In the JournalsPerspective

Tezepelumab lowers asthma exacerbations vs. placebo

When compared with placebo, tezepelumab lowered clinically significant asthma exacerbations in adults with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids, regardless of blood eosinophil counts at trial onset.

The results of the phase 2 trial were published recently in the New England Journal of Medicine.

“... In some patients, asthma remains uncontrolled despite the use of available recommended therapies,” Jonathan Corren, MD, of the allergy and immunology department at the David Geffen School of Medicine at the University of California, Los Angeles, and colleagues wrote.

Researchers randomly assigned 584 adults whose asthma was uncontrolled despite receiving long-acting beta-agonist therapy and medium-to-high doses of inhaled glucocorticoids into one of four groups: 70-mg tezepelumab every 4 weeks (low dose; n = 145); 210-mg tezepelumab every 4 weeks (medium dose; n = 145); 280-mg tezepelumab every 2 weeks (high dose; n = 146); and placebo every 2 weeks for the trial’s duration (n = 148). The primary endpoint was the yearly rate of asthma exacerbations at week 52.

Corren and colleagues found that annualized asthma exacerbation rates were 0.26 for the low-dose group (61% fewer exacerbations); 0.19 for the medium-dose group (71% fewer exacerbations); 0.22 for the high-dose group (66% fewer exacerbations); and 0.67 for the placebo group. Corren and colleagues also noted that these results mirrored each other, regardless of blood eosinophil counts at baseline.

In addition, researchers wrote that the prebronchodilator forced expiratory volume in 1 second at week 52 was higher in all tezepelumab groups vs. placebo; specifically, the difference was 0.12 liters with the low dose (P = 0.01), 0.11 liters with the medium dose (P = 0.02), and 0.15 liters with the high dose (P = 0.002).

The most common adverse events were, in order, asthma, nasopharyngitis, headache and bronchitis. Two patients in the medium-dose group, three patients in the high-dose group, and one patient in the placebo group had to stop their respective regimen because of adverse events.

“These findings highlight the potential advantages of targeting an upstream cytokine such as [thymic stromal lymphopoietin], which may affect disease activity more broadly than inhibition of a single downstream pathway,” Corren and colleagues wrote. “Future studies involving large, ethnically diverse populations of patients with uncontrolled asthma using the best available small-molecule therapies, including high-dose inhaled glucocorticoids plus [long-acting beta-agonist], will be important to demonstrate the clinical importance of our findings.” – by Janel Miller

Disclosure: Corren reports he receives grant support, lecture fees and honoraria from Genentech; lecture fees from and serves on an advisory board for Teva Pharmaceuticals; grant support from Sanofi; consulting fees from and serves on an advisory board for Vectura Group; and grant support and consulting fees from Regeneron. Please see the study for a full list of the other researchers’ relevant disclosures.

When compared with placebo, tezepelumab lowered clinically significant asthma exacerbations in adults with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids, regardless of blood eosinophil counts at trial onset.

The results of the phase 2 trial were published recently in the New England Journal of Medicine.

“... In some patients, asthma remains uncontrolled despite the use of available recommended therapies,” Jonathan Corren, MD, of the allergy and immunology department at the David Geffen School of Medicine at the University of California, Los Angeles, and colleagues wrote.

Researchers randomly assigned 584 adults whose asthma was uncontrolled despite receiving long-acting beta-agonist therapy and medium-to-high doses of inhaled glucocorticoids into one of four groups: 70-mg tezepelumab every 4 weeks (low dose; n = 145); 210-mg tezepelumab every 4 weeks (medium dose; n = 145); 280-mg tezepelumab every 2 weeks (high dose; n = 146); and placebo every 2 weeks for the trial’s duration (n = 148). The primary endpoint was the yearly rate of asthma exacerbations at week 52.

Corren and colleagues found that annualized asthma exacerbation rates were 0.26 for the low-dose group (61% fewer exacerbations); 0.19 for the medium-dose group (71% fewer exacerbations); 0.22 for the high-dose group (66% fewer exacerbations); and 0.67 for the placebo group. Corren and colleagues also noted that these results mirrored each other, regardless of blood eosinophil counts at baseline.

In addition, researchers wrote that the prebronchodilator forced expiratory volume in 1 second at week 52 was higher in all tezepelumab groups vs. placebo; specifically, the difference was 0.12 liters with the low dose (P = 0.01), 0.11 liters with the medium dose (P = 0.02), and 0.15 liters with the high dose (P = 0.002).

The most common adverse events were, in order, asthma, nasopharyngitis, headache and bronchitis. Two patients in the medium-dose group, three patients in the high-dose group, and one patient in the placebo group had to stop their respective regimen because of adverse events.

“These findings highlight the potential advantages of targeting an upstream cytokine such as [thymic stromal lymphopoietin], which may affect disease activity more broadly than inhibition of a single downstream pathway,” Corren and colleagues wrote. “Future studies involving large, ethnically diverse populations of patients with uncontrolled asthma using the best available small-molecule therapies, including high-dose inhaled glucocorticoids plus [long-acting beta-agonist], will be important to demonstrate the clinical importance of our findings.” – by Janel Miller

Disclosure: Corren reports he receives grant support, lecture fees and honoraria from Genentech; lecture fees from and serves on an advisory board for Teva Pharmaceuticals; grant support from Sanofi; consulting fees from and serves on an advisory board for Vectura Group; and grant support and consulting fees from Regeneron. Please see the study for a full list of the other researchers’ relevant disclosures.

    Perspective
    Michael Blaiss

    Michael Blaiss

    This study showed tezepelumab decreased the annual asthma exacerbations in severe asthma patients. Tezepelumab was shown to block further upstream in the Type 2 high allergic pathway than previous biologics released for asthma. It was interesting that the patients who appeared to be the sickest responded the best to this treatment and were also using the highest amounts of corticosteroids. This is important because all corticosteroids have so many long-term side effects that can affect the patient. It’s important to do anything that we can to reduce the need for oral corticosteroids in patients with asthma. 

    One of the most interesting components of this study is that researchers looked at patients that fall under both the Type 2 high asthma inflammations and Type 2 low asthma inflammation who had a low IgE level and low eosinophils. We don’t currently have a lot of treatments for these type of severe asthma patients. Right now, we use microlide antibiotics and anti-fungal agents which are not approved by the FDA. We do have bronchial thermoplasty which is approved by the FDA, which is highly beneficial. It was exciting to see that the asthma exacerbation rate was decreased in not only the Type 2 high but also the Type 2 low severe asthma population.

    • Michael Blaiss, MD
    • Executive medical director, American College of Allergy, Asthma and Immunology Clinical professor of pediatrics, Medical College of Georgia

    Disclosures: Blaiss reports serving on a safety panel affiliated with this study, but resigned before receiving data.

    Perspective
    Xavier Soler

    Xavier Soler

    Asthma is a heterogeneous disease with very different clinical manifestations (phenotypes) and mechanisms implicated (endotypes). Many patients with more severe disease remain uncontrolled despite conventional therapies, such as inhaled corticosteroids, inhaled bronchodilators and oral leukotriene modifiers. This heterogeneity leads to variable patient responses to therapy.

    In this phase 2, randomized, double-blind, placebo-controlled trial, Corren and coauthors evaluated the efficacy and safety of tezepelumab — a new human monoclonal antibody specific for a substance called epithelial-cell-derived cytokine thymic stromal lymphopoietin — in patients whose asthma remained uncontrolled despite treatment with long-acting beta-agonists and medium-to-high doses of inhaled steroids. Patients treated with tezepelumab had lower rates of asthma exacerbations. The findings are relevant as tezepelumab improved asthma control in a relatively large sample of patients with moderate to severe disease. Its effect involves different pathways implicated in asthma and could reduce airway inflammation and therefore improve symptoms in a subgroup of difficult-to-control asthma patients.

    In the United States and Europe, omalizumab, mepolizumab and reslizumab are other monoclonal antibodies commercially available for the treatment of poorly controlled asthma. The repertoire of biologic agents is expanding and precision medicine recognizes that even in patients with similar presentations of disease, the underlying mechanisms can be diverse, leading to variable response to a specific drug. Therefore, the broad-spectrum biologic tezepelumab may help treat those cases by acting at an earlier stage of the inflammatory cascade compared with available single-pathway biologics (eg, IL-5 blocking agents). This may help in cases in which multiple mechanisms are involved. Theoretically, these findings have the potential advantages of targeting an earlier stage cytokine, which may affect disease activity more broadly.

    However, the superiority and safety profile of tezepelumab compared with other available (or under development) biologics needs to be investigated in future studies. Given the available new therapies, it would be important to develop a classification system (including biomarkers) to stratify treatment decisions and the optimal drug regimen that is easy to implement in the field. Some questions remain unanswered such as how to diagnose and optimally treat different asthma types or what biomarkers can be used to predict optimal responses of individual patients with asthma targeted biologics such as tezepelumab.

    • Xavier Soler, MD, PhD
    • Associate professor of medicine Associate director, Airway Research and Clinical Trials Center University of California, San Diego

    Disclosures: Soler reports receiving unrestricted grant support from Grifols USA, and serving on advisory boards for Pearl Pharmaceuticals, Astra Zeneca, Boheringer Ingelheim and Proterixbio.