Safety, pharmacokinetics and dose-response characteristics of GSK2269557, an inhaled PI3Kδ inhibitor under development for the treatment of COPD

Cahn, Anthony; Hamblin, J. Nicole; Begg, Malcolm; Wilson, Robert; Dunsire, L.; Sriskantharajah, Srividya; Montembault, Mickael; Leemereise, Claudia; Galinanes-Garcia, Laura; Watz, Henrik; Kirsten, Anne-Marie; Fuhr, Rainard; Hessel, Edith M.

doi:10.1016/j.pupt.2017.08.008

Cited by 66 publications

(72 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It would therefore be of importance to determine whether inhaled PI3Kδ inhibitors could alleviate the respiratory manifestations of APDS while reducing the risk of the adverse effects associated with systemic inhibition. Moreover, the results may also be relevant to other conditions, such as COPD 17 , where PI3Kδ may be activated by non-genetic mechanisms. Overall, our findings suggest that in subjects with increased PI3Kδ activity prophylactic administration of PI3Kδ inhibitors may help alleviate the course of S. pneumoniae infection.…”

Section: Discussionmentioning

confidence: 89%

“…Given that APDS patients are more susceptible to S. pneumoniae , we sought to determine whether nemiralisib, an inhaled PI3Kδ inhibitor which is in development for the treatment and prevention of COPD excacerbations 17, 18 , would alter susceptibility to airway infections. We treated mice with nemiralisib and then infected them intranasally with S. pneumoniae.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we have explored mechanisms by which PI3Kδ hyperactivation drives susceptibility to S. pneumoniae infection. We found that the administration of the PI3Kδ-selective inhibitor nemiralisib (GSK-22696557) 17, 18 reduced the severity of pneumococcal disease in wild-type mice. To investigate this further, we generated a p110δ E1020K mouse model that accurately recapitulates the genetics and immunological phenotype of APDS, and displays increased susceptibility to S. pneumoniae infection.…”

Section: Introductionmentioning

confidence: 96%

See 2 more Smart Citations

PI3Kδ hyper-activation promotes the development of B cells that exacerbateStreptococcus pneumoniaeinfection in an antibody-independent manner

Stark

Chandra

Chakraborty

et al. 2018

Preprint

View full text Add to dashboard Cite

Streptococcus pneumoniae is a major cause of pneumonia and a leading cause of death 1world-wide. Antibody-mediated immune responses can offer protection against repeated 2 exposure to S. pneumoniae, yet vaccines only offer partial protection. Patients with 3 Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated 4 a conditional knockin mouse model of this disease and identified a CD19 + B220 -B cell 5 subset that is induced by PI3Kδ signaling, is resident in the lungs, and which promotes 6 increased susceptibility to S. pneumoniae during the early phase of infection via an 7 antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves 8 survival rates following S. pneumoniae infection in wild-type mice and in mice with 9 activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the 10 severity of S. pneumoniae infection, representing a novel therapeutic target. 11 100 2B). This pattern resembles results found in patients with APDS 10 . In wild-type and 101 p110δ E1020K-GL cells, the PI3Kδ-selective inhibitor nemiralisib reduced PIP3 to the background 102 level observed in p110δ D910A cells, which, as expected, were insensitive to nemiralisib ( Fig 103 2A, B). 104 105 PIP3 binds to the protein kinase AKT, supporting its phosphorylation on Thr308 and 106 subsequent activation. Western blotting of purified p110δ E1020K-GL T cells showed increased 107AKT phosphorylation following stimulation with anti-CD3 and anti-CD28 antibodies 108 compared to wild-type cells, whereas AKT phosphorylation in p110δ D910A T cells was below 109 the limit of detection ( Fig 2C). In B cells, both basal and anti-IgM-induced phosphorylation of 110 AKT were elevated in p110δ E1020K-GL cells, while strongly diminished in p110δ D910A B cells (Fig 111 2D). The phosphorylation of ERK and the AKT effector proteins, FOXO and S6, were similarly 112 affected. All phosphorylation events in wild-type and p110δ E1020K-GL cells were reduced to 113 the levels observed in p110δ D910A cells by inhibition with nemiralisib. As expected, p110δ 114 protein expression was not affected by the E1020K or D910A mutations (Figs 2C, D). 115 116

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

See 1 more Smart Citation

PI3Kδ hyper-activation promotes the development of B cells that exacerbateStreptococcus pneumoniaeinfection in an antibody-independent manner

Stark

Chandra

Chakraborty

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…In summary, the science to date supports the potential of PI3Kδ inhibition as a novel therapeutic approach for patients with COPD, able to act on top of corticosteroids, capable of improving antibacterial defense in the respiratory tract, and able to inhibit secretion of inflammatory mediators …”

mentioning

confidence: 96%

“…Nemiralisib was rapidly absorbed into plasma following a single inhaled nemiralisib 100‐2000 μg in moderate to severe COPD patients with stable disease with a maximum peak at approximately 2 hours . Following repeat administration, accumulation in plasma was approximately 2‐ to 3‐fold from day 1 to day 7.…”

mentioning

confidence: 99%

Evaluation of the Safety, Tolerability, and Pharmacokinetics of GSK2269557 (Nemiralisib) Administered Via Dry Powder Inhaler to Healthy Japanese Subjects

Ino

Wilson

Terao

et al. 2018

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

The aim of the study was to assess the safety, tolerability, and pharmacokinetics of single and repeat doses of nemiralisib administered via a dry powder inhaler to healthy Japanese subjects. This was a single-center, double-blind, randomized, placebo-controlled, parallel, single-and repeat-ascending-dose study. Thirty-six healthy Japanese male subjects were randomized to receive either 1 dose strength of nemiralisib or placebo. The study consisted of a screening period, a single-dose session (session 1), a repeat-dose session (session 2), a 10-day washout period between the sessions, and then a follow-up visit 10 ± 1 days after the last dose of session 2. No serious adverse events were reported. No clinically significant abnormalities were found in clinical laboratory results, vital signs, or spirometry results. Generally, exposure (maximum observed plasma concentration [C max ] and area under the concentration-time curve [AUC]) increased with dose in an approximately proportional manner. Plasma T max was achieved rapidly at approximately 0.08 hours, and the terminal elimination half-life (T 1/2 ) was approximately 40 hours. T max and T 1/2 did not change between days or doses in the single-and repeat-dose sessions. Following 10 daily doses of 200, 500, and 700 μg nemiralisib, accumulation was observed, and the ratios (session 2, day 10:session 1) for Ro(AUC 0-24 ) and R(C max ) were 2.4-3.0 and 1.5-1.7, respectively. Steady state was achieved by 6-7 days, based on trough observed plasma drug concentration (C trough ) values.

show abstract

PI3K signalling in chronic obstructive pulmonary disease and opportunities for therapy

Moradi

Jarrahi

Ahmadi

et al. 2021

The Journal of Pathology

View full text Add to dashboard Cite

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterised by airway inflammation and progressive obstruction of the lung airflow. Current pharmacological treatments include bronchodilators, alone or in combination with steroids, or other anti-inflammatory agents, which have only partially contributed to the inhibition of disease progression and mortality. Therefore, further research unravelling the underlying mechanisms is necessary to develop new anti-COPD drugs with both lower toxicity and higher efficacy. Extrinsic signalling pathways play crucial roles in COPD development and exacerbations. In particular, phosphoinositide 3-kinase (PI3K) signalling has recently been shown to be a major driver of the COPD phenotype. Therefore, several small-molecule inhibitors have been identified to block the hyperactivation of this signalling pathway in COPD patients, many of them showing promising outcomes in both preclinical animal models of COPD and human clinical trials. In this review, we discuss the critically important roles played by hyperactivated PI3K signalling in the pathogenesis of COPD. We also critically review current therapeutics based on PI3K inhibition, and provide suggestions focusing on PI3K signalling for the further improvement of the COPD phenotype.

show abstract

Safety, pharmacokinetics and dose-response characteristics of GSK2269557, an inhaled PI3Kδ inhibitor under development for the treatment of COPD

Cited by 66 publications

References 20 publications

PI3Kδ hyper-activation promotes the development of B cells that exacerbateStreptococcus pneumoniaeinfection in an antibody-independent manner

PI3Kδ hyper-activation promotes the development of B cells that exacerbateStreptococcus pneumoniaeinfection in an antibody-independent manner

Evaluation of the Safety, Tolerability, and Pharmacokinetics of GSK2269557 (Nemiralisib) Administered Via Dry Powder Inhaler to Healthy Japanese Subjects

PI3K signalling in chronic obstructive pulmonary disease and opportunities for therapy

Contact Info

Product

Resources

About