Stratified Medicine in Primary Biliary Cirrhosis (PBC): Understanding Disease Mechanisms and Targeting Therapies (UK-PBC) View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2013-2018

FUNDING AMOUNT

4842137.0 GBP

ABSTRACT

Primary Biliary Cirrhosis (PBC) is a chronic liver disease affecting 20,000 patients in the UK. The aim of our project is to transform our capacity to treat it. The problem is that whereas many PBC patients respond well to treatment with a drug called ursodeoxycholic acid ("urso") around 30% do not. We now know that when people don't respond to urso they run a real risk of their liver disease getting worse over time, leading ultimately to cirrhosis with all its complications and for which the only treatment is liver transplantation. The goal of the UK-PBC project, which is supported by academic centres, doctors, patient groups and industry throughout the UK, is to understand why it is that some people don't respond to urso, to find better ways of predicting who will and won't respond, and to identify the best way to treat people who don't respond (a number of drugs have been suggested as sensible treatments for people who don't respond to urso but at present we don't know how and in whom to use them). We are working with patient groups to recruit over half of all urso non-responding PBC patients in Britain (we have already recruited a third) making this a truly unique study. Our preparatory studies have already shed light on why people are at risk of PBC, and have shown that PBC is less likely to respond to treatment in young patients and in men. We now need to know why and to know what we can do about it. The UK-PBC study will be in 3 sections. In the 1st section we will work with the PBC Foundation to recruit patients and to organise to collect important clinical information, together with a blood sample. The clinical information will allow us to identify whether someone has responded to urso or not (as well as how bad their symptoms are). The blood samples will allow us to understand key aspects of people's make up, including their genes and the way their immune system works, and the differences in make up between people who do and don't respond to urso. In addition to the main group of patients we will invite a smaller group of patients who are at very high risk of not responding to urso (those in whom PBC was diagnosed below the age of 50), or who have already not responded, to take part in a more detailed study in which we explore the actual damage to their liver in the 2nd section of the study. In the 2nd section of our study we will explore what is different about PBC in people who do and don't respond to urso. This will allow us to identity the processes that cause non-response and to identify the best possible treatments for people who don't respond. It is thought that PBC is caused by the immune system mis-identifying the cells that line the bile duct and trying to reject them. This leads to damage to the bile ducts which impairs bile flow. Bile, which is toxic, then builds up in the liver causing more damage to the bile ducts and thus further bile duct injury. Injury eventually leads to scarring, and ultimately cirrhosis. In the second study section we will explore whether people who don't respond to urso have a more aggressive immune response than responders, have more toxic bile, have bile duct cells that react differently to injury (coping less well) or are more susceptible to liver scarring. Critically, all of these potential causes match up to existing potential treatments, or areas where new treatments can be developed rapidly. In the 3rd section we will work with patient groups and industry partners to develop a national approach to studying new drugs in PBC to make it easier and more cost-effective to explore new drugs; a step which will encourage companies to want to develop new treatments which will ultimately benefit patients. We also begin to develop a national approach to treatment of PBC so that all patients benefit from the best possible treatments. Our goal is nothing less than a transformation in our understanding of how to treat this significant disease Technical Summary Primary biliary cirrhosis (PBC) is the commonest autoimmune liver disease and a significant cause of morbidity and mortality. Ursodeoxycholic acid (UDCA), the only licensed therapy, slows progression to cirrhosis, but response is inadequate or absent in around 30% of patients, with non-responders facing a 5-fold increased risk of death or need for liver transplant. There is substantial industry interest in novel approaches to treating UDCA non-responders, but little information is available regarding mechanisms underpinning failure to respond to UDCA precluding informed decision making about which agents to take to clinical trial as second-line therapies. We will further develop the 5000 person UK-PBC patient cohort, the largest and best characterised in the world, by targetting recruitment of existing UDCA non-responding patients, and those at high risk of future non-response (for reasons of age), and will utilise it to explore the mechanisms of UDCA non-response. We will work with our industrial and patient-group partners to develop and deliver innovative clinical trials of stratified therapy, and will explore structured approaches to the future delivery of care nationally in PBC. The multi-disciplinary UK-PBC research consortium (www.UK-PBC.com) is fully established and has published landmark clinical and mechanistic studies. A multi-strand approach will be used in which patients will be recruited, pheno-, sero- and genotyped and stratified for UDCA response. A nested cohort of highly informative high-risk/non-responding patients will undergo more detailed cell- & tissue-based study with correlation of biological and clinical outcomes. Mechanistic themes addressing the core pathological processes in PBC will be able to access informative patients to undertake studies aimed at addressing the mechanisms and markers of non-response and identifying optimal therapeutic approaches. Our goal is to move to targeted clinical intervention by the end of the funding period. More... »

URL

https://gtr.ukri.org/project/39FE6A03-3CF4-4226-8016-BB9CF55F572A

Related SciGraph Publications

  • 2020-08-26. Understanding Fatigue in Primary Biliary Cholangitis in DIGESTIVE DISEASES AND SCIENCES
  • 2019-07-08. Position statement on access to care in rare liver diseases: advancements of the European reference network (ERN) RARE-LIVER in ORPHANET JOURNAL OF RARE DISEASES
  • 2019-03-04. PBC: Better Solutions to Beat Feeling Beat in DIGESTIVE DISEASES AND SCIENCES
  • 2019-01-15. Development and adaptation of patient-reported outcome measures for patients who experience itch associated with primary biliary cholangitis in JOURNAL OF PATIENT-REPORTED OUTCOMES
  • 2018-05-08. Are Clinicians Ready for Safe Use of Stratified Therapy in Primary Biliary Cholangitis (PBC)? A Study of Educational Awareness in DIGESTIVE DISEASES AND SCIENCES
  • 2016-07-19. Long-Term Fenofibrate Treatment in Primary Biliary Cholangitis Improves Biochemistry but Not the UK-PBC Risk Score in DIGESTIVE DISEASES AND SCIENCES
  • 2016-07-19. BAT117213: Ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial in BMC GASTROENTEROLOGY
  • 2016-05-26. Changing Nomenclature for PBC from “Primary Biliary Cirrhosis” to “Primary Biliary Cholangitis” in JOURNAL OF GASTROENTEROLOGY
  • 2015-09-22. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways in NATURE COMMUNICATIONS
  • 2015-02-03. Novel therapeutic targets in primary biliary cirrhosis in NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY
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        "description": "Primary Biliary Cirrhosis (PBC) is a chronic liver disease affecting 20,000 patients in the UK. The aim of our project is to transform our capacity to treat it. The problem is that whereas many PBC patients respond well to treatment with a drug called ursodeoxycholic acid (\"urso\") around 30% do not. We now know that when people don't respond to urso they run a real risk of their liver disease getting worse over time, leading ultimately to cirrhosis with all its complications and for which the only treatment is liver transplantation. The goal of the UK-PBC project, which is supported by academic centres, doctors, patient groups and industry throughout the UK, is to understand why it is that some people don't respond to urso, to find better ways of predicting who will and won't respond, and to identify the best way to treat people who don't respond (a number of drugs have been suggested as sensible treatments for people who don't respond to urso but at present we don't know how and in whom to use them). We are working with patient groups to recruit over half of all urso non-responding PBC patients in Britain (we have already recruited a third) making this a truly unique study. Our preparatory studies have already shed light on why people are at risk of PBC, and have shown that PBC is less likely to respond to treatment in young patients and in men. We now need to know why and to know what we can do about it.\n\nThe UK-PBC study will be in 3 sections. 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In the 1st section we will work with the PBC Foundation to recruit patients and to organise to collect important clinical information, together with a blood sample. The clinical information will allow us to identify whether someone has responded to urso or not (as well as how bad their symptoms are). The blood samples will allow us to understand key aspects of people's make up, including their genes and the way their immune system works, and the differences in make up between people who do and don't respond to urso. In addition to the main group of patients we will invite a smaller group of patients who are at very high risk of not responding to urso (those in whom PBC was diagnosed below the age of 50), or who have already not responded, to take part in a more detailed study in which we explore the actual damage to their liver in the 2nd section of the study. In the 2nd section of our study we will explore what is different about PBC in people who do and don't respond to urso. This will allow us to identity the processes that cause non-response and to identify the best possible treatments for people who don't respond. It is thought that PBC is caused by the immune system mis-identifying the cells that line the bile duct and trying to reject them. This leads to damage to the bile ducts which impairs bile flow. Bile, which is toxic, then builds up in the liver causing more damage to the bile ducts and thus further bile duct injury. Injury eventually leads to scarring, and ultimately cirrhosis. In the second study section we will explore whether people who don't respond to urso have a more aggressive immune response than responders, have more toxic bile, have bile duct cells that react differently to injury (coping less well) or are more susceptible to liver scarring. Critically, all of these potential causes match up to existing potential treatments, or areas where new treatments can be developed rapidly. In the 3rd section we will work with patient groups and industry partners to develop a national approach to studying new drugs in PBC to make it easier and more cost-effective to explore new drugs; a step which will encourage companies to want to develop new treatments which will ultimately benefit patients. We also begin to develop a national approach to treatment of PBC so that all patients benefit from the best possible treatments. Our goal is nothing less than a transformation in our understanding of how to treat this significant disease Technical Summary Primary biliary cirrhosis (PBC) is the commonest autoimmune liver disease and a significant cause of morbidity and mortality. Ursodeoxycholic acid (UDCA), the only licensed therapy, slows progression to cirrhosis, but response is inadequate or absent in around 30% of patients, with non-responders facing a 5-fold increased risk of death or need for liver transplant. There is substantial industry interest in novel approaches to treating UDCA non-responders, but little information is available regarding mechanisms underpinning failure to respond to UDCA precluding informed decision making about which agents to take to clinical trial as second-line therapies. We will further develop the 5000 person UK-PBC patient cohort, the largest and best characterised in the world, by targetting recruitment of existing UDCA non-responding patients, and those at high risk of future non-response (for reasons of age), and will utilise it to explore the mechanisms of UDCA non-response. We will work with our industrial and patient-group partners to develop and deliver innovative clinical trials of stratified therapy, and will explore structured approaches to the future delivery of care nationally in PBC. The multi-disciplinary UK-PBC research consortium (www.UK-PBC.com) is fully established and has published landmark clinical and mechanistic studies. A multi-strand approach will be used in which patients will be recruited, pheno-, sero- and genotyped and stratified for UDCA response. A nested cohort of highly informative high-risk/non-responding patients will undergo more detailed cell- & tissue-based study with correlation of biological and clinical outcomes. Mechanistic themes addressing the core pathological processes in PBC will be able to access informative patients to undertake studies aimed at addressing the mechanisms and markers of non-response and identifying optimal therapeutic approaches. Our goal is to move to targeted clinical intervention by the end of the funding period.
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