Analysis of Vector Shedding Following Treatment with Delandistrogene Moxeparvovec (SRP-9001), an Investigational rAAVrh74-Based Gene Therapy for Duchenne Muscular Dystrophy (DMD)
Jyoti Malhotra1, Elizabeth Smith1, Sarah Lewis1, Xiaolan Zhang1, Damon Asher1, Shufang Wang1, Lilly East1, Rachael Potter1, Louise Rodino-Klapac1
1Sarepta Therapeutics, Inc.
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.