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 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 severe COVID-19 were randomized 1:1 (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).
ABSTRACT
Background: Monitoring genomic variation of SARS-CoV-2 is crucial in mitigating adaptation to the human host and developing effective treatments that safeguard global health. Bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that have demonstrated potent SARS-CoV-2 neutralizing activity in both pre-clinical and clinical settings and have distinct but overlapping binding sites. Here, the selection and characterization of variants in a pre-clinical setting is presented alongside the impact of emerging variants on antibody binding affinity and viral neutralization potency. Methods: Variant selection was carried out via directed evolution of the receptor binding domain (RBD) and serial passage of authentic SARS-CoV-2 in the presence of bamlanivimab and etesevimab individually or in combination. Sequence confirmed, putative-resistance variants identified in both selection methodologies were incorporated into different assessment platforms (VSV-based SARS-CoV-2 pseudovirus neutralization, a yeast RBD display hACE2 competition, and binding affinity to mAb and hACE2) to evaluate potency loss of the selecting mAb and test activity against the mAb combination. Results: Serial passage of SARS-CoV-2 and directed evolution of the RBD protein were unable to select for resistant viral variants under the pressure of mAb combination therapy. In the same experimental paradigm, variants were identified when each mAb was evaluated alone (E484D/K/Q, F490S, Q493R, and S494P for bamlanivimab and K417N, D420N and N460K/S/T/Y for etesevimab). Neutralization and binding assessments confirmed reduced susceptibility of the variants to the single selecting mAb with 50-fold or greater reductions in potency. Importantly, aside from the Q493R variant, all other resistant viruses were neutralized by the mAb combination therapy. Conclusion: In vitro selection studies using single mAbs, bamlanivimab or etesevimab, identified key positions within the SARS-CoV-2 S-protein that have potential for viral resistance in the clinic, whereas similar studies with the mAb combination therapy were unable to select variants. Binding and competition assays confirmed the neutralization phenotyping data and indicates the mechanism of resistance is due to a reduction in binding affinity. The preclinical selection and functional characterization of resistant viral variants directly supports the observation that mAb combination therapy results in a lower frequency of treatment-emergent resistance in clinical treatment studies.