Btk Inhibitor RN983 Delivered by Dry Powder Nose-only Aerosol Inhalation Inhibits Bronchoconstriction and Pulmonary Inflammation in the Ovalbumin Allergic Mouse Model of Asthma.
In allergen-induced asthma, activated mast cells start the lung inflammatory process with degranulation, cytokine synthesis, and mediator release. Bruton's tyrosine kinase (Btk) activity is required for the mast cell activation during IgE-mediated secretion.



This study characterized a novel inhaled Btk inhibitor RN983 in vitro and in ovalbumin allergic mouse models of the early (EAR) and late (LAR) asthmatic response.



RN983 potently, selectively, and reversibly inhibited the Btk enzyme. RN983 displayed functional activities in human cell-based assays in multiple cell types, inhibiting IgG production in B-cells with an IC50 of 2.5 ± 0.7 nM and PGD2 production from mast cells with an IC50 of 8.3 ± 1.1 nM. RN983 displayed similar functional activities in the allergic mouse model of asthma when delivered as a dry powder aerosol by nose-only inhalation. RN983 was less potent at inhibiting bronchoconstriction (IC50(RN983) = 59 μg/kg) than the β-agonist salbutamol (IC50(salbutamol) = 15 μg/kg) in the mouse model of the EAR. RN983 was more potent at inhibiting the antigen induced increase in pulmonary inflammation (IC50(RN983) = <3 μg/kg) than the inhaled corticosteroid budesonide (IC50(budesonide) = 27 μg/kg) in the mouse model of the LAR.



Inhalation of aerosolized RN983 may be effective as a stand-alone asthma therapy or used in combination with inhaled steroids and β-agonists in severe asthmatics due to its potent inhibition of mast cell activation.
Hoffmann-La Roche Inc. , Pharma Research and Early Development, DTA Inflammation, Nutley, New Jersey.
Jonathan E
JE
Phillips
Hoffmann-La Roche Inc. , Pharma Research and Early Development, DTA Inflammation, Nutley, New Jersey.
Lorena
L
Renteria
Hoffmann-La Roche Inc. , Pharma Research and Early Development, DTA Inflammation, Nutley, New Jersey.
Lisa
L
Burns
Hoffmann-La Roche Inc. , Pharma Research and Early Development, DTA Inflammation, Nutley, New Jersey.
Paul
P
Harris
Hoffmann-La Roche Inc. , Pharma Research and Early Development, DTA Inflammation, Nutley, New Jersey.
Ruoqi
R
Peng
Hoffmann-La Roche Inc. , Pharma Research and Early Development, DTA Inflammation, Nutley, New Jersey.
Carla M T
CM
Bauer
Hoffmann-La Roche Inc. , Pharma Research and Early Development, DTA Inflammation, Nutley, New Jersey.
Dramane
D
Laine
Hoffmann-La Roche Inc. , Pharma Research and Early Development, DTA Inflammation, Nutley, New Jersey.
Christopher S
CS
Stevenson
D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000420:Albuterol / Q000008:administration & dosage; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019819:Budesonide / Q000008:administration & dosage; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D058995:Dry Powder Inhalers; D005938:Glucocorticoids / Q000008:administration & dosage; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D010793:Phthalazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011014:Pneumonia / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D015230:Prostaglandin D2 / Q000276:immunology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000008:administration & dosage* / Q000493:pharmacokinetics
D058666:Adrenergic beta-2 Receptor Agonists; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D016207:Cytokines; D005938:Glucocorticoids; D007074:Immunoglobulin G; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C000621144:RN983 compound; D019819:Budesonide; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D000420:Albuterol; D015230:Prostaglandin D2
dust feed; inhaled therapy; jet mill; lung function; pharmacokinetics; pre-clinical