Results from the NAVIGATOR study of tezepelumab showed that treatment of adults and adolescents with severe, uncontrolled asthma with the new biologic led to a large reduction in exacerbations requiring hospital stays and ED visits.
Tezepelumab, codeveloped by Amgen and AstraZeneca, has a novel mechanism of action. It blocks thymic stromal lymphopoietin (TSLP), which is a cytokine produced by epithelial cells. TSLP levels correlate with airway obstruction, severity of disease, and glucocorticoid resistance. TSLP is involved in T2 inflammation within the airway, but also plays a role in the interactions between airway cells and immune cells, which doesn’t rely only solely on T2 inflammation. That broad mechanism of action distinguishes tezepelumab from most other biologics for the treatment of asthma, which are more targeted.
“By working at the top of the cascade, tezepelumab helps stop inflammation at a key source. Clinical trials with tezepelumab showed a clinical benefit in patients irrespective of their baseline biomarker level, including patients with low eosinophil levels at baseline,” said Jean-Pierre Llanos-Ackert, MD, who is executive medical director and global medical affairs lead for tezepelumab at Amgen.
Dr. Praveen Akuthota
The primary endpoint data look robust, according to Praveen Akuthota, MD, who is an associate professor of medicine at the University of California, San Diego, and comoderated the session at the American Thoracic Society’s virtual international conference, where the research was presented. The study was also published on May 13, 2021, in the New England Journal of Medicine. The conference session included updated results.
The drug holds promise, but more study is needed. “The question really will be, how is this drug different from the existing biologics? How much better is this drug in patients who have borderline T2 biomarkers, or even low T2. The study does show some efficacy in patients whose T2 signals may not be as robust. We’ll have to see with ongoing longitudinal data, how this drug positions, compared to the other agents. It’s obviously exciting, though, to have another option, given that we know what our current armamentarium of agents there are still nonresponders,” said Dr. Akuthota in an interview.
The other comoderator in the session, Laura Crotty Alexander, MD, commented: “It seems like it might work possibly even better than some that are directly covering one pathway only. Hopefully, this agent will be efficacious in a broader population than some of the more targeted biologics.” Dr. Alexander is an associate professor of medicine at the University of California, San Diego, and section chief of pulmonary critical care at the Veterans Affairs San Diego Healthcare System.
She pointed out that physicians often think of asthma patients in broad brush terms, as high or low T2, or T2 high and Th1 or neutrophilic or obese, but many patients present a more complicated picture. “There is some overlap across those phenotypes, such that an agent that works really well for one group doesn’t mean that it won’t have an impact, especially clinically, on some of these other phenotypes,” said Dr. Alexander.
Dr. Akuthota agreed. “Having options for patients whose biomarkers are not maybe as clear is, I think, important.”
Promising results
The study included 1,059 patients aged 12-80 who received 210 mg tezepelumab or placebo. Over 52 weeks, the treatment group had a 79% reduction in exacerbations requiring hospitalization or an ED visit, compared with placebo (rate ratio, 0.21; 95% confidence interval, 0.12-0.37), and an 85% reduction in exacerbations requiring hospitalization (RR, 0.15; 95% CI, 0.07-0.33). The drug increased the time to first exacerbation requiring hospitalization that required hospitalization or an ED visit, reducing risk by 65% (hazard ratio, 0.35; 95% CI, 0.22-0.56).
Fewer patients in the treatment group than placebo used asthma-related health care resources, including: ED visits (32 vs. 94), unscheduled visit to a specialist (285 vs. 406), telephone calls to a health care provider (234 vs. 599), ambulance transport (5 vs. 22), and home visits from a health care provider (18 vs. 22). Fewer patients in the tezepelumab group had hospital stays (3.2% vs. 7.0%), and they had a lower total number of hospital days (108 vs. 497) and days in the ICU (0 vs. 31).
The study was funded by Amgen and AstraZeneca. Dr. Llanos-Ackert is an employee of Amgen. Dr. Alexander has no relevant financial disclosures. Dr. Akuthota has consulted for AstraZeneca and participated in their clinical trials.