Clinical Pharmacology Approaches to Predict Efficacy of Monoclonal Antibodies Against Emerging SARS-CoV-2 Variants.

The onset of the global COVID-19 pandemic created an urgent need for therapeutic monoclonal antibody (mAb) development, while the rapid mutation of the SARS-CoV-2 virus and emergence of new variants presented a moving target for validation of efficacy. Since it is virtually impossible to conduct randomized controlled trials in the context of a continually evolving variant landscape, other sources of data can inform ongoing effectiveness and appropriate dosing of existing treatments against new variants. This may include data from in vitro neutralization testing, real-world studies, and clinical pharmacology studies. There are various clinical pharmacology approaches available to aid in dose selection of COVID-19 mAbs, and the approach used for initial dose selection may differ from that used to justify dose modifications in light of new variants. At present, there is no universally accepted approach that has been shown to work in all circumstances, and most of the available methods lack validation against clinical data. Here, we provide an overview of the different pharmacological approaches available for mAb dose selection or dose adjustments, outlining advantages and limitations of each as well as assumptions, data requirements, and key learnings for each method based on experiences with COVID-19 mAb development over the last 4 years. Future mAb development programs for COVID-19 or other viral infections with pandemic potential should take into consideration lessons learned from the COVID-19 pandemic and devise clinical development programs that generate data to help address new emerging variants of concern in a rapidly evolving virus landscape.