Phase 3 RCT of C5a-Specific Vilobelimab in Severe COVID-19 Pneumonia

Abstract

Background: Blocking the C5a-C5aR axis in COVID-19 patients could improve outcomes by limiting myeloid cell infiltration in damaged organs and preventing excessive lung inflammation and endothelialitis.

Aims and Objectives: Vilobelimab (VILO), an anti-C5a mAb that preserves the membrane attack complex (MAC), was tested in a Phase III adaptively designed multicenter, double-blind placebo (P)-controlled study for survival in critically ill COVID-19 patients.

Methods: COVID-19 pneumonia patients (N=369; VILO n=178, P n=191) within 48 hrs of intubation were randomly assigned to receive 6, 800 mg infusions of VILO or P on top of standard of care. Primary outcome was 28-day all-cause mortality.

Results: 28-day all-cause mortality was 31.7% VILO vs 41.6% P (Kaplan-Meier estimates; Cox regression site stratified, HR 0.73; 95%CI:0.50-1.06; P=0.094) with a 22.7% relative mortality reduction to Day 60. In predefined primary outcome analysis without site stratification, VILO significantly reduced 28-day mortality (HR 0.67; 95%CI:0.48-0.96; P=0.027); needed to treat number, 10 to save 1. VILO significantly reduced 28-day mortality in severe patients with baseline WHO ordinal scale score of 7 (n=237, HR 0.62; 95%CI:0.40-0.95; P=0.028) or severe ARDS/PaO2/FiO2≤100 mmHg (n=98, HR 0.55; 95%CI:0.30-0.98; P=0.044) or eGFR<60 mL/min/1.73m2 (n=108, HR 0.55; 95%CI:0.31-0.96; P=0.036). Treatment emergent AEs were 90.9% VILO vs 91.0% P. Infections were comparable; VILO (62.9%), P (59.3%). Serious AEs were 58.9% VILO, 63.5% P.

Conclusion: VILO reduced mortality at 28 to 60 days in severe COVID-19 pneumonia patients with no increase in infections suggesting the importance of targeting C5a while preserving MAC.