Clinical and Virological Response to a Neutralizing Monoclonal Antibody for Hospitalized Patients with COVID-19

Abstract

BACKGROUND Bamlanivimab, a neutralizing monoclonal antibody given in combination with remdesivir, did not improve outcomes among hospitalized COVID-19 patients based on an early futility assessment. In this final study report, we evaluate an a priori hypothesis that greater benefit of bamlanivimab would be identified in those without detectable endogenous neutralizing antibody levels at study entry, especially if viral levels were high. METHODS Hospitalized COVID-19 patients were randomized to receive bamlanivimab (7000mg) or placebo and followed for 90 days for sustained recovery (home for 14 consecutive days); recovery rate ratios (RRRs) are cited. RESULTS Among 314 participants (163 on bamlanivimab and 151 on placebo), the median time to sustained recovery was 19 days and RRR=0.99 (95% CI: 0.79-1.22; p=0.89). At entry, 50% evidenced production of anti-spike neutralizing antibodies; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels ≥ 1,000 ng/L. Among those without and with antibodies at study entry, the RRRs were 1.24 (95% CI: 0.90-1.70) and 0.74 (95% CI: 0.54-1.00) (p=0.02 for interaction). The RRRs were elevated for those with plasma antigen or nasal viral RNA levels above versus below median at entry, and was greatest for those without antibodies and with elevated antigen or viral RNA levels: 1.48 (95% CI: 0.99-2.23), 1.94 (1.25-3.00), respectively (p<0.05 for all interactions). Hazard ratios for safety outcomes also differed by serostatus at entry. CONCLUSIONS Sustained recovery after administration of bamlanivimab versus placebo differed by presence of neutralizing antibodies at study entry, especially if participants had markers of elevated viral replication. ClinicalTrials.gov number, NCT04501978.

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

“…Among patients with endogenous anti-SARS-CoV-2 antibodies, trends toward worse clinical outcomes among patients treated with BRII-196 plus BRII-198 than treated with placebo were observed in this trial, although the 95% CIs crossed unity and the study was underpowered for subgroup analyses. This finding is consistent with findings reported in other recent trials for bamlanivimab 27 and casirivimab plus imdevimab. 23 Theoretically, neutralising monoclonal antibodies might cause harm in some patients through antibody-dependent enhancement of inflammation or viral replication, or both; 30 , 31 however, evidence of clinically important antibody-dependent enhancement has not been clearly observed in trials to date.…”

“…Meanwhile, point estimates for patients positive at baseline for neutralising antibodies who were treated with BRII-196 plus BRII-198 were found to usually indicate worse outcomes. These results for BRII-196 plus BRII-198, which were based on underpowered subgroup analyses and should be interpreted with caution, are similar to findings reported for bamlanivimab 27 and casirivimab plus imdevimab, 23 in which subgroup analyses by endogenous antibody status indicated that patients hospitalised with COVID-19 without endogenous anti-SARS-CoV-2 antibodies potentially benefited from neutralising monoclonal antibody therapies, whereas those with endogenous antibodies did not. Future studies assessing neutralising monoclonal antibody therapies among patients hospitalised with COVID-19 should assess antibody status to understand if these findings are broadly applicable to monoclonal antibody therapies and if only patients without endogenous anti-SARS-CoV-2 antibodies should be targeted for treatment.…”

Efficacy and Safety of SARS-CoV-2 Neutralizing Antibody JS016 in Hospitalized Chinese Patients with COVID-19: a Phase 2/3, Multicenter, Randomized, Open-Label, Controlled Trial

“…Third, patients with an incompetent immune response or high viral load might be more likely to benefit from neutralizing antibody therapy. The presence of intrinsic neutralizing antibodies was unknown in our study, but studies on bamlanivimab and REGN-COV2 both reported greater clinical benefits from neutralizing antibody treatment for patients without the presence of neutralizing antibodies at study entry, especially those with elevated antigen or viral RNA levels ( 20 – 22 ). Fourth, viruses may develop mutations leading to neutralizing antibody resistance either through natural evolution or due to the selection pressure of treatment ( 23 , 24 ).…”

“…Bamlanvimab (LY-CoV555) with or without the combination of etesevimab (LY-CoV06 or JS016) decreased viral load and risk of COVID-19 related hospitalization among outpatients compared with those who received placebo but did not improve clinical outcomes among hospitalized patients ( 16 – 19 ). Further analyses showed a potentially higher rate of sustained recovery among patients without intrinsic neutralizing antibodies at study entry ( 20 ). REGN-COV2, a neutralizing antibody cocktail of casirivimab (REGN10933) and imdevimab (REGN10987), improved viral clearance and possibly prevented hospitalization among nonhospitalized patients within 7 days since symptom onset, especially those who had an incompetent immune response or high viral load at baseline ( 21 ).…”

The role of spike protein entry inhibitors in the treatment of mild-to-moderate covid-19 in nonhospitalized patients

“…Henceforth, these entry inhibitors should not be used in countries where these Omicron sublineages are prevalent, including some States in the USA. 77 Sotrovimab (Xevudy) is a fully human neutralizing IgG monoclonal antibody which was derived from convalescent plasma from a patient who survived SARS-CoV. It has a high affinity for binding to a highly conserved epitope of SARS-CoV-1 and SARS-CoV-2 spike glycoprotein outside the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif.…”