Tozorakimab to Prevent COPD Exacerbations

Many patients with chronic obstructive pulmonary disease (COPD) have exacerbations despite receiving standard-of-care inhaled maintenance therapy. Dysregulated interleukin-33 signaling is implicated in the pathogenesis of COPD. Tozorakimab is a monoclonal antibody that inhibits the activity of interleukin-33.

In two replicate phase 3 trials (OBERON and TITANIA), we enrolled adults with COPD who were current or former smokers and had a history of exacerbations in the previous year despite receiving stable standard-of-care inhaled maintenance therapy. There were no eligibility criteria related to blood eosinophil count. Patients were randomly assigned to receive add-on subcutaneous tozorakimab (300 mg) or placebo every 4 weeks for 52 weeks. The primary end point was the annualized rate of moderate or severe exacerbations that occurred over a 52-week period among former smokers, and the first key secondary end point was the annualized rate of moderate or severe exacerbations in the overall population. Safety was also assessed.

The overall population in OBERON included 446 patients in the tozorakimab group and 431 in the placebo group, and in TITANIA included 438 in the tozorakimab group and 435 in the placebo group. The annualized rate of moderate or severe exacerbations among former smokers was 1.34 events in the tozorakimab group and 1.90 events in the placebo group (rate ratio, 0.71; 95% confidence interval [CI], 0.57 to 0.88; P = 0.002) in OBERON, and 1.37 events and 2.07 events, respectively (rate ratio, 0.66; 95% CI, 0.55 to 0.80; P<0.001), in TITANIA. In the overall population, the annualized rate of moderate or severe exacerbations was 1.41 events in the tozorakimab group and 2.00 events in the placebo group (rate ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001) in OBERON, and 1.44 events and 2.03 events, respectively (rate ratio, 0.71; 95% CI, 0.59 to 0.84; P<0.001), in TITANIA. Adverse events occurred in 70.4% of the patients in the tozorakimab group and in 77.2% of those in the placebo group in OBERON, and in 80.1% and 79.8%, respectively, in TITANIA.

Among patients with COPD, treatment with tozorakimab resulted in a significantly lower rate of moderate or severe exacerbations than placebo in the cohort of former smokers and in the overall population of current and former smokers. (Funded by AstraZeneca; OBERON ClinicalTrials.gov number, NCT05166889; TITANIA ClinicalTrials.gov number, NCT05158387.).