RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -γ selectivity, suppresses COPD inflammation

• Published in: The European respiratory journal Vol. 50; no. 4; p. 1700188
• Main Authors: Charron, Catherine E, Russell, Paul, Ito, Kazuhiro, Lea, Simon, Kizawa, Yasuo, Brindley, Charlie, Singh, Dave
• Format: Journal Article
• Language: English
• Published: England European Respiratory Society Journals Ltd 01.10.2017
• Subjects: Adrenal Cortex Hormones - therapeutic use; Adult; Aged; Animal models; Animals; Anti-Inflammatory Agents - pharmacology; Bronchodilators; Cell culture; Chronic obstructive pulmonary disease; Cigarette smoke; Cigarette Smoking - adverse effects; Clinical trials; Corticosteroids; Disease Models, Animal; Double-Blind Method; Enzyme inhibitors; Epithelial cells; Epithelial Cells - metabolism; Female; Forced Expiratory Volume - drug effects; Humans; Inflammation; Kinases; Lipopolysaccharides; Lung diseases; Macrophages; Macrophages - metabolism; Male; Malondialdehyde; MAP kinase; Mice; Middle Aged; Monocytes; Monocytes - metabolism; Naphthalenes - therapeutic use; Obstructive lung disease; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Polyinosinic:polycytidylic acid; Protein kinase; Protein Kinase Inhibitors - pharmacology; Pulmonary Disease, Chronic Obstructive - drug therapy; Pulmonary Disease, Chronic Obstructive - physiopathology; Pyrazoles - therapeutic use; Sputum; Sputum - cytology; United Kingdom; United Kingdom
• ISSN: 0903-1936; 1399-3003
• DOI: 10.1183/13993003.00188-2017

Novel anti-inflammatory approaches targeting chronically activated kinase pathways in chronic obstructive pulmonary disease (COPD) are needed. We evaluated RV568, a p38 mitogen-activated protein kinase-α and -γ and SRC family kinase inhibitor, in cellular and models relevant to COPD and examined its safety and efficacy in COPD patients.The anti-inflammatory activities of RV568 were tested in primary cultured monocytes, macrophages and bronchial epithelial cells and in lipopolysaccharide and cigarette smoke-exposed murine models. RV568 was evaluated in a 14-day trial in COPD patients.RV568 showed potent anti-inflammatory effects in monocytes and macrophages, which were often greater than those of corticosteroids or the p38 inhibitor Birb796. RV568 combined with corticosteroid had anti-inflammatory effects suggestive of a synergistic interaction in poly I:C-stimulated BEAS-2B cells and in the cigarette smoke model. In COPD patients, inhaled RV568 (50 µg and 100 µg) improved pre-bronchodilator forced expiratory volume in 1 s (69 mL and 48 mL respectively) and significantly reduced sputum malondialdehyde (p<0.05) compared to placebo, although there were no changes in sputum cell counts. Adverse events during RV568 and placebo treatment were similar.RV568 shows potent anti-inflammatory effects on cell and animal models relevant to COPD. RV568 was well-tolerated and demonstrated a modest clinical benefit in a 14-day COPD clinical trial.