Human mAb improves exacerbation rates, lung function, and quality of life

Treatment with the human monoclonal antibody tezepelumab reduced exacerbation rates and improved lung function, asthma control, and quality of life in patients with severe, uncontrolled asthma, according to results from the NAVIGATOR trial.

While monoclonal antibodies that target IgE or type 2 (T2) cytokines (interleukin-4, -5, and -13) and their receptors improve disease control for many patients with severe asthma, current biologic agents are unsuitable for a wide swath of patients, “particularly those with nonallergic or noneosinophilic phenotypes,” Andrew Menzies-Gow, MD, of Royal Brompton Hospital in London, and colleagues explained in The New England Journal of Medicine.

Tezepelumab, a human monoclonal antibody (IgG2λ) that binds to thymic stromal lymphopoietin (TSLP)—an epithelial-cell-derived cytokine correlated with airway obstruction, disease severity, and glucocorticoid resistance—showed some success for this population in the phase IIb PATHWAY trial, reducing the annualized rate of asthma exacerbations by up to 71%, irrespective of baseline levels of inflammatory biomarkers and allergic status.

Menzies-Gow and colleagues conducted the phase III, multicenter, randomized, double-blind, placebo-controlled NAVIGATOR trial to further evaluate the efficacy and safety of tezepelumab in patients ages 12-80 years with severe, uncontrolled asthma.

“The annualized rate of asthma exacerbations was significantly lower with tezepelumab than with placebo among adults and adolescents with severe, uncontrolled asthma, including those with low blood eosinophil counts (<300 cells per microliter) at baseline,” they reported, confirming the results of the PATHWAY trial.

They also found that, compared with placebo, tezepelumab led to significant improvements in forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire–6 (ACQ-6) scores, Asthma Quality of Life Questionnaire (standardized) for patients 12 years of age or older (AQLQ[S]+12) scores, and weekly mean Asthma Symptom Diary (ASD) scores, as well as substantial reductions in exacerbations that resulted in hospitalization or an emergency department visit.

The phase III NAVIGATOR trial was conducted from Nov. 23, 2017 through Sept. 8, 2020, at 297 sites spread across 18 countries. The study cohort was comprised of patients ages 12-80 years with physician-diagnosed asthma who had received medium- or high-dose inhaled glucocorticoids for at least 12 months before screening and at least one additional controller medication—with or without oral glucocorticoids—for at least three months prior to date of informed consent. Additional inclusion criteria included FEV1 less than 80% of predicted normal value (<90% for patients ages 12-17 years) during the run-in period; postbronchodilator FEV1 reversibility of at least 12% and at least 200 ml documented during the 12 months before screening or during the run-in period; and at least two asthma exacerbations in the 12 months prior to date of informed consent.

Following a five-to-six-week screening and run-in period, a total of 1,062 patients were randomized 1:1 to receive either 210 mg subcutaneous tezepelumab (n=529) or placebo (n=532) every four weeks for 52 weeks. Patients were stratified by geographic region (Asia-Pacific, central and eastern Europe, western Europe and Australia, North America, South America, or other) and age (adults or adolescents). At 52 weeks, patients entered a 12-week post-treatment follow-up period or the long-term extension study, the DESTINATION trial, the study authors explained.

The study’s primary end point was annualized exacerbation rate over a period of 52 weeks—”this endpoint was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter,” Menzies-Gow and colleagues noted. Secondary end points included FEV1 and ACQ-6 (range, 0 [no impairment] to 6 [maximum impairment]), AQLQ (range, 1 [maximum impairment] to 7 [no impairment]), and ASD (range, 0 [no symptoms] to 4 [worst possible symptoms] scores.

“The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P<0.001),” the study authors found. “In patients with a blood eosinophil count of less than 300 cells per microliter, the annualized rate was 1.02 (95% CI, 0.84 to 1.23) with tezepelumab and 1.73 (95% CI, 1.46 to 2.05) with placebo (rate ratio, 0.59; 95% CI, 0.46 to 0.75; P<0.001).” Tezepelumab also bested placebo for all secondary outcomes:

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  • Prebronchodilator FEV1: 0.23 versus 0.09 liters; difference, 0.13 liters (95% CI, 0.08 to 0.18; P<0.001).
  • ACQ-6: −1.55 versus −1.22; difference, −0.33 (95% CI, −0.46 to −0.20; P<0.001).
  • AQLQ: 1.49 versus 1.15; difference, 0.34 (95% CI, 0.20 to 0.47; P<0.001).
  • ASD: −0.71 versus −0.59; difference, −0.12 (95% CI, −0.19 to −0.04; P=0.002).

The frequencies and types of adverse events did not differ meaningfully between the two groups, the study authors added; a total of 77.1% of patients in the tezepelumab and 80.8% in the placebo group reported an adverse event, and 9.8% and 13.7% reported a serious adverse event, respectively. The percentage of patients who discontinued treatment was 6.8% and 10.7% for the tezepelumab and placebo groups, respectively—the percentages for each group who discontinued due to adverse events was 2.1% and 3.6%, respectively. The most common adverse events were nasopharyngitis, upper respiratory tract infection, headache, and asthma (which was more frequent in the placebo group than the tezepelumab group).

The incidence of severe infections and cancer did not differ between the two groups; two deaths were reported during the trial period, both in the placebo group.

Menzies-Gow and colleagues cited the relatively short trial duration (52 weeks), strict inclusion criteria—which excluded important subgroups, including smokers and those with certain coexisting conditions—and small number of adolescent participants as limitations to their study.

  1. Treatment with the human monoclonal antibody tezepelumab reduced exacerbation rates and improved lung function, asthma control, and quality of life in patients with severe, uncontrolled asthma.

  2. Tezepelumab might present a treatment option for patients with nonallergic or noneosinophilic phenotypes of severe, uncontrolled asthma who do not respond to current biologic agents.

John McKenna, Associate Editor, BreakingMED™

The NAVIGATOR trial was funded by AstraZeneca and Amgen.

Menzies-Gow reported receiving grants, advisory board fees, lecture fees, and consulting fees from and serving as a trial investigator for AstraZeneca, receiving advisory board fees from GlaxoSmithKline, receiving advisory board fees and lecture fees from Novartis, receiving lecture fees from Roche, receiving advisory board fees, lecture fees, and remuneration for travel and accommodation during conference attendance from Teva, receiving advisory board fees and consulting fees from Sanofi, and receiving consulting fees from Vectura.

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Topic ID: 89,195,730,192,195,63,925