Vilobelimab in Combination with Tocilizumab May Synergistically Improve Mortality in Critically Ill COVID-19 Patients: A Post-hoc Analysis of the Phase III PANAMO Study

Critcal Care Abstracts Posters (K)

Original Investigation Posters

10/09/2024 10:20 am - 11:05 am

Vilobelimab, an anti-C5a complement blocker, significantly reduced 28-day all-cause mortality in a global study of critically ill, septic and moderate to severe ARDS COVID-19 patients on top of standard-of-care (SoC) (PANAMO, N=368: NCT04333420; Vlaar et al. 2022). Vilobelimab treated patients 28-day mortality was 32% vs placebo at 42% (HR 0.67, 95%CI:0.48-0.96, p=0.027). SoC included concomitant corticosteroids (97%) and anti-thrombotic agents (98%). In addition, ~20% of patients received immunomodulators, predominantly tocilizumab over baricitinib. C5a is involved in IL-6 generation in neutrophils in vitro and experimental sepsis (Riedemann et al., 2003, 2004). C5a receptor (C5aR1) expression is strongly transcriptionally upregulated by IL-6 in experimental settings of inflammation and particularly sepsis (Mäck et al., 2001; Riedemann et al., 2002). Inhibition of IL-6 greatly reduces the C5aR1 expression on neutrophils. A post-hoc analysis was performed to evaluate whether any prior or concomitant treatment with tocilizumab provided additional survival benefit on top of vilobelimab and SoC. A mechanism of action is proposed to describe this potential synergistic interaction between vilobelimab and tocilizumab.

A post-hoc Cox regression subgroup analysis was performed for 28- and 60-Day all-cause mortality in patients with or without prior or concomitant use of tocilizumab when receiving vilobelimab+SoC (Vilo+ or Vilo-) or placebo+SoC (Plc+ or Plc-). In addition, safety was assessed for all groups.

Sixty-one (61) patients were administered tocilizumab in the Vilo+ and Plc+ groups. Demographics of these subgroups were generally well-balanced and comparable to the overall study. In this analysis of the Vilo+ (n=30) and Plc+ (n=31) groups, the Kaplan Meier point estimate for 28-Day all-cause mortality was 7.1% vs 42.3% (HR 0.14; 95%CI:0.03-0.62, p=0.010). Day 60 all-cause mortality was 18.9% vs 49.1% (HR 0.30; 95%CI:0.11-0.82, p=0.019), respectively. The number needed to treat was 2.8 for Day 28 and 3.3 for Day 60, respectively. By comparison, the Vilo- (n=143) group had a 28-Day mortality of 37.7% vs 41.7% for the Plc- group (n=154) (HR 0.81; 95%CI:0.56-1.18, p=0.274), Plc- and Plc+ having similar outcomes. Though length of hospital stay was greater in the vilobelimab groups due to greater survival overall, treatment emergent adverse events (TEAEs) occurred in >80% of patients in all groups. Related TEAEs were similar in the Vilo+ and Plc+ groups (31.0% vs 25.8%). Serious TEAEs, however, occurred in fewer patients in the Vilo+ (44.8%) compared to Plc+ (67.7%) which was comparable to Vilo- (63.4%) and Plc- (61.8%). Infections and infestations overall were slightly lower in Vilo+ (55.2%) vs Plc+ (64.5%).

In addition to corticosteroid and anti-thrombotic agent administration, this post-hoc analysis with a small number of patients demonstrates that the co-administration of vilobelimab with tocilizumab may have further potential to improve survival in critically ill COVID-19 patients.

The co-administration of vilobelimab and tocilizumab suggests an interplay between C5a- and IL-6-induced inflammatory pathways involved in septic and ARDS COVID-19 patients. Co-administration of vilobelimab and tocilizumab may result in a synergistic survival benefit for certain critically ill ARDS patients. Prospective randomized studies are warranted to further study this observed promising effect.