Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19
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Abstract
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% (IC 99 ).
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 IC 99 .
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.
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SciScore for 10.1101/2022.03.10.22272100: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Patients or their legally authorized representatives provided written informed consent and child/adolescent assent, as appropriate, prior to participation. Sex as a biological variable not detected. Randomization STUDY DESIGN: This portion of the BLAZE-4 trial (NCT04634409) is a randomized, single-dose, Phase 1/2 study in ambulatory patients in the United States, presenting with mild-to-moderate COVID-19, within 3 days of first positive test for SARS-CoV-2 infection. Blinding not detected. Power Analysis For the placebo-controlled cohort (Low-risk), the sample size was determined with 84% power and an assumed PHVL rate of 28% in the placebo arm and 12% in the BEB and BEB+BAM+ETE arms at … SciScore for 10.1101/2022.03.10.22272100: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Patients or their legally authorized representatives provided written informed consent and child/adolescent assent, as appropriate, prior to participation. Sex as a biological variable not detected. Randomization STUDY DESIGN: This portion of the BLAZE-4 trial (NCT04634409) is a randomized, single-dose, Phase 1/2 study in ambulatory patients in the United States, presenting with mild-to-moderate COVID-19, within 3 days of first positive test for SARS-CoV-2 infection. Blinding not detected. Power Analysis For the placebo-controlled cohort (Low-risk), the sample size was determined with 84% power and an assumed PHVL rate of 28% in the placebo arm and 12% in the BEB and BEB+BAM+ETE arms at Day 7. Table 2: Resources
Antibodies Sentences Resources To define baseline serostatus, a qualitiative assay (Roche, Elecsys® Anti-SARS-CoV-2) confirmed the presence or absence of antibodies specific only to the nucleocapsid protein of SARS-CoV-2. DOSE JUSTIFICATION: The IV target therapeutic doses of 175 mg BEB, 700 mg BAM, and 1400 mg ETE were selected using PK/PD modeling17,24 in order to identify a dose resulting in a drug concentration above IC90 in ≥90% of patients for ≥28 days, and in maximum viral load reduction13,23. Anti-SARS-CoV-2suggested: NoneExperimental Models: Organisms/Strains Sentences Resources Three different SARS-CoV-2 isolates were tested from three different lineages; WA1 (Washington 1 isolate; 2019-nCoV/USA-WA1/2020, CDC [USBI, BEI]), delta (B.1.617.2; obtained from Dr. Andy Pekosz at Johns Hopkins Bloomberg School of Public Health; hCoV-19/USA/MD-HP05285/2021), and omicron (B.1.1.529/BA.1); obtained from Dr. Mehul Suthar at Emory; GISAID accession #EPI_ISL_7171744). B.1.617.2suggested: NoneB.1.1.529/BA.1)suggested: NoneResults from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:There are several limitations to this study. The study limited recruitment exclusively to the United States. As noted previously, placebo-controlled data was limited to patients at Low risk for severe disease. Thus, we could not demonstrate statistically significant differences in viral clearance or rapid resolution of symptoms in patients at increased risk for severe disease between two active therapies at a time when circulating variants largely remained susceptible to BAM+ETE. This proof-of-concept study was also not powered to examine improvements in clinical outcomes in those with active treatment; however, the proportion of patients with COVID-19 related hospitalization and all cause mortality are in line with similar observations with other mAbs to SARS-CoV-2. Finally, this study was conducted over the spring and summer of 2021, prior to the emergence of omicron in November 2021. There are no clinical data evaluating the clinical efficacy of BEB in patients infected with omicron; however, non-clinical pseudovirus data with all sublineages of omicron (including BA.2 ) and confirmatory authentic omicron SARS-CoV-2 virus neutralization assays presented here indicate that BEB is effective in neutralizing omicron20. Moreover, this same limitation would be applicable to any EUA product studied at an earlier phase of the pandemic, and for which surrogates of antiviral efficacy would also be required. The BLAZE-4 study enrolled its last patient in July 2021. At that time, the ...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04634409 Completed A Study of Immune System Proteins in Participants With Mild … NCT03383419 Recruiting Transplant of Redeemed Organs by Judicious Administration of… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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