VTX-PID as a novel recombinant immunoglobulin G-degrading enzyme (IdeS) for efficient AAV-based gene therapy in participants with neutralizing antibodies: results of the phase I first-in-human NAVIgATE study.

Introduction: Pre-existing anti-adeno-associated virus (AAV) neutralizing antibodies (NAbs) can impair AAV-mediated gene delivery. VTX-PID (imlifidase) is a streptococcal protease that specifically cleaves immunoglobulin G (IgG) antibodies. NAVIgATE was a first-in-human study of VTX-PID. Methods: This double-blind controlled study (EUCT number: 2023-503892-83-00) randomized 35 healthy men, stratified by baseline anti-AAV3B NAb levels (intermediate [≤ 1:45] or high [>1:45]) to receive ascending VTX-PID doses (0.075-0.6 mg/kg) or placebo. The primary endpoint was safety. Key secondary endpoints included levels of anti-AAV3B NAbs and total antibodies (TAbs). Results: VTX-PID resulted in substantial reductions in total IgG, undigested IgG, anti-AAV3B TAb and NAb levels across all doses, followed by gradual full recovery, with effects being sustained longer (2-5 days) at the highest doses. All participants with intermediate NAb levels achieved durable noninhibitory NAb levels (titer ≤1:5), while those with high NAb levels showed reduction but did not reach the noninhibitory level. Most participants experienced VTX-PID-related treatment-emergent adverse events, primarily musculoskeletal complaints of predominately mild to moderate intensity and fully reversible. Transient mild to moderate infusion-associated reactions occurred in four participants, and reversible liver function test elevations in three. Discussion: VTX-PID effectively depleted anti-AAV3B NAbs, with a dose-dependent effect in magnitude and duration. The safety profile was manageable, with few temporary inflammatory events and self-resolving liver enzyme elevations. VTX-PID 0.3 mg/kg was identified as the appropriate dose based on its safety and efficacy profile. In the population with intermediate NAb levels, the 2- to 5-day depletion in anti-AAV3B NAbs supports VTX-PID as a promising pretreatment approach to open a window of opportunity of up to 5 days, broadening eligibility for systemic AAV-based gene therapies.