Expression of SGCA and Safety Following Treatment With Patidistrogene Bexoparvovec in Patients With LGMD2D/R3: Results From a Phase 1b Study

Topic:

Clinical Trials

Poster Number: 319 T

Author(s):

Anne Connolly, MD, Nationwide Children’s Hospital, Columbus, Ohio, USA , Crystal Proud, MD, Children’s Hospital of the King’s Daughters, Norfolk, VA, USA, Kyle Cochran, MS, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Tao Feng, PhD, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Jen Ahner, PhD, Sarepta Therapeutics, Joy Haugh, BSN, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Nikki Larter, PhD, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Stephen Baine, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Louise R. Rodino-Klapac, PhD, Sarepta Therapeutics, Inc., Cambridge, MA, USA

Background: Limb-girdle muscular dystrophy subtype 2D/R3 (LGMD2D/R3), caused by pathogenic variants in the α-sarcoglycan ( ) gene, leads to progressive muscle loss. Patidistrogene bexoparvovec (SRP-9004) is an investigational rAAVrh74-based gene therapy designed to deliver full-length transgene and optimally express functional α-sarcoglycan protein (α-SG) in patients diagnosed with LGMD2D/R3.
Objectives: To report 60-day α-SG expression and 90-day safety findings from the phase 1b, multi-site, open-label DISCOVERY trial (NCT01976091).
Methods: Eligible male or female patients received an infusion of 7.41 × 10¹³ vg/kg. The primary endpoint was safety; secondary endpoints included day 60 transgene transduction and α-SG expression by percent positive fibers (PPF) and western assay. Mean (SD) change in creatine kinase (CK) levels was also analyzed.
Results: Four patients aged 11 to 51 years were enrolled (ambulatory: n=3, mean age, 11 years, mean (SD) weight, 51.8 (15.7) kg; non-ambulatory: n=1, age 51 years, weight, 68.9 kg). There were 2 treatment-related serious adverse events (AEs): 1 ambulatory 11-year-old patient with grade 3 (severe) hepatotoxicity, which resolved with corticosteroids, and 1 non-ambulatory 51-year-old patient with grade 5 (fatal) acute hepatic failure 77 days after dosing. At 60 days, all patients had mostly mild to moderate treatment-related treatment-emergent AEs, including nausea, fatigue, hepatotoxicity, and increased transaminases. In the 3 ambulatory patients, these mostly resolved within 90 days of onset. Overall α-SG expression was consistent at day 60 (N=4): mean (SD) change in PPF was 15.6% (13.2%) and 14.7% (15.4%) for western assay. Delivery of transgene increased membrane colocalization of α- and γ-sarcoglycan subunits indicating sarcoglycan complex restoration within the dystrophin-associated protein complex (DAPC). CK levels were reduced by 53.1% (36.0%) from baseline to day 90.
Conclusions: Expression of full-length α-SG, restoration of the DAPC, and CK reduction levels indicate patidistrogene bexoparvovec elicits a biological cascade in muscle likely to lead to clinical benefit. The fatal acute hepatic failure event in this trial was similar to other fatal events observed with AAV-based gene therapy across multiple indications. Such events serve as a reminder of the need for regular hepatic monitoring following gene therapy administration. The SRP-9004 program is currently paused.