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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
- Source :
- The Journal of pharmacology and experimental therapeutics. 367(3)
- Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Spirometry
Adult
Male
medicine.medical_specialty
Vital capacity
Indazoles
Indoles
Vital Capacity
Placebo
Gastroenterology
Piperazines
law.invention
03 medical and health sciences
Phosphatidylinositol 3-Kinases
Young Adult
0302 clinical medicine
Randomized controlled trial
Double-Blind Method
law
Internal medicine
Forced Expiratory Volume
Administration, Inhalation
medicine
Clinical endpoint
Humans
Adrenergic beta-2 Receptor Agonists
Oxazoles
Asthma
Aged
Pharmacology
Cross-Over Studies
medicine.diagnostic_test
business.industry
Middle Aged
medicine.disease
Crossover study
Bronchodilator Agents
030104 developmental biology
030228 respiratory system
Tolerability
Molecular Medicine
Female
business
Subjects
Details
- ISSN :
- 15210103
- Volume :
- 367
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Accession number :
- edsair.doi.dedup.....55c74573c52a1163a28caf2a191302b7