Optimising Primary Therapy in Primary Biliary Cholangitis

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? 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. 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. Our clinical objectives are to: a) Establish the concept of complete disease remission, validating an enhanced disease modifying therapy treatment model; b) Establish the impact of that regimen on PBC symptoms; 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. Our translational research objectives are to: d) Assess the link between biochemical remission and mechanistic (senescence) improvement in a liver biopsy sub-study, evaluating a novel blood chemokine marker. f) Determine whether, in those who achieve biochemical remission, ongoing elevation of mechanistic biomarkers predicts future biochemical relapse. 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. Primary outcome is disease remission, defined as normal alkaline phosphatase and bilirubin, at 6 months. 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. 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. 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.