Abstract
Rationale Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses.
Objective We evaluated efficacy and safety of ecleralimab, a potent inhaled neutralizing antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma.
Methods This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18–60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once daily inhaled ecleralimab or placebo. Primary endpoints were to evaluate the allergen-induced change in forced expiratory volume (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3–7h) and maximum percentage fall (LAR%) on Day 84, and safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (FeNO) were secondary and exploratory endpoints.
Measurements and Main Results Twenty-eight subjects were randomised to ecleralimab (n=15) or placebo (n=13). On Day 84, ecleralimab significantly attenuated LAR AUC3–7h by 64% (p=0.008), LAR% by 48% (p=0.029) and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0–2h (p=0.097) and EAR% (p=0.105). FeNO levels were significantly reduced from baseline throughout the study (p<0.05) except at 24 h post-allergen (Day 43 and Day 85). Overall, ecleralimab was safe and well-tolerated.
Conclusion Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation and was safe in subjects with mild atopic asthma.
Footnotes
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Conflict of interest: GMG reports grants and personal fees from AstraZeneca, grants from Biohaven, grants from Genentech, grants from BioGaia, outside the submitted work.
Conflict of interest: JMH reports grants from Novartis AG, during the conduct of the study; grants from AltamiraPharma GmbH, grants from Astellas Pharma GmbH, AstraZeneca AB, Bayer AG, Beiersdorf AG, Boehringer Ingelheim Pharma GmbH & Co. KG, CSL Behring GmbH, Desitin Arzneimittel GmbH, F. Hoffmann-La Roche AG, Genentech, Inc., GlaxoSmithKline GmbH & Co. KG, Janssen Pharmaceuticals NV, M&p Pharma AG, Novartis AG, Sanofi-Aventis Deutschland GmbH, UCB Pharma GmbH and personal fees from Boehringer Ingelheim Pharma GmbH & Co. KG, from CSL Behring GmbH, Merck & Co, Inc., Nocion Therapeutics, Inc., HAL Allergy Group, Novartis AG outside the submitted work. JMF reported receipt of research funding from Novartis which was paid directly to UBC for the completion of this study and has also been in receipt of AllerGen CIHR and NIH grant funding unrelated to the current study.
Conflict of interest: LPB reports receiving grants from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Sanofi-Regeneron, personal fees from AstraZeneca, GlaxoSmithKline, Merck, Novartis, Sanofi-Regeneron and honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events outside of the submitted work.
Conflict of interest: DWC reports receiving grants from Department of Medicine University of Saskatchewan, AstraZeneca, Novartis, CSACI and AllerGen NCE outside of the submitted work.
Conflict of interest: BD has nothing to declare. SK reports receiving personal fees from Novartis outside of the submitted work.
Conflict of interest: OK reports receiving personal fees from Sanofi, Novartis, Boehringer Ingelheim, Adagio, AstraZeneca, Santhera and Chiesi outside the submitted work.
Conflict of interest: RL reports receiving personal fees from Novartis, AstraZeneca, GlaxoSmithKline, Sanofi Genzyme and Valeo Pharma Inc. outside of the submitted work.
Conflict of interest: HW reports receiving grants and personal fees from Novartis, AstraZeneca, GlaxoSmithKline, Chiesi and Boehringer Ingelheim outside of the submitted work.
Conflict of interest: SG, MJ, PP are employees of Novartis Institutes of Biomedical Research.
Conflict of interest: MC was an employee of Novartis during the time of the study.
Conflict of interest: IJ and JL are employees of Novartis Pharma AG.
Conflict of interest: HC is an employee of Novartis Pharmaceuticals Corporation.
Conflict of interest: POB has obtained grants in aid of research from Novartis for the conduct of the current study, as well as from AstraZeneca, Medimmune, Biohaven, Merck and Bayer for research outside the current study and received personal fees for consulting or speaker fees from AstraZeneca, GSK, Medimmune, Chiesi, Menarini, and Covis.
Conflict of interest: This manuscript is dedicated to the memory of Dr. J Mark FitzGerald.
- Received June 10, 2022.
- Accepted October 24, 2022.
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