TY - JOUR T1 - A multicentre, randomised, double-blind, placebo-controlled, crossover study to investigate the efficacy, safety, tolerability and pharmacokinetics of repeat doses of inhaled nemiralisib in adults with persistent, uncontrolled asthma JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.249516 SP - jpet.118.249516 AU - Sanjeev Khindri AU - Anthony Cahn AU - Malcolm Begg AU - Mickael Montembault AU - Claudia Leemereise AU - Yi Cui AU - Annabel Hogg AU - Hannah Wajdner AU - Shuying Yang AU - Jon Roberston AU - J Nicole Hamblin AU - Andrea Ludwig-Sengpiel AU - Oliver Kornmann AU - Edith Hessel Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/09/14/jpet.118.249516.abstract N2 - Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase involved in leukocyte recruitment and activation. Activation of PI3Kδ has been linked to airway inflammation and asthma pathogenesis. This randomised, double-blind, placebo-controlled, crossover study investigated the efficacy, safety, tolerability and pharmacokinetics of a PI3Kδ inhibitor, nemiralisib (GSK2269557), in patients with persistent, uncontrolled asthma. Patients (n=50) received once-daily inhaled nemiralisib (1000 µg) or placebo for 28 days, with a crossover to the alternative treatment following a 4-week washout period. Spirometry demonstrated no discernible difference in trough forced expiratory volume in 1 second (FEV1) from baseline (adjusted posterior median 7 mL; 95% credible interval -83 mL, 102 mL) between nemiralisib and placebo treatment at Day 28 (primary endpoint). These results were supported by most secondary endpoints, including weighted mean FEV1 (0-4 h) and change in trough forced vital capacity at Day 28. Nemiralisib was generally well-tolerated, with few side effects except for post-inhalation cough (nemiralisib: 35%; placebo: 9%). At Day 28, sputum interleukin (IL)-5, IL-13, IL-6 and IL-8 levels were reduced by a median of 17%, 7%, 15% and 8%, respectively, when comparing nemiralisib with placebo (n=15 [IL-5, IL-8] or 16 [IL-6, IL-13]; posterior probability of a true ratio >0%: 78%, 64%, 76% and 63%, respectively). These results suggest that nemiralisib inhibited PI3Kδ locally; however, this did not translate into meaningful clinical improvement. Further studies will investigate the potential efficacy of nemiralisib in patients with asthma with other specific more severe phenotypes, including those who are colonised with bacteria and frequently exacerbate.   ER -