Inhaled anti-TSLP antibody fragment, ecleralimab, blocks responses to allergen in mild asthma

  • Eur Respir J. 2023 Mar 9;61(3):2201193. doi: 10.1183/13993003.01193-2022.
Gail M Gauvreau  1  2 ,  Jens M Hohlfeld  3  2 ,  J Mark FitzGerald  4  2 ,  Louis-Philippe Boulet  5 ,  Donald W Cockcroft  6 ,  Beth E Davis  6 ,  Stephanie Korn  7 ,  Oliver Kornmann  8 ,  Richard Leigh  9 ,  Irvin Mayers  10 ,  Henrik Watz  11 ,  Sarah S Grant  12 ,  Monish Jain  12 ,  Maciej Cabanski  12 ,  Peter E Pertel  12 ,  Ieuan Jones  13 ,  Jean R Lecot  13 ,  Hui Cao  14 ,  Paul M O'Byrne  15
Affiliations
  • 1. Department of Medicine, McMaster University, Hamilton, ON, Canada [email protected].
  • 2. These authors contributed equally to this work.
  • 3. Fraunhofer Institute for Toxicology and Experimental Medicine and Hannover Medical School, Hannover, Germany.
  • 4. Centre for Lung Health, University of British Columbia, Vancouver, BC, Canada.
  • 5. Québec Heart and Lung Institute, Laval University, Québec, QC, Canada.
  • 6. Division of Respirology, Critical Care and Sleep Medicine, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
  • 7. IKF Pneumologie Mainz and Thoraxklinik, Heidelberg, Germany.
  • 8. IKF Pneumologie Frankfurt, Clinical Research Centre Respiratory Diseases, Frankfurt, Germany.
  • 9. Department of Medicine, Cumming School of Medicine, Calgary, AB, Canada.
  • 10. Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • 11. Pulmonary Research Institute at Lungen Clinic Grosshansdorf, Airway Research Centre North (ARCN), German Centre for Lung Research (DZL), Grosshansdorf, Germany.
  • 12. Novartis Institutes of Biomedical Research, Cambridge, MA, USA.
  • 13. Novartis Pharma AG, Basel, Switzerland.
  • 14. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
  • 15. Department of Medicine, McMaster University, Hamilton, ON, Canada.
PMID: 36822634 DOI: 10.1183/13993003.01193-2022
Abstract

Background: Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising 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 end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (F ENO) were secondary and exploratory end-points.

Results: 28 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). F ENO 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.

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