Transcriptomic and proteomic assessment of tocilizumab response in a randomized controlled trial of patients hospitalized with COVID-19

Haridha Shivram; Jason A Hackney; Carrie M Rosenberger; Anastasia Teterina; Aditi Qamra; Olusegun Onabajo; Jacqueline McBride; Fang Cai; Min Bao; Larry Tsai; Aviv Regev; Ivan O Rosas; Rebecca N Bauer

doi:10.1016/j.isci.2023.107597

Transcriptomic and proteomic assessment of tocilizumab response in a randomized controlled trial of patients hospitalized with COVID-19

iScience. 2023 Aug 11;26(9):107597. doi: 10.1016/j.isci.2023.107597. eCollection 2023 Sep 15.

Affiliations

¹ Genentech, South San Francisco, CA 94080, USA.
² Hoffmann-La Roche Ltd, Mississauga, ON L5N 5M8, Canada.
³ Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

High interleukin (IL)-6 levels are associated with greater COVID-19 severity. IL-6 receptor blockade by tocilizumab (anti-IL6R; Actemra) is used globally for the treatment of severe COVID-19, yet a molecular understanding of the therapeutic benefit remains unclear. We characterized the immune profile and identified cellular and molecular pathways modified by tocilizumab in peripheral blood samples from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial of the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19. We identified markers of inflammation, lymphopenia, myeloid dysregulation, and organ injury that predict disease severity and clinical outcomes. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab and identified novel pharmacodynamic biomarkers. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysregulation associated with severe COVID-19, indicating greater anti-inflammatory activity relative to placebo and potentially leading to faster recovery in patients hospitalized with COVID-19.

Keywords: Omics; Pharmaceutical science; Virology.