Tezepelumab Improves Severe Asthma Exacerbation, Disease Control in Phase 3 NAVIGATOR

Andrew Menzies-Gow, MD

New findings from the phase 3 NAVIGATOR trial show investigative monoclonal antibody tezepelumab is associated with reduced exacerbations and improved lung function and disease control versus placebo among patients with severe, uncontrolled asthma.

The new research, featuring patients aged 12-80 years old, show a wide-reaching effect of the thymic stromal lmphoypoietin (TSLP) inhibitor when administered subcutaneously over 1 year of care.

Investigators, led by Andrew Menzies-Gow, MD, of the Royal Brompton Hospital in London, sought to observe the efficacy and safety of the investigative drug from AstraZeneca and Amgen, following clinical trial successes showing inhibition of the asthma pathogenesis-implicated cytokine which tezepelumab targets is associated with symptomatic benefit.

Their multicenter, randomized, double-blind, placebo-controlled trial compared 210 mg tezepelumab to placebo placebo, administered subcutaneously every 4 weeks over 52 weeks of assessment. They sought a primary endpoint of annualized asthma exacerbation rate over the 52-week period. Menzies-Gow and colleagues additionally assessed their endpoint among patients with blood eosinophil counts of <300 cells/mL at baseline.

The team additionally sought secondary endpoints of tezepelumab’s effect on forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire-6 (ACQ-6), with 0 representing no asthma impairment and 6 representing maximum impairment.

Additional assessments included the Asthma Quality of Life Questionnaire (AQLQ) ranging from 1 (maximum impairment) to 7 (no impairment), and the Asthma Symptom Diary (ASD), ranging from 0 (no symptoms) to 4 (worst possible symptoms).

Their patient population included 1061 patients aged 12-80 years old with severe, uncontrolled asthma, randomized to either tezepelumab (n = 529) or placebo (n = 532).

Patients administered therapy reported 0.93 annualized asthma exacerbation rates (95% CI, 0.80 – 1.07), versus 2.10 among placebo recipients (95% CI, 1.84 – 2.39; P <.001).

Among patients with blood eosinophil counts <300 cells/mL, annualized rate with tezepelumab was 1.02 (95% CI, 0.84 – 1.23) versus 1.73 with placebo (95% CI, 1.46 – 2.05).

Prebronchodilator FEV1improvements were greater at 52 weeks among patients administered tezepelumab versus placebo (0.23 L vs 0.09 L; difference, 0.13 L; P <.001). Scores on ACQ-6, AQLQ, and ASD were additionally improved among tezepelumab patients at week 52 versus placebo.

Adverse events were generally as frequent and at the same level of severity among tezepelumab- and placebo-treated patients, investigators noted.

The findings would indicate metrics of severe asthma—including exacerbations, lung function, asthma control, and quality of life—were significantly improved with 52 weeks of tezepelumab versus placebo.

“Tezepelumab simultaneously reduced blood eosinophil count and levels of FENO and IgE; these findings suggest that the drug suppresses multiple inflammatory pathways,” investigators wrote. “The effect of tezepelumab on these biomarker levels may be related to decreased interleukin-5 and interleukin-13 levels.”

In an interview with HCPLive during the American Academy of Allergy, Asthma & Immunology (AAAAI) 2021 Virtual Sessions, Menzies-Gow discussed NAVIGATOR findings showing tezepelumab’s associated benefit in reduced hospitalization risk among treated patients with severe asthma.

At the time of the findings, he discussed the unique mechanisms of tezepelumab in treating asthma which make it among the most interesting treatment candidates in the disease space.

“The excitement around tezepelumab is really around its unique mechanism of action,” he explained. “With tezepelumab, we’re targeting TSLP—so we’re going upstream, we’re looking at one of the epithelial-derived cytokines, which really drives all the downstream inflammation.”

Fellow tezepelumab investigator Jonathan Corren, MD, a Los Angeles-based allergist, told HCPLive last year that the biologic therapy may have atopic disease treatment properties that would make it applicable to inflammatory conditions beyond asthma.

“Because the drug may have very profound effects in modifying the type 2 inflammatory response, we’ll have to examine the possibility that you can give it for shorter periods of time,” Corren explained. “But that’s not well established.”

The study, “Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma,” was published online in The New England Journal of Medicine.