Treatment of Viral-induced Acute Respiratory Distress Syndrome (ARDS) With Vilobelimab: A Focus on C5a Inhibition

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Abstract Introduction: Neutrophil activation induced by C5a and the resulting inflammatory cascade causes vascular injury to lung tissue leading to Acute Respiratory Distress Syndrome (ARDS). Unlike upstream C5 inhibitors which prevent the generation of C5b (Figure 1a), part of the membrane attack complex (MAC) that mitigates certain bacterial infections, vilobelimab is a first-in-class, targeted C5a antibody with high selectivity that strongly binds to C5a blocking its inflammatory effects. Vilobelimab not only blocks C5a generated as part of the complement pathways but also the “extrinsic pathway” which is not blocked by C5 inhibitors. Vilobelimab's specific mechanism inhibits neutrophil activation and the resulting inflammatory cascade while preserving MAC (Figure 1b). In <5% of patients, SARS-CoV-2 infection results in severe COVID-19 ARDS. Vilobelimab's mode of action and the positive Phase III PANAMO study results in critically ill COVID-19 patients serving as an example of a new pharmaceutical invention for respiratory virus-induced ARDS. Methods: Critically ill COVID-19 patients were treated with 800mg vilobelimab within 48 hours of intubation on Day 1 and then on Days 2, 4, 8, 15 and 22. An age-adjusted censored time-to-event variable using Cox regression without site stratification was used to assess 28-day all-cause mortality comparing the treatment arm, vilobelimab + standard-of-care (SOC) vs placebo + SOC in moderate and severe COVID-19 ARDS patients. Results: Phase 3 PANAMO study enrolled critically ill COVID-19 patients with moderate (PaO2/FiO2 ≤200; n=268) and severe (PaO2/FiO2 ≤100; n=98) ARDS. Standard-of-care was corticosteroids (97%) and anticoagulant prophylaxis (98%) with ∼20% of patients receiving tocilizumab or baricitinib as part of SOC. Among these patients, hazard ratios (HR) were 0.75 (CI 95%: 0.48-1.16, p=0.19) in moderate and 0.55 (CI 95%: 0.30-0.98, p=0.044) favoring vilobelimab for survival outcome. The Kaplan Meier point estimate showed an absolute difference of 5.5% in moderate and 19.5% in severe COVID-19 ARDS for 28-day mortality. Conclusion: Hospitalized and intubated COVID-19 ARDS patients have >50% mortality. Vilobelimab, by blocking C5a, inhibiting neutrophil activation and disrupting the inflammatory cascade demonstrated improved survival among COVID-19 ARDS patients. Other respiratory viruses are known to induce C5a as part of their pathophysiology causing ARDS. As a result, the mode of action of vilobelimab may lend itself to broad application in the treatment of virus-induced ARDS. Well-controlled clinical studies are necessary to support this hypothesis.

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