Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19

BACKGROUND: Bebtelovimab is a potent, fully human IgG1 monoclonal antibody (mAb) targeting the S-protein of SARS-CoV-2, with broad neutralizing activity to all currently known SARS-CoV-2 variants of concern, including omicron variant lineages. Specialized developmental approaches accelerated the initiation of a clinical trial designed to evaluate the efficacy and safety of bebtelovimab alone (BEB) or together with bamlanivimab (BAM) and etesevimab (ETE) delivered via slow intravenous push for the treatment of mild-to-moderate COVID-19. METHODS: This portion of the phase 2, BLAZE-4 trial (J2X-MC-PYAH; NCT04634409) enrolled 714 patients (between May and July 2021) with mild-to-moderate COVID-19 within 3 days ([≤]3 days) of laboratory diagnosis of SARS-CoV-2 infection. Patients at low risk for severe COVID-19 were randomized 1:1:1 (double-blinded) to placebo, BEB 175 mg, or BEB 175 mg+BAM 700 mg+ETE 1400 mg (BEB+BAM+ETE). Patients at high risk for progression to severe COVID-19 were randomized 2:1 (open-label) to BEB or BEB+BAM+ETE, and a subsequent treatment arm enrolled patients to BEB+BAM+ETE using Centers for Disease Control and Prevention (CDC) updated criteria for High-risk. All treatments were administered intravenously over [≥]30 seconds (open-label BEB) or [≥]6.5 minutes (all other treatment arms). For the placebo-controlled patients (termed Low-risk), the primary endpoint was the proportion of patients with persistently high viral load (PHVL) (log viral load >5.27) on Day 7. For the open-label patients (termed High-risk), the primary endpoint was safety. In nonclinical studies, SARS-CoV-2 isolates were tested using an endpoint neutralization assay to measure BEB's inhibitory concentration greater than 99% (IC99). RESULTS: Baseline viral sequencing data were available from 611 patients; 90.2% (n=551) aligned with a variant of interest or concern (WHO designation), with the majority infected with delta (49.8%) or alpha (28.6%) variants. Among the Low-risk patients, PHVL occurred in 19.8% of patients treated with placebo, as compared to 12.7% (p=0.132) of patients treated with BEB+BAM+ETE and 12.0% (p=0.097) of patients treated with BEB, a 36% and 40% relative risk reduction, respectively. Viral load-area under the curve analysis from baseline to Day 11 showed statistically signficant reductions for patients treated with BEB (p=0.006) and BEB+BAM+ETE (p=0.043) compared to patients who received placebo. Time to sustained symptom resolution was reduced by a median of 2 days for patients treated with BEB (6 days; p=0.003) and 1 day for patients treated with BEB+BAM+ETE (7 days; p=0.289) compared to placebo (8 days). The incidence of COVID-19-related hospitalization or all-cause deaths by day 29 were similar across treatment arms, as expected given the patients' risk status (the Low risk cohorts had a Low risk of hospitalization, and High risk cohorts received only active therapy without placebo). Overall, safety results were consistent with previous studies investigating mAbs targeting SARS-CoV-2. The proportion of patients with treatment emergent adverse events (AEs) were 9.7% in Low-risk (n=37/380) and 14.7% in High-risk (n=48/326) patients treated with BEB or BEB+BAM+ETE; majority of AEs were considered mild or moderate in severity. Serious AEs were reported in 2.1% of High-risk patients (n=7/326), including one death (a cerebrovascular accident); 1 serious AE was reported among Low-risk patients. In an in vitro neutralization assay, BEB neutralized the omicron isolate (BA.1) with <2.44ng/ml estimated IC99. CONCLUSIONS: In patients with mild-to-moderate COVID-19, treatment with BEB or BEB+BAM+ETE was associated with greater viral clearance, a reduction in time to sustained symptom resolution, and safety results consistent with mAbs that target SARS-CoV-2. Integration of clinical findings with in vitro neutralization of emerging viral variants offered a pragmatic framework for investigating the efficacy of a new antiviral mAb agent, as demonstrated by bebtelovimab.