PT  - JOURNAL ARTICLE
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 Robertson
AU  - J. Nicole Hamblin
AU  - Andrea Ludwig-Sengpiel
AU  - Oliver Kornmann
AU  - Edith M. Hessel
TI  - A Multicentre, Randomized, 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
AID  - 10.1124/jpet.118.249516
DP  - 2018 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 405--413
VI  - 367
IP  - 3
4099  - http://jpet.aspetjournals.org/content/367/3/405.short
4100  - http://jpet.aspetjournals.org/content/367/3/405.full
SO  - J Pharmacol Exp Ther2018 Dec 01; 367
AB  - 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 randomized, 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, 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 hours) 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 14, 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 colonized with bacteria and frequently exacerbate.