Tozorakimab Curbs Multiple COPD Inflammatory Pathways, ERS Data Show

An anti–IL-33 monoclonal antibody showing efficacy signals in chronic obstructive pulmonary disease (COPD) appears to do more than quiet the eosinophil-driven inflammation that has anchored most COPD biologic development to date. New proteomic data show tozorakimab (AstraZeneca) also dampens antiviral and neutrophilic signaling pathways in the airway, according to a late-breaking mechanistic analysis of the phase 2a FRONTIER-4 study presented at the European Respiratory Society Congress, held September 5-9, 2026, in Barcelona, Spain.¹

IL-33 exists in 2 bioactive forms, reduced and oxidized, that signal through separate receptors, ST2 and RAGE/epidermal growth factor receptor (EGFR), respectively, and dysregulation of both arms has been implicated in COPD. Tozorakimab is designed to block signaling from both forms, differentiating it from biologics that target only the IL-4/13 or IL-5 axis.

What the New Proteomic Analysis Found

FRONTIER-4 (NCT04631016) randomized 135 adults with moderate-to-severe COPD and chronic bronchitis 1:1 to tozorakimab 600 mg (n = 67) or placebo (n = 68), administered subcutaneously every 4 weeks for 28 weeks.^1,2 As part of a smaller proteomic sub-study, researchers analyzed samples from the nasal lining fluid of 99 patients and from the coughed-up lung mucus of 50 patients at baseline and again 28 weeks later from 90 and 36 patients, respectively. Using the NULISA 250 Inflammatory Panel, a targeted proteomics platform, they tracked which immune pathways were active before and after treatment and sorted the signals into 3 categories: type 1 (T1, antiviral-cytotoxic), type 2 (T2, allergic-eosinophilic), and type 3 (T3, neutrophilic-epithelial), plus a broader set of other inflammation-related markers.

In nasal samples, tozorakimab was associated with reduced protein activity compared with placebo across all 3 categories. In sputum, the effect was narrower, with inhibition seen predominantly in T1 and T2 proteins, which the investigators attributed partly to differences in the cellular composition of the 2 sample types. Beyond the 3 core categories, tozorakimab was linked to downregulation of proteins across several additional immune-response categories in nasal lining fluid, with more mixed results in sputum. Only IL-5 in nasal lining fluid remained statistically significant after correction for multiple comparisons.

How Does This Build on the Original FRONTIER-4 Results?

The proteomic findings extend FRONTIER-4's original clinical findings. In that earlier analysis, tozorakimab did not meet its primary end point of change in pre-bronchodilator forced expiratory volume in 1 second (FEV₁) at week 12 in the intent-to-treat population, but it did show numerical improvements in FEV₁ and fewer COPD exacerbations, along with reductions in circulating T2 biomarkers and mucus plugging, in a subgroup of patients at high risk of exacerbations.² The new mechanistic data were positioned by the authors as context ahead of the phase 3 LUNA program, which is testing tozorakimab in a larger population of symptomatic patients with COPD and a history of exacerbations.³

In late March 2026, AstraZeneca reported that tozorakimab met its primary end point in both the OBERON (NCT05166889) and TITANIA (NCT05158387) trials, reducing the annualized rate of moderate-to-severe COPD exacerbations compared with placebo in former smokers, the trials’ primary population.⁴

“These trial results suggest that targeting the IL-33 pathway with tozorakimab delivers meaningful clinical benefit in a trial representing a broad COPD population, independent of smoking status and eosinophilic levels,” Frank Sciurba, MD, FCCP, professor of Pulmonary and Critical Care Medicine at the University of Pittsburgh and chief investigator of the LUNA program, said in a statement at the time.

Why Might Targeting Beyond Type 2 Inflammation Matter?

Only about 20% to 40% of patients with COPD show the signs of T2 inflammation.⁵ The first biologic approved for COPD, dupilumab (Dupixent; Sanofi and Regeneron), was approved only for patients with the eosinophilic phenotype, a marker of T2 inflammation, based on the phase 3 BOREAS and NOTUS trial results, which has left the patients without a clear T2 signature with no biologic option.⁶ 

An agent capable of modulating T1, T2, and T3 pathways simultaneously could address a larger share of the COPD population than eosinophil-selective therapies.

For tozorakimab, if the eosinophil-independent effect holds up in the complete data set, it would mark a departure from the biomarker-gated access pathway used for dupilumab and other T2-targeted respiratory biologics.

References

1. De Palo G, Cheemalavagu N, Kelly A, et al. Tozorakimab modulates COPD airway biology beyond type 2 inflammation: insights from the Ph2 FRONTIER-4 study. Presented at: ERS Congress 2026; September 5-9, 2026; Barcelona, Spain.
2. Singh D, Guller P, Reid F, et al. A phase 2a trial of the IL-33 monoclonal antibody tozorakimab in patients with COPD: FRONTIER-4. Eur Respir J. 2025;66(1):2402231. doi:10.1183/13993003.02231-2024
3. Watz H, Sciurba FC, Bonini M, et al. Phase III LUNA clinical programme: design of four randomised, double-blind, placebo-controlled studies assessing the efficacy and safety of tozorakimab in patients with symptomatic COPD and a high risk of exacerbations. BMJ Open Respir Res. 2026;13(1):e004145. doi:10.1136/bmjresp-2026-004145
4. Tozorakimab met primary endpoint in both OBERON and TITANIA phase III trials in patients with COPD. News release. AstraZeneca. March 27, 2026. Accessed September 6, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/tozorakimab-met-primary-endpoint-in-oberon-titania-phase-iii-trials-in-patients-with-copd.html
5. Vanetti M, Visca D, Ardesi F, Zappa M, Pignatti P, Spanevello A. Eosinophils in chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2025:19:17534666251335800. doi:10.1177/17534666251335800
6. McCormick B. FDA approves dupilumab as first biologic treatment for COPD. AJMC^®. September 27, 2024. Accessed September 6, 2026. https://www.ajmc.com/view/fda-approves-dupilumab-as-first-biologic-treatment-for-copd