gsk2269557 and Pulmonary-Disease--Chronic-Obstructive

Management of acute exacerbations of chronic obstructive pulmonary disease (COPD) is sometimes inadequate leading to either prolonged duration and/or an increased risk of recurrent exacerbations in the period following the initial event.. To evaluate the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ inhibitor, in patients experiencing an acute exacerbation of COPD.. There was no difference in change from baseline FEV. The addition of nemiralisib to standard-of-care treatment for 12 weeks did not improve lung function or re-exacerbations in patients with, and following an acute exacerbation of COPD. However, this study demonstrated that large clinical trials recruiting acutely exacerbating patients can successfully be conducted.

Topics: Bronchodilator Agents; Double-Blind Method; Forced Expiratory Volume; Humans; Indazoles; Indoles; Oxazoles; Phosphatidylinositol 3-Kinases; Piperazines; Pulmonary Disease, Chronic Obstructive

While current therapies reduce symptoms in chronic obstructive pulmonary disease (COPD) patients, substantial unmet need remains and novel treatments are highly desired. Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase specifically expressed in leucocytes and involved in their recruitment and activation. This study evaluated the safety, pharmacokinetics (PK) and dose-response characteristics of inhaled GSK2269557, a PI3Kδ inhibitor, in moderate-to-severe COPD patients with stable disease.. In this randomised, double-blind, placebo controlled, parallel group study, patients received once daily inhaled treatment with GSK2269557 1000 μg or placebo for 14 days (Part A, primary aim safety, N = 28 patients). In part B of the study (primary aim pharmacodynamic dose-response, N = 36 patients), GSK2269557 100, 200, 500, 700, 1000, 2000 μg or placebo was given for 14 days. In both Part A and B, GSK2269557 was added to the usual maintenance therapy. Safety, PK assessments and induced sputum collection for cytokine analysis were conducted at baseline and after 7 and 14 days of treatment. Adverse events (AEs) were monitored throughout.. In Part A, mean age was 61.7 years (SD 6.7), 29% were females, and mean FEV. In this study, inhaled GSK2269557 had an acceptable safety profile for progression into larger studies in COPD patients. Moreover, inhalation of GSK2269557 resulted in suppression of sputum IL-8 and IL-6 levels, consistent with the known anti-inflammatory activity of a PI3Kδ inhibitor. Inhibition of inflammatory cytokines in the airway compartment may contribute to the potential therapeutic benefit of a PI3Kδ inhibitor in chronically inflamed COPD patients.

Topics: Administration, Inhalation; Aged; Class I Phosphatidylinositol 3-Kinases; Cytokines; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Indazoles; Indoles; Male; Middle Aged; Oxazoles; Piperazines; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Sputum; Treatment Outcome

Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.

Topics: Administration, Inhalation; Animals; Asthma; Female; Humans; Indazoles; Indoles; Isoenzymes; Male; Microsomes; Molecular Docking Simulation; Ovalbumin; Oxazoles; Phosphoinositide-3 Kinase Inhibitors; Piperazines; Pneumonia; Pulmonary Disease, Chronic Obstructive; Rabbits; Rats; Rats, Sprague-Dawley; Respiratory Tract Diseases; Stereoisomerism; Structure-Activity Relationship; Sulfonamides; Th2 Cells