Anti-CD14 treatment in patients with severe COVID-19: Clinical and biological effects in a Phase 2 randomized open-label adaptive platform clinical trial.

CD14-dependent innate immunity contributes to poor outcomes in COVID-19 pneumonia. We tested the clinical and biological efficacy of a blocking monoclonal antibody to CD14 (IC14) for treatment of severe COVID-19 pneumonia and the utility of a biomarker of CD14 pathway activation in predicting outcome. We report a preplanned secondary analysis of the I-SPY COVID Trial, which enrolled hospitalized patients with severe COVID-19 pneumonia at 19 medical centers in the U.S. who required high-level respiratory support. Participants were randomized to receive either intravenous IC14 (4 mg/kg on Day 1, then 2 mg/kg on Days 2-4) (N=67) or standard care (N=76). Primary endpoints included time-to-recovery, defined as the first two-day period on ≤6L/min O2, and mortality. In predefined secondary analyses, we tested the association between IC14 treatment and mortality in patients with high or low baseline plasma presepsin (sCD14-ST), a biomarker of CD14 pathway activity, and the effects of IC14 on plasma biomarkers of pharmacodynamics, injury and inflammation. IC14 treatment did not improve time-to-recovery or 28-day mortality in the overall population, and the trial was stopped due to meeting futility criteria for the time-to-recovery endpoint. However, a predefined sub-group analysis showed that IC14 treatment was associated with a numerical reduction in 28-day mortality in participants with high (above median) baseline presepsin levels (N=47) [Hazard Ratio for mortality (HRm)): 0.52, 95% credible interval (CrI): 0.22-1.22, posterior probability HRm<1 (Pr (HRm<1|Data))=0.93]. IC14 treatment increased plasma sCD14, a pharmacodynamic marker and decreased plasma inflammatory biomarkers, including IL-8, RAGE, VEGF, and presepsin. Although IC14 treatment did not improve overall clinical outcomes, this new secondary analysis shows that IC14 had the expected pharmacodynamic and biological effects, and that baseline plasma presepsin concentrations may identify patients likely to respond to IC14 treatment. Further trials are needed to determine the efficacy of IC14 treatment in acute lung injury and the value of presepsin to identify patients most likely to respond. Clinicaltrials.gov: NCT04488081.