IL-33 Inhibition Reduces COPD Exacerbations in Phase III Trials

TARGETING interleukin-33 (IL-33) signalling significantly reduced moderate-to-severe chronic obstructive pulmonary disease (COPD) exacerbations in two Phase III trials involving patients who continued to experience flare-ups despite standard inhaled maintenance therapy.

The OBERON and TITANIA trials demonstrated reductions in annualised exacerbation rates of 29–34% among former smokers receiving an investigational IL-33-targeting monoclonal antibody compared with placebo. Similar reductions were observed in the overall study populations, which included both current and former smokers. The findings provide further evidence for the potential role of targeted anti-inflammatory therapies in COPD management.

Investigating IL-33 as a Therapeutic Target

COPD is a heterogeneous respiratory condition characterised by persistent airflow limitation and recurrent exacerbations, which contribute to disease burden, reduced quality of life, and healthcare utilisation.

Although inhaled maintenance therapies remain central to COPD management, some patients continue to experience moderate-to-severe exacerbations despite treatment.

Dysregulated IL-33 signalling has been implicated in COPD pathogenesis, prompting interest in therapies targeting this inflammatory pathway.

To investigate the clinical effects of IL-33 inhibition, researchers conducted two replicate randomised, placebo-controlled Phase III trials: OBERON and TITANIA.

Both trials enrolled adults with COPD who were current or former smokers and had experienced exacerbations during the preceding year despite receiving stable standard-of-care inhaled maintenance therapy.

Participants were randomly assigned to receive an investigational monoclonal antibody targeting IL-33 or placebo, administered subcutaneously every four weeks for 52 weeks alongside existing treatment.

No eligibility restrictions were applied based on blood eosinophil counts.

The primary endpoint was the annualised rate of moderate or severe exacerbations among former smokers, while the first key secondary endpoint assessed exacerbation rates across the overall population.

Significant Reductions in COPD Exacerbations

The OBERON trial included 877 patients, of whom 446 received IL-33-targeted treatment and 431 received placebo.

TITANIA enrolled 873 patients, with 438 assigned to active treatment and 435 to placebo.

Among former smokers in OBERON, annualised moderate-to-severe exacerbation rates were 1.34 events per patient-year in the treatment group and 1.90 in the placebo group.

This corresponded to a 29% lower exacerbation rate (rate ratio [RR] 0.71; 95% CI 0.57–0.88; p=0.002).

In TITANIA, the corresponding rates were 1.37 and 2.07 events per patient-year, representing a 34% reduction (RR 0.66; 95% CI 0.55–0.80; p<0.001).

The results were consistent across both trials, meeting the primary efficacy endpoint in the former-smoker populations.

However, these figures represent relative reductions in annualised exacerbation rates rather than the proportion of patients who avoided an exacerbation.

Benefits Observed Across Current and Former Smokers

The researchers also evaluated treatment effects in the overall trial populations, which included current and former smokers.

In OBERON, annualised exacerbation rates were 1.41 events per patient-year in the active-treatment group compared with 2.00 in the placebo group, corresponding to a 30% reduction (RR 0.70; 95% CI 0.58–0.85; p<0.001).

Similarly, TITANIA reported rates of 1.44 and 2.03 events per patient-year, respectively, representing a 29% reduction (RR 0.71; 95% CI 0.59–0.84; p<0.001).

These findings indicate that the treatment effect was statistically significant in the combined population of current and former smokers.

However, because the overall population included former smokers, these results do not independently establish the magnitude of benefit among current smokers alone.

Although the trials did not restrict enrolment according to blood eosinophil counts, the reported findings also do not establish whether treatment effects were consistent across different eosinophil subgroups.

Further analyses would be needed to determine whether specific inflammatory characteristics influence treatment response.

Safety Findings and Clinical Implications

Adverse event rates were broadly comparable between treatment and placebo groups across both Phase III trials.

In OBERON, adverse events occurred in 70.4% of patients receiving IL-33-targeted treatment compared with 77.2% receiving placebo. In TITANIA, the corresponding proportions were 80.1% and 79.8%, respectively.

These findings contribute to the growing evidence surrounding the safety and efficacy of IL-33 inhibition in COPD, with both trials demonstrating significant reductions in moderate-to-severe exacerbations over the 52-week treatment period.

The consistency of the efficacy findings across two large trials highlights the potential of targeting IL-33 signalling as an additional therapeutic approach for patients who continue to experience exacerbations despite standard inhaled maintenance therapy.

Importantly, the trials included patients regardless of blood eosinophil count, providing evidence from a broad population of current and former smokers with COPD.

The researchers concluded that IL-33-targeted treatment significantly reduced moderate-to-severe exacerbation rates compared with placebo in both former smokers and the overall study populations.

Further research into longer-term outcomes and treatment responses across different patient subgroups could help establish how IL-33 inhibition may contribute to more personalised COPD management.

Reference

Sciurba FC et al. OBERON and TITANIA Trial Investigators; OBERON Trial Investigators; TITANIA Trial Investigators. Tozorakimab to Prevent COPD Exacerbations. N Engl J Med. 2026 Oct 29;395(17):1703-1716.