ABSTRACT
Background: Morbidity and mortality due to coronavirus disease 2019 (COVID-19) may in part be due tointerleukin-6 (IL-6)-mediated hyperinflammation. The IL-6 receptor-targeted monoclonal antibody tocilizumab (TCZ)has been repurposed to treat COVID-19-related hyperinflammation, but prospective data are lacking. Given TCZ'srisks of secondary infection and potential blunting of the adaptive immune response and its finite supply, study of theefficacy, safety, and dose response of TCZ for the treatment of COVID-19-related hyperinflammation is needed. Methods: We conducted an adaptive phase 2 study of low-dose (LD) TCZ in hospitalized, non-mechanicallyventilated adult patients with COVID-19 pneumonitis and evidence of hyperinflammatory syndrome, with C-reactiveprotein (CRP) ≥ 40 micrograms per milliliter. Dose cohorts were determined by a trial Operations Committee, withthe initial doses of 80 or 200 milligrams, depending on the magnitude of CRP elevation and epidemiologic riskfactors. Doses were decreased to 40 mg and 120 mg after interim assessment. The primary objective was to assessthe relationship of dose to clinical improvement in temperature and oxygen requirement and biochemical responseby CRP. Results: 32 patients received LD TCZ. 25 of 32 (78%) patients receiving LD TCZ at any dose achieved feverresolution. In terms of dose-response, fever resolution in 24 hours was observed in 6 of 8 (75%) who received 200milligrams, 3 of 4 (75%) who received 120 milligrams, 11 of 15 (73%) who received 80 milligrams, and 5 of 5 (100%)who received 40 milligrams (p = 0.80 for response rate difference). Biochemical response consistent withinterleukin-6 pathway inhibition, corresponding to a ≥ 25% CRP decline, after a single dose of LD TCZ wasobserved in 5 of 8 (63%) who received 200 milligrams, 4 of 4 (100%) who received 120 milligrams, 10 of 15 (67%)who received 80 milligrams, and 5 of 5 (100%) who received 40 milligrams (p = 0.34 for response rate difference).100% of patients achieved CRP response within two doses of LD TCZ. Within the 28-day follow-up period, 5 (16%)patients died. For patients who recovered, median time to clinical recovery was 4 days (interquartile range, 2-5).Clinically presumed and/or cultured bacterial superinfections were reported in 4 (12.5%) patients. Correlativebiologic studies examining anti-SARS-CoV-2 antibody production across a range of TCZ doses are presentedseparately (abstract A-22514927). Conclusions: LD TCZ, in addition to standard of care, was associated with improvement of clinicalhyperinflammation parameters in hospitalized adult patients with COVID-19 pneumonitis. No relationship betweenTCZ dose and clinical or biochemical response relationship was identified. Results of the COVIDOSE trial provide arationale for a randomized, controlled trial of LD TCZ versus standard of care in those patients with COVID-19pneumonitis who have evidence of hyperinflammation. (COVIDOSE, ClinicalTrials.gov number, NCT04331795 .).
ABSTRACT
Tocilizumab (TCZ), an interleukin-6 (IL-6) receptor-blocking monoclonal antibody, is used to treat variousrheumatologic conditions and cytokine release syndrome in CAR-T cell therapy and has been repurposed to treatCOVID-19-related hyperinflammation. There are limited data available reporting how TCZ affects the immuneresponse in the context of COVID-19. To investigate this question, we recruited patients treated with TCZ as part ofa COVID-19 biobanking protocol (A-28063295) to study immune parameters that might be affected. We enrolled 19patients who were treated with a range of 40-200mg TCZ as part of a low-dose TCZ trial (COVIDOSE, reportedseparately as abstract A-94803796), and 11 patients who received 400mg TCZ on a standard-of-care expanded-access basis. As IL-6 acts as a stimulant of B-cell proliferation, plasma cell maturation, and antibody responses, weevaluated whether blocking the IL-6 receptor with TCZ therapy impairs antibody generation to SARS-CoV-2. Toevaluate antibody levels in these patients, we performed ELISAs against the SARS-CoV-2 spike glycoprotein and itsreceptor-binding domain (RBD). The spike glycoprotein, a structural protein of SARS-CoV-2, is a crucial componentin the recognition, attachment, and entry of the virus into host cells. Specifically, the RBD is responsible for bindingthe ACE2 receptor on human cells, and likely serves as a major target for neutralizing antibodies. To establish if theformation and persistence of antibodies was affected by TCZ treatment, we analyzed serum and plasma sampleslongitudinally from 29 patients treated with TCZ and 26 control patients. To account for potential variability betweenplates, the measured optical density (OD) values were normalized to the OD for COVID-19-negative control serumat 1:50 dilution, and the same negative control was tested on each plate. Titers were calculated as the linearinterpolation of the inverse dilution at which the normalized OD value crossed a threshold of 1, representing themaximum OD measured for the negative control. Anti-spike and anti-RBD antibodies increased significantly overtime in both TCZ-treated patients and controls (p < 0.005 for both). Increasing antibody titers throughout the diseasecourse followed a similar trajectory in TCZ-treated patients compared to control patients, suggesting that TCZtreatment does not impede the generation of antibodies to SARS-CoV-2. Additionally, TCZ-treated patients achievedcomparable maximal observed antibody titers to control patients (average maximal log10 (titer) of 5.42 and 4.96 forspike and of 4.39 and 4.44 for RBD, respectively). These data suggest that TCZ does not impair the induction ofanti-SARS-CoV-2 antibodies.