The safety and efficacy advantage of blocking C5a vs C5 in critically ill, COVID-19 patients: results from PANAMO, a phase 3 randomized controlled trial
Presenter: Bruce P. Burnett, PhD;VP, Head of Medical Affairs, InflaRx GmbH, InflaRx Pharmaceuticals, Inc., Fuquay-Varina, NC, United States.
Direct C5a inhibition by vilobelimab, in findings from the randomized, controlled phase 3 PANAMO study, resulted in a survival benefit for critically ill patients with COVID-19 without increasing infections, according to Bruce P. Burnett, PhD; VP, Head of Medical Affairs, InflaRx GmbH, InflaRx Pharmaceuticals, Inc., Fuquay-Varina, NC, United States. Unlike agents with upstream C5 blockade, vilobelimab presumably preserves the membrane attack complex (MAC) which triggers lysis of pathogens, Burnett said in an oral presentation at Infectious Disease Week 2023.
Elucidating a hypothesis regarding a potential role of C5a in COVID-19-induced vascular injury, Burnett noted that SARS-CoV-2 infection activates the complement system, leading to C5a generation. C5a, in turn, activates neutrophils via C5aR, leading to increased adherence to endothelial cells, tissue damage via generation of reactive oxygen species, granular enzyme release, and cell death by neutrophil extracellular traps (NETosis). C5a induces tissue factor release from neutrophils and endothelial cells, promoting coagulation and leading to fibrin formation. Finally, thrombin, plasmin, and other enzymes can directly cleave C5 to C5a, leading to microangiopathy with thrombosis.
Vilobelimab is an anti-C5a monoclonal antibody that preserves MAC. It was tested in the PANAMO study, a phase 3 multicenter, double-blind, randomized, placebo-controlled trial to determine its effect on survival in critically ill patients with COVID-19.
PANAMO investigators recruited 368 COVID-19 patients (mean age 56.3 years; 68.5% male) who had been intubated within 48 hours of randomization to 6 intravenous infusions of either vilobelimab 800 mg (n = 177) or placebo (n=190) on top of standard of care. Twenty-eight day all-cause mortality was the primary endpoint. Blood samples were assessed by enzyme-linked immunoassay at screening, day 8, and at hospital discharge for vilobelimab and C5a levels. No meningococcal vaccination or prophylactic antibiotics were used in the study.
For the primary endpoint, Burnett reported Kaplan-Meier estimates showing a 28-day mortality rate of 31.7% for vilobelimab vs 41.6% for placebo (hazard ratio 0.67, 95% confidence interval 0.48–0.96, P < .05), with similar results for the 60-day secondary mortality endpoint. All 3 prespecified subgroup analyses for more severe patients (based on baseline World Health Organization COVID-19 ordinal scale, severity of acute respiratory distress syndrome based on the PaO2/FiO2 ratio, and baseline estimated glomerular filtration rate), suggested a benefit of vilobelimab in terms of lower mortality risk.
Burnett said also that on day 8 after 3 infusions, mean vilobelimab trough levels were 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). While C5a was highly elevated and comparable between groups at screening (vilobelimab mean 130.3 ng/mL, placebo mean 123.2 ng/mL), by day 8 C5a levels were reduced 87% with vilobelimab (mean 16.8 ng/mL, P < .001) vs an increase with placebo (mean 129.8 ng/mL). Sparse day 8 sampling revealed C5a levels remaining high for placebo and low for vilobelimab throughout the study.
Serious adverse event rates were similar at 58.9% for vilobelimab and 63.5% for placebo; treatment-emergent adverse event rates were 90.9% and 91.0% for vilobelimab and placebo, respectively. The fact that per 100 patient-days, infection incidence was comparable wit vilobelimab and placebo was presumably attributable to the preservation of MAC, Burnett said.
“PANAMO is the largest, properly powered study to show a reduction in 28-day all-cause mortality in invasive mechanically ventilated patients.” Burnett concluded, “Results from this phase 3 study show that direct C5a inhibition by vilobelimab, while presumably preserving the membrane attack complex as opposed to upstream C5 blockade, results in a survival benefit for critically ill COVID-19 patients without increasing infections.”
On April 4, 2023, the FDA issued an Emergency Use Authorization for the use of vilobelimab for the treatment of COVID-19 in hospitalized adults when it is administered within 48 hours of mechanical ventilation or extracorporeal membrane oxygenation. (Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization for Gohibic. 2023. Available at: https://www.fda.gov/media/166824/download).
Disclosures. Burnett disclosed that he is an employee of lnflaRx Pharmaceuticals, Inc. and has received stock options as part of his employment compensation.
PANAMO is sponsored by lnflaRx GmbH and partly funded by the German Federal Government through grant number 16LW 0113 (Vilo-Covid).
Reference
Vlaar APJ, Witzenrath M, van Paassen P, et al. Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med 2022; 10(12):1137–1146. doi:10.1016/S2213-2600(22)00297-1