Tezepelumab Misses Primary Endpoint in Phase 2a COURSE Trial of Moderate to Very Severe COPD

In adults with moderate to very severe chronic obstructive pulmonary disease (COPD) the thymic stromal lymphopoietin inhibitor tezepelumab failed to significantly reduce the annualized rate of moderate or severe disease exacerbations over 52 weeks vs placebo, the primary endpoint of the phase 2a COURSE study. (NCT04039113).

The findings, published in The Lancet Respiratory Medicine, specifically reported an annualized rate of 1.75 for tezepelumab compared with 2.11 for placebo (rate ratio [RR], 0.83; 90% CI, 0.64-1.06; 95% CI, 0.61-1.11; P =.10), a nonsignificant change.

Subgroup analyses of the study population, however, revealed variable efficacy based on baseline blood eosinophil counts (BEC), suggesting potential benefits in specific subgroups.

Led by Dave Singh, MD, Professor of Clinical Pharmacology and Respiratory Medicine, Manchester University NHS Foundation Trust, University of Manchester, COURSE investigators also reported the annualized rate of moderate or severe COPD exacerbations over 52 weeks in patients with a baseline BEC of less than 150 cells/μL was 2.04 in the tezepelumab arm compared with 1.71 in the placebo arm (RR 1.19, 95% CI, 0·75–1·90), 1.64 compared with 2.47 (RR 0.66, 95% CI, 0.42-1.04) in participants with a baseline BEC of 150 cells/μL to less than 300 cells/μL, and 1.20 compared with 2.24 (RR 0.54, 95% CI, 0.25-1.15) in participants with a baseline BEC of 300 cells/μL or higher.1

The double-blind, randomized, multisite, placebo-controlled trial enrolled 333 participants across 10 countries in between July 30, 2019, and Oct 4, 2022. Participants had moderate to very severe airflow limitation, were receiving triple inhaled maintenance therapy, and had at least 2 moderate-to-severe COPD exacerbations in the 12 months before enrollment. The cohort for analysis was 44% women, predominantly White, and had a mean age of 67.2 years. Participants were randomly assigned to receive tezepelumab 420 mg subcutaneously every 4 weeks for up to 52 weeks. The primary endpoint was the annualized rate of moderate or severe COPD exacerbations over 52 weeks and findings were stratified by baseline blood eosinophil counts (BECs).

“The potential for redundancy in signaling effects, particularly the possibility that alternative pathways might induce or perpetuate an inflammatory state even when a specific pathway is inactivated, represents a crucial consideration when evaluating the effect of monoclonal antibodies in COPD," Mario Cazzola, Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Italy, and colleagues wrote in a related editorial.2 "Nevertheless, some observations warrant further investigation before reaching a conclusive negative assessment of the efficacy of tezepelumab in COPD.”

Cazzola also suggested that given the study period overlapped with the height of COVID-19 pandemic, a "post-hoc analysis with attention to SARS-CoV-2 presence, age, and vaccination status might provide insights into why tezepelumab performed variably across the study population." Such a follow-up, he said, could help determine whether certain subgroups might benefit from the drug," again noting that the medication should not be dismissed entirely for treatment of COPD.2

In terms of safety, adverse events (AEs) occurred in 81% of participants in the tezepelumab group and 75% of those receiving placebo. Occurrence of serious AEs was similar (30%) across the 2 groups. Singh and colleagues reported 5 deaths during the study, none of which were determined to be causally related to study treatment.1

While acknowledging the failure of the study to meet its primary endpoint in this vulnerable population, the study authors concluded that "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.”

References

Singh D, Brightling CE, Rabe KF, et al. 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. Lancet Respir. Med. 2025:13(1):47-58. doi:10.1016/S2213-2600(24)00324-2

Cazzola M, Rogliani P, Matera MG. Evaluating tezepelumab for COPD: a missed target or unmet potential? Lancet Respir. Med. 2025:13(1): 5-6. DOI: 10.1016/S2213-2600(24)00381-3