Efficacy and Safety of Garadacimab in Combination with Standard of Care Treatment in Patients with Severe COVID-19

Abstract

Background Garadacimab, a fully human IgG4 monoclonal antibody, inhibits the kallikrein–kinin pathway at a key initiator, activated coagulation factor XII (FXIIa), and may play a protective role in preventing the progression of COVID-19. This phase 2 study evaluated the efficacy and safety of garadacimab plus standard of care (SOC) versus placebo plus SOC in patients with severe COVID-19. Methods Patients hospitalised with COVID-19 were randomised (1:1) to a single intravenous dose of garadacimab (700 mg) plus SOC or placebo plus SOC. Co-primary endpoint was incidence of endotracheal intubation or death between randomisation and Day 28. All-cause mortality, safety and pharmacokinetic/pharmacodynamic parameters were assessed. Results No difference in incidence of tracheal intubation or death (p = 0.274) or all-cause mortality was observed (p = 0.382). Garadacimab was associated with a lower incidence of treatment-emergent adverse events (60.3% vs 67.8%) and fewer serious adverse events (34 vs 45 events) versus placebo. No garadacimab-related deaths or bleeding events were reported, including in the 45.9% (n = 28/61) of patients who received concomitant heparin. Prolonged activated partial thromboplastin time (aPTT), and increased coagulation factor XII (FXII) levels were observed with garadacimab versus placebo to Day 14, whilst FXIIa-mediated kallikrein activity (FXIIa-mKA) was suppressed to Day 28. Conclusion In patients with severe COVID-19, garadacimab did not confer a clinical benefit over placebo. Transient aPTT prolongation and suppressed FXIIa-mKA showed target engagement of garadacimab that was not associated with bleeding events even with concomitant anticoagulant use. The safety profile of garadacimab was consistent with previous studies in patients with hereditary angioedema. ClinicalTrials. gov Identifier NCT04409509. Date of registration: 28 May, 2020.

Activated Coagulation FXII: A Unique Target for In Vivo Molecular Imaging

“…22 The first clinical studies targeting FXIIa indicate that indeed hemostasis is not impaired and there is no indication of an increased bleeding risk caused by FXIIa inhibition. [23][24][25][26] An im previously portant difference in this study compared with previous work using nonconjugated 3F7 as a therapeutic agent in carotid thrombosis is the administration of 3F7-NIR after the injury had been induced, rather than allowing the antibody to circulate beforehand. 22 This reflects the most common clinical use of targeted imaging agents: when a patient presents with a suspected thrombotic event.…”

“…22 The first clinical studies targeting FXIIa indicate that indeed hemostasis is not impaired and there is no indication of an increased bleeding risk caused by FXIIa inhibition. 23–26…”

“…24 Furthermore, a phase 2 study for the treatment of patients with severe COVID-19 did not show significant clinical benefits but confirmed the safety profile of garadacimab, with no bleeding even in combination with heparin. 25,26 Here, we investigate the potential of 3F7 as a novel molecular imaging tool to identify thrombi and ultimately diagnose thrombotic disease in patients.…”