nemiralisib (GSK2269557) / GSK - LARVOL DELTA

Selective PI3Kγ Inhibition Attenuates Chemotherapy-Induced Intestinal Mucositis without Compromising the Anticancer Properties of Irinotecan. (PubMed, Eur J Pharmacol) - "C57BL/6 male mice received vehicle (1% DMSO, 10 ml/kg, p.o.), irinotecan alone or in combination with AS-605240 (a PI3Kγ inhibitor, 10 mg/kg, p.o.) or GSK2269557 (a PI3Kδ inhibitor, 3 mg/kg, p.o.). PI3Kγ inhibition attenuates chemotherapy-associated intestinal mucositis without compromising the anticancer efficacy of irinotecan. However, selective inhibition of PI3Kδ exacerbates the inflammatory response and tissue damage."

Journal • Colorectal Cancer • Infectious Disease • Inflammation • Mucositis • Oncology • Septic Shock • Solid Tumor • FOXP3 • IL1B • PIK3CD • PIK3CG • TLR2 • TLR4 • TLR9

Animal models to assess potential post-inhalation irritant effects associated with inhaled drugs. (ERS 2024) - "To validate the assay, rats or guinea-pigs were exposed to a series of inhaled compounds (AZD9164, CHF6523 and Nemiralisib) given as dry powder that induced drop in FEV1 or cough as adverse event in humans. No effect was observed with BDP. These data demonstrate that it is possible to assess the potential irritant effects associated with inhaled drugs using a head-out plethysmography applied to the inhalation system, thus helping in the selection of molecules devoid of such effects."

Preclinical • Cough • Inflammation • Respiratory Diseases

Efficacy of Nemiralisib in Chronic Obstructive Pulmonary Disease: A Systematic Review. (PubMed, Clin Ther) - "Because of insufficient data, this systematic review could not make any definitive statement regarding the efficacy of nemiralisib in COPD patients. In terms of safety, nemiralisib was generally well tolerated. Further trials are required to explore the efficacy of this drug."

Journal • Review • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

An open label trial of nemiralisib, an inhaled PI3 kinase delta inhibitor for the treatment of Activated PI3 kinase Delta Syndrome. (PubMed, Pulm Pharmacol Ther) - P2 | "In this study investigating a small number of subjects with APDS, nemiralisib appeared to be safe and well-tolerated. However, data from this study do not support the hypothesis that inhaled treatment with nemiralisib would benefit patients with APDS."

Journal • Cough • Immunology • Infectious Disease • Respiratory Diseases • PIK3CD

Immune cells transcriptome-based drug repositioning for multiple sclerosis. (PubMed, Front Immunol) - "We obtained 50 hub target genes for CD4 T cells in Fingolimod for MS, 15 hub target genes for Plasmacytoid dendritic cells (pDCs) and 7 hub target genes for Peripheral blood mononuclear cells (PBMC) in interferon-β (IFN-β) for MS. 6 candidate drugs targeting two or more hub targets (Fostamatinib, Copper, Artenimol, Phenethyl isothiocyanate, Aspirin and Zinc) were obtained...We obtained 69 candidate drugs targeting two target pathways. We found that applying candidate drugs that target both the "PI3K-Akt signaling pathway" and "Chemokine signaling pathway" (e.g., Nemiralisib and Umbralisib) or applying tyrosine kinase inhibitors (e.g., Fostamatinib) may be potential therapies for the treatment of MS."

Journal • CNS Disorders • Infectious Disease • Multiple Sclerosis • CD19 • CD4 • IFNB1

FUNCTIONAL SCREENING OF PI3K INHIBITORS STRATIFIES RESPONDERS TO IDELALISIB AND INDICATES DRUG CLASS ACTIVITY IN IDELALISIB-REFRACTORY CLL (EHA 2022) - "Aims To characterize functional responses to 10 PI3Ki in CLL To study PI3Ki drug class activity in idelalisib-refractory CLL To investigate whether ex vivo drug sensitivity can predict in vivo treatment responses Methods CLL cells from patients that were treatment naïve (n=7), idelalisib refractory (n=9), or on idelalisib treatment (longitudinal samples from n=6 patients) were screened against 10 PI3Ki (buparlisib, compound 7n, copanlisib, duvelisib, idelalisib, nemiralisib, pictilisib, pilaralisib, umbralisib, ZSTK474), both alone and in combination with the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax...Ex vivo drug testing on CLL cells from a patient who presented with relapsed disease after sequential treatment with FCR, ibrutinib, idelalisib and venetoclax revealed sensitivity to PI3Ki+venetoclax treatment...Conclusion Our findings indicate PI3Ki drug class activity in idelalisib-refractory CLL, and suggest that ex vivo drug sensitivity may guide precision..."

IO biomarker • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • BCL2 • CASP3

Physiologically Based Pharmacokinetic Modelling of Inhaled Nemiralisib: Mechanistic Components for Pulmonary Absorption, Systemic Distribution, and Oral Absorption. (PubMed, Clin Pharmacokinet) - "Fully mechanistic inhaled PBPK models such as the model described herein could be applied for cross molecule assessments with respect to lung retention and systemic exposure, both in terms of pharmacology and toxicology, and may facilitate clinical indication selection."

Journal • PK/PD data • Respiratory Diseases • PIK3CD

Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials. (PubMed, Int J Chron Obstruct Pulmon Dis) - "We provide evidence for nemiralisib-evoked changes in neutrophil migration phenotype in stable COPD but not AECOPD, despite improving lung function in the latter group. We conclude that induced sputum can be used for measuring evidence of alteration of neutrophil phenotype in stable patients, and our study provides a data set of the sputum transcriptomic changes during recovery from AECOPD."

Clinical • Journal • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Nemiralisib in Patients with an Acute Exacerbation of COPD: Placebo-Controlled, Dose-Ranging Study. (PubMed, Int J Chron Obstruct Pulmon Dis) - "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."

Clinical • Journal • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

An Inhaled PI3Kδ Inhibitor Improves Recovery in Acutely Exacerbating COPD Patients: A Randomized Trial. (PubMed, Int J Chron Obstruct Pulmon Dis) - P2 | "These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group."

Clinical • Journal • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] PI3Kγd Inhibitor, AZD8154, Demonstrates Improved Efficacious Profile Over PI3Kd Selective Inhibitor, GSK2269557, in a Rat Model of Asthma (ATS 2021) - "These data suggest that a dual PI3Kγδ inhibitor has an improved therapeutic profile compared to the selective PI3Kδ inhibitor, GSK557. Furthermore, these data suggest that AZD8154 may not trigger the increase in coughing which was observed for GSK557. Together these data indicate that AZD8154 may be an effective treatment for people suffering from asthma."

Preclinical • Asthma • Eosinophilia • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

"Very elegant way from @GSK - Application of C–H Functionalization in the Development of a Concise and Convergent Route to the Phosphatidylinositol-3-kinase Delta Inhibitor Nemiralisib https://t.co/xMzbOBNYVp" (@LenaicRummler)

Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial. (PubMed, Lancet Respir Med) - P3 | "In patients with uncontrolled moderate or severe asthma on ICS/LABA, adding UMEC improved lung function but did not lead to a significant reduction in moderate and/or severe exacerbations. For such patients, single-inhaler FF/UMEC/VI is an effective treatment option with a favourable risk-benefit profile. Higher dose FF primarily reduced the rate of exacerbations, particularly in patients with raised biomarkers of type 2 airway inflammation. Further confirmatory studies into the differentiating effect of type 2 inflammatory biomarkers on treatment outcomes in asthma are required to build on these exploratory findings and further guide clinical practice."

Clinical • Journal • P3 data • Asthma • Cardiovascular • Immunology • Infectious Disease • Pain • Pulmonary Embolism • Respiratory Diseases

[VIRTUAL] Captain Study: Simultaneous Step-Up to High Dose Fluticasone Furoate and Addition of Umeclidinium for the Treatment of Inadequately Controlled Asthma (ATS-I 2020) - P3 | "Following an ICS/LABA run-in period, patients were randomized to receive once-daily FF/vilanterol (VI) (100/25, 200/25 mcg) or FF/UMEC/VI (100/31.25/25, 100/62.5/25, 200/31.25/25, 200/62.5/25 mcg) via Ellipta dry powder inhaler. Increasing FF dose and adding UMEC in a single step represents a therapeutic option for patients with asthma that are inadequately controlled on FF/VI 100/25 mcg. Funding GSK (study 205715/NCT02924688)."

Late-breaking abstract • Asthma • Respiratory Diseases

Safety, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of Repeat Doses of Inhaled GSK2269557 in Patients With APDS/PASLI (clinicaltrials.gov) - P2; N=5; Completed; Sponsor: GlaxoSmithKline; Active, not recruiting ➔ Completed; N=20 ➔ 5

Clinical • Enrollment change • Trial completion • CRP • PIK3CD

An innovative approach to characterize clinical ADME and pharmacokinetics of the inhaled drug nemiralisib using an intravenous microtracer combined with an inhaled dose, and an oral radiolabel dose in healthy male subjects. (PubMed, Drug Metab Dispos) - "The work includes features such as intravenous [14C] tracer administration concomitant with an inhalation dose to describe pharmacokinetics, entero-test bile sampling to characterize biliary elimination pathways and a full metabolic profile in plasma and excreta. In addition we describe equations that can be used to estimate parameters such as fraction absorbed (Fabs), the proportion of drug escaping first pass extraction through the gut wall and liver (Fg and Fh) and hepatic extraction (Eh) which, to the authors knowledge, have never been published before."

Clinical • Journal • PK/PD data • Respiratory Diseases

A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Multiple Doses of GSK2269557 Administered as a Dry Powder to Chronic Obstructive Pulmonary Disease (COPD) Patients (clinicaltrials.gov) - P2; N=30; Not yet recruiting; Sponsor: GlaxoSmithKline

New P2 trial • Biosimilar • Immunology • Myositis

A Study to Investigate the Efficacy, Safety, and Tolerability of Repeat Doses of Inhaled GSK2269557 in Adults With Persistent, Uncontrolled Asthma (clinicaltrials.gov) - P2; N=50; Recruiting; Sponsor: GlaxoSmithKline; Not yet recruiting ➔ Recruiting

Enrollment open • Asthma • Biosimilar • Chronic Obstructive Pulmonary Disease

Study to Evaluate the Safety, Tolerability and Pharmacokinetics of GSK2269557 Administered Via the ELLIPTA Dry Powder Inhaler to Healthy Subjects (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: GlaxoSmithKline; Not yet recruiting ➔ Recruiting

Enrollment open • Biosimilar • Chronic Obstructive Pulmonary Disease • Immunology

Safety, Tolerability, and Pharmacokinetics of a New Formulation of Nemiralisib Administered via a Dry Powder Inhaler to Healthy Individuals. (PubMed, Clin Ther) - P1 | "After single-dose inhalation of 500 and 750 μg of nemiralisib from the Ellipta DPI in healthy individuals, plasma PK data were well defined, and as predicted based on previous PK and APSD data, exposure was increased with the new formulation. Nemiralisib was well tolerated with no new safety issues identified. These data supported progression of nemiralisib to a Phase IIb study in patients with chronic obstructive pulmonary disease. ClinicalTrials.gov identifier: NCT03189589."

Clinical • Journal • PK/PD data

Safety, Pharmacokinetics and Dose-response Characteristics of GSK2269557, an Inhaled PI3Kδ Inhibitor Under Development for the Treatment of COPD (ATS 2017) - "In this study, inhaled GSK2269557 had an acceptable safety profile for progression into larger studies in COPD patients and 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 airways may contribute to the potential therapeutic benefit of a PI3Kδ inhibitor in chronically inflamed COPD patients.n*Post hoc analysis"

Clinical • Retrospective data • Biosimilar • Chronic Obstructive Pulmonary Disease • Immunology

Dose Finding Study of Nemiralisib (GSK2269557) in Subjects With an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD) (clinicaltrials.gov) - P2b; N=1250; Not yet recruiting; Sponsor: GlaxoSmithKline

New P2b trial • Biosimilar • Chronic Obstructive Pulmonary Disease • Immunology • Respiratory Diseases

GSK: R&D Event (GSK) - Anticipated regulatory submission in COPD exacerbation in 2021-2025 

Anticipated regulatory • Immunology

GSK: R&D Event (GSK) - Anticipated data from P2 trial in COPD in 2016; Anticipated initiation of P2b trial in COPD at the end of 2016 or beginning of 2017

Anticipated new P2b trial • Anticipated P2 data • Immunology

Captain Study: Simultaneous Step-Up to High Dose Fluticasone Furoate and Addition of Umeclidinium for the Treatment of Inadequately Controlled Asthma (ATS 2020) - P3 | "Following an ICS/LABA run-in period, patients were randomized to receive once-daily FF/vilanterol (VI) (100/25, 200/25 mcg) or FF/UMEC/VI (100/31.25/25, 100/62.5/25, 200/31.25/25, 200/62.5/25 mcg) via Ellipta dry powder inhaler. Increasing FF dose and adding UMEC in a single step represents a therapeutic option for patients with asthma that are inadequately controlled on FF/VI 100/25 mcg. Funding GSK (study 205715/NCT02924688)."

Late-breaking abstract