Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial

The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived “alarmin.” Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biol...

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Published in:Journal of allergy and clinical immunology Vol. 148; no. 3; pp. 790 - 798
Main Authors: Kelsen, Steven G., Agache, Ioana O., Soong, Weily, Israel, Elliot, Chupp, Geoffrey L., Cheung, Dorothy S., Theess, Wiebke, Yang, Xiaoying, Staton, Tracy L., Choy, David F., Fong, Alice, Dash, Ajit, Dolton, Michael, Pappu, Rajita, Brightling, Christopher E.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.09.2021
Subjects:
asthma exacerbations
eosinophils
IL-33
severe asthma
ST2
ST2
asthma exacerbations
Feno
AE
SAE
severe asthma
ICS
eosinophils
IL-33
AER
T2
ISSN:0091-6749, 1097-6825, 1097-6825
Online Access:Get full text
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Summary:The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived “alarmin.” Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. This study evaluated astegolimab efficacy and safety in patients with severe asthma. This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured ∼30 patients who were eosinophil-high (≥300 cells/μL) and ∼95 patients who were eosinophil-low (<300 cells/μL) per arm. Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups. Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated. [Display omitted]
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ISSN:0091-6749
1097-6825
1097-6825
DOI:10.1016/j.jaci.2021.03.044