Tezepelumab normalizes serum interleukin-5 and -13 levels in patients with severe, uncontrolled asthma

Abstract

Asthma is a chronic, heterogeneous disease of the airways that involves a multitude of inflammatory processes triggered by various airborne stimuli. Thymic stromal lymphopoietin (TSLP)—an epithelial cell–derived cytokine produced in response to triggers such as allergens, viruses, or pollutants—has a central role in activating and maintaining downstream inflammatory processes in asthma.1Gauvreau GM Sehmi R Ambrose CS Griffiths JM. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma.Expert Opin Ther Targets. 2020; 24: 777-792Crossref PubMed Scopus (49) Google Scholar Tezepelumab is an anti-TSLP human monoclonal antibody. In the PATHWAY phase 2b (NCT02054130) and NAVIGATOR phase 3 (NCT03347279) studies, tezepelumab significantly reduced exacerbation rates vs placebo in patients with severe, uncontrolled asthma.2Corren J Parnes JR Wang L et al.Tezepelumab in adults with uncontrolled asthma.N Engl J Med. 2017; 377: 936-946Crossref PubMed Scopus (505) Google Scholar,3Menzies-Gow A Corren J Bourdin A et al.Tezepelumab in adults and adolescents with severe, uncontrolled asthma.N Engl J Med. 2021; 384: 1800-1809Crossref PubMed Scopus (139) Google ScholarImportant downstream drivers of the asthma inflammatory response include the type 2 cytokines interleukin (IL)-5 and IL-13. The major cellular sources of IL-5 are type 2 T helper (TH2) cells and type 2 innate lymphoid cells (ILC2s). IL-5 acts as an amplifier of eosinophilic inflammation by enhancing eosinophil maturation, proliferation, and survival,4Adachi T Alam R. The mechanism of IL-5 signal transduction.Am J Physiol. 1998; 275: C623-C633Crossref PubMed Google Scholar which may result in airway remodeling.5Pelaia C Paoletti G Puggioni F et al.Interleukin-5 in the pathophysiology of severe asthma.Front Physiol. 2019; 10: 1514Crossref PubMed Scopus (79) Google Scholar IL-13, produced largely by TH2 cells, ILC2s, mast cells, and basophils, contributes to immunoglobulin E synthesis and may lead to elevated fractional exhaled nitric oxide levels, airway hyperresponsiveness, and mucus hypersecretion.6Corren J. Role of interleukin-13 in asthma.Curr Allergy Asthma Rep. 2013; 13: 415-420Crossref PubMed Scopus (130) Google Scholar Biomarkers of IL-5 and IL-13 activity—blood eosinophil counts and fractional exhaled nitric oxide levels—were substantially reduced after TSLP blockade with tezepelumab in PATHWAY.2Corren J Parnes JR Wang L et al.Tezepelumab in adults with uncontrolled asthma.N Engl J Med. 2017; 377: 936-946Crossref PubMed Scopus (505) Google Scholar This post hoc analysis aimed to evaluate serum IL-5 and IL-13 levels before and after treatment with tezepelumab in PATHWAY participants relative to levels observed in a separate cohort of healthy individuals.PATHWAY was a multicenter, randomized, double-blind, placebo-controlled study conducted at 108 sites across 12 countries. The full study design and inclusion criteria have been described previously.2Corren J Parnes JR Wang L et al.Tezepelumab in adults with uncontrolled asthma.N Engl J Med. 2017; 377: 936-946Crossref PubMed Scopus (505) Google Scholar Eligible patients were current nonsmokers, aged 18 to 75 years, with severe asthma that was inadequately controlled with medium- or high-dose inhaled corticosteroids (fluticasone dry powder or equivalent, 250-500 μg/d or >500 μg/d, respectively) plus a long-acting β2-agonist. Participants (N = 550) were randomized 1:1:1:1 to receive subcutaneous doses of tezepelumab 70 mg every 4 weeks (n = 138), 210 mg every 4 weeks (n = 137), 280 mg every 2 weeks (n = 137), or placebo every 2 weeks (n = 138), for 52 weeks. Serum samples from healthy volunteers (n = 50) who had not been clinically diagnosed as having any disorders, were not taking any prescription medications, and were age matched with the PATHWAY population were obtained from a vendor (Bioreclamation, Westbury, New York) and processed similarly to the PATHWAY samples. Simoa ultrasensitive immunoassays (Quanterix, Lexington, Massachusetts) were used to determine serum IL-5 and IL-13 levels in PATHWAY participants at baseline and week 52 and in healthy individuals. The lowest limit of detection and lowest limit of quantitation were 0.004 pg/mL and 0.033 pg/mL, respectively, for IL-5, and 0.002 pg/mL and 0.008 pg/mL, respectively, for IL-13. Tezepelumab data presentation focuses on the 210 mg every 4 weeks dose group, the regimen being used in phase 3 studies.At baseline, serum IL-5 and IL-13 levels were nominally significantly higher in PATHWAY participants than in healthy individuals (Fig 1A, B). Median (range) IL-5 levels at baseline were 0.68 (0.04-80.16) pg/mL and 0.66 (0.03-15.00) pg/mL in the tezepelumab 210 mg every 4 weeks and placebo groups, respectively, compared with 0.34 (0.07-1.50) pg/mL in the healthy cohort (Fig 1A). Median (range) IL-13 levels at baseline were 0.03 (0.01-0.63) pg/mL and 0.04 (0.01-0.63) pg/mL in the tezepelumab 210 mg every 4 weeks and placebo groups, respectively, vs 0.01 (0.01-0.10) pg/mL in the healthy cohort (Fig 1B). At week 52, serum IL-5 and IL-13 levels in the placebo cohort (IL-5, median [range] 0.70 [0.03-6.10] pg/mL; IL-13, 0.03 [0.01-0.85] pg/mL) were similar to levels observed at baseline in both the placebo and tezepelumab 210 mg every 4 weeks groups (Fig 1A, B). After 52 weeks of tezepelumab treatment, serum IL-5 and IL-13 levels were nominally significantly reduced (IL-5, median [range] 0.25 [0.03-5.07]; IL-13, 0.02 [0.01-0.90]) and approached the levels observed in healthy individuals (Fig 1A, B).In summary, this analysis found that baseline IL-5 and IL-13 levels were nominally significantly higher in patients with severe, uncontrolled asthma participating in the PATHWAY study than in a separate cohort of age-matched healthy individuals. After 52 weeks of treatment, tezepelumab reduced IL-5 and IL-13 levels in patients with severe, uncontrolled asthma to levels approaching those observed in the healthy cohort. These findings suggest that TSLP inhibition may function to normalize levels of proinflammatory mediators in patients with severe, uncontrolled asthma. Importantly, these tezepelumab-mediated reductions in serum cytokines may be associated with reduced asthma exacerbations, improved lung function, and improved health-related quality of life.2Corren J Parnes JR Wang L et al.Tezepelumab in adults with uncontrolled asthma.N Engl J Med. 2017; 377: 936-946Crossref PubMed Scopus (505) Google Scholar,3Menzies-Gow A Corren J Bourdin A et al.Tezepelumab in adults and adolescents with severe, uncontrolled asthma.N Engl J Med. 2021; 384: 1800-1809Crossref PubMed Scopus (139) Google ScholarThe group comparisons presented here provide benchmark healthy ranges that researchers may reference to determine whether patients exhibit normal or abnormal levels of IL-5 and IL-13. The levels of IL-5 we observed in patients with severe asthma were similar to those found in studies of benralizumab (median at baseline, 0.4-2.5 pg/mL).7Pham TH Damera G Newbold P Ranade K. Reductions in eosinophil biomarkers by benralizumab in patients with asthma.Respir Med. 2016; 111: 21-29Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Of note, IL-13 levels in this study were considerably lower than those reported in previous studies8Arima K Umeshita-Suyama R Sakata Y et al.Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma.J Allergy Clin Immunol. 2002; 109: 980-987Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar,9Shehata IH Mostafa MM Ziada KW Saeed AM. Role of IL-13 in the pathogenesis of bronchial asthma.Egypt J Immunol. 2007; 14: 19-27PubMed Google Scholar; this may be because of differences in assay sensitivity used to quantify IL-13, in patient disease severity, or in the use of background medications such as corticosteroids that may suppress type 2 cytokine production.10Kaur M Reynolds S Smyth LJ Simpson K Hall S Singh D. The effects of corticosteroids on cytokine production from asthma lung lymphocytes.Int Immunopharmacol. 2014; 23: 581-584Crossref PubMed Scopus (16) Google ScholarThe mechanism by which TSLP inhibition reduces serum IL-5 and IL-13 levels in patients with severe asthma has not yet been fully elucidated, but it likely results from a dampening of the TSLP-driven inflammatory cascade triggered by insults to the airway epithelium and release of TSLP by other airway cell types, leading to reduced activity of type 2 cytokine-producing inflammatory cells. In particular, TSLP up-regulates dendritic cell activity, thereby accelerating the differentiation of naive T cells to TH2 cells, and activates ILC2s.1Gauvreau GM Sehmi R Ambrose CS Griffiths JM. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma.Expert Opin Ther Targets. 2020; 24: 777-792Crossref PubMed Scopus (49) Google Scholar Therefore, blocking TSLP activity would be expected to reduce levels of type 2 cytokines, such as IL-5 and IL-13.There were some limitations to this analysis. First, the healthy cohort was matched with the PATHWAY cohorts based on age, but not for other demographics or baseline characteristics. Second, the healthy cohort contained a smaller number of participants than the PATHWAY cohorts. Nevertheless, the findings of this analysis further support the potential benefits of tezepelumab in patients with severe, uncontrolled asthma. Asthma is a chronic, heterogeneous disease of the airways that involves a multitude of inflammatory processes triggered by various airborne stimuli. Thymic stromal lymphopoietin (TSLP)—an epithelial cell–derived cytokine produced in response to triggers such as allergens, viruses, or pollutants—has a central role in activating and maintaining downstream inflammatory processes in asthma.1Gauvreau GM Sehmi R Ambrose CS Griffiths JM. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma.Expert Opin Ther Targets. 2020; 24: 777-792Crossref PubMed Scopus (49) Google Scholar Tezepelumab is an anti-TSLP human monoclonal antibody. In the PATHWAY phase 2b (NCT02054130) and NAVIGATOR phase 3 (NCT03347279) studies, tezepelumab significantly reduced exacerbation rates vs placebo in patients with severe, uncontrolled asthma.2Corren J Parnes JR Wang L et al.Tezepelumab in adults with uncontrolled asthma.N Engl J Med. 2017; 377: 936-946Crossref PubMed Scopus (505) Google Scholar,3Menzies-Gow A Corren J Bourdin A et al.Tezepelumab in adults and adolescents with severe, uncontrolled asthma.N Engl J Med. 2021; 384: 1800-1809Crossref PubMed Scopus (139) Google Scholar Important downstream drivers of the asthma inflammatory response include the type 2 cytokines interleukin (IL)-5 and IL-13. The major cellular sources of IL-5 are type 2 T helper (TH2) cells and type 2 innate lymphoid cells (ILC2s). IL-5 acts as an amplifier of eosinophilic inflammation by enhancing eosinophil maturation, proliferation, and survival,4Adachi T Alam R. The mechanism of IL-5 signal transduction.Am J Physiol. 1998; 275: C623-C633Crossref PubMed Google Scholar which may result in airway remodeling.5Pelaia C Paoletti G Puggioni F et al.Interleukin-5 in the pathophysiology of severe asthma.Front Physiol. 2019; 10: 1514Crossref PubMed Scopus (79) Google Scholar IL-13, produced largely by TH2 cells, ILC2s, mast cells, and basophils, contributes to immunoglobulin E synthesis and may lead to elevated fractional exhaled nitric oxide levels, airway hyperresponsiveness, and mucus hypersecretion.6Corren J. Role of interleukin-13 in asthma.Curr Allergy Asthma Rep. 2013; 13: 415-420Crossref PubMed Scopus (130) Google Scholar Biomarkers of IL-5 and IL-13 activity—blood eosinophil counts and fractional exhaled nitric oxide levels—were substantially reduced after TSLP blockade with tezepelumab in PATHWAY.2Corren J Parnes JR Wang L et al.Tezepelumab in adults with uncontrolled asthma.N Engl J Med. 2017; 377: 936-946Crossref PubMed Scopus (505) Google Scholar This post hoc analysis aimed to evaluate serum IL-5 and IL-13 levels before and after treatment with tezepelumab in PATHWAY participants relative to levels observed in a separate cohort of healthy individuals. PATHWAY was a multicenter, randomized, double-blind, placebo-controlled study conducted at 108 sites across 12 countries. The full study design and inclusion criteria have been described previously.2Corren J Parnes JR Wang L et al.Tezepelumab in adults with uncontrolled asthma.N Engl J Med. 2017; 377: 936-946Crossref PubMed Scopus (505) Google Scholar Eligible patients were current nonsmokers, aged 18 to 75 years, with severe asthma that was inadequately controlled with medium- or high-dose inhaled corticosteroids (fluticasone dry powder or equivalent, 250-500 μg/d or >500 μg/d, respectively) plus a long-acting β2-agonist. Participants (N = 550) were randomized 1:1:1:1 to receive subcutaneous doses of tezepelumab 70 mg every 4 weeks (n = 138), 210 mg every 4 weeks (n = 137), 280 mg every 2 weeks (n = 137), or placebo every 2 weeks (n = 138), for 52 weeks. Serum samples from healthy volunteers (n = 50) who had not been clinically diagnosed as having any disorders, were not taking any prescription medications, and were age matched with the PATHWAY population were obtained from a vendor (Bioreclamation, Westbury, New York) and processed similarly to the PATHWAY samples. Simoa ultrasensitive immunoassays (Quanterix, Lexington, Massachusetts) were used to determine serum IL-5 and IL-13 levels in PATHWAY participants at baseline and week 52 and in healthy individuals. The lowest limit of detection and lowest limit of quantitation were 0.004 pg/mL and 0.033 pg/mL, respectively, for IL-5, and 0.002 pg/mL and 0.008 pg/mL, respectively, for IL-13. Tezepelumab data presentation focuses on the 210 mg every 4 weeks dose group, the regimen being used in phase 3 studies. At baseline, serum IL-5 and IL-13 levels were nominally significantly higher in PATHWAY participants than in healthy individuals (Fig 1A, B). Median (range) IL-5 levels at baseline were 0.68 (0.04-80.16) pg/mL and 0.66 (0.03-15.00) pg/mL in the tezepelumab 210 mg every 4 weeks and placebo groups, respectively, compared with 0.34 (0.07-1.50) pg/mL in the healthy cohort (Fig 1A). Median (range) IL-13 levels at baseline were 0.03 (0.01-0.63) pg/mL and 0.04 (0.01-0.63) pg/mL in the tezepelumab 210 mg every 4 weeks and placebo groups, respectively, vs 0.01 (0.01-0.10) pg/mL in the healthy cohort (Fig 1B). At week 52, serum IL-5 and IL-13 levels in the placebo cohort (IL-5, median [range] 0.70 [0.03-6.10] pg/mL; IL-13, 0.03 [0.01-0.85] pg/mL) were similar to levels observed at baseline in both the placebo and tezepelumab 210 mg every 4 weeks groups (Fig 1A, B). After 52 weeks of tezepelumab treatment, serum IL-5 and IL-13 levels were nominally significantly reduced (IL-5, median [range] 0.25 [0.03-5.07]; IL-13, 0.02 [0.01-0.90]) and approached the levels observed in healthy individuals (Fig 1A, B). In summary, this analysis found that baseline IL-5 and IL-13 levels were nominally significantly higher in patients with severe, uncontrolled asthma participating in the PATHWAY study than in a separate cohort of age-matched healthy individuals. After 52 weeks of treatment, tezepelumab reduced IL-5 and IL-13 levels in patients with severe, uncontrolled asthma to levels approaching those observed in the healthy cohort. These findings suggest that TSLP inhibition may function to normalize levels of proinflammatory mediators in patients with severe, uncontrolled asthma. Importantly, these tezepelumab-mediated reductions in serum cytokines may be associated with reduced asthma exacerbations, improved lung function, and improved health-related quality of life.2Corren J Parnes JR Wang L et al.Tezepelumab in adults with uncontrolled asthma.N Engl J Med. 2017; 377: 936-946Crossref PubMed Scopus (505) Google Scholar,3Menzies-Gow A Corren J Bourdin A et al.Tezepelumab in adults and adolescents with severe, uncontrolled asthma.N Engl J Med. 2021; 384: 1800-1809Crossref PubMed Scopus (139) Google Scholar The group comparisons presented here provide benchmark healthy ranges that researchers may reference to determine whether patients exhibit normal or abnormal levels of IL-5 and IL-13. The levels of IL-5 we observed in patients with severe asthma were similar to those found in studies of benralizumab (median at baseline, 0.4-2.5 pg/mL).7Pham TH Damera G Newbold P Ranade K. Reductions in eosinophil biomarkers by benralizumab in patients with asthma.Respir Med. 2016; 111: 21-29Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Of note, IL-13 levels in this study were considerably lower than those reported in previous studies8Arima K Umeshita-Suyama R Sakata Y et al.Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma.J Allergy Clin Immunol. 2002; 109: 980-987Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar,9Shehata IH Mostafa MM Ziada KW Saeed AM. Role of IL-13 in the pathogenesis of bronchial asthma.Egypt J Immunol. 2007; 14: 19-27PubMed Google Scholar; this may be because of differences in assay sensitivity used to quantify IL-13, in patient disease severity, or in the use of background medications such as corticosteroids that may suppress type 2 cytokine production.10Kaur M Reynolds S Smyth LJ Simpson K Hall S Singh D. The effects of corticosteroids on cytokine production from asthma lung lymphocytes.Int Immunopharmacol. 2014; 23: 581-584Crossref PubMed Scopus (16) Google Scholar The mechanism by which TSLP inhibition reduces serum IL-5 and IL-13 levels in patients with severe asthma has not yet been fully elucidated, but it likely results from a dampening of the TSLP-driven inflammatory cascade triggered by insults to the airway epithelium and release of TSLP by other airway cell types, leading to reduced activity of type 2 cytokine-producing inflammatory cells. In particular, TSLP up-regulates dendritic cell activity, thereby accelerating the differentiation of naive T cells to TH2 cells, and activates ILC2s.1Gauvreau GM Sehmi R Ambrose CS Griffiths JM. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma.Expert Opin Ther Targets. 2020; 24: 777-792Crossref PubMed Scopus (49) Google Scholar Therefore, blocking TSLP activity would be expected to reduce levels of type 2 cytokines, such as IL-5 and IL-13. There were some limitations to this analysis. First, the healthy cohort was matched with the PATHWAY cohorts based on age, but not for other demographics or baseline characteristics. Second, the healthy cohort contained a smaller number of participants than the PATHWAY cohorts. Nevertheless, the findings of this analysis further support the potential benefits of tezepelumab in patients with severe, uncontrolled asthma. Medical writing support was provided by Richard Claes, PhD, of PharmaGenesis London, London, United Kingdom, with funding from AstraZeneca and Amgen, Inc, in accordance with Good Publication Practice 3 guidelines (http://www.ismpp.org/gpp3).

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