Efficacy and safety of garadacimab in patients with severe COVID-19

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.

Dynamic collaboration in a crisis: creating a low-cost ventilator and test facility

During the initial stages of the COVID-19 pandemic a major concern was the shortage of ventilators. Engineering initiatives were started to mitigate this concern. This article details the response at the National Physical Laboratory (NPL) to this potential shortage. The technologies and product development behind NPL's PocketVent ventilator, by a team working remotely amidst a crisis, are explored. Underpinning the product was the creation of a traceable test facility, that allowed the initial three prototype devices to be narrowed to one. PocketVent was created within five months and offers pressure and volume controlled ventilation, with a clear road-map to implement constant-pressure mode, alongside a comprehensive documentation pack. The team were recipients of the Royal Academy of Engineering's President's Special Award for Pandemic Service. © 2022 IOP Publishing Ltd.