BARCELONA, Spain — Add-on treatment with tozorakimab, a first-in-class monoclonal antibody targeting interleukin-33 (IL-33), significantly reduces the yearly rate of moderate and severe COPD exacerbations in patients receiving stable standard-of-care inhaled maintenance therapy.

Results from the replicate phase 3 OBERON and TITANIA trials, presented at the European Respiratory Society (ERS) 2026 International Congress and simultaneously published in The New England Journal of Medicine, demonstrated up to a 34% vs ~30% reduction in exacerbations among former smokers vs the overall study population. Efficacy was observed regardless of baseline blood eosinophil counts (BECs), airflow obstruction severity, or smoking status.

“Tozorakimab significantly reduces the annualized rate of moderate and severe exacerbations versus placebo,” said lead investigator Frank C. Sciurba, MD, professor of medicine at the University of Pittsburgh School of Medicine in Pittsburgh, Pennsylvania. “Tozorakimab, a first-in-class biologic, demonstrates a valuable potential therapeutic agent for our patients with COPD who continue to exacerbate despite guideline-based therapy.”

Addressing an Upstream Unmet Need

Despite maximum inhaled triple or dual maintenance therapy, over 50% of patients with COPD remain at a high risk for frequent exacerbations, which accelerate lung function decline, diminish quality of life, and increase mortality risk. Existing approved biologics in COPD remain restricted to patients displaying an inadequately controlled eosinophilic phenotype.

When airway lining cells are damaged by cigarette smoke, ambient pollution, or viral pathogens, they release IL-33 as an early alarm. Unlike downstream targets, IL-33 acts as an upstream driver of disease through two distinct bioactive forms. Reduced IL-33 binds ST2 receptors on inflammatory cells, driving type 1, type 2, and type 3/17 neutrophilic and eosinophilic inflammation. Oxidized IL-33 binds to receptor for advanced glycation end products and epidermal growth factor receptor complexes on epithelial cells, driving airway mucus hypersecretion and structural remodeling.

Tozorakimab targets both pathways simultaneously by neutralizing both active states of the cytokine. By locking onto reduced IL-33, tozorakimab halts acute cellular inflammation while physically preventing the protein from oxidizing into its tissue-remodeling form.

Trial Findings

OBERON (NCT05166889) and TITANIA (NCT05158387) were 52-week, double-blind, randomized, placebo-controlled trials. Adult patients aged 40 years or older with COPD, a smoking history of 10 pack-years or more, and at least two moderate or one severe exacerbation in the preceding year were randomly assigned to receive subcutaneous tozorakimab (300 mg every 4 weeks) or a matching placebo added to background inhaled triple (~90%) or dual (~10%) therapy. Enrolled patients represented Global Initiative for Chronic Obstructive Lung Disease stage I-IV severity and were included regardless of baseline BEC.

• OBERON: Enrolled 446 vs 431 patients in the tozorakimab group vs the placebo group.
• TITANIA: Enrolled 438 vs 435 patients in the tozorakimab group vs the placebo group.

The primary endpoint was the annualized moderate-to-severe exacerbation rate in former smokers. The trials reported:

• In OBERON, the rate was 1.34 vs 1.90 events/y with tozorakimab vs placebo, representing a 29% reduction.
• In TITANIA, the rate was 1.37 vs 2.07 events/y with tozorakimab vs placebo, representing a 34% reduction.

The first key secondary endpoint included the overall population, including current smokers:

• In OBERON, the annualized rate was 1.41 vs 2.00 events/y, a 30% reduction.
• In TITANIA, the annualized rate was 1.44 vs 2.03 events/y, a 29% reduction.

Separation between the active treatment and placebo arms occurred early and was sustained throughout the 52-week treatment period.

To evaluate whether the drug’s benefits held across different clinical profiles, investigators conducted a prespecified pooled analysis of both trials. The results demonstrated broad, consistent efficacy across a range of disease subgroups, addressing several historical gaps in COPD treatment:

• Across BEC. Unlike currently approved biologics that depend on elevated eosinophils, tozorakimab reduced exacerbation rates across all blood eosinophil levels. Patients with baseline counts < 150 cells/µL — a group with high unmet need and few targeted options — achieved a 23% reduction in exacerbation rate. Protection increased at higher baseline thresholds, showing a 34% reduction in those with ≥ 150 cells/µL and a 43% reduction in those with ≥ 300 cells/µL.
• Across airflow obstruction levels. Therapeutic benefits were maintained regardless of underlying lung function severity. Patients with moderate airflow limitation (forced expiratory volume in 1 second [FEV₁] > 50% predicted) experienced a 34% reduction in exacerbations, while those with severe or very severe impairment (FEV₁ ≤ 50% predicted) saw a 27% reduction.
• Across smoking statuses. Clinical efficacy extended across both former and active smokers, though former smokers derived greater benefit. Treatment led to a 32% vs 21% reduction among former smokers vs current smokers.

Addressing an audience question on why tozorakimab succeeded where other anti-IL-33 or anti-ST2 agents previously failed or produced mixed results in COPD trials, Sciurba commented: “IL-33 is a very complex molecule. It has multiple conformational states, and where the antibody binds on that molecule plausibly makes a difference, and that very well may have been the case with this molecule.”

Expert Perspective

Lena Uller, PhD, professor of respiratory immunopharmacology at Lund University in Lund, Sweden, highlighted the significance of moving therapy upstream to the airway epithelium.

“With tozorakimab, we will really move more upstream towards the airway epithelium and have more response towards these innate immune challenges. By blocking this response, we could affect inflammation, not just type 2 inflammation but bronchial hyperreactivity and exacerbation,” Uller said during her presentation discussion. “I think IL-33 might be a new interesting therapeutic target in COPD [because] it really sits at the interface between repeated epithelial injury that we know occurs in COPD patients and that IL-33 can act on multiple inflammatory pathways.”

Uller said that because IL-33 acts on structural tissue components, including smooth muscle cells, fibroblasts, and endothelial cells, targeting it hits broad disease mechanisms. “Given the heterogeneity of COPD, we need to hit very broadly when it comes to the pathogenesis,” she said. “For future research, we should for sure move towards a more personal treatment approach, and [these] studies show that this might be possible.”

Sciurba reported receiving consultation fees from AstraZeneca, Genentech, GSK, Merck, Sanofi, Regeneron, United Therapeutics Corporation, and Uniquity Bio. The studies were funded by AstraZeneca. Uller declared having no conflicting financial relationships.

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.