Tezepelumab Fails Study Endpoint of Reducing Moderate-to-Severe COPD Exacerbations

Credit: Healthed

Tezepelumab was not seen to reduce the annualized rate of moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations, thus failing the primary endpoint of COURSE, a phase 2a trial (NCT04039113).¹

“A significant reduction was not observed in the annualized 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,” lead investigator Dave Singh, MD, Professor of Clinical Pharmacology and Respiratory Medicine, Manchester University NHS Foundation Trust, University of Manchester, and colleagues wrote.¹

Results from the trial were reported by Singh and colleagues in Lancet Respiratory Medicine. COURSE was a double-blind, randomized, placebo-controlled trial that enrolled 333 patients across 90 sites in 10 countries in Asia, Europe, and North America 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.¹

“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. Nevertheless, some observations warrant further investigation before reaching a conclusive negative assessment of the efficacy of tezepelumab 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

In their editorial, Cazzola and colleagues point out that one group of patients with a Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 classification, “dual bronchodilation frequently reduces moderate COPD exacerbations even in the absence of inhaled corticosteroids, particularly in patients with eosinophil counts of less than 150 cells per μL”, raising the question of why these patients should be treated with tezepelumab. They also speculated on the effect that SARS-CoV-2 infection may have affected the study’s results, with the study being conducted during the height of the COVID-19 pandemic.²

Participants were 44% female (n = 145), 88% White (n = 293), had a mean age of 67.2 years (standard deviation [SD], 7.0]), and were randomized to receive tezepelumab 420 mg (n = 165) or placebo (n = 168) 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. Investigators also stratified by baseline blood eosinophil counts (BECs) in a prespecified subgroup analysis.¹

Singh and colleagues found that the annualized rate of moderate or severe COPD exacerbations over 52 weeks was 1.75 in the tezepelumab group compared with 2.11 in the placebo group (rate ratio, 0.83 [90% CI, 0.64–1.06]; one-sided P = .10), which represented a nonsignificant change and thus did not meet the trial’s primary endpoint.¹

In subgroup analyses, the annualized rate of moderate or severe COPD exacerbations over 52 weeks in patients with a baseline BEC of less than 150 cells per μL was 2.04 in the tezepelumab arm compared with 1.71 in the placebo arm (rate ratio, 1.19 [95% CI, 0·75–1·90]), 1.64 compared with 2.47 (rate ratio, 0.66 [95% CI, 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 compared with 2.24 (rate ratio, 0.54 [95% CI, 0.25-1.15]) in patients with a baseline BEC of 300 cells per μL or higher.¹

In terms of safety, adverse events (AEs) occurred in 133 (81%) of 165 patients in the tezepelumab group and 126 (75%) of 168 patients in the placebo group. Serious AEs occurred in 49 (30%) patients in the tezepelumab group and 50 (30%) patients in the placebo group. There were 5 deaths during the study treatment period, 2 in the tezepelumab group and 3 in the placebo group, which were not determined to be causally related to study treatment by investigator assessment.¹

“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. This could help to determine whether certain subgroups might benefit from the drug, rather than dismissing it entirely for COPD treatment,” Cazzola and colleagues wrote.²

REFERENCES

1. 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): p47-58.

2. Evaluating tezepelumab for COPD: a missed target or unmet potential? Lancet Respir. Med. 2025:13(1): p5-6.