New data on tozorakimab, an anti‑IL‑33 monoclonal antibody, suggest it may calm several inflammatory pathways that drive COPD, not just the eosinophil‑linked signals that have dominated earlier biologic research. The findings were unveiled during the European Respiratory Society Congress in September 2026, where the data were presented as a late‑breaking abstract.
Proteomic study shows multi‑pathway suppression
The late‑breaking analysis came from the phase 2a FRONTIER‑4 trial, which enrolled 135 adults with moderate‑to‑severe disease and chronic bronchitis. Participants received either 600 mg of the therapy subcutaneously every four weeks for 28 weeks or a matching placebo.
Researchers collected nasal lining fluid from 99 patients and sputum from 50, then repeated sampling after the treatment period for 90 and 36 subjects respectively. Using the NULISA 250 Inflammatory Panel, they categorized protein activity into type 1 (antiviral‑cytotoxic), type 2 (allergic‑eosinophilic) and type 3 (neutrophilic‑epithelial) pathways. The NULISA 250 platform quantifies dozens of cytokines and chemokines, enabling a granular view of airway inflammation.
In nasal samples, the biologic lowered protein signals across all three categories compared with placebo. Sputum showed a narrower effect, mainly in type 1 and type 2 markers, a difference the authors linked to distinct cellular make‑up of the two sample types. Differences in cellular composition—epithelial‑dominant nasal fluid versus neutrophil‑rich sputum—likely drive the distinct protein responses.
Beyond the core groups, several additional immune‑response proteins were down‑regulated in nasal fluid, while sputum results were mixed. After statistical correction, only IL‑5 in nasal lining fluid remained significant.
Earlier trial results and the move to phase 3
The proteomic findings build on the original FRONTIER‑4 outcomes, which did not meet the primary endpoint of change in pre‑bronchodilator FEV1 at week 12. Nevertheless, the study reported numerical FEV1 gains, fewer exacerbations and reduced circulating type 2 biomarkers in a high‑risk subgroup.
In March 2026, AstraZeneca announced that the antibody met primary endpoints in both the OBERON (NCT05166889) and TITANIA (NCT05158387) phase 3 trials, cutting the annualized rate of moderate‑to‑severe exacerbations among former smokers.
“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,” said Dr Frank Sciurba, chief investigator of the LUNA program.
The LUNA program now tests the agent in a larger cohort of symptomatic patients with a history of exacerbations. If the eosinophil‑independent effect holds, it could break the biomarker‑gated model that limits current biologics such as dupilumab, which is approved only for the eosinophilic phenotype.
Patients without a clear type 2 signature have had few options; only about 20‑40 % of the COPD population exhibits T2 inflammation. An approach that simultaneously modulates type 1, type 2 and type 3 pathways could therefore reach a substantially larger segment.
The data also reveal that IL‑33 operates in two bioactive forms, reduced and oxidized, that signal through distinct receptors, ST2 and RAGE/EGFR. By blocking both routes, the antibody differs from agents that target only the IL‑4/13 or IL‑5 axis.
This mechanism suggests the antibody could affect disease driven by viral‑like triggers, eosinophils, or neutrophilic inflammation.
Potential impact on COPD management
Given that exacerbations drive hospitalizations and mortality, any reduction in their frequency is clinically important. The phase 3 results already show a statistically significant drop in moderate‑to‑severe events, a finding that aligns with the mechanistic suppression observed in the proteomic sub‑study.
For patients, the prospect of a single injection every month that tackles several inflammatory routes is appealing.
Overall, the emerging evidence positions the antibody as a potential first‑line biologic for a wider COPD audience, moving beyond the narrow eosinophilic niche that has defined the field for years.
A new era may be dawning.
