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

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

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.

The proposed project is predicated on delivery of impact to both patients and industry. The potential beneficiaries of this project include patients with PBC, the NHS, and Industrial partners.

PBC PATIENTS: It is now clear (and the outline data from UK-PBC confirm this) that there is significant unmet need in PBC, with an important sub-group of patients failing to respond to current licensed therapy. The goal of the UK-PBC project is to understand the biology of non-response and to improve therapy by targetting, evaluating, and, where needed, developing second-line therapies. UK-PBC will also provide a platform for future studies of therapy for the important and life altering symptoms of PBC, although this is not the primary focus of the current application. Benefit to patients will therefore come through improved therapy for, typically young, high-risk patients. Successful applications of second line therapy will both lengthen survival and, we would anticipate, improve the quality of life of patients. The patient groups are strong advocates for UK-PBC and have played a critical role in developing the project to its current form. They will be the major beneficiaries of project impact.

THE NHS: PBC represents an important cause of end-stage liver disease with up to 10% of liver transplants in the UK still being for end-stage PBC. The development and application of effective second-line therapy would benefit the NHS through reducing the need for liver transplantation in end-stage disease (an extremely costly treatment) and by reducing the costs associated with its clinical manifestations (variceal bleeding, management in intensive care units etc). Clearly, should effective second-line therapy reduce the need for transplant in PBC there will be additional beneficiaries, namely patients with other forms of chronic liver disease for whom transplant is necessary and whose chances of receiving an organ will be increased if the need for organ use in PBC is reduced. Depending on the nature of effective second-line therapy there is also significant potential for a fundamental change in delivery of care in PBC, with a move away from specialist clinics for the majority of patients, who are in fact low risk, to targeted therapy delivered in a primary care setting. This aspect is addressed in more detail in the pathways to impact document. UK-PBC is fully engaged with exploring pathways to enhance care delivery in PBC as well as undertaking the mechanistic studies outlined in this proposal.

INDUSTRY: There is considerable industrial interest in PBC. There are, however, key questions we need to answer regarding identification of the most appropriate second-line therapies, how to identify potential recipients, and how to deliver effective trials. There is also a need for more robust biomarkers to identify high risk disease allowing a change in treatment paradigm to more effective therapy given earlier in the disease course. The UK-PBC platform will provide a unique opportunity to explore the mechanistic basis of failure to respond to primary therapy, allowing informed decision making regarding second-line agents. The infrastructure and patient cohorts of UK-PBC will also provide a unique platform to undertake focussed second-line therapy trials in PBC. The potential offered here is reflected in the interest shown by industry in the UK-PBC initiative, with companies investing in the programme as well as offering support. In addition to pharmaceutical company interest the opportunities around enhanced sero-diagnosis and biomarker development to enable better characterisation of risk in this disease have proved to be of significant interest to biomarker and serology companies who are also partners in the project.

The UK-PBC consortium members have a strong track record of delivering impact in PBC and the infrastructure provided by a stratified medicine programme would transform our capacity to benefit patients.