Title: Optimising Primary Therapy in Primary Biliary Cholangitis
Funder: Medical Research Council

Abstract: PBC AND ITS IMPACT: PBC (short for primary biliary cholangitis) is a liver disease where there is damage to the tubes, or bile ducts, that drain bile out of the liver and into the bowel. Bile that can’t drain builds up in the body, damaging the liver. Over 80% of people with PBC experience symptoms for which we don’t have any treatment. Up to 40% people can go on to develop significant scarring of the liver (cirrhosis) which can present a real risk to life. _x000D_ _x000D_ PBC TREATMENTS & THEIR LIMITATIONS: Although we have treatments for PBC the way we use them means, we think, that patients don’t get as much benefit from them as they could. Finding new ways to use them could make a real difference to peoples’ lives. The first treatment, that all people diagnosed with PBC get, is with a tablet called ursodeoxycholic acid (“urso” to most patients), which has some benefit for most patients. However, most people with PBC taking it only partly respond, and fewer than one in four person returns to normal (in terms of their blood tests; the key way we watch liver disease in the clinic). This is important, as it has recently been shown that only returning blood tests to normal will be enough to remove risk of PBC causing cirrhosis and putting patients’ lives at risk. _x000D_ _x000D_ People who don’t show enough of a response to “urso” over a year are at present offered more powerful add-on drugs (including one called obeticholic acid (OCA)). However, when used in this way, these medicines are again only partially effective, with fewer than 40% of people getting full control of their disease. This is especially a problem amongst younger individuals, who have the most difficult to treat PBC._x000D_ _x000D_ Scientists, doctors and patients (through the UK-wide PBC Foundation (www.pbcfoundation.org.uk)), have worked together to show that the problem with PBC that doesn’t respond properly to treatment is one of a “vicious cycle” of damage to the bile ducts. The cells lining the bile ducts stop working, entering a “zombie state” where they are still alive but don’t work properly (the technical term for this is senescence). Without effective treatment this becomes irreversible. Importantly, this is not prevented by urso. Our experiments in animals, however, suggest that OCA can prevent or even reverse development of this zombie state if given early enough in the disease. _x000D_ _x000D_ There is one further important piece of the jigsaw. If we are going to use treatments such as OCA better by giving them to people who need them earlier in the disease we need to have ways of working out who will benefit. We have developed a scoring system which accurately identifies the people who need better treatment from the beginning of the disease. This will allow us to target better treatment earlier in the disease at people who need it, stopping the bile duct cells turning into zombie cells and reversing the vicious cycle._x000D_ _x000D_ OUR PROPOSED TRIAL: 106 people newly diagnosed with PBC and who are at risk of not responding to urso will receive either the combination of urso and OCA or urso together with a dummy tablet (a placebo). After six months of treatment we will assess whether the combination of OCA and urso is more effective than UDCA and placebo for bringing PBC fully under control. We will also explore how useful a brand new blood test might be in allowing us to assess the “zombie” state of bile duct cells before and during treatment. Complete control of PBC is, we believe, attainable.

Lay abstract: RESEARCH QUESTION: In high risk patients with primary biliary cholangitis (PBC), can early intervention with obeticholic acid (OCA) induce sustained disease remission, and is this effect mediated through reversal of biliary epithelial cell (BEC) senescence? _x000D_ _x000D_ BACKGROUND: PBC is a rare autoimmune liver disease that has significant ongoing unmet needs despite current therapy, including risk of cirrhosis development and life-impairing symptoms. We currently use a step-up model, wherein 1st-line ursodeoxycholic acid (UDCA) is given for a minimum of 12 months before more efficacious ‘add-on’ therapy is considered for non-responding patients. We believe that this ‘waiting to fail’ approach, focused on the needs of patients at lowest risk, allows a key process of BEC senescence to become established, driving accelerated bile duct loss. Our pre-clinical mouse modelling has shown that early use of the farnesoid X receptor agonist OCA, currently only used as a 2nd-line therapy following UDCA failure, reverses BEC senescence, changing the clinical course of disease. _x000D_ _x000D_ AIMS & OBJECTIVES: Our aim is to explore a new paradigm for disease-modifying treatment of PBC; risk-informed early treatment stratification with patients at increased risk offered UDCA + OCA combination from disease outset and a treatment goal of complete biochemical remission._x000D_ _x000D_ Our clinical objectives are to:_x000D_ a) Establish the concept of complete disease remission, validating an enhanced disease modifying therapy treatment model; _x000D_ b) Establish the impact of that regimen on PBC symptoms;_x000D_ c) Assess whether remission is sustained following reversion to standard of care UDCA monotherapy to determine whether early combination therapy reverses the disease process rather than merely suspending it. _x000D_ _x000D_ Our translational research objectives are to: _x000D_ d) Assess the link between biochemical remission and mechanistic (senescence) improvement in a liver biopsy sub-study, evaluating a novel blood chemokine marker._x000D_ f) Determine whether, in those who achieve biochemical remission, ongoing elevation of mechanistic biomarkers predicts future biochemical relapse. _x000D_ _x000D_ METHODS: Double-blind randomised placebo-controlled trial of OCA in 106 newly diagnosed PBC patients at significant risk of not achieving remission in response to 1st-line therapy with UDCA alone, randomised 1:1 to either OCA or placebo, alongside UDCA standard of care. Participants will then be followed up for a further 6 months after the end of the intervention period to assess remission maintenance._x000D_ _x000D_ Primary outcome is disease remission, defined as normal alkaline phosphatase and bilirubin, at 6 months._x000D_ _x000D_ Secondary and experimental outcomes include reversal of BEC senescence on liver biopsy, improvement in a chemokine-based marker, remission maintenance 6 months after discontinuation of primary combination therapy, and the impact on symptoms and quality of life._x000D_ _x000D_ TIMELINES FOR DELIVERY: First patient first visit by 1.10.2022 with a 24 month recruitment period and 12 months follow-up (6 months on therapy to primary efficacy outcome, and 6 months off therapy). Last patient last visit 1.10.2025._x000D_ _x000D_ ANTICIPATED IMPACT & DISSEMINATION: The key deliverable will be a new treatment paradigm for PBC focused on enhanced early disease modification and supported by a novel mechanistic biomarker. There is an established advanced PBC therapy network in place in England which will facilitate uptake in practice.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL