Antibody therapy reverses biological signatures of COVID-19 progression

Understanding who is at risk of progression to severe COVID-19 is key to effective treatment. We studied correlates of disease severity in the COMET-ICE clinical trial that randomized 1:1 to placebo or to sotrovimab, a monoclonal antibody for the treatment of SARS-CoV-2 infection. Several laboratory parameters identified study participants at greater risk of severe disease, including a high neutrophil-lymphocyte ratio (NLR), a negative SARS-CoV-2 serologic test and whole blood transcriptome profiles. Sotrovimab treatment in these groups was associated with normalization of NLR and the transcriptomic profile, and with a decrease of viral RNA in nasopharyngeal samples. Transcriptomics provided the most sensitive detection of participants who would go on to be hospitalized or die. To facilitate timely measurement, we identified a 10-gene signature with similar predictive accuracy. In summary, we identified markers of risk for disease progression and demonstrated that normalization of these parameters occurs with antibody treatment of established infection.

Effect of the Neutralizing SARS-CoV-2 Antibody Sotrovimab in Preventing Progression of COVID-19: A Randomized Clinical Trial

ImportanceOlder patients and those with underlying comorbidities infected with SARS-CoV-2 may be at increased risk of hospitalization and death from COVID-19. Sotrovimab is a neutralizing antibody designed for treatment of high-risk patients to prevent COVID-19 progression. ObjectiveTo evaluate the efficacy and safety of sotrovimab in preventing progression of mild to moderate COVID-19 to severe disease. DesignRandomized, double-blind, multicenter, placebo-controlled, phase 3 study. Setting57 centers in 5 countries. ParticipantsNonhospitalized patients with symptomatic, mild to moderate COVID-19 and at least 1 risk factor for disease progression. InterventionPatients were randomized (1:1) to an intravenous infusion of sotrovimab 500 mg or placebo. Main Outcomes and MeasuresThe primary efficacy outcome was the proportion of patients with COVID-19 progression, defined as all-cause hospitalization longer than 24 hours for acute illness management or death through day 29. Key secondary outcomes included the proportion of patients with COVID-19 progression, defined as emergency room visit, hospitalization of any duration, or death, and proportion of patients developing severe/critical respiratory COVID-19 requiring supplemental oxygen. ResultsAmong 1057 patients randomized (sotrovimab, 528; placebo, 529), all-cause hospitalization longer than 24 hours or death was significantly reduced with sotrovimab (6/528 [1%]) vs placebo (30/529 [6%]) by 79% (95% CI, 50% to 91%; P<.001). Secondary outcome results further demonstrated the effect of sotrovimab in reducing emergency room visits, hospitalization of any duration, or death, which was reduced by 66% (95% CI, 37% to 81%; P<.001), and severe/critical respiratory COVID-19, which was reduced by 74% (95% CI, 41% to 88%; P=.002). No patients receiving sotrovimab required high-flow oxygen, oxygen via nonrebreather mask, or mechanical ventilation compared with 14 patients receiving placebo. The proportion of patients reporting adverse events was similar between treatment groups; sotrovimab was well tolerated, and no safety concerns were identified. Conclusions and RelevanceAmong nonhospitalized patients with mild to moderate COVID-19, a single 500-mg intravenous dose of sotrovimab prevented progression of COVID-19, with a reduction in hospitalization and need for supplemental oxygen. Sotrovimab is a well-tolerated, effective treatment option for patients at high risk for severe morbidity and mortality from COVID-19. Trial RegistrationClinicalTrials.gov Identifier: NCT04545060

Early Covid-19 Treatment With SARS-CoV-2 Neutralizing Antibody Sotrovimab

BackgroundCoronavirus disease 2019 (Covid-19) disproportionately results in hospitalization and death in older patients and those with underlying comorbidities. Sotrovimab is a pan-sarbecovirus monoclonal antibody designed to treat such high-risk patients early in the course of disease, thereby preventing Covid-19 progression. MethodsIn this ongoing, multicenter, double-blind, phase 3 trial, nonhospitalized patients with symptomatic Covid-19 and at least one risk factor for disease progression were randomized (1:1) to an intravenous infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was the proportion of patients with Covid-19 progression, defined as hospitalization longer than 24 hours or death, through day 29. ResultsIn this preplanned interim analysis, which included an intent-to-treat population of 583 patients (sotrovimab, 291; placebo, 292), the primary efficacy endpoint was met. The risk of Covid-19 progression was significantly reduced by 85% (97.24% confidence interval, 44% to 96%; P = 0.002) with a total of three (1%) patients progressing to the primary endpoint in the sotrovimab group versus 21 (7%) patients in the placebo group. All five patients admitted to intensive care, including one who died by day 29, received placebo. Safety was assessed in 868 patients (sotrovimab, 430; placebo, 438). Adverse events were reported by 17% and 19% of patients receiving sotrovimab and placebo, respectively; serious adverse events were less common with sotrovimab (2%) versus placebo (6%). ConclusionSotrovimab reduced progression of Covid-19 in patients with mild/moderate disease, was well tolerated, and no safety signals were identified. Funded by Vir Biotechnology, Inc. and GlaxoSmithKline; ClinicalTrials.gov NCT04545060

The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2

Sotrovimab (VIR-7831) and VIR-7832 are dual action monoclonal antibodies (mAbs) targeting the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sotrovimab and VIR-7832 were derived from a parent antibody (S309) isolated from memory B cells of a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) survivor. Both mAbs contain an "LS" mutation in the Fc region to prolong serum half-life. In addition, VIR-7832 encodes an Fc GAALIE mutation that has been shown previously to evoke CD8+ T-cells in the context of an in vivo viral respiratory infection. Sotrovimab and VIR-7832 neutralize wild-type and variant pseudotyped viruses and authentic virus in vitro. In addition, they retain activity against monoclonal antibody resistance mutations conferring reduced susceptibility to previously authorized mAbs. The sotrovimab/VIR-7832 epitope continues to be highly conserved among circulating sequences consistent with the high barrier to resistance observed in vitro. Furthermore, both mAbs can recruit effector mechanisms in vitro that may contribute to clinical efficacy via elimination of infected host cells. In vitro studies with these mAbs demonstrated no enhancement of infection. In a Syrian Golden hamster proof-of concept wildtype SARS-CoV-2 infection model, animals treated with sotrovimab had less weight loss, and significantly decreased total viral load and infectious virus levels in the lung compared to a control mAb. Taken together, these data indicate that sotrovimab and VIR-7832 are key agents in the fight against COVID-19.