A Quantitative Modeling and Simulation Framework to Support Candidate and Dose Selection of Anti‐SARS‐CoV‐2 Monoclonal Antibodies to Advance Bamlanivimab Into a First‐in‐Human Clinical Trial

Abstract

Neutralizing monoclonal antibodies (mAb), novel therapeutics for the treatment of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2), have been urgently researched from the start of the pandemic. The selection of the optimal mAb candidate and therapeutic dose were expedited using open‐access in silico models. The maximally effective therapeutic mAb dose was determined through two approaches; both expanded on innovative, open‐science initiatives. A physiologically‐based pharmacokinetic (PBPK) model, incorporating physicochemical properties predictive of mAb clearance and tissue distribution, was used to estimate mAb exposure that maintained concentrations above 90% inhibitory concentration of in vitro neutralization in lung tissue for up to 4 weeks in 90% of patients. To achieve fastest viral clearance following onset of symptoms, a longitudinal SARS‐CoV‐2 viral dynamic model was applied to estimate viral clearance as a function of drug concentration and dose. The PBPK model‐based approach suggested that a clinical dose between 175 and 500 mg of bamlanivimab would maintain target mAb concentrations in the lung tissue over 28 days in 90% of patients. The viral dynamic model suggested a 700 mg dose would achieve maximum viral elimination. Taken together, the first‐in‐human trial (NCT04411628) conservatively proceeded with a starting therapeutic dose of 700 mg and escalated to higher doses to evaluate the upper limit of safety and tolerability. Availability of open‐access codes and application of novel in silico model‐based approaches supported the selection of bamlanivimab and identified the lowest dose evaluated in this study that was expected to result in the maximum therapeutic effect before the first‐in‐human clinical trial.

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

“…The phase 2 single-dose level of BEB (175 mg) was selected using PK/PD modeling which leveraged results from multiple BAM+ETE studies. 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 Overall, the safety data was consistent with other clinical trials investigating neutralizing mAbs to SARS-CoV-2.…”

“…The phase 2 single-dose level of BEB (175 mg) was selected using PK/PD modeling which leveraged results from multiple BAM+ETE studies. 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 .…”

“…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.…”

“…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 .…”

“…Leveraging the extensive clinical evidence that support the efficacy of neutralizing mAbs in reducing SARS-CoV-2 viral load 9,10,13-16 , candidate mAbs that maintain potency against emerging variants can be identified through the use of in vitro assays and pharmacokinetic (PK) modeling approaches 17 . In vitro virus neutralization experiments have shown to be consistent with clinical activity of authorized neutralizing mAbs, including their use for determining when an antibody should and should not be used for a particular variant 4,18,19 .…”