Delving into the Latest Updates on Danirixin with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Danirixin (USAN/INN), DNX, GSK-1325756

+ [3]

Target

CXCR2

Mechanism

CXCR2 antagonists(C-X-C motif chemokine receptor 2 antagonists)

Therapeutic Areas

Infectious DiseasesRespiratory DiseasesEndocrinology and Metabolic Disease

Active Indication-

Inactive Indication

Influenza, HumanMalnutritionPulmonary Disease, Chronic Obstructive+ [1]

Originator Organization

GSK Plc

Active Organization-

Inactive Organization

GSK Plc

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC19H21ClFN3O4S

InChIKeyNGYNBSHYFOFVLS-LBPRGKRZSA-N

CAS Registry954126-98-8

A Two Part, Randomized, Open-label, Cross Over Study in Healthy Elderly Participants to Evaluate the Relative Bioavailability of Hydrobromide Salt Tablet Formulations of Danirixin in the Fed and Fasted States, and to Evaluate the Effect of Food and Gastric Acid Secretion Suppression on Danirixin Pharmacokinetics Following Administration of Hydrobromide Salt Tablets

This 2-part study will be carried out on healthy elderly subjects to evaluate relative bioavailability of danirixin formulations. Part A will support the selection of the formulation and Part B will assess food effect, bioavailability and pharmacokinetic (PK) profile of selected formulation from Part A. Danirixin is currently administered with food, therefore the investigation of food effect for the selected formulation could potentially enable dosing without food. Approximately 16 subjects will be included in Part A and approximately 24 subjects will be included in Part B. Both parts will include a screening phase, treatment phase with in-between washout period and a follow-up phase.

Start Date07 Mar 2018

Sponsor / Collaborator

GSK Plc

NCT03250689 / TerminatedPhase 2

Randomized Double Blind (Sponsor Unblind) Study Evaluating the Effect of 14 Days of Treatment With Danirixin (GSK1325756) on Neutrophil Extracellular Traps (NETs) Formation in Participants With Stable Chronic Obstructive Pulmonary Disease (COPD)

The inflammation associated with COPD is characterized by a prominent infiltration of neutrophils in lung tissue and airways. The CXC chemokine receptor type 2 (CXCR2) plays a pivotal role in neutrophil recruitment to the lungs resulting in progressive fibrosis, airway stenosis, and destruction of the lung parenchyma characteristic of COPD. There is a paucity of novel therapies that target these symptoms, and there are no currently available therapies that modify disease progression in COPD. Danirixin (GSK1325756) is a selective CXCR2 antagonist being developed as a potential anti-inflammatory agent for the treatment of COPD and influenza. This study is a mechanistic study which aims to evaluate the effect of danirixin in reducing neutrophil extracellular traps (NETs) formation (or NETosis). Subjects will be randomized (3:1) to receive danirixin hydrobromide (HBr) 35 milligram (mg) orally twice daily or matching placebo for 14 days. Subjects may continue to use rescue medication(s) and inhaled COPD maintenance medication(s) during the study. The study will consist of a screening period of up to 30 days, a 2 week treatment period, and a 1-week follow-up visit via phone call. Approximately 50 subjects will be screened to obtain approximately 24 subjects to complete the study.

Start Date15 Nov 2017

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with Danirixin

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100 Translational Medicine associated with Danirixin

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100 Patents (Medical) associated with Danirixin

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118

Literatures (Medical) associated with Danirixin

01 Dec 2024·BIOCHEMICAL PHARMACOLOGY

Carvedilol through ß1-Adrenoceptor blockade ameliorates glomerulonephritis via inhibition of oxidative stress, apoptosis, autophagy, ferroptosis, endoplasmic reticulum stress and inflammation

Article

Author: Lin, San-Chi ; Cheng, Yu-Hsuan ; Lin, Wei-Yu ; Hsu, Shih-Ping ; Chien, Chiang-Ting ; Liu, Pei-Yu

Glomerulonephritis (GN) is one of the main causes of end stage renal disease and requires an effective treatment for inhibiting GN. Renal nerves through efferent (RENA) and afferent (RANA) innervation to glomeruli regulate the glomerular function. We delineated the role of RENA and RANA on anti-Thy1.1-induced GN. Female Wistar rats were divided into Control, Thy1.1 plus anti-Thy1.1, bilaterally renal nerve denervation (DNX) plus anti-Thy1.1, and topical capsaicin to bilateral renal nerves for selective ablation of RANA (DNAX) plus anti-Thy1.1. We examined RANA and RENA response to anti-Thy1.1 and compared the effect of DNX or DNAX on urinary oxidative stress, renal gp91, tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), apoptosis, autophagy, ferroptosis, antioxidant enzymes, endoplasmic reticulum (ER) stress and inflammation by western blot. Anti-Thy1.1 significantly enhanced RENA, but did not affect RANA. DNX significantly decreased TH and CGRP expression, whereas DNAX only reduced CGRP expression. Anti-Thy1.1 significantly increased glomerulosclerosis injury, urinary protein, electron paramagnetic resonance signals of alpha-(4-pyridyl-N-oxide)-N-tert-butylnitrone adducts, 8-isoprostane and nitrotyrosine levels, NADPH oxidase gp91phox (gp91), macrophage/monocyte (ED-1), GRP-78, Beclin-1/LC3-II, Bax/caspase-3/poly(ADP-ribose) polymerase expression, inflammatory cytokines levels and decreased renal Copper/Zinc superoxide dismutase, Cystine/glutamate transporter (xCT) and Glutathione peroxidase 4 (GPX4) expression vs. Control. The enhanced oxidative parameters or reduced antioxidant defense by anti-Thy1.1 were significantly attenuated by DNX but not DNAX. Additionally, oral ß1-adrenoceptor antagonist-Carvedilol at an early stage reduced anti-Thy1.1 increased proteinuria level and oxidative parameters. Our data suggest that DNX and ß1-adrenoceptor antagonist-Carvedilol efficiently attenuate oxidative stress, inflammation, ER stress, autophagy, ferroptosis and apoptosis in GN.

01 Nov 2024·BIOMEDICAL CHROMATOGRAPHY

Revealing the optimal traditional processing methods and its protective effects against febrile seizures of Arisaema cum bile

Article

Author: He, Su‐Rong ; Wu, Xu ; Song, Yi‐Jun ; Zhang, Qiao ; Zou, Ting ; Zhang, Meng‐Meng ; Wang, Jing ; Wang, Chang‐Li ; Zhao, Chong‐Bo

Abstract:

Arisaema cum bile (known as Dan Nanxing in Chinese, DNX) is a herbal medicine used for treating febrile seizure (FS), which commonly prepared by using Arisaematis Rhizoma and animal bile. This study was designed to explore the optimal processing time of DNX and its potential mechanism on the anti‐FS effect. A total of 17 volatile organic compounds (VOCs) were the characteristic ones to distinguish different fermentation stages of DNX by using gas chromatography–ion mobility spectrometry (GC‐IMS), such as 2‐heptanone monomer, and heptanal monomer. DNX with fermentation for 3 months had an obvious pattern of VOCs with others, which could be regarded as the optimal fermentation time. The Enterococcus and Staphylococcus might be the core bacteria on the production of VOCs. Additionally, DNX (2.8 g/kg, p.o.) reversed hot water bath‐induced FSs of rats, as indicated by increased seizure latency and decreased seizure duration time. It also prevented hippocampal neuronal loss, increased GABAAR, and decreased GRIA1 expression. At the genus level, relative abundance of Enterococcus and Akkermansia were enriched after DNX treatment. These findings suggested that fermentation for 3 months might be the optimal process time for DNX, and DNX possess an anti‐FS effect through regulating neurotransmitter disorder and gut microbiota.

20 Jun 2024·Journal of clinical oncology : official journal of the American Society of Clinical Oncology

Mitoxantrone Versus Liposomal Daunorubicin in Induction of Pediatric AML With Risk Stratification Based on Flow Cytometry Measurement of Residual Disease

Article

Author: Cheuk, Daniel ; Palle, Josefine ; Hasle, Henrik ; Fernandez Navarro, Jose Maria ; Pasauliene, Ramune ; Arad-Cohen, Nira ; Lausen, Birgitte ; Zeller, Bernward ; De Moerloose, Barbara ; Jahnukainen, Kirsi ; Kovalova, Zanna ; Saks, Kadri ; Kaspers, Gertjan ; Norén-Nyström, Ulrika ; Juul-Dam, Kristian Løvvik ; Abrahamsson, Jonas ; Tierens, Anne ; Jan Pronk, Cornelis

PURPOSE:

Measurable residual disease (MRD) by using flow cytometry after induction therapy is strongly prognostic in pediatric AML, and hematopoietic stem-cell transplant (hSCT) may counteract a poor response. We designed a phase III study with intensified response-guided induction and MRD-based risk stratification and treated poor induction response with hSCT. The efficacy of liposomal daunorubicin (DNX) in induction was compared with mitoxantrone.

METHODS:

The study planned to randomly assign 300 patients, but the production of DNX ceased in 2017. One hundred ninety-four patients were randomly assigned to mitoxantrone or experimental DNX in induction 1. Ninety-three non–randomly assigned patients served as an observation cohort. Primary end point was fraction of patients with MRD <0.1% on day 22 after induction 1. Patients with MRD ≥15% after induction 1 or ≥0.1% after induction 2 or FLT3-ITD with NPM1 wildtype were stratified to high-risk therapy, including hSCT.

RESULTS:

Outcome for all 287 children was good with 5-year event-free survival (EFS5y) 66.7% (CI, 61.4 to 72.4) and 5-year overall survival (OS5y) 79.6% (CI, 75.0 to 84.4). Overall, 75% were stratified to standard-risk and 19% to high-risk. There was no difference in the proportion of patients with MRD <0.1% on day 22 after induction 1 (34% mitoxantrone, etoposide, araC [MEC], 30% DNX, P = .65), but the proportion increased to 61% for MEC versus 47% for DNX ( P = .061) at the last evaluation before induction 2. EFS5y was significantly lower, 56.6% (CI, 46.7 to 66.5) versus 71.9% (CI, 63.0 to 80.9), and cumulative incidence of relapse (CIR) was higher, 35.1% (CI, 25.7 to 44.7) versus 18.8% (CI, 11.6 to 27.2) for DNX. The inferior outcome for DNX was only in standard-risk patients with EFS5y 55.3% (CI, 45.1 to 67.7) versus 79.9% (CI, 71.1 to 89.9), CIR 39.5% (CI, 28.4 to 50.3) versus 18.7% (CI, 10.5 to 28.7), and OS5y 76.2% (CI, 67.2 to 86.4) versus 88.6% (CI, 81.4 to 96.3). As-treated analyses, including the observation cohort, supported these results. For all high-risk patients, 85% received hSCT, and EFS5y was 77.7 (CI, 67.3 to 89.7) and OS5y was 83.0 (CI, 73.5 to 93.8).

CONCLUSION:

The intensification of induction therapy with risk stratification on the basis of response to induction and hSCT for high-risk patients led to improved outcomes. Mitoxantrone had a superior anti-leukemic effect than liposomal daunorubicin.

100 Deals associated with Danirixin

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External Link

KEGG	Wiki	ATC	Drug Bank
D10387	-	-	DB11922

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Influenza, Human	Phase 2	US	GSK Plc	01 Jun 2015
Influenza, Human	Phase 2	AU	GSK Plc	01 Jun 2015
Influenza, Human	Phase 2	ZA	GSK Plc	01 Jun 2015
Pulmonary Disease, Chronic Obstructive	Phase 2	US	GSK Plc	13 Feb 2014
Pulmonary Disease, Chronic Obstructive	Phase 2	DE	GSK Plc	13 Feb 2014
Respiratory Syncytial Virus Infections	Phase 1	US	GSK Plc	13 Jan 2014
Malnutrition	Phase 1	US	GSK Plc	14 Apr 2010

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03034967 (Pubmed \| Respir Res) Manual	Phase 2	Pulmonary Disease, Chronic Obstructive	614	Danirixin	(yhbbiungfu) = There were no improvements in E-RS:COPD, CAT or SGRQ-C scores in participants treated with any dose of danirixin compared to placebo. lrbdxuamfa (rguttipzpr ) View more	Negative	12 Jun 2020
				placebo
NCT03170232 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	54	placebo (Placebo)	ckvepvmfbz(vyaegudtwa) = pcikjwcebv zptsymqnma (xfkzuejayl, tzcsdvomgz - tvalznsxqq) View more	-	05 Feb 2020
				DNX HBr (DNX HBr 35 mg)	ckvepvmfbz(vyaegudtwa) = yrpiejciji zptsymqnma (xfkzuejayl, lkkzxldzeu - rdsynpqijs) View more
NCT03034967 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	614	Standard of care (Placebo)	huhegqoeez(prczfhdgag) = xgmkokewfg msygxdjaov (bumxziksqq, ancuorkipb - wggcpqfuao) View more	-	29 Nov 2019
				Standard of care+Danirixin (Danirixin 5 mg)	huhegqoeez(prczfhdgag) = ozttduozae msygxdjaov (bumxziksqq, bmzzipaorp - thcqvyblbg) View more
NCT03250689 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	19	placebo (Placebo)	ktndxpenxo(ulpgyombzp) = whbswngndq jzffhxllog (qlfstrvkib, wujrknzmcf - ijcwkihnxr) View more	-	08 Nov 2019
				Danirixin Hydrobromide (Danirixin Hydrobromide 35 mg)	ktndxpenxo(ulpgyombzp) = bozbawfrrt jzffhxllog (qlfstrvkib, abhdqectss - bmgvpixcxg) View more
NCT03136380 (GSK study 206817, CTgov)	Phase 1	Pulmonary Disease, Chronic Obstructive	34	placebo (Part 1: Placebo (Fed))	fhopxabfoe(bnaqxmrgdt) = jpuchjrfmz utzotcrjgd (zufebikpgc, bnikmkxqqt - dvuhucthui) View more	-	18 Apr 2019
				GSK1325756H (Part 1: GSK1325756H 10 mg (Fed))	fhopxabfoe(bnaqxmrgdt) = qhyqcwjcku utzotcrjgd (zufebikpgc, iesjjmpnwh - fabdrkzexr) View more
NCT02927431 (GSK study 201023, Pubmed \| Open Forum Infect Dis)	Phase 2	Influenza, Human	10	Danirixin 15mg + oseltamivir 75mg	cmauenyqea(ihglbyaiuw) = iarvoxrvqk tcwxcdvgfx (oqirrfsouu, 2.95 - 5.71)	-	01 Apr 2019
				Danirixin 50mg + oseltamivir 75mg	cmauenyqea(ihglbyaiuw) = kenyntavuf tcwxcdvgfx (oqirrfsouu, 2.71 - 5.25)
NCT03136380 (GSK study 206817, ERS2018)	Phase 1	Well Aging	-	Danirixin 10mg	khvzfaxzbf(bfergyfuky) = dxgzzjyijj rgqtxtbfgg (rxfvxflngw ) View more	Positive	15 Sep 2018
				Danirixin 50mg	khvzfaxzbf(bfergyfuky) = ntztvqsiiv rgqtxtbfgg (rxfvxflngw ) View more
NCT02927431 (GSK study 201023, CTgov)	Phase 2	Influenza, Human	10	Placebo (Placebo + OSV)	wgvdpjyrup(nvwbmuiajj) = wsgnlpjutu fejhynhueh (vngsfeyltw, ktgjllbvpi - fgwrnozcmb) View more	-	02 Jul 2018
				DNX (DNX 15 mg + OSV)	wgvdpjyrup(nvwbmuiajj) = rieppubldk fejhynhueh (vngsfeyltw, jaocotqyzc - mbbxkorqjn) View more
NCT02469298 (201682, CTgov)	Phase 2	Influenza, Human	45	Danirixin (DNX) (Danirixin (DNX) 75 mg)	hpavoynogb(nwgehpdejd) = kyucggmztf qcyijbfloh (pzvxnkvwlf, oqbzppffbf - yglhjomtiy) View more	-	24 Aug 2017
				Placebo (PBO) (Placebo (PBO))	hpavoynogb(nwgehpdejd) = umlvzxnwxj qcyijbfloh (pzvxnkvwlf, neqtvfvjbg - jgqxsbxjwm) View more
NCT02130193 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	102	DNX (DNX 50 mg)	uswcrrgckp(ltxmzjjmru) = fjxdjecoph fcbbtlhgqe (kusoaobrrz, scyrqkynkb - utxfqzdqab) View more	-	18 May 2017
				placebo (Placebo)	uswcrrgckp(jbioytxnzp) = ztezbzhuty ntpdabhpgk (eyordgyvfw, hjwpdaqnyi - dzobkjqlgn) View more