Analysis of Vector Shedding Following Treatment with Delandistrogene Moxeparvovec (SRP-9001), an Investigational rAAVrh74-Based Gene Therapy for Duchenne Muscular Dystrophy (DMD) (P5-8.013)

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Objective: To evaluate extent and magnitude of vector shedding following delandistrogene moxeparvovec (SRP-9001) administration. Background: Delandistrogene moxeparvovec is an investigational gene transfer therapy developed to address the root cause of 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 naive individuals through exposure to vector shed from treated patients is a point to consider for healthcare providers and the Duchenne community. Design/Methods: We evaluated 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 naive mice to determine 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. Disclosure: Jyoti Malhotra has nothing to disclose. Dr. Smith has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc. Dr. Smith has stock in Sarepta Therapeutics. Sarah Lewis has received stock or an ownership interest from Sarepta. Mrs. Zhang has nothing to disclose. Mr. Asher has received personal compensation for serving as an employee of Sarepta Therapeutics. Mr. Asher has stock in Sarepta Therapeutics. Shufang Wang has received personal compensation for serving as an employee of Sarepta Therapeutics INC. Shufang Wang has received stock or an ownership interest from Sarepta Therapeutics INC. Mrs. East has received personal compensation for serving as an employee of Sarepta Therapeutics. Rachael Potter has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc.. Ms. Rodino-Klapac has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received intellectual property interests from a discovery or technology relating to health care.

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