Safety, ?-Sarcoglycan Expression, and Functional Outcomes From Systemic Gene Transfer of rAAVrh74.MHCK7.hSGCB in LGMD2E/R4

Clinical Trials
62
Louise R Rodino-Klapac, PhD, Sarepta Therapeutics, Inc.
Eric R Pozsgai, Sarepta Therapeutics, Inc.
Sarah Lewis, Sarepta Therapeutics, Inc.
Danielle Griffin, Sarepta Therapeutics, Inc.
Aaron S Meadows, Sarepta Therapeutics, Inc.
Kelly J Lehman, APN, Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital
Kathleen Church, MSW, CCRP, Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital
Natalie Reash, DPT, The Abigail Wexner Research Institute at Nationwide Children's Hospital
Megan Iammarino, DPT, The Abigail Wexner Research Institute at Nationwide Children's Hospital
Brenna Powers, Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital
Lindsay Alfano, DPT, PCS, The Abigail Wexner Research Institute at Nationwide Children's Hospital
Linda Lowes, PhD, Abigail Wexner Research Institute at Nationwide Children's Hospital
Erica Koenig, Sarepta Therapeutics, Inc.
Sarah Neuhaus, Sarepta Therapeutics, Inc.
Xiaoxi Li, Sarepta Therapeutics, Inc.
Jerry Mendell, MD, Nationwide Children’s Hospital

Background: Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is caused by mutations in the ?-sarcoglycan gene (SGCB), resulting in loss of SGCB protein and, subsequently, an absence of the dystrophin-associated protein complex (DAPC) at the sarcolemma. LGMD 2E/R4 manifests as progressive hip/shoulder muscle weakness.
Objective: This first-in-human, phase 1/2 trial (NCT03652259) evaluated SRP-9003, a self-complementary rAAVrh74.MHCK7.hSGCB construct designed to restore SGCB protein production.
Methods: Patients aged 4–15 years with SGCB mutation (both alleles) received 1 SRP-9003 IV infusion: Cohort 1 (n=3), 1.85×10^13 vg/kg; Cohort 2 (n=3), 7.41×10^13 vg/kg. Endpoints included safety (primary), SGCB protein expression (secondary), and function (North Star Assessment for Limb-girdle Type Muscular Dystrophies [NSAD], time to rise [TTR], 4-stair climb [4-sc], 100-meter timed test [100m], 10-meter timed test [10m]).
Results: Previously reported results: Year 1 (Y1) for Cohort 2 and Year 2 (Y2) for Cohort 1 showed that as of January 2021, SRP-9003 was well tolerated; adverse events occurred early and were manageable. Immunofluorescence showed robust SGCB expression and correct sarcolemmal localization post treatment, leading to DAPC reconstitution, maintained to Y2 (Cohort 1). SRP-9003–treated patients showed functional improvements, maintained at Y2 in Cohort 1 (NSAD, +5.7 points; TTR, -0.6 s; 4-sc, -0.3 s; 100m, -2.8 s; 10m, -0.2 s) and Y1 in Cohort 2 (NSAD, +4 points; TTR, -1.1 s; 4-sc, -0.4 s; 100m, -7.9 s; 10m, -0.6 s). Post hoc analysis showed improved NSAD outcomes versus untreated natural history cohort (9.2-point difference, Y2; 95% CI, 3.2?15.1). An update with 3-year functional data for Cohort 1 and 2-year protein expression and functional data for Cohort 2 will be presented.
Conclusions: These data suggest long-term efficacy of SRP-9003 therapy, supporting advancement of the clinical development program.