Safety and efficacy of pre-treatment with imlifidase prior to AAV-based gene therapy in non-human primates with pre-existing anti-AAVrh74 antibodies

Delandistrogene moxeparvovec (SRP-9001) is an investigational rAAV vector-based gene therapy (GT), designed to compensate for missing dystrophin in Duchenne muscular dystrophy by delivering a transgene, via an AAV vector (AAVrh74), that encodes SRP-9001 dystrophin, an engineered dystrophin protein that retains key functional domains of the wild-type protein. Anti-AAV antibodies may impact GT safety and efficacy, precluding use in otherwise eligible patients. We assessed the ability of imlifidase, an endopeptidase that cleaves IgG, to lower anti-AAVrh74 antibodies. This was a two-part study in female cynomolgus monkeys. Part 1: single (Day 1) or once-daily (QD) dose (Days 1–14) of oral prednisolone (1 mg/kg/day) and IV imlifidase (10 mg/kg/dose, Day 1) followed by IV AAVrh74.CMV.eGFP (1.33x10¹⁴ vg/kg/dose, Day 3) in both anti-AAVrh74 antibody-negative and -positive animals. Part 2: QD prednisolone (Days 1–62 or Days 1–96) and single (Day 1) or repeated (Days 1 and 36) imlifidase or saline control and/or AAVrh74.CMV.eGFP (Day 3 or Days 3 and 38). Animals were observed for ≥59 days. We assessed biodistribution, eGFP expression, immunologic responses, histopathology, and imlifidase PK/PD. Imlifidase dosing prior to AAVrh74-eGFP in anti-AAVrh74 antibody-seropositive animals (titer range: 1:800–1:1600) decreased the anti-AAVrh74 antibody response. The decrease resulted in efficient transduction (measured by droplet digital PCR) and expression (measured by immunofluorescent quantification) of AAVrh74.CMV.eGFP relative to animals with the same antibody titers that did not receive imlifidase. No adverse events or deaths occurred after GT dosing. No imlifidase-related adverse immuno-toxicologic or histopathologic findings were found. Imlifidase lowered anti-AAVrh74 total antibody titers, allowing for safe administration of AAV-based GT in seropositive animals. These findings may help enable treatment in people currently excluded due to pre-existing antibodies against AAVrh74. Delandistrogene moxeparvovec (SRP-9001) is an investigational rAAV vector-based gene therapy (GT), designed to compensate for missing dystrophin in Duchenne muscular dystrophy by delivering a transgene, via an AAV vector (AAVrh74), that encodes SRP-9001 dystrophin, an engineered dystrophin protein that retains key functional domains of the wild-type protein. Anti-AAV antibodies may impact GT safety and efficacy, precluding use in otherwise eligible patients. We assessed the ability of imlifidase, an endopeptidase that cleaves IgG, to lower anti-AAVrh74 antibodies. This was a two-part study in female cynomolgus monkeys. Part 1: single (Day 1) or once-daily (QD) dose (Days 1–14) of oral prednisolone (1 mg/kg/day) and IV imlifidase (10 mg/kg/dose, Day 1) followed by IV AAVrh74.CMV.eGFP (1.33x10¹⁴ vg/kg/dose, Day 3) in both anti-AAVrh74 antibody-negative and -positive animals. Part 2: QD prednisolone (Days 1–62 or Days 1–96) and single (Day 1) or repeated (Days 1 and 36) imlifidase or saline control and/or AAVrh74.CMV.eGFP (Day 3 or Days 3 and 38). Animals were observed for ≥59 days. We assessed biodistribution, eGFP expression, immunologic responses, histopathology, and imlifidase PK/PD. Imlifidase dosing prior to AAVrh74-eGFP in anti-AAVrh74 antibody-seropositive animals (titer range: 1:800–1:1600) decreased the anti-AAVrh74 antibody response. The decrease resulted in efficient transduction (measured by droplet digital PCR) and expression (measured by immunofluorescent quantification) of AAVrh74.CMV.eGFP relative to animals with the same antibody titers that did not receive imlifidase. No adverse events or deaths occurred after GT dosing. No imlifidase-related adverse immuno-toxicologic or histopathologic findings were found. Imlifidase lowered anti-AAVrh74 total antibody titers, allowing for safe administration of AAV-based GT in seropositive animals. These findings may help enable treatment in people currently excluded due to pre-existing antibodies against AAVrh74.