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First‐in‐Human Study With the Inhaled TLR9 Oligonucleotide Agonist AZD1419 Results in Interferon Responses in the Lung, and Is Safe and Well‐Tolerated
Author(s) -
Jackson Sam,
Candia Albert F.,
Delaney Stephen,
Floettmann Simone,
Wong Clifford,
Campbell John D.,
Kell Sariah,
Lum Jeremy,
Hessel Edith M.,
Traquina Paula,
McHale Mark,
Robinson Ian,
Bell John,
Fuhr Rainard,
Keeling David,
Coffman Robert L.
Publication year - 2018
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.938
Subject(s) - medicine , tlr9 , agonist , endotype , pathophysiology , toll like receptor 9 , dosing , disease , immunology , pharmacology , lung , asthma , inhalation , receptor , anesthesia , biology , biochemistry , gene expression , gene , dna methylation
Current asthma treatments address symptoms rather than the underlying disease pathophysiology, a better understanding of which has led to the identification of the Th2 high endotype. The activation of Toll‐like receptors to induce Type I interferons directly in the lungs represents a novel therapeutic approach to reset this underlying Th2 pathophysiology with the potential to provide long‐term disease modification. We present the nonclinical data and phase I clinical profile of an inhaled TLR9 agonist, AZD1419, a C‐type CpG designed to induce interferon in the lung. In healthy volunteers, AZD1419 was found to be safe and well‐tolerated. Target engagement in the lung was demonstrated at all dose levels tested. No evidence of tolerization or amplification of responses was evident on repeated dosing and 15.4 mg was defined as the maximum tolerated dose. AZD1419 clinical data supports its continued development as a potentially disease‐modifying therapeutic in asthma.