[Translation] A Long-term Safety and Tolerability Study of Linerixibat for the Treatment of Cholestatic Pruritus in Subjects with Primary Biliary Cholangitis

主要：评价linerixibat长期治疗患PBC胆汁淤积性瘙痒的受试者的安全性和耐受性次要：表征linerixibat长期治疗对患PBC胆汁淤积性瘙痒的受试者疾病负担和健康相关生活质量（QoL）的影响表征linerixibat长期治疗对患PBC胆汁淤积性瘙痒的受试者疾病负担和健康相关生活质量（QoL）的影响 *仅第1组受试者表征linerixibat长期治疗对患PBC胆汁淤积性瘙痒的受试者的影响探索性：评价linerixibat对肝脏纤维化和疾病进展的无创标志物的影响 **仅第2组受试者（如获得）

[Translation]

Primary: To evaluate the safety and tolerability of long-term linerixibat treatment in subjects with cholestatic pruritus due to PBC Secondary: To characterize the effect of long-term linerixibat treatment on disease burden and health-related quality of life (QoL) in subjects with cholestatic pruritus due to PBC Characterize the effect of long-term linerixibat treatment on disease burden and health-related quality of life (QoL) in subjects with cholestatic pruritus due to PBC *Group 1 subjects only Characterize the effect of long-term linerixibat treatment in subjects with cholestatic pruritus due to PBC Exploratory: To evaluate the effect of linerixibat on non-invasive markers of liver fibrosis and disease progression **Group 2 subjects only (if available)

Start Date10 Feb 2023

Sponsor / Collaborator

GlaxoSmithKline (China) Investment Co., Ltd.

NCT05435170 / CompletedPhase 1

A Phase I, Randomized, Open-label, Single Dose, 2 Period, Crossover Study to Evaluate the Effect of Food on the Pharmacokinetics of Linerixibat Tablets in Healthy Adult Participants

This study will evaluate the effect of food on the Pharmacokinetic (PK) and Pharmacodynamic (PD) parameters of linerixibat administered in fed and fasted states in heathy adult participants

Start Date11 Aug 2022

Sponsor / Collaborator

GSK Plc

NCT05393076 / CompletedPhase 1

A Phase 1, Open-label, Single-dose Study to Evaluate the Pharmacokinetics and Safety of Linerixibat in Adults With Moderate Hepatic Impairment and Healthy Matched Control Participants

This is a phase 1, open-label, single-dose study in adults with moderate hepatic impairment (defined as Child-Pugh B cirrhosis) and matched healthy control participants with normal hepatic function. All participants in both cohorts (moderate hepatic impairment and matched healthy controls) will receive a single dose of the study drug, linerixibat. The purpose of this study is to assess the effect of hepatic impairment on the pharmacokinetics (PK) and safety of linerixibat.

Start Date19 Jul 2022

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with Linerixibat

100 Translational Medicine associated with Linerixibat

100 Patents (Medical) associated with Linerixibat

Literatures (Medical) associated with Linerixibat

01 Jan 2024·JHEP reports : innovation in hepatology

Combined inhibition of bile salt synthesis and intestinal uptake reduces cholestatic liver damage and colonic bile salts in mice

Article

Author: van de Graaf, Stan F J ; van Dasselaar, Rychon D J ; Oude Elferink, Ronald P J ; Beuers, Ulrich ; Nijmeijer, Bart A ; Bolt, Isabelle ; Kunst, Roni F

Background & Aims:

Intestine-restricted inhibitors of the apical sodium-dependent bile acid transporter (ASBT, or ileal bile acid transporter) are approved as treatment for several inheritable forms of cholestasis but are also associated with abdominal complaints and diarrhoea. Furthermore, blocking ASBT as a single therapeutic approach may be less effective in moderate to severe cholestasis. We hypothesised that interventions that lower hepatic bile salt synthesis in addition to intestinal bile salt uptake inhibition provide added therapeutic benefit in the treatment of cholestatic disorders. Here, we test combination therapies of intestinal ASBT inhibition together with obeticholic acid (OCA), cilofexor, and the non-tumorigenic fibroblast growth factor 15 (Fgf15)/fibroblast growth factor 19 (FGF19) analogue aldafermin in a mouse model of cholestasis.

Methods:

Wild-type male C57Bl6J/OlaHsd mice were fed a 0.05% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and received daily oral gavage with 10 mg/kg OCA, 30 mg/kg cilofexor, 10 mg/kg ASBT inhibitor (Linerixibat; ASBTi), or a combination. Alternatively, wild-type male C57Bl6J/OlaHsd mice were injected with adeno-associated virus vector serotype 8 (AAV8) to express aldafermin, to repress bile salt synthesis, or to control AAV8. During a 3-week 0.05% DDC diet, mice received daily oral gavage with 10 mg/kg ASBTi or placebo control.

Results:

Combination therapy of OCA, cilofexor, or aldafermin with ASBTi effectively reduced faecal bile salt excretion. Compared with ASBTi monotherapy, aldafermin + ASBTi further lowered plasma bile salt levels. Cilofexor + ASBTi and aldafermin + ASBTi treatment reduced plasma alanine transaminase and aspartate transaminase levels and fibrotic liver immunohistochemistry stainings. The reduction in inflammation and fibrogenesis in mice treated with cilofexor + ASBTi or aldafermin + ASBTi was confirmed by gene expression analysis.

Conclusions:

Combining pharmacological intestinal bile salt uptake inhibition with repression of bile salt synthesis may form an effective treatment strategy to reduce liver injury while dampening the ASBTi-induced colonic bile salt load.

Impact and Implications:

Combined treatment of intestinal ASBT inhibition with repression of bile salt synthesis by farnesoid X receptor agonism (using either obeticholic acid or cilofexor) or by expression of aldafermin ameliorates liver damage in cholestatic mice. In addition, compared with ASBT inhibitor monotherapy, combination treatments lower colonic bile salt load.

01 Jul 2023·Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association

New Treatment Paradigms in Primary Biliary Cholangitis

Review

Author: Levy, Cynthia ; Hirschfield, Gideon ; Manns, Michael

Primary biliary cholangitis (PBC) is an archetypal autoimmune disease. Chronic lymphocytic cholangitis is associated with interface hepatitis, ductopenia, cholestasis, and progressive biliary fibrosis. People living with PBC are frequently symptomatic, experiencing a quality-of-life burden dominated by fatigue, itch, abdominal pain, and sicca complex. Although the female predominance, specific serum autoantibodies, immune-mediated cellular injury, as well as genetic (HLA and non-HLA) risk factors, identify PBC as autoimmune, to date treatment has focused on cholestatic consequences. Biliary epithelial homeostasis is abnormal and contributes to disease. The impact of cholangiocyte senescence, apoptosis, and impaired bicarbonate secretion enhances chronic inflammation and bile acid retention. First-line therapy is a non-specific anti-cholestatic agent, ursodeoxycholic acid. For those with residual cholestasis biochemically, obeticholic acid is introduced, and this semisynthetic farnesoid X receptor agonist adds choleretic, anti-fibrotic, and anti-inflammatory activity. Future PBC licensed therapy will likely include peroxisome proliferator activated receptor (PPAR) pathway agonists, including specific PPAR-delta agonism (seladelpar), as well as elafibrinor and saroglitazar (both with broader PPAR agonism). These agents dovetail the clinical and trial experience for off-label bezafibrate and fenofibrate use. Symptom management is essential, and encouragingly, PPAR agonists reduce itch; IBAT inhibition (eg, linerixibat) also appears promising for pruritus. For those where liver fibrosis is the target, NOX inhibition is being evaluated. Earlier stage therapies in development include therapy to impact immunoregulation in patients, as well other approaches to treating pruritus (eg, antagonists of MrgprX4). Collectively the PBC therapeutic landscape is exciting. Therapy goals are increasingly proactive and individualized and aspire to rapidly achieve normal serum tests and quality of life with prevention of end-stage liver disease.

01 Jul 2023·Hepatology research : the official journal of the Japan Society of Hepatology

Japanese subgroup analysis of GLIMMER: A global Phase IIb study of linerixibat for the treatment of cholestatic pruritus in patients with primary biliary cholangitis

Article

Author: McLaughlin, Megan M ; Das, Sugato ; Tanaka, Atsushi ; Notsumata, Kazuo ; Ito, Hiroshi ; Atsukawa, Masanori ; Tsuji, Keiji ; Suyama, Akari ; von Maltzahn, Robyn

Abstract:

Aim:

To compare patient characteristics and outcomes between the overall and Japanese populations of GLIMMER.

Methods:

GLIMMER was a multicenter, double‐blind, randomized, placebo‐controlled, Phase IIb study evaluating linerixibat for the treatment of pruritus in patients with primary biliary cholangitis.

Results:

In total, 147 patients were randomized in the GLIMMER overall population with 38 patients comprising the Japanese population. Demographics and baseline clinical characteristics were similar across treatment groups and between both populations. A reduction in mean worst daily itch score from baseline to week 16 (primary endpoint) was seen in all groups, with the largest reduction observed with linerixibat 40 mg twice daily (BID; −2.92 [95% confidence interval: −5.07, −0.76] and −2.86 [95% confidence interval: −3.76, −1.95] for Japanese and overall populations, respectively). The highest proportion of responders was generally in the 40 mg BID group in both populations regardless of the responder definition applied. Improvements in health‐related quality of life were generally consistent in both populations. In the Japanese and overall populations, on‐treatment drug‐related adverse events were reported in 25% and 19% of patients in the placebo group and 0%–86% and 31%–78% of patients in the linerixibat groups, respectively. Consistent with the mechanism of action, the most common events were gastrointestinal in nature. The effects of linerixibat on pharmacodynamic biomarkers favored BID dosing.

Conclusions:

Therapeutic responses and safety of linerixibat were consistent between the Japanese and overall populations of GLIMMER. Linerixibat may provide an effective treatment option for cholestatic pruritus in patients with primary biliary cholangitis.

Clinical Trial Registration:

NCT02966834.

News (Medical) associated with Linerixibat

12 Jun 2024

·www.fiercebiotech.com

GSK signs AI pact with Ochre to pinpoint source of liver diseases

GSK’s interest in Ochre Bio lies in the company’s platform that allows livers to stay alive for a few days for the extraction of tissue samples. GSK and Ochre Bio will work together in a $37.5 million partnership to pinpoint the drivers of liver disease. The new partnership, announced Wednesday morning, will see GSK access Ochre’s computational biology, cellular and perfused human organ platforms to generate human liver data sets that can be used to better understand the biology of the liver. The goal, of course, is to eventually develop therapeutics to address liver diseases. The companies did not specify what indications they plan to target, however, GSK said the collaboration would complement its disease area focus in hepatology. The U.K. pharma has clinical assets in primary biliary cholangitis, metabolic dysfunction-associated steatohepatitis, cholestatic pruritus and hepatitis B, the latter of which dominates a large portion of its early-stage pipeline. GSK is advancing bepirovirsen in a phase 3 trial for chronic hepatitis B as a functional cure for the infection. The pharma expects annual sales of 2 billion pounds sterling ($2.57 billion) for the med. Also in phase 3 from the liver portfolio is linerixibat for cholestatic pruritus in primary biliary cholangitis, a condition that causes intense itch that is not satisfied by scratching. “In addition to our programs in MASH to hepatitis B, we are committed to addressing unmet need in liver disease by generating unique data in human-derived systems. Ochre Bio’s platform will provide GSK with foundational data sets to create AI models allowing us to better understand liver function and disease for the development of novel medicines,” said Kim Branson, senior vice president and global head of AI and machine learning at GSK, in a Wednesday statement. GSK’s interest in Ochre lies in the biotech’s platform that allows livers to stay alive for a few days for the extraction of tissue samples. GSK’s in-house AI and machine learning experts will analyze the data from the partnership and use it to build better models and, thus, more precise experiments for developing new liver disease therapeutics. The $37.5 million deal will include both co-exclusive and nonexclusive data licenses, but full details were not released.

Phase 3Phase 2

26 Mar 2021

·www.globenewswire.com

Newer approaches for the management of Cholestatic Pruritus treatment outlook

Los Angeles, USA, March 25, 2021 (GLOBE NEWSWIRE) -- Newer approaches for the management of Cholestatic Pruritus treatment outlook Cholestatic Pruritus clinical trials are ongoing with novel agents that demonstrate potential efficacious options in the future. The key players such as Escient Pharmaceuticals, Cara Therapeutics, GlaxoSmithKline, CymaBay Therapeutics, Mirum Pharmaceuticals, and others are developing Cholestatic Pruritus therapies to improve treatment outlook. DelveInsight’s “Cholestatic Pruritus Pipeline Insight” report provides comprehensive insights about 6+ companies and 6+ pipeline drugs in the Cholestatic Pruritus pipeline landscapes. It comprises Cholestatic Pruritus pipeline drug profiles, including clinical and non-clinical stage products. It also includes the Cholestatic Pruritus therapeutics assessment by product type, stage, route of administration, and molecule type and further highlights the inactive Cholestatic Pruritus pipeline products. Some of the key takeaways of the Cholestatic Pruritus Pipeline Report Get an overview of pipeline landscape @ Cholestatic Pruritus Clinical Trial Analysis Cholestasis is a reduction in bile flow because of the impaired secretion by hepatocytes or due to the obstruction of bile flow through intra-or extra-hepatic bile ducts. Furthermore, Pruritus is a distressing manifestation of both intra-hepatic cholestasis and extra-hepatic biliary obstruction. Cholestatic Pruritus Pipeline Therapeutics GSK2330672 is a selective inhibitor of human IBAT and is designed to be a non-absorbable agent restricted to the gastrointestinal (GI) tract. The drug is expected to block the uptake of bile acids (BAs) in the terminal ileum, increase their excretion in the faeces and reduce the amount of BAs returning to the liver via enterohepatic circulation. Therefore, the treatment of PBC patients with oral GSK2330672 is postulated to reduce the concentrations of BAs in the systemic circulation, and in turn, improve pruritus. The company has completed the Phase II stage of clinical development, and the drug is currently conducting phase III trials. Research and Development Phase III Clinical Studies NCT04167358: In July 2020, GlaxoSmithKline initiated a trial titled “Long-term Safety and Tolerability Study of Linerixibat for the Treatment of Cholestatic Pruritus in Participants With Primary Biliary Cholangitis”. The trial is currently recruiting participants with an estimated enrollment of 75 participants and is expected to be completed by December 2024. Phase II Results:In 2020, GlaxoSmithKline announced further progression in its R&D pipeline with the data presentation of linerixibat, an investigational product for the potential treatment of Cholestatic Pruritus in patients with Primary Biliary Cholangitis (PBC). The dose of linerixibat showed significant improvements from baseline in measures of quality of life, including social and emotional domains of the disease-specific patient-reported instrument, PBC-40, in the overall population. Due to the mechanism of action of linerixibat, the most common adverse events were diarrhoea and abdominal pain. For further information, refer to the detailed report @ Cholestatic Pruritus Emerging Drugs Scope of Cholestatic Pruritus Pipeline Drug Insight Key Questions regarding Current Cholestatic Pruritus Treatment Landscape and Emerging Therapies Answered in the Pipeline Report Table of Contents Get a customised pipeline report @ Cholestatic Pruritus Drugs Pipeline Report Related Reports DelveInsight's Cholestatic Pruritus - Market Insights, Epidemiology and Market Forecast - 2030 report provides the detailed overview of the disease and in depth understanding of historical and forecasted epidemiology. DelveInsight's Cholestatic Pruritus - Epidemiology Forecast 2030 report delivers an in-depth understanding of the disease, historical, and forecasted epidemiology of Cholestatic Pruritus in the United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom), and Japan. DelveInsight’s Shingles- Market Insights, Epidemiology and Market Forecast - 2030 report provides an in-depth understanding of historical. DelveInsight's Schistosomiasis - Market Insights, Epidemiology and Market Forecast - 2030 report provides the detailed overview of the disease and in depth understanding of historical and forecasted epidemiology. DelveInsight's Parainfluenza Virus Infection - Market Insights, Epidemiology and Market Forecast - 2030 report provides a detailed understanding of historical and forecasted epidemiology. DelveInsight's NSCLC - Market Insights, Epidemiology and Market Forecast - 2030 report provides the detailed overview of the disease and in depth understanding of historical and forecasted epidemiology. DelveInsight's Nephrotic Syndrome (NS) Etiologies - Epidemiology Forecast 2030 report delivers an in-depth understanding of the disease, historical, and forecasted epidemiology of Nephrotic Syndrome (NS) Etiologies in the United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom), and Japan. The Meibomian Gland Dysfunction market report provides current treatment practices, emerging drugs, Meibomian Gland Dysfunction market share of the individual therapies. DelveInsight' s Lactose Intolerance Market Insights, Epidemiology and Market Forecast 2030 report provides the detailed overview of the disease and in depth understanding of historical market and forecasted epidemiology. About DelveInsightDelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports Pharma companies by providing comprehensive end-to-end solutions to improve their performance.

Small molecular drug

100 Deals associated with Linerixibat

External Link

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cholestatic pruritus	Phase 3	US	GSK Plc	14 Jul 2020
Cholestatic pruritus	Phase 3	CN	GSK Plc	14 Jul 2020
Cholestatic pruritus	Phase 3	JP	GSK Plc	14 Jul 2020
Cholestatic pruritus	Phase 3	AR	GSK Plc	14 Jul 2020
Cholestatic pruritus	Phase 3	BE	GSK Plc	14 Jul 2020
Cholestatic pruritus	Phase 3	BR	GSK Plc	14 Jul 2020
Cholestatic pruritus	Phase 3	BG	GSK Plc	14 Jul 2020
Cholestatic pruritus	Phase 3	CA	GSK Plc	14 Jul 2020
Cholestatic pruritus	Phase 3	CZ	GSK Plc	14 Jul 2020
Cholestatic pruritus	Phase 3	FR	GSK Plc	14 Jul 2020

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03992014 (CTgov)	Phase 1	Cholestasis	6	Linerixibat (Linerixibat 90 mg Oral Tablets + [14C] Linerixibat 100 μg IV)	yhzlhsnlnb(dopttjvimq) = gnyucmnhok fngjfkpxxv (kdnyhfsven, dyhiysvmfr - wbgftkrwwd) View more	-	26 Jun 2020
				[14C]-Linerixibat ([14C]-Linerixibat 90 Milligram Oral Solution)	pwqnaxobut(qapfvfcdiy) = isbttqacsq audrmcurhn (zfeciqrbgw, legsprmccp - wwekbarpji) View more
NCT02202161 (CTgov)	Phase 2	Diabetes Mellitus, Type 2	70	placebo+GSK2330672+metformin (Placebo)	htbvtjnkuo(mybonveesc) = lrgbnnbbjf kqdafpeyvu (noaoszumnv, whdscvcufv - sjcsnhlkxb) View more	-	06 Nov 2017
				GSK2330672 (GSK2330672 10 mg BID)	htbvtjnkuo(mybonveesc) = ufkrbcmsqc kqdafpeyvu (noaoszumnv, xnwofdvlez - vuupcubdcg) View more
NCT01929863 (CTgov)	Phase 2	Diabetes Mellitus, Type 2	16	GSK2330672+Metformin (Treatment A-GSK2330672 + Metformin)	inamcbzgwz(rqtytqfrbn) = yufqttoenc lbzduppkpu (inhpdwtckp, deluybyctm - tdxtaugemp) View more	-	16 Aug 2017
				Placebo+Metformin (Treatment B-Placebo + Metformin)	inamcbzgwz(rqtytqfrbn) = phjeuzxftq lbzduppkpu (inhpdwtckp, kprrhcntjn - ukrtiklisp) View more
NCT01899703 (Pubmed \| Lancet) Manual	Phase 2	Pruritus \| Primary Biliary Cholangitis	22	GSK2330672	npoxdrgprg(zrauryxmcb) = Diarrhoea was the most frequent adverse event during treatment with GSK2330672 (seven with GSK2330672 vs one with placebo) and headache was the most frequent adverse event during treatment with placebo (seven with placebo vs six with GSK2330672). kbqiodzaqt (jzzevxkmwe )	Positive	18 Mar 2017
				Placebo

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