Abstract: medRxiv preprint doi: https://doi.org/10.1101/2022.03.10.22272100; this version posted March 12, 2022. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .
Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly
neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19.
Authors: Michael Dougan, MD, PhD1; Masoud Azizad, MD2, Peter Chen, MD3; Barry Feldman,
MD4; Matthew Frieman, PhD5; Awawu Igbinadolor, MD6; Princy Kumar, MD7; Jason Morris,
MD8; Jeffrey Potts, MD9; Lauren Baracco, BS5; Lisa Macpherson, MSPHc10; Nicole L.
Kallewaard, PhD10; Dipak R. Patel, MD, PhD10; Matthew M. Hufford, PhD10; Linda Wietecha,
MSc10; Emmanuel Chigutsa, PhD10; Sarah L. Demmon, MS10; Bryan E. Jones, PhD10; Ajay Nirula,
MD, PhD10; Daniel M. Skovronsky, MD, PhD10; Mark Williams, MD, FCCM, FCCP10; Robert L.
Gottlieb, MD, PhD11.
Affiliations: 1Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;
2Valley Clinical Trials, Northridge, CA, USA; 3Cedars–Sinai Medical Center, Los Angeles, CA,
USA; 4Millennium Medical Group, Farmington Hills, MI, USA; 5University of Maryland School
of Medicine, Baltimore, MD; 6Monroe Biomedical Research, Monroe, NC, USA; 7Georgetown
University, Washington, DC, USA; 8Clinical Trials of Southwest Louisiana, Lake Charles, LA,
USA; 9Great Lakes Research Group, Inc., Bay City, MI, USA; 10Eli Lilly and Company,
Indianapolis, IN, USA. 11Baylor University Medical Center and Baylor Scott & White Research
Institute, Dallas, TX, USA;
Corresponding author: Robert L. Gottlieb, MD, PhD, Baylor University Medical Center and
Baylor Scott & White Research Institute, Dallas, TX, USA. E-mail:
Robert.Gottlieb@BSWHealth.org. Phone: +1-214-820-6856 (Office).
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
1
medRxiv preprint doi: https://doi.org/10.1101/2022.03.10.22272100; this version posted March 12, 2022. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .
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-tomoderate 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 COVID19 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..
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'abstract': '<jats:sec><jats:title>BACKGROUND</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>This portion '
'of the phase 2, BLAZE-4 trial (J2X-MC-PYAH; <jats:ext-link '
'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" '
'xlink:href="NCT04634409">NCT04634409</jats:ext-link>) 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<jats:sub>99</jats:sub>).</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>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<jats:sub>99</jats:sub>.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>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.</jats:p></jats:sec>',
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