The efficacy and safety of levilimab in severely ill COVID-19 patients not requiring mechanical ventilation: results of a multicenter randomized double-blind placebo-controlled phase III CORONA clinical study

Abstract

Objective and design The aim of this double-blind, placebo-controlled, phase III CORONA clinical trial was to evaluate the efficacy and safety of IL-6 receptor inhibitor levilimab (LVL) in subjects with severe COVID-19. Subjects The study included 217 patients. The eligible were men and non-pregnant women aged 18 years or older, hospitalized for severe COVID-19 pneumonia. Treatment 206 subjects were randomized (1:1) to receive single subcutaneous administration of LVL 324 mg or placebo, both in combination with standard of care (SOC). 204 patients received allocated therapy. After the LVL/placebo administration in case of deterioration of symptoms, the investigator could perform a single open-label LVL 324 mg administration as the rescue therapy. Methods The primary efficacy endpoint was the proportion of patients with sustained clinical improvement on the 7-category ordinal scale on Day 14. All efficacy data obtained after rescue therapy administration were considered missing. For primary efficacy analysis, all subjects with missing data were considered non-responders. Results 63.1% and 42.7% of patients in the LVL and in the placebo groups, respectively, achieved sustained clinical improvement on Day 14 (P = .0017). The frequency of adverse drug reactions was comparable between the groups. Conclusion In patients with radiologically confirmed SARS-CoV-2 pneumonia, requiring or not oxygen therapy (but not ventilation) with no signs of other active infection administration of LVL + SOC results in an increase of sustained clinical improvement rate. Trail registration The trial is registered at the US National Institutes of Health (ClinicalTrials.gov; NCT04397562).

Potential Pathophysiological Mechanisms Underlying Multiple Organ Dysfunction in Cytokine Release Syndrome

“…Its mechanism and efficacy in rheumatoid arthritis are similar to those of clazakizumab [ 118 ]. Other drugs in the same category are sarilumab and levilimab [ 119 , 120 ].…”

Application of Monoclonal Antibody Drugs in Treatment of COVID-19: a Review

“…Of patients in levilimab and placebo groups, 63.1% and 42.7%, respectively, achieved stable clinical improvement on day 14 (P = 0.0017). The frequency of adverse reactions was comparable between the groups [53].…”

“…Although IL-6 inhibitors have not yet been officially registered in clinical guidelines for the treatment of COVID-19, they have been widely used in pilot studies. For example, levilimab (an IL-6 blocker) was assessed in critically ill patients with COVID-19 who did not require artificial lung ventilation [53]. There were also randomized controlled trials using IL-6 blockers versus standard treatment or placebo for people with COVID-19 regardless of disease severity [54].…”

Molecular signaling pathways, pathophysiological features in various organs, and treatment strategies in SARS-CoV2 infection

“…Also, a network meta-analysis demonstrated that sarilumab and tocilizumab alone or in combination with standard care such as corticosteroids might have similar effects and probably decrease the mortality rate in severe COVID-19 patients ( Zeraatkar et al, 2021 ). In one double-blind and placebo-controlled phase III clinical trial, the efficacy and safety of levilimab have been investigated in severe COVID-19 patients who do not need mechanical ventilation, and it was shown that administration of levilimab combined with standard treatment leads to an enhanced sustained clinical improvement rate ( Lomakin et al, 2021 ). An observational cohort study demonstrated that siltuximab has beneficial effects in rapidly progressing COVID-19 patients requiring ventilatory support for decreasing cytokine-drive hyper-inflammation and mortality.…”