Analysis of vector shedding following treatment with delandistrogene moxeparvovec, an investigational rAAVrh74-based gene therapy for DMD


Clinical Trials

Poster Number: 87


Jyoti Malhotra, Sarepta Therapeutics, Elizabeth (Liz) Smith, Sarepta Therapeutics, Sarah Lewis, Sarepta Therapeutics, Inc., Xiaolan Zhang, Sarepta Therapeutics, Inc., Damon Asher, Sarepta Therapeutics, Inc., Shufang Wang, Sarepta Therapeutics, Inc., Lilly East, Sarepta Therapeutics, Rachael Potter, Sarepta Therapeutics, Inc., Louise Rodino-Klapac, PhD, Sarepta Therapeutics, Inc.

Background: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy developed to address the root cause of Duchenne muscular dystrophy (DMD) through targeted skeletal and cardiac muscle expression of SRP-9001 dystrophin protein, which contains key functional domains of dystrophin. The hypothetical risk of seroconversion in treatment-naïve individuals through exposure to vector shed from treated patients is a point for healthcare providers and the Duchenne community to consider.

Objective: To evaluate the extent and magnitude of vector shedding following delandistrogene moxeparvovec administration.

Methods: We evaluated the extent of vector shedding and clearance following a single administration of delandistrogene moxeparvovec (1.33×1014 vg/kg body weight) in ENDEAVOR (NCT04626674; Study 103; N=20), a Phase 1 study in patients with DMD. Delandistrogene moxeparvovec vector exposure in saliva, urine, and feces was quantified by droplet digital polymerase chain reaction. In a nonclinical study, we tested naïve mice to determine the risk of AAVrh74 seroconversion following mucosal vector exposure, with doses based on exposure levels (vector genome copies) demonstrated in nonclinical and clinical studies. Mice were exposed to AAVrh74.CMV.eGFP via optic exposure and intramuscularly. Antibody levels were measured by AAVrh74 ELISA at baseline and 4 weeks post-delivery.

Results: Following treatment in ENDEAVOR, the percentage decrease in amount of vector shed was >99% in saliva (n=12), urine (n=18), and feces (n=11) by Week 4. In mice, topical optical delivery of the AAVrh74 vector at relevant concentrations did not produce seropositivity or detectable vector genomes throughout tissues at doses based on clinical vector shedding levels.

Conclusions: Clinical findings show that peak vector shedding occurs in the first few days after delandistrogene moxeparvovec administration and exponentially declines to insignificant levels by Week 4. In mice, seroconversion was not observed by relevant exposure route at relevant concentrations. Results suggest that the risk of seroconversion following exposure to vector shed by individuals treated with AAVrh74-based gene therapy may be very low.

This study was sponsored by Sarepta Therapeutics and funded by Sarepta Therapeutics and F. Hoffmann-La Roche Ltd.