ABSTRACT
Introduction: Garadacimab (GAR;CSL312), a fully human IgG4 monoclonal antibody, inhibits the kallikrein-kinin pathway at a key initiator, FXIIa, and may play a protective role in the progression of COVID-19 related respiratory disease. Aims and objectives: This placebo (PL)-controlled study evaluated efficacy and safety of GAR plus standard of care (SOC) vs PL plus SOC in patients (pts) with severe COVID-19. Method(s): Pts were randomised (1:1) to GAR (700 mg IV) or PL plus SOC. Primary endpoint was incidence of endotracheal intubation (TI) or death up to Day 28. Key secondary endpoints included all-cause mortality and safety (reporting of AEs). aPTT, FXII levels and FXIIa-mediated kallikrein activity (FXIIa-mKA) were measured to indicate target activation. Result(s): In the ITT analysis set (N=124), baseline demographics were balanced between study groups (GAR, n=63;PL, n=61). Incidence of TI or death was 22% for GAR vs 26% (P=0.274) for PL. No difference in all-cause mortality was observed (crude rate: GAR 17.5% vs PL 18.0%). GAR was associated with fewer TEAEs (60.3% vs 67.8%) and SAEs (34 vs 45 events) vs PL. No GAR-related deaths or bleeding were reported, despite permitted heparin coadministration. aPTT prolongation and increased FXII levels were observed with GAR vs PL to Day 14, while FXIIa-mKA was suppressed to Day 28. Conclusion(s): In pts with severe COVID-19, GAR did not confer a clinical benefit over PL. Transient aPTT prolongation and suppressed FXIIa-mKA showed target engagement of GAR that was not associated with bleeding even with co-administered heparin. The safety profile of GAR in pts with severe COVID-19 was benign, as reported in pts treated with GAR for hereditary angioedema.