Randomized, double-blind, controlled trial of human anti-LIGHT monoclonal antibody in COVID-19 acute respiratory distress syndrome

Abstract

BACKGROUND.Severe coronavirus disease 2019 (COVID-19) infection is associated with a dysregulated immune response, which can result in cytokine release syndrome and acute respiratory distress syndrome (ARDS). Patients with COVID-19-associated ARDS have elevated free serum levels of the cytokine lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT; also known as TNFSF14). Such patients may benefit from LIGHT neutralization therapy.METHODS. This randomized, double-blind, multicenter, proof-of-concept trial enrolled adults hospitalized with COVID-19-associated pneumonia and mild to moderate ARDS. Patients received standard of care plus a single dose of CERC-002 or placebo. The primary endpoint was the proportion of patients receiving CERC-002 who remained alive and free of respiratory failure through day 28. Safety was assessed via adverse event monitoring. RESULTS.For most of the 83 enrolled patients, standard of care included systemic corticosteroids (88.0%) or remdesivir (57.8%). A higher proportion of patients remained alive and free of respiratory failure through day 28 after receiving CERC-002 (83.9%) versus placebo (64.5%; P = .044), including in patients ≥60 years (76.5% vs 47.1%, respectively; P = .042).Mortality rates were 7.7% (CERC-002) and 14.3% (placebo) at day 28 and 10.8% and 22.5%, respectively, at day 60. Treatment-emergent adverse events were less frequent with CERC-002 than placebo. CONCLUSION.For patients with COVID-19-associated ARDS, adding CERC-002 to standard of care treatment reduces LIGHT levels and might reduce the risk of respiratory failure and death. TRIAL REGISTRATION. ClinicalTrials.gov NCT04412057.

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“…Amelioration of cytokine storm by inhibiting LIGHT is hypothesized. FDA has given Investigational New Drug status to CERC-002, an anti-LIGHT monoclonal antibody for clinical trials in patients exhibiting cytokine storm induced ARDS for assessing the efficacy and safety of this potential therapeutic target (Perlin et al 2021 ).…”

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“… 25 These changes trigger the development of pulmonary infiltration, lung edema, endothelial inflammation, abnormal immune activation, and vascular thrombosis resulting in the impairment of alveolar homeostasis and the development of ARDS. 26 …”

“…25 These changes trigger the development of pulmonary infiltration, lung edema, endothelial inflammation, abnormal immune activation, and vascular thrombosis resulting in the impairment of alveolar homeostasis and the development of ARDS. 26 Different studies illustrated that MM might cause ARDS due to lung involvement by neoplastic plasma cells due to diffuse alveolar infiltration. 27 However, ARDS had been reported in MM without pulmonary parenchymal infiltration, which might be due to osteolytic rib changes and the development of the flail chest.…”

“…In severe SARS‐CoV‐2 infection, the release of damage‐associated molecular patterns (DAMPs) from infected cells stimulates toll‐like receptors 4 (TLR4) with subsequent release of proinflammatory 25 . These changes trigger the development of pulmonary infiltration, lung edema, endothelial inflammation, abnormal immune activation, and vascular thrombosis resulting in the impairment of alveolar homeostasis and the development of ARDS 26 …”