BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.).
| Discipline Area | Score |
|---|---|
| Respirology/Pulmonology |  |
| Internal Medicine | |
| Family Medicine (FM)/General Practice (GP) |  |
| General Internal Medicine-Primary Care(US) | |
This “ab” drug appears to prevent less than one COPD exacerbation per year, on average. It will likely be very expensive and will fall to our pulmonary colleagues to prescribe and monitor.
This is statistically significant but is it clinically important? There was a small difference in exacerbation rates with no difference in respiratory quality of life. This is likely also to be priced well beyond measured cost-effectiveness.
Phase 3 multicenter trials that show significant decline in COPD exacerbation rates with tozorakimab in smokers and ex-smokers regardless of eosinophil levels. This will likely become an addition to standard therapy for patients with frequent COPD exacerbations.
This pair of RCTs shows that the anti-IL-33 biologic tozorakima added on to triple inhaled therapy for COPD reduced the risk for moderate-to-severe exacerbations. Together with the recent RCTs of astegolimab (which targets the IL-33 receptor ST2), these studies provide the first clear evidence that blocking the IL-33 pathway can be effective in the clinical management of patients with COPD patients at high risk for exacerbations. These drugs are also the first biologics to demonstrate clear efficacy in patients with COPD with low levels of eosinophils.