the Treatment of Limb-Girdle Muscular Dystrophy Type 2E/R4. News release. Sarepta Therapeutics. December 18, 2024. Accessed March 13, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-completes-enrollment-emergene-phase-3
3. Mendell JR, Pozsgai ER, Lewis S, et al. Gene therapy with bidridistrogene xeboparvovec for limb-girdle muscular dystrophy type 2E/R4: phase 1/2 trial results. Nature Medicine. 2024;30:199-206. doi:10.1038/s41591-023-02730-9