Long-Term Safety of Bidridistrogene Xeboparvovec After 5-Year Follow-up From a Phase 1/2 Trial

Topic:

Clinical Trials

Poster Number: P223

Author(s):

Jerry Mendell, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Anne M. Connolly, MD, Nationwide Children’s Hospital, Columbus, Ohio, USA, Zarife Sahenk, Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, USA, Linda Cripe, MD, Nationwide Children's, Kan Hor, MD, Nationwide Children's Hospital and The Ohio State University, Emily Branic, FNP, Nationwide Children’s Hospital, Wenhua Hu, PhD, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Herb Stevenson, MD, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Pierre Lebahar, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Louise R Rodino-Klapac, PhD, Sarepta Therapeutics, Inc., Cambridge, MA, USA

Background: Limb-girdle muscular dystrophy 2E/R4 (LGMD2E/R4) is caused by mutations in the β-sarcoglycan ( ) gene, leading to SGCB deficiency and consequent muscle loss. Bidridistrogene xeboparvovec, a recombinant adeno-associated virus serotype rh74 (rAAVrh74) vector containing the transgene, is designed to deliver to skeletal and cardiac muscle of subjects with confirmed diagnosis of LGMD2E/R4. Here we report long-term safety over a 5-year follow-up from a phase 1/2 study of bidridistrogene xeboparvovec (NCT03652259, SRP-9003-101).
Methods: Patients aged 4 to 15 years with mutations at both alleles were eligible to enroll. At baseline, all patients were negative for antibodies against AAVrh74 and scored ≥40% of normal on the 100-meter timed test. Patients received bidridistrogene xeboparvovec as a single one-time intravenous dose of 1.85×10¹³ vg/kg (cohort 1) or 7.41×10¹³ vg/kg (cohort 2). The primary endpoint was to evaluate safety of bidridistrogene xeboparvovec.
Results: Six ambulant patients across 2 cohorts were treated as of April 2024. Cohort 1 (n=3) mean (SD) age at baseline was 10.0 (5.20) years and 33% (n=1) of patients were male. Cohort 2 (n=3) mean (SD) age was 10.0 (1.73) years and 67% (n=2) were male. Among the 25 treatment-related treatment-emergent adverse events (TR-TEAEs), the majority were mild (13 of 25) or moderate (10 of 25) in severity, and 2 (of 25) were severe. The most common TR-TEAEs (≥10%) occurred within 90 days post infusion and included vomiting and increased gamma-glutamyltransferase. All TR-TEAEs resolved with clinical care and conservative management and did not recur. The 2 severe (Grade 3) TR-TEAEs resolved with clinical care: acute liver injury (cohort 1) resolved with hospitalization, and dehydration (cohort 2) resolved with appropriate care and medication.
Conclusions: Patients treated with bidridistrogene xeboparvovec demonstrated a safety profile that was favorable and sustained over 4- to 5-year follow-up, with the majority of TR-TEAEs occurring within 90 days post infusion. Further confirmation is needed with larger sample sizes from pivotal studies.