Pharmacokinetic and Pharmacodynamic Evaluation of Bidridistrogene Xeboparvovec in an Aged Murine Model of Limb-Girdle Muscular Dystrophy Type 2E/R4.

Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is an ultra-rare autosomal recessive disorder caused by mutations in SGCB, the gene that encodes for β-sarcoglycan (SGCB), a component of the dystrophin-associated protein complex that stabilizes muscle fibers during contractions. Bidridistrogene xeboparvovec is an investigational adeno-associated virus-mediated gene transfer therapy designed to deliver a codon-optimized, full-length human SGCB and induce targeted expression of functional human SGCB protein. Interim safety and efficacy data from a clinical trial in patients with LGDM2E/R4 aged 4-15 years (NCT03652259) support further clinical development of bidridistrogene xeboparvovec. However, less is known about the effects of this agent in patients with more advanced LGMD2E/R4, who on average are older and heavier, which prompted their inclusion in studies VOYAGENE (NCT05876780, phase 1) and EMERGENE (NCT06246513, phase 3). In the preclinical study presented here, we delivered bidridistrogene xeboparvovec (0.185 × 1013 vg/kg, 0.37 × 1013 vg/kg, 0.74 × 1013 vg/kg, 1.85 × 1013 vg/kg, or 7.4 × 1013 vg/kg) to Sgcb-/- mice aged 27-42 weeks (n = 4 per dose) with age-matched saline-treated Sgcb-/- and C57BL/6J mice used as controls. Approximately 12 weeks after administration, we observed SGCB expression and found evidence of reduction in muscle fibrosis, reduction in muscle damage, and restoration of muscle force. Overall, a dose-dependent increase in vector exposure across tissue types was observed, with a nonlinear, exposure-dependent increase in both SGCB expression and functional improvement that reached saturation at 7.4 × 1013 vg/kg. Pharmacokinetic and pharmacodynamic analyses demonstrated a robust relationship between vector biodistribution, SGCB expression, and muscle force, further supporting clinical development of bidridistrogene xeboparvovec at the highest dose (7.4 × 1013 vg/kg), across a broad LGMD2E/R4 population and regardless of disease progression.