Bebtelovimab, Alone and Together with Bamlanivimab and Etesevimab, as a Broadly Neutralizing Monoclonal Antibody Treatment and a Slow Intravenous Push Option for Ambulatory COVID-19

ABSTRACT

RATIONALE Bebtelovimab is a potent, fully human monoclonal antibody targeting the S-protein of SARS-CoV-2, with broad neutralizing activity to all variants of concern (including Omicron), based on non-clinical assays. This study aimed to evaluate the efficacy and safety of bebtelovimab alone (BEB) or together with bamlanivimab (BAM) and etesevimab (ETE) for the treatment of mild-tomoderate COVID-19, delivered via slow intravenous push.METHODS: This portion of the phase 2 BLAZE-4 trial (NCT4634409) enrolled 706 patients (between May and July 2021) with mild-tomoderate COVID-19 within 3 days of first laboratory diagnosis of SARS-CoV-2 infection. Patients at low-risk for severe COVID-19 were randomized 111 (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 severe COVID-19 were randomized 11 (open-label) to BEB or BEB+BAM+ETE;a subsequent treatment arm enrolled patients to BEB+BAM+ETE using CDC expanded 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 population (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 population (termed high-risk), the primary endpoint was safety outcomes and statistics were descriptive. RESULTS: Baseline sequencing data was available for 611 patients, 90.2% (n=551) aligned with a variant of interest or concern (WHO designation), with the majority infected with Delta (49.8%) and Alpha (28.6%) variants. For the low-risk population, active treatment arms had a numerically lower proportion of patients with PHVL compared to placebo, albeit not at a level of statistical signficance (see Table). Viral load-area under the curve analysis from baseline to Day 11 showed signficant reduction for patients treated with BEB compared to placebo. Time to sustained symptom resolution was significantly improved among patients who received BEB relative to placebo. As expected, the incidence of COVID-19-related hospitalization or all-cause deaths by day 29 were similar within the low-risk population. Overall, results were similar between patients in low-risk and high-risk populations receiving active treatment (see Table). The majority of treatment emergent adverse events (AEs) were mild-to-moderate in low-risk (n=36/380,9.5%) and high-risk patients (n=46/326,14.1%). Serious AEs were reported in 7/326 (2.1%) high-risk patients;none were reported in low-risk patients.CONCLUSION: The safety and efficacy data support the further development of bebtelovimab delivered via slow intravenous push of at least 30 seconds. (Table Presented).