- Patel, Jatin;
- Bass, Damon;
- Beishuizen, Albertus;
- Bocca Ruiz, Xavier;
- Boughanmi, Hatem;
- Cahn, Anthony;
- Colombo, Hugo;
- Criner, Gerard;
- Davy, Katherine;
- de-Miguel-Díez, Javier;
- Doreski, Pablo;
- Fernandes, Sofia;
- François, Bruno;
- Gupta, Anubha;
- Hanrott, Kate;
- Hatlen, Timothy;
- Inman, Dave;
- Isaacs, John;
- Jarvis, Emily;
- Kostina, Natalia;
- Kropotina, Tatiana;
- Lacherade, Jean-Claude;
- Lakshminarayanan, Divya;
- Martinez-Ayala, Pedro;
- McEvoy, Charlene;
- Meziani, Ferhat;
- Monchi, Mehran;
- Mukherjee, Sumanta;
- Muñoz-Bermúdez, Rosana;
- Neisen, Jessica;
- OShea, Ciara;
- Plantefeve, Gaëtan;
- Schifano, Lorrie;
- Schwab, Lee;
- Shahid, Zainab;
- Shirano, Michinori;
- Smith, Julia;
- Sprinz, Eduardo;
- Summers, Charlotte;
- Terzi, Nicolas;
- Tidswell, Mark;
- Trefilova, Yuliya;
- Williamson, Russell;
- Wyncoll, Duncan;
- Layton, Mark
BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. METHODS: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. RESULTS: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. CONCLUSIONS: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.