Complement activation in a phase Ib study of fordadistrogene movaparvovec for Duchenne muscular dystrophy.

Thrombotic microangiopathy (TMA) has been reported as an uncommon but severe adverse effect of recombinant adeno-associated virus (rAAV)-based gene therapy. Here, we describe in detail the occurrences of clinically evident TMA following infusion of the rAAV9-based therapy fordadistrogene movaparvovec (1 or 3 × 1014 vg/kg) in 22 participants with Duchenne muscular dystrophy (DMD). Three participants experienced clinical evidence of TMA. Platelet levels rapidly decreased 7-10 days post infusion, together with C3 and C4 depletion and elevated C5b-9 after ∼7 days. Peak vector blood concentration was observed for 4-7 days, and type 1 interferon cytokine levels increased within 2-7 days. Each affected participant was hospitalized and received supportive care and anti-complement therapy. Anti-AAV9 immunoglobulin M (IgM) and IgG were detected within days post infusion, and participants with TMA demonstrated a particularly rapid rise of neutralizing antibodies and total antibody to AAV9 in the first 1-2 weeks post infusion. Limited early time points from other participants were not assessed for complement activation. With appropriate monitoring of early time points following AAV exposure, TMA can be successfully managed. However, these early events should be considered related to the benefit-risk profile when using rAAV-based gene therapy for the treatment of DMD. ClinicalTrials.gov identifier: NCT03362502.