Abstract Rationale Interleukin-33 (IL-33), an alarmin cytokine, is implicated in the initiation and progression of asthma.1 Tozorakimab uniquely inhibits the reduced IL-33red–ST2 and oxidized IL-33ox–RAGE/EGFR pathways.2 FRONTIER-3 (NCT04570657) was a phase 2a, proof-of-concept study investigating tozorakimab in adults with moderate-to-severe, early-onset asthma. Although FRONTIER-3 did not meet its primary endpoint, improved pre-BD-FEV1 levels were observed with tozorakimab in patients with ≥2 prior exacerbations. Tozorakimab also reduced serum levels of the type 2 (T2) cytokines, IL-5 and IL-13.1 This study evaluated further pharmacodynamic responses and the mechanism of action (MoA) of tozorakimab in patients from FRONTIER-3 using novel Minimally-Invasive Precision Sampling (MIPS) of the nasal airway as a surrogate for the lung. Methods Nasal lining fluid (nasosorption), nasal tissue (Rhino-Pro curettage) and blood (PAXgene RNA tube) were collected at baseline, week 4 and week 16 from asthma patients receiving tozorakimab (300 and 600 mg) or placebo Q4W. Biomarker studies used RNA sequencing (AstraZeneca), immunoassays (Mesoscale Discovery) and proteomics (NULISA, Alamar). Results Target engagement for tozorakimab in the nasal airway was confirmed with increased concentrations of free IL-33red (via complexing with tozorakimab) and decreased concentrations of IL-33ox.3 At weeks 4 and 16, tozorakimab reduced T2 cytokines associated with airway inflammation and mucus production, as well as type 1 (T1) inflammatory chemokines associated with NK and other T1-immune cell recruitment, and immune responses to viral infection in nasal lining fluid compared with placebo (Table 1). Tozorakimab also inhibited similar T2 and T1 inflammatory gene-expression pathways compared with baseline levels. Furthermore, tozorakimab enhanced gene-expression pathways associated with airway epithelial ciliation. In contrast to the airway, blood transcriptomics provided limited insight into tozorakimab pharmacodynamics and MoA, but showed concordance with T2 inflammatory pathway inhibition in the airway. Conclusions This study used MIPS of the nasal airway of asthma patients from FRONTIER-3 to demonstrate tozorakimab’s broad impact on airway inflammation and epithelial remodeling is potentially differentiated from T2-targeted asthma biologics. The greater impact of tozorakimab on airway inflammatory and epithelial remodeling pathways, relative to circulating biomarkers, is consistent with evidence that IL-33 is a locally active alarmin.4 These results provide insights into the potentially differentiated MoA of tozorakimab and enable optimal MIPS strategies for analyses of the ongoing phase 2b study in uncontrolled moderate-to-severe asthma patients (UMBRIEL, NCT06932263). 1Corren J et al. ERJOpenRes 2025;00183–2025. 2England E et al. SciRep 2023;13:9825. 3Reid HM et al. FrontPharmacol 2023;14:1296188. 4Scott IC et al. MucosalImmunol 2025;18:312–15. This abstract is funded by: AstraZeneca
Rytelewski et al. (Fri,) studied this question.