IL-33 Inhibitor Tozorakimab Cuts COPD Exacerbations
The biologic drug tozorakimab, which targets interleukin-33, significantly reduced the rate of moderate and severe exacerbations in patients with COPD
The first-in-class biologic tozorakimab reduced flare-ups for a broad range of patients with chronic obstructive pulmonary disease. These results come from two large phase III trials presented at the European Respiratory Society Congress in Barcelona and published in the New England Journal of Medicine.
Frank Sciurba, MD, of the University of Pittsburgh, presented the findings. He stated the monoclonal antibody, which targets the inflammatory protein interleukin-33, shows potential for COPD patients who continue to have exacerbations despite standard inhaled therapy.
Trial Design and Patient Population
The OBERON and TITANIA trials were replicate, double-blind studies with nearly 900 participants each. Patients were adults with COPD, both current and former smokers, who had experienced at least two moderate or one severe exacerbation in the past year while on stable maintenance therapy. The mean age across study arms was 67 to 68 years, and approximately 65% of participants were men.
Patients received a 300 mg subcutaneous injection of tozorakimab or a placebo every four weeks for 52 weeks, in addition to their usual care. Unlike previous trials for other biologics in COPD, these studies did not restrict enrollment based on patients' blood eosinophil counts.
Efficacy Results Across Populations
Tozorakimab met its primary endpoint, significantly lowering the annualized rate of moderate or severe exacerbations over one year. The benefit was seen both in former smokers and in the overall trial populations that included current smokers.
The key efficacy data from the two trials are shown in the table below.
| Population & Trial | Annualized Exacerbation Rate (Tozorakimab) | Annualized Exacerbation Rate (Placebo) | Relative Risk (95% CI) |
|---|---|---|---|
| Former Smokers - OBERON | 1.34 | 1.90 | 0.71 (0.57-0.88) |
| Former Smokers - TITANIA | 1.37 | 2.07 | 0.66 (0.55-0.80) |
| Overall - OBERON | 1.41 | 2.00 | 0.70 (0.58-0.85) |
| Overall - TITANIA | 1.44 | 2.03 | 0.71 (0.59-0.84) |
Supporting improvements were also seen in lung function and respiratory symptom scores. The change in a key quality-of-life questionnaire score trended positively but did not reach statistical significance.
Mechanism and Differentiation
Tozorakimab works by inhibiting IL-33, a protein that drives multiple inflammatory pathways linked to COPD. This mechanism is distinct from other approved biologics for COPD, such as dupilumab and mepolizumab, which target different interleukin pathways.
Lena Uller, PhD, MSc, of Lund University, served as a discussant for the presentation. She noted the drug's upstream action on the airway epithelium. "If we can block this response, we could have an effect on inflammation, not only T2 inflammation, but bronchial hyperactivity and exacerbation," Uller said.
Sciurba addressed why tozorakimab succeeded where other IL-33-targeting agents have failed in COPD trials. "IL-33 is a very complex molecule," he explained. Where the antibody binds to the molecule may be a critical factor for tozorakimab's activity.
Safety and Regulatory Path
Adverse events were common and similar between groups in both trials. Serious safety signals were rare. Major adverse cardiovascular events occurred in 0.4% of the tozorakimab group versus 0% with placebo in the pooled analysis. Deaths from serious adverse events were numerically similar between groups.
The investigators acknowledged that monitoring for rare safety events requires longer follow-up in larger populations. They also noted limitations, including a lack of systematic monitoring for adherence to background inhaled therapy.
Manufacturer AstraZeneca announced the drug is under priority review by the U.S. Food and Drug Administration. A decision on approval is expected in early 2027.
