An open label, experimental medicine investigation of the safety and tolerability of 400 mg b.i.d. GSK2586184 in patients with moderate to severely active ulcerative colitis (200208) - 200208 (JAK)

Start Date09 Jan 2014

Sponsor / Collaborator

GlaxoSmithKline BV

NCT02000453

/ TerminatedPhase 1

An Open Label, Experimental Medicine Investigation of the Safety and Tolerability of 400 mg b.i.d. GSK2586184 in Patients With Moderate to Severely Active Ulcerative Colitis.

This is an open label exploratory study to investigate the safety of 400 milligram (mg ) twice a day (b.i.d.) GSK2586184 in patients with moderate to severe, active ulcerative colitis (UC). Study medication will be administered orally (as tablets), twice daily, for up to 8 weeks (56 days). Study medication will be taken with food. Each subject will have 6 out-patient visits: Screening (Day -30 to -1); Baseline and Start of treatment (Day 1); Week 2 (Day 14); Week 4 (Day 28); Week 8 (Day 56); and Follow-up (Week 12; Day 84). Visit windows for weeks 2, 4 and 8 will be + 2 days. The primary objective of this study is to assess the safety and tolerability of GSK2586184. The primary endpoints to measure safety are laboratory tests (including haematology, clinical chemistry and serum creatinine), vital signs, 12-lead electrocardiogram (ECG), physical examination, and adverse event reporting. These are standard measurements to evaluate safety.

Start Date20 Dec 2013

Sponsor / Collaborator

GSK Plc

NCT01953835

/ CompletedPhase 1

A Two-part Healthy Volunteer Study to Investigate Both the Interaction of GSK2586184 With Rosuvastatin and Simvastatin and to Compare the Pharmacokinetics of Two Different Formulations of GSK2586184

This study is a Phase I, two-part, open-label study designed to evaluate the effect of repeated doses of GSK2586184 on the pharmacokinetics (PK) of Simvastatin and Rosuvastatin in healthy volunteers (Cohort A), and to evaluate the pharmacokinetics of a new tablet formulation of GSK2586184 in healthy male volunteers (Cohort B). Cohort A is a single sequence drug interaction study in which 28 subjects (14 female and 14 male subjects) will be enrolled. Each subject will receive single doses of Simvastatin and Rosuvastatin on two occasions, once alone and once following administration of repeated doses of GSK2586184. Cohort B is a 3-way crossover PK study in which 9 male subjects will be randomized (3 subjects to each treatment sequence). Each subject will receive a single dose of the standard formulation of GSK2586184 with food and two doses of a new formulation of GSK2586184, once with food and once in a fasted state, according to their treatment sequence, with a 3-day wash out between doses. The primary aim of the study is to investigate the effects of GSK2586184 on the pharmacokinetics of the 2 statins and to assess the impact of dosing with and without food on a new formulation of GSK2586184 tablet.

Start Date04 Oct 2013

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with Solcitinib

100 Translational Medicine associated with Solcitinib

100 Patents (Medical) associated with Solcitinib

Literatures (Medical) associated with Solcitinib

01 Apr 2023·Drugs

Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline

Article

Author: Mok, Chi Chiu

Despite the uncertainty of the pathogenesis of systemic lupus erythematosus, novel small molecules targeting specific intracellular mechanisms of immune cells are being developed to reverse the pathophysiological processes. These targeted molecules have the advantages of convenient administration, lower production costs, and the lack of immunogenicity. The Janus kinases, Bruton's tyrosine kinases, and spleen tyrosine kinases are important enzymes for activating downstream signals from various receptors on immune cells that include cytokines, growth factor, hormones, Fc, CD40, and B-cell receptors. Suppression of these kinases impairs cellular activation, differentiation, and survival, leading to diminished cytokine actions and autoantibody secretion. Intracellular protein degradation by immunoproteasomes, levered by the cereblon E3 ubiquitin ligase complex, is an essential process for the regulation of cellular functions and survival. Modulation of the immunoproteasomes and cereblon leads to depletion of long-lived plasma cells, reduced plasmablast differentiation, and production of autoantibodies and interferon-α. The sphingosine 1-phosphate/sphingosine 1-phosphate receptor-1 pathway is responsible for lymphocyte trafficking, regulatory T-cell/Th17 cell homeostasis, and vascular permeability. Sphingosine 1-phosphate receptor-1 modulators limit the trafficking of autoreactive lymphocytes across the blood-brain barrier, increase regulatory T-cell function, and decrease production of autoantibodies and type I interferons. This article summarizes the development of these targeted small molecules in the treatment of systemic lupus erythematosus, and the future prospect for precision medicine.

01 Feb 2023·Biochemical pharmacology

JAK-STAT signaling as an ARDS therapeutic target: Status and future trends

Review

Author: Zhang, Yuanteng ; Luo, Peihua ; Gao, Zizheng ; Yang, Xiaochun ; He, Qiaojun ; Yang, Bo ; Yan, Hao ; Jiang, Feng ; Xu, Zhifei

Acute respiratory distress syndrome (ARDS) is characterized by noncardiogenic pulmonary edema. It has a high mortality rate and lacks effective pharmacotherapy. With the outbreak of COVID-19 worldwide, the mortality of ARDS has increased correspondingly, which makes it urgent to find effective targets and strategies for the treatment of ARDS. Recent clinical trials of Janus kinase (JAK) inhibitors in treating COVID-19-induced ARDS have shown a positive outcome, which makes the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway a potential therapeutic target for treating ARDS. Here, we review the complex cause of ARDS, the molecular JAK/STAT pathway involved in ARDS pathology, and the progress that has been made in strategies targeting JAK/STAT to treat ARDS. Specifically, JAK/STAT signaling directly participates in the progression of ARDS or colludes with other pathways to aggravate ARDS. We summarize JAK and STAT inhibitors with ARDS treatment benefits, including inhibitors in clinical trials and preclinical studies and natural products, and discuss the side effects of the current JAK inhibitors to reveal future trends in the design of JAK inhibitors, which will help to develop effective treatment strategies for ARDS in the future.

31 Dec 2022·Pharmaceutical biology

Pseudolycorine chloride ameliorates Th17 cell-mediated central nervous system autoimmunity by restraining myeloid-derived suppressor cell expansion

Article

Author: Li, Limei ; Zhu, Xinying ; Leng, Xiao ; Wang, Yantang ; Yang, Fan ; Li, Juan ; Zhang, Gan ; Mo, Chunfen

CONTEXT:

The alkaloids of Narcissus tazetta L. var. Chinensis Roem (Amaryllidaceae) have antitumor and antiviral activities. However, the immunopharmacological effects of one of its constituents, pseudolycorine chloride (PLY), have not been reported yet.

OBJECTIVE:

We evaluated the effect of PLY on myeloid-derived suppressor cells (MDSCs) expansion and differentiation into monocyte-like MDSCs (M-MDSCs) and examined whether PLY alleviates Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS).

MATERIALS AND METHODS:

In vitro, MDSCs were treated with PLY (0.67, 2 and 6 μM) or solcitinib (10 μM, positive control) for 48 or 96 h, and their proliferation, expansion, and differentiation into M-MDSCs were examined by flow cytometry. Myelin oligodendrocyte glycoprotein (MOG_35-55) was used to induce EAE in female C57BL/6 mice, and the mice were treated with 40 mg/kg/d PLY or 1 mg/kg/d FK-506 (tacrolimus, positive control) for 21 days. Inflammatory infiltration, spinal cord demyelination, and MDSCs and Th17 cells infiltration into the spinal cord were examined using haematoxylin and eosin staining, Luxol fast blue staining, and immunofluorescence, respectively.

RESULTS:

In vitro, PLY (IC50/24 h = 6.18 μM) significantly inhibited IL-6 and GM-CSF-induced MDSCs proliferation, expansion and differentiation into M-MDSCs at all concentrations used. However, these concentrations did not show cytotoxicity. In mice, PLY (40 mg/kg) treatment alleviated EAE and inhibited inflammatory infiltration, demyelination, and MDSCs and Th17 cells infiltration into the spinal cord.

DISCUSSION AND CONCLUSIONS:

PLY may be an excellent candidate for the treatment of MS and other autoimmune diseases.

News (Medical) associated with Solcitinib

08 Aug 2014

·www.biospace.com

Galapagos NV, GlaxoSmithKline Abandon Joint Drug Project Due To Adverse Effects

Galapagos, GlaxoSmithKline Abandon Joint Drug Project Due To Adverse Effects var switchTo5x=true; stLight.options({publisher: "0341611e-38a4-415d-9e18-75e093ff27e0", doNotHash: false, doNotCopy: false, hashAddressBar: false}); August 8, 2014 By Krystle Vermes , BioSpace.com Breaking News Staff Belgian biotech firm Galapagos has announced that its partner, GlaxoSmithKline , has stopped their joint drug development project , according to Reuters. The company reportedly did so out of concerns about the adverse effects that could come from the drug. The two companies were working to develop a drug called GSK2586184, which would have been used to treat ulcerative colitis and psoriasis. GlaxoSmithKline decided to stop the joint project because they determined that it would not mix well with certain types of cholesterol drugs. GlaxoSmithKline is considering next steps in the process now that development has ceased. Until then, Galapagos is not authorized to comment on the matter. Investors of Galapagos now wonder if they should be concerned about other drugs in its portfolio, such as JAK1 inhibitors and GLPG0634, which is the company’s most developed product. GLPG0634 is the result of a partnership with the U.S. group, AbbVie . This drug is designed to treat rheumatoid arthritis in patients. “I think investors are now worried about the company’s main product which is a large part of its valuation,” KBC Securities analyst Jan De Kerpel told Reuters. Galapagos has carried out testing for GLPG0634 and has not seen any adverse side effects, which would mean that investors have little to worry about. However, the recent news on its joint project coming to a standstill has resulted in the drop of shares to a two-year low. As 2014 winds down, Galapagos claims that it will have more cash than originally thought when the year comes to an end. This is primarily because of its sale of its services division. Galapagos is on pace to have 175 million (approximately $234 million U.S. dollars) Euros at the end of 2014, which is 5 million above its initial prediction. Galapagos has fluctuated numerous times throughout the year. In March, it forecasted its revenue to be 180 million, but then lowered it to 100 million as the result of expected payouts from drug development programs. However, the future looks bright for Galapagos as of now. Several test results are slated to become available to the company within the next 18 months. As a result, shares may increase in value. Regardless of what happens with this shelved project with GlaxoSmithKline, Galapagos has established a presence in the industry that will carry it through the controversy. Read more recent phase II news . var switchTo5x=true;

Financial StatementPhase 2License out/inClinical Trial Failure

100 Deals associated with Solcitinib

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Systemic Lupus Erythematosus	Phase 2	Greece	GSK Plc	11 Dec 2012
Plaque psoriasis	Phase 2	Germany	GSK Plc	29 Nov 2012
Colitis, Ulcerative	Phase 1	Netherlands	GSK Plc	20 Dec 2013
Psoriasis	IND Application	China	GlaxoSmithKline Research & Development Ltd.	17 Oct 2013
Psoriasis	IND Application	China	GlaxoSmithKline Intellectual Property (No.2) Ltd.	17 Oct 2013
Psoriasis	IND Application	China	GlaxoSmithKline (China) Investment Co., Ltd.	17 Oct 2013

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01782664 (CTgov)	Phase 2	Plaque psoriasis	68	Placebo	hjiaccuzmm = zphbskqvlh guaqypcgzt (glwzecgrkd, vyxlvpzoge - mlsnkousbp) View more	-	03 Aug 2017
NCT01777256 (JAK115919, Pubmed \| Lupus) Manual	Phase 2	Systemic Lupus Erythematosus	50	GSK2586184	qhnfaghmzh(lveuvormcc) = Shortly thereafter, significant safety data were identified, including elevated liver enzymes in six patients (one confirmed and one suspected case of Drug Reaction with Eosinophilia and Systemic Symptoms), leading to immediate dosing cessation. otbvbcxzrf (unjxkigspq )	Negative	01 Nov 2016
NCT01777256 (JAK115919, Pubmed \| Lupus) Manual	Phase 2	Systemic Lupus Erythematosus	50	Placebo		Negative	01 Nov 2016

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