A randomized, placebo-controlled trial of the BTK inhibitor zanubrutinib in hospitalized patients with COVID-19 respiratory distress: immune biomarker and clinical findings.

Summary

Zanubrutinib produced broad anti-inflammatory biomarker changes (reduced multiple cytokines and inflammatory signaling; preserved serologic response) in hospitalized COVID-19 patients with respiratory distress, but did not improve 28-day respiratory failure-free survival or time to room air versus placebo. Concomitant steroid/antiviral therapy and small sample size likely limited detectable clinical effects.

Key Findings

• No significant difference versus placebo in 28-day respiratory failure-free survival or time to room air (cohort 1, n=63).
• Significant reductions in multiple cytokines (e.g., G-CSF, IL-10, MCP-1, IL-4, IL-13) with preserved serologic responses.
• Single-cell transcriptomics showed downregulation of IL-6/IL-8/IL-1β pathways and JAK1/STAT3/TYK2 signaling, with γδ T-cell activation.

Clinical Implications

BTK inhibition with zanubrutinib should not be expected to improve clinical recovery in hospitalized COVID-19 respiratory distress under standard-of-care co-therapies; biomarker effects may justify testing in different cytokine-driven contexts.

Limitations

• Small sample size and early discontinuation in cohort 2 reduce power and generalizability.
• High use of concomitant steroids/antivirals may mask additional clinical benefit.

Future Directions

Assess BTK inhibition in settings with less concurrent immunosuppression, earlier disease stages, or other cytokine-driven syndromes; explore biomarker-guided enrichment.