Efficacy and safety of tezepelumab versus placebo in adults with moderate to very severe chronic obstructive pulmonary disease (COURSE): a randomised, placebo-controlled, phase 2a trial

Background: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, which has shown increased expression in patients with chronic obstructive pulmonary disease (COPD) compared with healthy individuals. We aimed to assess the efficacy and safety of tezepelumab in patients with moderate to very severe COPD despite receiving triple inhaled therapy.

Methods: COURSE was a double-blind, randomised, placebo-controlled, phase 2a trial across 90 sites in ten countries in Asia, Europe, and North America. Eligible participants were aged 40-80 years, had moderate to very severe airflow limitation, were receiving triple inhaled maintenance therapy, and had at least two moderate to severe COPD exacerbations in the 12 months before enrolment. Patients were randomly assigned (1:1) to receive tezepelumab 420 mg or placebo subcutaneously every 4 weeks for up to 52 weeks. Randomisation was stratified by geographical region and by number of exacerbations in the 12 months before enrolment. Participants, investigators, site staff, and the study sponsor were masked to treatment assignment. The primary endpoint was the annualised rate of moderate or severe COPD exacerbations over 52 weeks. A prespecified subgroup analysis assessed the primary endpoint in patients grouped by baseline blood eosinophil counts (BECs). Efficacy and safety were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04039113 (completed).

Findings: Between July 30, 2019, and Oct 4, 2022, 333 patients (mean age 67·2 years [SD 7·0]; 145 [44%] female and 188 [56%] male; 293 [88%] White, 34 [10%] Asian, and four [1%] Black or African American) were randomly assigned and treated with tezepelumab (n=165) or placebo (n=168). The annualised rate of moderate or severe COPD exacerbations over 52 weeks was 1·75 for tezepelumab versus 2·11 for placebo (rate ratio 0·83 [90% CI 0·64-1·06]; p=0·10 [one-sided]; the primary endpoint was not met). In prespecified subgroup analyses, the annualised rate of moderate or severe COPD exacerbations over 52 weeks was 2·04 with tezepelumab versus 1·71 with placebo (rate ratio 1·19 [95% CI 0·75-1·90]) in patients with a baseline BEC of less than 150 cells per μL, 1·64 versus 2·47 (0·66 [0·42-1·04]) in patients with a baseline BEC of 150 cells per μL to less than 300 cells per μL, and 1·20 versus 2·24 (0·54 [0·25-1·15]) in patients with a baseline BEC of 300 cells per μL or higher. Adverse events occurred in 133 (81%) of 165 patients in the tezepelumab group and 126 (75%) of 168 patients in the placebo group. Serious adverse events occurred in 49 (30%) patients in the tezepelumab group and 50 (30%) patients in the placebo group. Five patients died while receiving study treatment: two in the tezepelumab group and three in the placebo group. No deaths were determined to be causally related to study treatment by investigator assessment.

Interpretation: A significant reduction was not observed in the annualised rate of moderate or severe COPD exacerbations with tezepelumab versus placebo. Further studies are required to evaluate the efficacy of tezepelumab in patients with moderate to very severe COPD, particularly in patients with a baseline BEC of 150 cells per μL or higher. Tezepelumab was well tolerated, with no safety concerns identified.

Funding: AstraZeneca and Amgen.