Tezepelumab fails to reduce severe COPD exacerbations

medwireNews: Treatment with the monoclonal antibody tezepelumab does not significantly reduce the annualized rate of moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations compared with placebo in most patients, indicate results from the COURSE trial.

There may be some tezepelumab benefit in individuals with a baseline blood eosinophil count (BEC) of 150 cells/μL or higher, according to prespecified and post-hoc analyses; however, “further studies are required,” say the researchers.

Sandhia Ponnarambil (AstraZeneca, Cambridge, UK) and colleagues remark: “Despite the availability of triple inhaled therapy (inhaled corticosteroid–LABA [inhaled long-acting β₂ agonist]–LAMA [inhaled long-acting muscarinic antagonist]), some patients with COPD still have recurring exacerbations and require hospitalization.”

As a result, “there remains an unmet need for therapies that reduce exacerbations for the broader population of patients at increased risk,” they say in The Lancet Respiratory Medicine.

Expression of the epithelial cytokine thymic stromal lymphopoietin (TSLP) is increased in patients with COPD. The team assessed whether tezepelumab, which blocks TSLP from interacting with its heterodimeric receptor, would reduce the rate of annual COPD exacerbations in this population.

A total of 333 adults (44% women) aged a mean of 67 years were randomly assigned to receive either tezepelumab 420 mg or placebo subcutaneously every 4 weeks for 48 weeks. All the participants had moderate to very severe COPD, with a post-bronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity of less than 0.7, and a post-bronchodilator FEV₁ of 20–80% of predicted normal values.

The participants had experienced two or more moderate to severe COPD exacerbations requiring hospitalization in the 12 months before trial enrollment despite receiving triple inhaled maintenance therapy.

After trial enrollment, severe COPD exacerbations were defined as those needing hospitalization or resulting in death, and moderate exacerbations as needing treatment with systemic corticosteroids for at least 3 days, or the use of antibiotics, explain Ponnarambil et al.

At 52 weeks, the annualized rate of moderate or severe COPD exacerbations was 1.75 for those taking tezepelumab versus 2.11 for those who received placebo, resulting in a nonsignificant reduction of 17% with the trial drug.

In a prespecified subgroup analysis where the patients were stratified according to baseline BECs, the annualized rate of moderate or severe COPD exacerbations was numerically lower in those who had higher baseline BEC and were assigned to receive tezepelumab. Specifically, the rate was 46% lower compared with placebo in those with a baseline BEC of at least 300 cells/μL (20% of the cohort) and 34% lower in those with a BEC of 150–300 cells/μL (40% of the cohort).

Conversely, in participants with a baseline BEC below 150 cells/μL (40% of the cohort), exacerbations were 19% higher in those assigned to receive tezepelumab compared with placebo.

This finding was echoed in a post-hoc analysis, report the researchers, where participants with a baseline BEC of at least 150 cells/μL receiving tezepelumab had a significant 37% reduced rate of annualized COPD exacerbations compared with their counterparts receiving placebo.

A similar proportion of individuals in the tezepelumab and placebo groups experienced adverse events, at 81% and 75%, respectively, most commonly COVID-19 and COPD, while the number of serious adverse events did not differ between the groups, at 30% each.

In an accompanying comment, Mario Cazzola (University of Rome ‘Tor Vergata’, Italy) and co-authors write that while the “negative proof-of-concept finding” suggests tezepelumab is not suitable for the majority of COPD patients, the result is “not wholly surprising.”

They point out that “the potential for redundancy in signalling 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, the commentators conclude that “[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.”

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Lancet Respir Med 2024; doi.org/10.1016/ S2213-2600(24)00324-2
Lancet Respir Med 2024; doi.org/10.1016/ S2213-2600(24)00381-3