danirixin (GSK1325756) / GSK - LARVOL DELTA

Inhibition of chemokine receptor CXCR2 attenuates postoperative peritoneal adhesion formation. (PubMed, Surgery) - "Inflammation plays an important role in the early stages of postoperative peritoneal adhesion formation, whereas collagen fibers and angiogenesis play important roles in the late stages. The CXCL2-CXCL3-CXCR2 signaling axis is an important link in the mechanism of postoperative peritoneal adhesion formation, and the application of CXCR2 inhibitors can alleviate the formation of postoperative peritoneal adhesions."

Journal • Gynecology • Inflammation • CXCL3 • CXCR2

CXCR2-Blocking Has Context-Sensitive Effects on Rat Glioblastoma Cell Line Outgrowth (S635) in an Organotypic Rat Brain Slice Culture Depending on Microglia-Depletion (PLX5622) and Dexamethasone Treatment. (PubMed, Int J Mol Sci) - "Our method allowed us to study the influence of three different factors-dexamethasone, PLX5622, and CXCL2-in a well-controlled, simplified, and straight-forward mechanistic manner, and at the same time in a more realistic ex vivo scenario compared to in vitro studies. In our model, we showed a GBM outgrowth enhancing synergism between CXCR2-blocking and Dex-treatment in the native condition, which was levelled by PLX5622-pretreatment."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CSF1 • CXCR2

High-Throughput Cellular Heterogeneity Analysis in Cell Migration at the Single-Cell Level. (PubMed, Small) - "This work further pinpoints synergistic drug combinations, including Bortezomib and Danirixin, to stop fast-moving cells. To explain the observed cell behaviors, single-cell morphological and molecular analysis were performed. These studies establish a novel technology to identify promising migration inhibitors for cancer treatment and relevant applications."

Heterogeneity • Journal • Breast Cancer • Oncology • Solid Tumor

New Insight into Drugs to Alleviate Atopic March via Network Pharmacology-Based Analysis. (PubMed, Curr Issues Mol Biol) - "The network analysis unveiled key targets against AM, and the MDT confirmed the affinity between significant compounds and targets. In this study, we described the significance of the eight uppermost targets (CCL2, CTLA4, CXCL8, ICAM1, IL10, IL17A, IL1B, and IL2) and eight ligands (Bindarit, CTLA-4 inhibitor, Danirixin, A-205804, AX-24 HCl, Y-320, T-5224, and Apilimod) against AM, providing a scientific basis for further experiments."

Journal • Allergic Rhinitis • Asthma • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CCL2 • CXCL8 • ICAM1 • IL10 • IL17A • IL1B • IL2

Exhaled volatile organic compounds and lung microbiome in COPD: a pilot randomised controlled trial. (PubMed, ERJ Open Res) - "In a pilot RCT, our exploratory objectives were feasibility of measuring VOCs via multiple techniques, assessing relationships between VOCs and Haemophilus colonisation and whether CXCR2 antagonism with danirixin altered lung microbiome composition in individuals with COPD...VOC measurement in clinical trials to identify subsets of COPD is feasible, but assessment of new VOC technologies must include concurrent GC-MS validation. Further work to standardise collection of VOCs and measuring a background or "housekeeper" VOC is required to understand and normalise individual VOC quantities."

Clinical • Journal • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases • CXCR2

Improved Decision-Making Confidence Using Item-Based Pharmacometric Model: Illustration with a Phase II Placebo-Controlled Trial. (PubMed, AAPS J) - "Patients received either oral danirixin 75 mg twice daily (n = 45) or placebo (n = 48) on top of standard of care over 52 weeks...The IRM showed a higher probability of a positive predictive value (34%) than MMRM (22%). An item model-based analysis data gave more precise estimates of drug effect than MMRM analysis for the same endpoint in this one case study."

Clinical • Journal • P2 data • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

CXCL8 Associated Dendritic Cell Activation Marker Expression and Recruitment as Indicators of Favorable Outcomes in Colorectal Cancer. (PubMed, Front Immunol) - "In vitro results suggested no significant growth or survival changes following treatment with an inhibitor of the CXCL8 receptor (CXCR1/2) such as reparixin or danirixin. Furthermore, CXCL8 induced DC migration in transwell migration assays. Taken together, our data suggested that targeting the CXCL8-CXCR2 axis might impede DC activation or recruitment, and this axis could be considered a favorable factor rather than a target for critical antitumor effects on CRC."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Immune Modulation • Inflammation • Movement Disorders • Oncology • Solid Tumor • CD8 • CD86 • CXCL8 • CXCR1 • CXCR2 • GZMB • IFNG

Randomized Study Evaluating the Effect of Danirixin on Neutrophil Extracellular Traps (NETs) in Chronic Obstructive Pulmonary Disease (COPD) (clinicaltrials.gov) - P2; N=24; Not yet recruiting; Sponsor: GlaxoSmithKline

Clinical • New P2 trial • Chronic Obstructive Pulmonary Disease • Immunology • ELANE • RETN

Randomized Study Evaluating the Effect of Danirixin on Neutrophil Extracellular Traps (NETs) in Chronic Obstructive Pulmonary Disease (COPD) (clinicaltrials.gov) - P2; N=19; Active, not recruiting; Sponsor: GlaxoSmithKline; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Chronic Obstructive Pulmonary Disease • Immunology • ELANE • RETN

Randomized Study Evaluating the Effect of Danirixin on Neutrophil Extracellular Traps (NETs) in Chronic Obstructive Pulmonary Disease (COPD) (clinicaltrials.gov) - P2; N=24; Recruiting; Sponsor: GlaxoSmithKline; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Chronic Obstructive Pulmonary Disease • Immunology • ELANE • RETN

Randomized Study Evaluating the Effect of Danirixin on Neutrophil Extracellular Traps (NETs) in Chronic Obstructive Pulmonary Disease (COPD) (clinicaltrials.gov) - P2; N=19; Terminated; Sponsor: GlaxoSmithKline; Active, not recruiting ➔ Terminated; Study terminated due to a change in the benefit-risk profile for danirixin in COPD.

Clinical • Trial termination • Chronic Obstructive Pulmonary Disease • Immunology • Respiratory Diseases • ELANE • RETN

Tumor-associated macrophages-mediated CXCL8 infiltration enhances breast cancer metastasis: Suppression by Danirixin. (PubMed, Int Immunopharmacol) - "Collectively, TAMs/CXCL8 could enhance BCSCs self-renewal and breast cancer metastasis, and these effects could be markedly abolished by Danirixin treatment, suppressing breast cancer progression consequently. Therefore, Danirixin could be considered as a novel and effective therapeutic strategy for breast cancer treatment without obvious toxicity to major organs."

Journal • Breast Cancer • Lung Cancer • Oncology • Solid Tumor • CXCL8

The discovery of novel small molecular CXCR2 antagonist by using ligand-based pharmacophore model (AACR 2018) - "...To date, four drug candidates are in clinical trials, including Danirixin, AZD5069, Reparixin and Ladarixin. The clinical indications of AZD5069 were expanded to metastatic head & neck cancer and metastatic pancreatic cancer, in combination with MEDI4736 (a PDL-1 inhibitor).As an excellent computational tool, the pharmacophore model, has been rapidly developed for the identification of novel hit/lead compounds for various targets, especially for proteins without crystal structures...Following optimization resulted in the discovery ofcompound D45 which showed not only potent CXCR2 antagonist activity with an IC50 value of 10 nM and 910-fold selectivity against CXCR1, but also good in vitro anti-tumor metastatic effect in wound healing assay. Moreover, compound D45 exhibitored promising druglikeness with more than 90% bioavailability in rat."

Head and Neck Cancer • Pancreatic Cancer

CXCL-8-dependent and -independent neutrophil activation in COPD: experiences from a pilot study of the CXCR2 antagonist danirixin. (PubMed, ERJ Open Res) - "The implications of these findings are significant for development of CXCR2 antagonists and other mechanisms targeting neutrophil activation or NETosis, suggesting that IL-8-dependent mechanisms will only work in a subset of COPD patients https://bit.ly/32SeisO."

Clinical • Journal • Chronic Obstructive Pulmonary Disease • Immunology • Respiratory Diseases • CXCL8 • CXCR2

Negative Food Effect of Danirixin: Use of PBPK Modelling to Explore the Effect of Formulation and Meal Type on Clinical PK. (PubMed, Pharm Res) - "Interactions between DNX and food components are the likely the source of the negative food effect via micellar entrapment, ion pairing and/or meal induced viscosity changes."

Clinical • Journal • KIM1

Evaluation of the Safety, Tolerability, Pharmacokinetics, and Food Effect of Danirixin Hydrobromide Tablets in Japanese Healthy Elderly Participants. (PubMed, Clin Pharmacol Drug Dev) - "The exposure to danirixin was lower in the fed state (low-fat meal) than in the fasted state (a 56% and 35% decrease in C and AUC , respectively). This first study of danirixin in Japanese healthy elderly participants showed a favorable safety profile with no drug-related adverse events and no clinically significant concerns in clinical laboratory values, vital signs, ocular examination, or electrocardiograms."

Clinical • Journal • PK/PD data • Chronic Obstructive Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Neutrophil Extracellular Traps and CXCR2 Antagonism in Chronic Obstructive Pulmonary Disease: A Pilot Randomized Control Study (ATS-I 2020) - P2 | "Study results were inconclusive in determining whether blocking CXCR2 antagonism via danirixin reduced NET formation or changed lung microbiome composition COPD patients due to the small number of study participants following early termination of the study. Funding: This study (GSK study 207551) was funded by GSK (NCT03250689)."

Clinical • Chronic Obstructive Pulmonary Disease • Respiratory Diseases • CXCL8 • CXCR2 • ELANE

CXCR2 antagonist for patients with chronic obstructive pulmonary disease with chronic mucus hypersecretion: a phase 2b trial. (PubMed, Respir Res) - P2 | "The robust placebo and study effects prohibited any conclusions on the efficacy of danirixin. However, the absence of a clear efficacy benefit and the observed increase in exacerbations in danirixin-treated groups suggests an unfavorable benefit-risk profile in patients with COPD."

Clinical • Journal • P2b data • Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Pneumonia • Respiratory Diseases • CXCR2

Safety, Tolerability and Clinical Effect of Danirixin in Adults With Influenza (clinicaltrials.gov) - P2; N=120; Not yet recruiting; Sponsor: GlaxoSmithKline

New P2 trial • Biosimilar • Immunology • Inflammation

Investigation of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy of Oral Danirixin in Symptomatic COPD Subjects With Mild to Moderate Airflow Limitation at Risk for Exacerbations (clinicaltrials.gov) - P2a; N=110; Recruiting; Sponsor: GlaxoSmithKline; Trial primary completion date: Jan 2016 ->Mar 2015

Trial primary completion date • Biosimilar • Chronic Obstructive Pulmonary Disease • Inflammation

Danirixin Dose Ranging Study in Participants With Chronic Obstructive Pulmonary Disease (COPD) (clinicaltrials.gov) - P2; N=600; Recruiting; Sponsor: GlaxoSmithKline; Not yet recruiting ➔ Recruiting

Enrollment open • Biosimilar • Chronic Obstructive Pulmonary Disease • Immunology

Study to Evaluate the Efficacy and Safety of Danirixin Co-administered With Oseltamivir in the Treatment of Adults Hospitalized With Influenza (clinicaltrials.gov) - P2; N=11; Terminated; Sponsor: GlaxoSmithKline; N=300 ➔ 11; Recruiting ➔ Terminated; Trial primary completion date: Jun 2019 ➔ May 2017; The study was stopped early due to lack of enrollment.

Enrollment change • Trial primary completion date • Trial termination • Biosimilar • Immunology

Neutrophil Extracellular Traps and CXCR2 Antagonism in Chronic Obstructive Pulmonary Disease: A Pilot Randomized Control Study (ATS 2020) - P2 | "Conclusion Measurement of NETs is feasible in a clinical trial. Study results were inconclusive in determining whether blocking CXCR2 antagonism via danirixin reduced NET formation or changed lung microbiome composition COPD patients due to the small number of study participants following early termination of the study.Funding: This study (GSK study 207551) was funded by GSK (NCT03250689)."

Clinical • CXCL8 • CXCR2 • ELANE

NETopathic Inflammation in Chronic Obstructive Pulmonary Disease and Severe Asthma. (PubMed, Front Immunol) - "The chemokine CXCR2 receptor regulates neutrophil activation and migration, and small molecule CXCR2 antagonists (e.g., AZD5069, danirixin) have been developed to selectively block neutrophilic inflammatory pathways. Clinical validation of this type could lead to novel therapeutics for multiple CXCR2-related NETopathologies. In this Review, we discuss the emerging role of NETs in the clinicopathobiology of COPD and severe asthma and provide an outlook on how novel NET-stabilizing therapies via CXCR2 blockade could be leveraged to disrupt NETopathic inflammation in disease-specific phenotypes."

Journal • Review

Effect of the CXCR2 antagonist danirixin on symptoms and health status in COPD. (PubMed, Eur Respir J) - No abstract available.

Journal