RNA Sequencing Analysis of Nasal Brushings From Participants Administered Rilzabrutinib 1200 MG Demonstrated an Impact on Multiple Pathways Relevant for Asthma

Résumé fourni par la source

Abstract RATIONALE: Rilzabrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor being investigated in asthma. In a phase 2 proof-of-concept study, rilzabrutinib was well tolerated, reduced loss of asthma control (LOAC) events, and provided clinically meaningful improvement in asthma control over 12 weeks vs placebo in participants with poorly controlled moderate-to-severe asthma. Here, the molecular mechanisms of rilzabrutinib are explored by analyzing changes in gene expression in pathways relevant to asthma. METHODS: An exploratory RNA sequencing (RNAseq) analysis was performed from nasal brushings collected during the phase 2, 12-week, double-blind, placebo-controlled, 2-staggered-cohort study in adults with moderate-to-severe asthma who were poorly controlled on inhaled corticosteroid (ICS)/long-acting β2 adrenergic agonist (LABA) therapy (NCT05104892). Participants were randomized 1:1 first to rilzabrutinib 800mg (400mg twice daily) or placebo, and then to rilzabrutinib 1200mg (400mg three times daily) or placebo added to medium-to-high-dose ICS/LABA, which was withdrawn Weeks 4-9. RNAseq data from the 1200mg cohort were analyzed using both supervised and unsupervised methods utilizing a gene set enrichment analysis. For the supervised analysis, there were 13 samples for placebo and 15 for rilzabrutinib at baseline and 13 for placebo and 13 for rilzabrutinib at Week 12. For the unsupervised analysis, samples that had a participant match at baseline and Week 12 (n=11 placebo, n=11 rilzabrutinib) were used. RESULTS: Rilzabrutinib 1200mg significantly downregulated gene expression in BTK pathways associated with the activation of eosinophils, mast cells, basophils, and B cells and asthma-related pathways (eg, B-cell activating factor, interleukin [IL]-33, granulocyte colony-stimulating factor, and IL-5) vs placebo. Rilzabrutinib 1200mg significantly upregulated pathways for ciliary function and organelle maintenance, which could be indicative of improvement in the epithelial tract since cilia are critical for cellular signaling, movement, and sensory perception. Pathways for cell cycle, DNA replication, cell development and differentiation, and transcriptional and epigenetic regulation were significantly downregulated with rilzabrutinib 1200mg, suggesting a reduction in cell proliferation, differentiation, and transcription. There was also an indication of general metabolic slowdown combined with suppression of pathways for programmed cell death, cell communication, and inflammatory/immune system functions. CONCLUSIONS: Rilzabrutinib 1200mg treatment is associated with BTK- and asthma-related pathway engagement in nasal respiratory epithelium, suggesting that rilzabrutinib 1200mg may prevent immune system activation, reduce tissue damage, and improve the respiratory tract in participants with moderate-to-severe asthma. Indeed, rilzabrutinib treatment resulted in reduced LOAC events and improvement in symptoms.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.