Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID‐19 Infection

Cosson, E.; O’Brien, Lisa M.; Ferguson-Sells, Lisa; Long, Amanda; Chien, Jenny Y.

doi:10.1002/cpt.2420

Cited by 31 publications

(30 citation statements)

References 13 publications

(25 reference statements)

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“…Since bamlanivimab does not bind significantly to Spike RBD with alterations at residue E484 ( 15 , 24 ), and as the epitopes for bamlanivimab and etesevimab lie within the spike RBD ( 25 , 26 ), titers against Spike RBD E484Q, NTD, or NCP proteins solely reflect the endogenous antibody response. Titers against the full-length spike protein and the Spike-RBD, were greater among cohorts that received bamlanivimab monotherapy (all doses), as anticipated ( 27 ), and bamlanivimab and etesevimab together compared with the placebo cohort, reflecting detection of bamlanivimab and/or etesevimab ( Figure 1 ). Tracking the endogenous antibody responses against SARS-CoV-2 proteins, titers were generally lowest at baseline, with levels increasing over time and peaking around day 29 followed by slight declines in titers through day 85.…”

Section: Resultsmentioning

confidence: 65%

Endogenous Antibody Responses to SARS-CoV-2 in Patients With Mild or Moderate COVID-19 Who Received Bamlanivimab Alone or Bamlanivimab and Etesevimab Together

et al. 2021

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BackgroundNeutralizing monoclonal antibodies (mAbs) to SARS-CoV-2 are clinically efficacious when administered early, decreasing hospitalization and mortality in patients with mild or moderate COVID-19. We investigated the effects of receiving mAbs (bamlanivimab alone and bamlanivimab and etesevimab together) after SARS-CoV-2 infection on the endogenous immune response.MethodsLongitudinal serum samples were collected from patients with mild or moderate COVID-19 in the BLAZE-1 trial who received placebo (n=153), bamlanivimab alone [700 mg (n=100), 2800 mg (n=106), or 7000 mg (n=98)], or bamlanivimab (2800 mg) and etesevimab (2800 mg) together (n=111). A multiplex Luminex serology assay measured antibody titers against SARS-CoV-2 antigens, including SARS-CoV-2 protein variants that evade bamlanivimab or etesevimab binding, and SARS-CoV-2 pseudovirus neutralization assays were performed.ResultsThe antibody response in patients who received placebo or mAbs had a broad specificity. Titer change from baseline against a receptor-binding domain mutant (Spike-RBD E484Q), as well as N-terminal domain (Spike-NTD) and nucleocapsid protein (NCP) epitopes were 1.4 to 4.1 fold lower at day 15-85 in mAb recipients compared with placebo. Neutralizing activity of day 29 sera from bamlanivimab monotherapy cohorts against both spike E484Q and beta variant (B.1.351) were slightly reduced compared with placebo (by a factor of 3.1, p=0.001, and 2.9, p=0.002, respectively). Early viral load correlated with the subsequent antibody titers of the native, unmodified humoral response (p<0.0001 at Day 15, 29, 60 and 85 for full-length spike).ConclusionsPatients with mild or moderate COVID-19 treated with mAbs develop a wide breadth of antigenic responses to SARS-CoV-2. Small reductions in titers and neutralizing activity, potentially due to a decrease in viral load following mAb treatment, suggest minimal impact of mAb treatment on the endogenous immune response.

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Section: Resultsmentioning

confidence: 65%

Endogenous Antibody Responses to SARS-CoV-2 in Patients With Mild or Moderate COVID-19 Who Received Bamlanivimab Alone or Bamlanivimab and Etesevimab Together

et al. 2021

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“…The PK/PD modeling approach was deemed reliable because the approach had been previously implemented to predict the efficacious doses of BAM+ETE, before any clinical trial data was available 17 . The clinical trial data later confirmed the model predictions of 700 mg BAM and 1400 mg ETE resulting in maximum drug effect; the PK/PD modeling approach described in Chigutsa et al, 2022 17 was further strengthened and refined through incorporating the BAM+ETE clinical trial data to update the model 24 . With the modeling platform now established and validated, the objective was to replace the potency (IC 90 ) of the drug in question in the model with that of the new drug in development (BEB) and determine the dose that would result in concentrations above IC 90 up to a 28 day period and a maximum reduction in viral load.…”

Section: Discussionmentioning

confidence: 75%

“…The IV target therapeutic doses of 175 mg BEB, 700 mg BAM, and 1400 mg ETE were selected using PK/PD modeling 17,24 in order to identify a dose resulting in a drug concentration above IC 90 in ≥90% of patients for ≥28 days, and in maximum viral load reduction 13,23 . The safety, tolerability, PK and pharmacodynamics (PD) of BAM alone or together with ETE (BAM+ETE) were determined in prior clinical studies (PYAA, PYAB, PYAH) 9,13,23 .…”

Section: Methodsmentioning

confidence: 99%

“…Viral load measurements from 699 patients in the Phase 2 portion of the BLAZE-4 study were taken over a 29 day period, pooled together and analyzed using a previously reported viral dynamic model 23 . Based on this timecourse modeling approach, administration of BEB or BEB+BAM+ETE had a significant effect in increasing the elimination rate of the virus (i.e.…”

Section: Viral Dynamic Modelingmentioning

confidence: 99%

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

Dougan

Azizad

Chen

et al. 2022

Preprint

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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.

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“…While in many cases, model‐based data integration is fundamentally necessary for guiding dose selection in clinical development and contributes importantly to regulatory review, high‐impact applications that have been pivotal in driving regulatory decision making deserve special mention. One such case is presented in this issue by Chigutsa et al ., for underwriting dosage of the severe acute respiratory syndrome coronavirus 2 (SARS‐Cov‐2) neutralizing antibodies bamlanivimab and etesevimab 12 . The authors applied population pharmacokinetic/pharmacodynamic (PK/PD) modeling to elucidate the relationship between time course of concentrations of these neutralizing antibodies and time course of reduction in viral load from data collected across two ongoing phase III trials.…”

Section: Midd In Anti‐infective Development: a Case For Integrating S...mentioning

confidence: 99%

Model‐Informed Drug Development: Connecting the Dots With a Totality of Evidence Mindset to Advance Therapeutics

Venkatakrishnan

Graaf

2021

Clin Pharma and Therapeutics

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The Merriam-Webster dictionary offers the essential meaning of a model as "a usually small copy of something," or "a set of ideas and numbers that describe the past, present, or future state of something." Model-informed drug development (MIDD) involves the strategic creation and integration of mathematical models for knowledge management, predictions, and decision making in pharmaceutical research and development. These models can "connect the dots" across various inputs related to drug properties, disease biology, patient characteristics and trial designs, transforming data to knowledge, enhancing efficiency in drug discovery and development, and maximizing therapeutic potential. This issue of Clinical Pharmacology and Therapeutics (CPT) includes Original Research Articles, Reviews, and Perspectives illustrating recent advances in established and emerging areas of MIDD, highlighting opportunities for interdisciplinary and cross-sector collaboration for enhancing impact.

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Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID‐19 Infection

Cited by 31 publications

References 13 publications

Endogenous Antibody Responses to SARS-CoV-2 in Patients With Mild or Moderate COVID-19 Who Received Bamlanivimab Alone or Bamlanivimab and Etesevimab Together

Endogenous Antibody Responses to SARS-CoV-2 in Patients With Mild or Moderate COVID-19 Who Received Bamlanivimab Alone or Bamlanivimab and Etesevimab Together

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

Model‐Informed Drug Development: Connecting the Dots With a Totality of Evidence Mindset to Advance Therapeutics

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