Publication
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
Christian E. Sandrock, Alexander Vlaar, Endry H.T. Lim, Bruce P. Burnett, Camilla Chong, Carina Zink, Robert Zerbib, Raymond Panas, Renfeng Guo, Niels Riedemann, and Diederik van de Beek
https://journal.chestnet.org/article/S0012-3692(24)02171-8/fulltext
Session Title
Critcal Care Abstracts Posters (K)
Session Type
Original Investigation Posters
Presented On
10/09/2024 10:20 am - 11:05 am
Purpose
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.
Methods
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.
Results
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%).
Conclusions
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.
Clinical Implications
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.