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Randomized Controlled Trial
. 2022 Jun;77(6):1786-1796.
doi: 10.1111/all.15197. Epub 2022 Feb 9.

Baseline type 2 biomarker levels and response to tezepelumab in severe asthma

Jonathan Corren  1 , Tuyet-Hang Pham  2 , Esther Garcia Gil  3 , Kinga Sałapa  4 , Pin Ren  5 , Jane R Parnes  6 , Gene Colice  7 , Janet M Griffiths  2
Affiliations
Randomized Controlled Trial

Baseline type 2 biomarker levels and response to tezepelumab in severe asthma

Jonathan Corren et al. Allergy. 2022 Jun.

Abstract

Background: Tezepelumab is a human monoclonal antibody that blocks activity of thymic stromal lymphopoietin (TSLP). In the phase IIb PATHWAY study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo in adults with severe, uncontrolled asthma. We evaluated the effects of tezepelumab in reducing type 2 (T2) inflammatory biomarker levels in the PATHWAY population, and the relationship between baseline T2 biomarker levels and AAER.

Methods: Adults with severe, uncontrolled asthma (n = 550) were randomized to tezepelumab (70 mg or 210 mg every 4 weeks, or 280 mg every 2 weeks) or placebo for 52 weeks. Blood eosinophil count, fractional exhaled nitric oxide (FeNO), and serum total immunoglobulin (Ig)E, interleukin (IL)-5, IL-13, periostin, thymus and activation-regulated chemokine (TARC), and TSLP were measured at baseline and over 52 weeks. AAERs were analyzed by baseline threshold (high/low) biomarker levels.

Results: Positive correlations were observed between T2 inflammatory biomarkers (blood eosinophil count, FeNO, IL-5, IL-13 and periostin) at baseline. At Week 52, treatment with tezepelumab 210 mg reduced all biomarker levels measured from baseline versus placebo. Exacerbations were reduced by 55-83% in the pooled tezepelumab cohort versus placebo, irrespective of baseline blood eosinophil count, FeNO, or serum total IgE, IL-5, IL-13, periostin, TARC, or TSLP, when these biomarkers were assessed individually.

Conclusion: At baseline, positive correlations between specific T2 inflammatory biomarkers were observed. Tezepelumab reduced multiple T2 inflammatory biomarkers, which indicates decreased airway inflammation, and reduced exacerbations irrespective of baseline T2 biomarker profiles in patients with severe asthma.

Keywords: asthma; biomarkers; inflammation.

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Conflict of interest statement

Dr. Corren received grants from AstraZeneca during the conduct of the study. He has also received grants from Genentech, Novartis, Optinose, Regeneron, Sanofi, and Teva, and has received personal fees from AstraZeneca, Genentech, Regeneron, and Sanofi. Ms Pham, Dr. Ren, Dr. Colice, and Dr. Griffiths are employees of AstraZeneca and own stock and stock options in AstraZeneca. Dr. Garcia Gil was an employee of AstraZeneca at the time of this study; she is a present employee of Almirall. Ms Sałapa is an employee of AstraZeneca. Dr. Parnes is an employee of Amgen Inc., and owns stock and stock options in Amgen Inc.

Figures

FIGURE 1
FIGURE 1
Baseline correlations between serum levels of IL‐5 and IL‐13 and other biomarkers of inflammation. Spearman correlation coefficients (r) are shown. Data are presented on the log scale. Abbreviations: FeNO, fractional exhaled nitric oxide; IL, interleukin; ppb, parts per billion
FIGURE 2
FIGURE 2
Median percentage change from baseline in biomarker levels over 52 weeks. Abbreviations: FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL, interleukin; MAD, median absolute deviation; Q4W, every 4 weeks; TARC, thymus and activation‐regulated chemokine
FIGURE 3
FIGURE 3
Median percentage change from baseline to Week 52 in biomarker levels. FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL, interleukin; ppb, parts per billion; Q4W, every 4 weeks; TARC, thymus and activation‐regulated chemokine
FIGURE 4
FIGURE 4
AAER by baseline biomarker category at Week 52. AAER = the total number of asthma exacerbations/total person‐year follow‐up in each group. *p values are nominal. Gray shaded area shows the response of the overall population. a n refers to the number of patients within each subgroup based on baseline status. bAAER reduction from baseline at Week 52 vs placebo was 62% with tezepelumab 70 mg Q4W, 71% with tezepelumab 210 mg Q4W, and 66% with tezepelumab 280 mg Q2W. cData based on tezepelumab 210 mg Q4W and 280 mg Q2W data only; IL‐5 and TARC were not measured in the tezepelumab 70 mg Q4W cohort. AAER, annualized asthma exacerbation rate; CI, confidence interval; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL, interleukin; ppb, parts per billion; Q2W, every 2 weeks; Q4W, every 4 weeks; RR, rate ratio; TARC, thymus and activation‐regulated chemokine; TSLP, thymic stromal lymphopoietin
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