Tezepelumab Reduced Severe Asthma Across Phenotypes in Phase 4 PASSAGE

Final results from the phase 4 PASSAGE study presented at the American Thoracic Society (ATS) 2026 International Conference in Orlando, Florida, suggest tezepelumab may provide meaningful clinical benefit across a broad spectrum of patients with severe uncontrolled asthma, including populations frequently excluded from biologic trials, such as active smokers and patients with comorbid chronic obstructive pulmonary disease (COPD). Pivotal trials often exclude these populations because of concerns that smoking-related airway inflammation may blunt treatment response.

The multicenter, single-arm, open-label study evaluated tezepelumab in a diverse US real-world cohort of 286 patients aged ≥ 12 years with severe asthma and ≥ 2 exacerbations in the previous year. Investigators specifically enrolled patients representing different inflammatory phenotypes and traditionally underrepresented populations, including Black/African American patients, adolescents, smokers with ≥ 10 pack-years, and patients with mild-to-moderate comorbid COPD.

According to study findings, annualized asthma exacerbation rates (AAERs) declined by 70% overall after 52 weeks of treatment with tezepelumab (95% confidence interval [CI], 63 to 75). Reductions across phenotypes and underrepresented populations ranged from 54% to 77%, with consistent improvements observed regardless of eosinophil count or allergic status.

“The PASSAGE study was really important [because it included] … populations that were not part of the phase 3 clinical program,” Njira Lugogo, MD, professor of internal medicine and director of the asthma program at the University of Michigan, said in an interview at ATS 2026. The [group]… I was most excited about [was patients] with comorbid COPD and…previous or current smokers, because we really don’t have data on those patients.”

Tezepelumab targets thymic stromal lymphopoietin (TSLP), an epithelial cytokine positioned upstream in the inflammatory cascade. Because TSLP can be activated by multiple triggers, including allergens, infections, pollutants, and environmental exposures, investigators have hypothesized the therapy may provide benefit across diverse asthma phenotypes.

PASSAGE findings appeared to support that premise. Patients with eosinophilic and allergic asthma demonstrated robust responses, but clinically meaningful improvements were also observed in patients without elevated eosinophils or perennial allergen sensitization.

Lugogo noted that this broad activity is particularly relevant in routine clinical practice, where many patients have overlapping triggers and mixed inflammatory profiles.

“The majority of patients in PASSAGE actually had multiple triggers,” Lugogo said. “As a clinician, it’s important to know I can treat a broad population of patients, and I can target some of those triggers that many of our patients are exposed to.”

In addition to reductions in exacerbations, PASSAGE demonstrated improvements across multiple patient-reported outcome measures. Clinically meaningful improvements were observed in the Asthma Control Questionnaire-6 (ACQ-6; 74%), Asthma Impairment and Risk Questionnaire (AIRQ; 63%), and St George’s Respiratory Questionnaire (SGRQ; 80%) scores in most patients at week 52. The team observed improvements in these scores across asthma phenotypes and underrepresented populations: ACQ-6 (64% to 86%), AIRQ (51% to 75%), and SGRQ (63% to 91%).

Investigators also reported gains in lung function. Mean pre-bronchodilator forced expiratory volume in 1 second (FEV1) increased by 0.12 L overall, with larger improvements (0.21 L increase) among patients with baseline FEV1 ≤ 80% predicted.

Safety findings were consistent with the known profile of tezepelumab. Serious adverse events were reported in 9.8% of patients during treatment, with no unexpected safety concerns identified.

Among patients with comorbid COPD and smokers, tezepelumab demonstrated treatment effects similar to those observed in the broader study population. Lugogo said the consistency of benefit in these groups was somewhat unexpected and could have important implications for biologic eligibility decisions in clinical practice.

“Some clinicians withhold biologics until patients stop smoking,” Lugogo said. “But it’s very difficult to stop smoking, and the steroids we are giving patients are toxic. This reassures us that we can treat these active smokers and people with a significant smoking history with biologics while working to reduce their reliance on tobacco products.”

Editor’s note: Relevant disclosures for Lugogo include GlaxoSmithKline, GENZYME CORPORATION, SANOFI-AVENTIS U.S, AstraZeneca Pharmaceuticals, Regeneron Pharmaceuticals, Incyte Corporation, and more.

References

Lugogo N, Akuthota P, Sumino K, et al. (Poster Board # P1428) Tezepelumab in Diverse Real-World Patients With Severe Asthma Across Different Phenotypes and Underrepresented Populations: Final Results from the US Phase 4 PASSAGE Study. Late breaker was presented at ATS 2026 on May 18.