Introduction: A C5a-specific mAb, vilobelimab (VILO), in a Phase 3 randomized, double-blind, placebo (P)-controlled study showed significant reduction in 28-d all-cause mortality in critically ill COVID-19 patients (pt) (Vlaar APJ et al. Lancel Respir Med 2022;10(12):1137-46).

Aims and Objectives: To compare mortality worldwide and by region in severe ARDS COVID-19 pt treated with VILO vs P.

Methods: COVID-19 pt (N=368; VILO n=177, P n=191) were intubated within 48 hrs before 6, 800mg infusions of VILO or P on top of standard-of-care. Prespecified and posthoc analyses were performed worldwide and by region [Western Europe (WE), South America (SA), Russia/South Africa (RSA)] for mortality in severe ARDS pt with PaO₂/FiO₂<100 mmHg.

Results: Median age (VILO 58 vs P 57 yrs), sex (~70% male) and severe ARDS pt were similar (VILO n=43, 24.3%; P n=55, 28.8%). VILO significantly reduced relative all-cause 28-d mortality worldwide in severe ARDS pt by 32.8% (HR 0.55; 95% CI:0.30-0.98;P=0.044). By region, VILO showed a nonsignificant 28-d mortality reduction trend (HR 0.37; 95% CI:0.11-1.22;P=0.058) in WE but SA (HR 1.03; 95% CI:0.040-2.70;P=0.944) and RSA (HR 0.37; 95% CI:0.11-1.22;P=0.102) showed lesser effects likely due to a younger P group median age in SA (VILO 50.0 vs P 45.5 yrs) and small numbers of severe ARDS pt in RSA. Treatment-emergent AEs, serious AEs and infection incidence per 100 pt days were equal per group with no meningococcal infections.

Conclusion: Vilobelimab demontrated a significant worldwide reduction in all-cause mortality in severe ARDS COVID-19 pt with detected differences in three prespecified regions which may have been impacted by low pt numbers and an uneven age distribution in SA.