Regional effects on efficacy and safety of vilobelimab in mechanically ventilated patients with severe COVID-19

ABSTRACT

Introduction: Poor outcomes in COVID-19 patients (pt) are associated with C5a-C5aR axis activation. A C5a-specific monoclonal antibody, vilobelimab (VILO), improves outcomes in critically ill COVID-19 pt in a Phase 3 randomized, double-blind, placebo (PLC)- controlled study [1]. Method(s) COVID-19 pt within 48 h of intubation were randomly assigned to receive 6, 800 mg infusions of VILO or PLC at a 11 ratio on top of standard of care. Predefined subgroup analyses by region and country were performed. Result(s) Forty-six (46) hospitals on 4 continents randomized 369 pt VILO (n = 178), PLC (n = 191). VILO significantly reduced 28- (HR 0.67;95% CI 0.48-0.96;p = 0.027) and 60-Day mortality (HR 0.67;95% CI 0.48-0.93, p = 0.0163) using a predefined, unstratified per protocol analysis. Mortality rates at 28- and 60-days and VILO treatment effects, however, differed substantially between regions Western Europe HR for 60-day mortality 0.59 [0.37-0.95], South Africa plus Russian Federation HR 0.62 [0.28-1.38] and South America HR 0.80 [0.46-1.39] (Fig. 1). The weak signal in South America is predominately driven by Brazil (n = 74), which showed a significant age imbalance with a median 9-years younger PLC group (44.5-years-old vs 53.5-years-old) with low 60-day mortality of ~ 32.5% in the PLC group versus ~ 43.3% in Western Europe. Adjusting for age group categories (<= 30, 31-40, 41-50, 51-60, > 60;Cox regression) for 60-day mortality changed the HR in Brazil (0.96 [0.44-2.10] for continuous age-adjustment) to values near the estimate for the entire study population (HR 0.77 [0.35-1.69] for age in categories), suggesting a by chance imbalance and not a statistically evident weaker effect in Brazil. Conclusion(s) Regional efficacy differences between the rest of the world and South America were driven by age imbalances between treatment groups, which do not diminish the robust efficacy signal for VILO in severe COVID-19.