Chris Ambrose, MD, MBA, is Franchise Head, US Biopharmaceuticals Medical, Respiratory, at AstraZeneca.

Chris Ambrose, MD, MBA

Findings from a post hoc analysis of the phase 3 DIRECTION study are shedding light on tezepelumab’s impact on exacerbations across different exacerbation trigger categories in patients with 

the American Thoracic Society (ATS) International Conference 2025

 and highlight reductions in exacerbations across multiple exacerbation trigger categories in patients treated with tezepelumab 210 mg in the 52-week DIRECTION study.

Primary results from DIRECTION showed tezepelumab reduced the annualized asthma exacerbation rate (AAER) over 52 weeks versus placebo by 74% (95% confidence interval [CI], 61-83; 

<.001) in a cohort of adult patients with severe, uncontrolled asthma in China, Republic of Korea, and the Philippines.

In the post hoc analysis presented at ATS, investigators assessed the AAER over 52 weeks in patients grouped by the following exacerbation trigger categories, as reported by investigators in the electronic case report form: infection, noninfectious inhaled trigger exposure (e.g. weather, air pollution, cold or dry air), and other (e.g. work, food, medicine) or unknown exposure. Results showed tezepelumab reduced the AAER over 52 weeks by 50% in exacerbations triggered by infection, 78% in exacerbations triggered by noninfectious inhaled trigger exposure, and 79% in exacerbations triggered by other or unknown exposure compared with placebo.

For further insight into these findings, the editorial team of 

 spoke with Chris Ambrose, MD, MPH, Franchise Head, US Biopharmaceuticals Medical, Respiratory, at AstraZeneca, in the following Q&A:

Can you explain tezepelumab’s mechanism of action and what is currently known about its use in asthma?

Tezepelumab (Tezspire) has a unique, first-in-class mechanism of action of blocking the activity of thymic stromal lymphopoietin (TSLP), a key epithelial cytokine that sits at the top of multiple inflammatory cascades. By blocking TSLP, tezepelumab interrupts the initiation and persistence of inflammation across multiple asthma phenotypes—making it effective in patients with and without elevated blood eosinophil counts.

Tezepelumab has consistently demonstrated efficacy in reducing asthma exacerbations and exacerbation-related emergency room and hospital visits, and improving lung function, symptom control, and quality of life, with the greatest improvements seen in those with elevated blood eosinophil counts. Additionally, per data presented at ATS 2025, adults with OCS-dependent severe asthma who initiated tezepelumab were able to substantially reduce or eliminate oral corticosteroid (OCS) use.

What did this post hoc analysis add to that understanding? What were some of the key findings?

 The analysis from the DIRECTION trial adds to the growing body of evidence supporting tezepelumab’s efficacy in reducing exacerbations among people living with severe asthma. DIRECTION was a randomized, placebo-controlled, Phase III trial evaluating the efficacy and safety of tezepelumab in adults with severe, uncontrolled asthma on medium to high-dose ICS and at least one additional asthma controller medication in China, South Korea, and the Philippines. Overall, 400 patients received tezepelumab 210 mg (n = 201) or placebo (n = 199). As reported previously, in DIRECTION tezepelumab reduced exacerbations by 74% (95% CI, 61–83; 

<.001) over 52 weeks compared to placebo.

This analysis examined asthma exacerbation rates in DIRECTION based on exacerbation triggers as reported by blinded study investigators. Exacerbation triggers were classified into three categories: infection (e.g. viral, bacterial), non-infectious inhaled triggers (e.g. allergens, weather, air temperature changes, air pollution, smells, smoke), and other/unknown.

Compared with placebo, tezepelumab reduced exacerbations over 52 weeks by 50% (95% CI, 11-72) for exacerbations triggered by infection, by 78% (95% CI, 41-92) for exacerbations triggered by noninfectious inhaled triggers and by 79% (95% CI, 63-88) for exacerbations triggered by other or unknown exposures.

What is the clinical significance of these data?

These results from the DIRECTION trial provide additional assurance that tezepelumab reduces exacerbations in patients with severe asthma across infectious and non-infectious exacerbation triggers. The findings align with tezepelumab’s mechanism of blocking the activity of TSLP, an epithelial cytokine released in response to numerous asthma triggers. As a result, patients and providers can be confident that tezepelumab can reduce asthma exacerbations across trigger types.

Editors’ note: Ambrose has relevant disclosures with AstraZeneca.

Ambrose CS, Yang X, Wang L, et al. Efficacy of Tezepelumab in Adults With Severe, Uncontrolled Asthma Across Multiple Exacerbation Trigger Types: The Phase 3 Direction Study [abstract]. Am J Respir Crit Care Med 2025;211:A5549. 

https://doi.org/10.1164/ajrccm.2025.211.Abstracts.A5549

Articles

Tezepelumab, a first-in-class biologic, has demonstrated significant efficacy in reducing asthma exacerbations across various trigger categories in patients with severe, uncontrolled asthma. The phase 3 DIRECTION study showed a 74% reduction in annualized asthma exacerbation rates compared to placebo. A post hoc analysis revealed reductions of 50% for infection-triggered exacerbations, 78% for noninfectious inhaled triggers, and 79% for other or unknown triggers. These findings underscore tezepelumab's potential to manage asthma exacerbations by targeting thymic stromal lymphopoietin (TSLP), a key cytokine in inflammatory pathways.

Findings from a post hoc analysis of the phase 3 DIRECTION study highlight tezepelumab’s consistent benefit on asthma exacerbations across trigger categories.