Margaret Corrigan

Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis:: a double-blind, randomised, placebo-controlled, crossover, phase 2a study

BACKGROUND Up to 70% of patients with primary biliary cholangitis develop pruritus (itch) during the course of their disease. Treatment of pruritus in primary biliary cholangitis is challenging and novel therapies are needed. Ursodeoxycholic acid, the standard first-line treatment for primary biliary cholangitis, is largely ineffective for pruritus. We investigated the efficacy and safety of GSK2330672, a selective inhibitor of human ileal bile acid transporter (IBAT), in patients with primary biliary cholangitis with pruritus. METHODS We conducted this phase 2a, double-blind, randomised, placebo-controlled, crossover trial in two UK medical centres. Following 2 weeks of open placebo run-in, patients were randomly assigned in a 1:1 ratio with a block size of 4 to receive GSK2330672 or placebo twice daily during two consecutive 14-day treatment periods in a crossover sequence. The treatment periods were followed by a 14-day single-blinded placebo follow-up period. The primary endpoints were safety of GSK2330672, assessed using clinical and laboratory parameters, and tolerability as rated by the Gastrointestinal Symptom Rating Scale. The secondary endpoints were changes in pruritus scores measured using the 0 to 10 numerical rating scale (NRS), primary biliary cholangitis-40 (PBC-40) itch domain score and 5-D itch scale, changes in serum total bile acids and 7 alpha hydroxy-4-cholesten-3-one (C4), and changes in the pharmacokinetic parameters of ursodeoxycholic acid and its conjugates. The trial was registered with ClinicalTrials.gov, number NCT01899703. FINDINGS Between March 10, 2014, and Oct 7, 2015, we enrolled 22 patients. 11 patients were assigned to receive intervention followed by placebo (sequence 1), and 11 patients were assigned to receive placebo followed by intervention (sequence 2). One patient assigned to sequence 2 withdrew consent prior to receiving randomised therapy. One patient did not attend the placebo follow-up period, but was included in the final analysis. GSK2330672 treatment for 14 days was safe with no serious adverse events reported. 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). After GSK2330672 treatment, the percentage changes from baseline itch scores were -57% (95% CI -73 to -42, p<0·0001) in the NRS, -31% (-42 to -20, p<0·0001) in the PBC-40 itch domain and -35% (-45 to -25, p<0·0001) in the 5-D itch scale. GSK2330672 produced significantly greater reduction from baseline than the double-blind placebo in the NRS (-23%, 95% CI -45 to -1; p=0·037), PBC-40 itch domain, (-14%, -26 to -1; p=0·034), and 5-D itch scale (-20%, -34 to -7; p=0·0045). After GSK2330672 treatment, serum total bile acid concentrations declined by 50% (95% CI -37 to -61, p<0·0001) from 30 to 15 μM, with a significant 3·1-times increase (95% CI 2·4 to 4·0, p<0·0001) in serum C4 concentrations from 7·9 to 24·7ng/mL. INTERPRETATION In patients with primary biliary cholangitis with pruritus, 14 days of ileal bile acid transporter inhibition by GSK2330672 was generally well tolerated without serious adverse events, and demonstrated efficacy in reducing pruritus severity. GSK2330672 has the potential to be a significant and novel advance for the treatment of pruritus in primary biliary cholangitis. Diarrhoea, the most common adverse event associated with GSK2330672 treatment, might limit the long-term use of this drug. FUNDING GlaxoSmithKline and National Institute for Health Research.

Autoimmune hepatitis: an approach to disease understanding and management

INTRODUCTION Autoimmune hepatitis is a chronic immune-mediated liver injury, frequently associated with progression to end-stage liver disease if untreated. Patients commonly present with hepatitis, positive immune serology, elevated immunoglobulins and compatible liver histology, in the absence of an alternative aetiology. SOURCES OF DATA Data for this review were obtained using PubMed. AREAS OF AGREEMENT Disease usually responds to steroids and azathioprine, and appears to be a manifestation of autoimmune predisposition triggered in genetically susceptible individuals exposed to likely environmental challenges. We provide an up-to-date approach to disease understanding and management along with the clinical approach to diagnosis and current treatment suggestions. AREAS OF CONTROVERSY Controversies such as second line therapies and novel markers of disease activity are introduced. GROWING POINTS Increased understanding of the immunoregulatory mechanisms behind autoimmune hepatitis has led to opportunities for new therapies. These are developed including a discussion of timely research studies relevant to future therapies for patients.

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) remains a disease of unknown etiology. The close association of PSC and inflammatory bowel disease (IBD), especially ulcerative colitis (UC), has been reconfirmed in numerous studies. Much has been learned about the pathogenesis, although the specific cause remains unknown. Copper overload and chronic hepatic bacterial infection have virtually been excluded as causes of PSC. Cytomegalovirus and reovirus remain under investigation. Familial clustering and HLA subtype similarities are seen in PSC with and without IBD. The finding of antineutrophil cytoplasmic antibodies (ANCA) in patients with PSC and those with UC suggests immunological features in the pathogenesis of PSC. Collected series of patients have better characterized clinical features of PSC. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) have provided both diagnostic features and means of therapeutic intervention. Treatment of PSC is symptomatic (pruritus control and vitamin deficiency correction); or experimental (D-penicillamine, ursodeoxycholic acid [UDCA], methotrexate, or corticosteroids). Liver transplantation remains the ultimate treatment for end-stage PSC. Statistical analyses of clinical and laboratory variables in PSC help to determine prognosis and proposed timing for transplantation to achieve maximal longevity and quality of life. PSC affects middle-aged people and is expensive to treat over the natural course of the disease, making it an economically and medically important disease.

Investigating the safety and activity of the use of BTT1023 (Timolumab), in the treatment of patients with primary sclerosing cholangitis (BUTEO): A single-arm, two-stage, open-label, multi-centre, phase II clinical trial protocol

Introduction Primary sclerosing cholangitis (PSC) is a progressive inflammatory liver disease characterised by relentless liver fibrosis and a high unmet need for new therapies. Preventing fibrosis represents an important area of interest in the development of vital new drugs. Vascular adhesion protein-1 (VAP-1) drives inflammation in liver disease, and provision of an antibody against VAP-1 blunts fibrosis in murine models of liver injury. Methods and analysis BUTEO is a single-arm, two-stage, open-label, multi-centre, phase II clinical trial. Up to 59 patients will receive treatment with anti-VAP monoclonal antibody, BTT1023, over a 78-day treatment period. Adults with PSC and a serum alkaline phosphatase (ALP) of at least 1.5 times the upper limit of normal will be included. Our primary outcome measure is a reduction in ALP by >25% from baseline to Day 99. Secondary outcome measures include safety and tolerability, changes pre therapy/post therapy in circulating serum VAP-1 as well as imaging findings. The first patient participant was recruited on 08 September 2015. Ethics and dissemination This protocol has been approved by the Research Ethics Committee (REC, reference 14/EM/1272). The first REC approval date was 06 January 2015 with three subsequent approved amendments. This article refers to protocol V3.0, dated 16 March 2016. Results will be disseminated via peer-reviewed publication and presentation at international conferences. Trial registration The trial is registered with the European Medicines agency (EudraCT: 2014-002393-37), the National Institute for Health Research (Portfolio ID: 18051) and ISRCTN: 11233255. The clinicaltrials.gov identifier is NCT02239211. Pre-results.

Aspects of the Pathophysiology of Primary Biliary Cirrhosis.

Primary biliary cirrhosis is a classical autoimmune liver disease and is present in around 1 in 1,000 women over the age of 40. It has a number of diagnostic characteristics consistent with autoimmune liver injury, in particular, the high specificity of circulating anti-mitochondrial antibodies. Histologically, the disease is reflected as a granulomatous lymphocytic cholangitis that consequently leads to small bile duct loss and cholestasis. Progressive disease is characterised by the development of a biliary cirrhosis, with end-stage features of liver disease ultimately impacting patient outcomes. Studies support a combination of environmental and genetic risk factors that coalesce to lead to loss of immunological tolerance and persistent biliary inflammation. Significant advances have occurred recently in understanding the genetic risk factors for disease, as well as utilising human and murine studies to characterise the nature of the biliary injury and cholestatic response.

Are Clinicians Ready for Safe Use of Stratified Therapy in Primary Biliary Cholangitis (PBC)? A Study of Educational Awareness

BackgroundPrimary Biliary Cholangitis (PBC, formerly cirrhosis), is a chronic cholestatic liver disease which until spring 2016 had a single licensed therapy, Ursodeoxycholic acid (UDCA). Approximately 30% of patients do not respond to UDCA, and are high-risk for progressing to end stage liver disease, transplantation or death. A new era of stratified medicine with second-line therapies to treat high-risk disease is emerging, with the first such second-line agent obeticholic acid recently receiving FDA and EMA approval and entering practice. Recent experience in the USA of inappropriate use and associated deaths has highlighted concerns as to whether clinicians have the knowledge to implement second-line therapies appropriately and safely.MethodsOnline survey of knowledge regarding optimal PBC management in Gastroenterologists and Hepatologists in the USA; the first 100 completed responses from each group used for analysis.Results80% of Hepatologists felt they were highly competent in their understanding of the importance of early diagnosis and early UDCA therapy in PBC compared with 65% of gastroenterologists. However, only 36% of Hepatologists and 30% of gastroenterologists felt competent at assessing response to UDCA. Competence in knowledge (mode of action, efficacy, and side effects) of second-line therapies and enrollment into trials was low among both groups.ConclusionSignificant knowledge gaps in clinicians managing PBC presents a problem in optimizing care. It is perhaps not surprising that knowledge of emerging second-line therapies is low, however more concerning is sub-optimal use of UDCA in real-life practice and the lack of confidence at assessing treatment response which should be a routine part of clinical practice to assess risk of disease progression and will be key in delivering stratified medicine.

Autoimmune liver disease: evaluating overlapping and cross-over presentations—a case-based discussion

The three classic autoimmune liver diseases are recognised based on identifying varying clinical, laboratory, histological and radiological features that collectively classify patients. In the absence of defined aetiological factors, it is recognised that disease spectrum is broad, and, in this context, it is not infrequent for disease boundaries to be blurred, leading to overlapping features that may be present at the time of diagnosis or may appear later in the course of disease. Given the absence of accepted diagnostic criteria for overlap/cross-over syndromes, alongside weak data for intervention, it is recommended that a multidisciplinary, patient-specific approach be used to establish individual treatment pathways.

PWE-426 Hepatology training in the uk – results from the bsg training survey 2014

Introduction Issues around hepatology service delivery and training in the UK have been highlighted by the recent Lancet Commission.1Currently, the majority of liver services are delivered by gastroenterologists with <6 months of hepatology. Increased numbers of specialists with advanced training are required to tackle the increasing burden of liver disease. Whilst guidelines exist to define minimum training requirements and competencies for all trainees,2training opportunities are variable. Method The 2014 trainee survey was sent to all UK trainees. 263/806 (32.6%) responded. Within the hepatology section of the survey, respondents were asked about future career plans, satisfaction with training, training opportunities and self assessed competence. Results Subspecialism: 8% of trainees plan to be a subspecialist hepatologist and 6% an academic hepatologist which is lower than those planning a career in general gastroenterology (16%), advanced endoscopy (12%) and IBD (10%). Overall experience: 68% of respondents rated themselves as either satisfied/very satisfied with their hepatology training. This is lower (p < 0.01) than overall gastroenterology training (82.9%), basic endoscopy (79.9%) and IBD (79.2%). Barriers to training: 25.3% of trainees who wished to undertake formal hepatology training identified a barrier to accessing this. The main barriers were lack of local training opportunities and not wishing to move region to access hepatology training. Opportunities: All trainees should have at least 12 months in a level 2 or 3 centre.2However of current senior trainees (ST6+) less than 70% reported spending 6 months or more in at least one of these centres. Self reported competence of senior trainees to act as a consultant in a district general hospital found that 50% felt they were not competent in post transplant, viral and autoimmune liver disease and 30% felt they were not competent managing complications of portal hypertension including variceal bleeding. Conclusion The results confirm variability in hepatology training. This exists not only in access to advanced training but also core training competencies. All deaneries should aim to organise training rotations to maximise the opportunities especially in the deaneries which do not contain a level 3 centre. Early exposure of all trainees to hepatology units and clinics may allow better understanding of training pathways and early career planning. Disclosure of interest None Declared. References Williams R, Aspinall R, Bellis M, Camps-Walsh G, Cramp M, Dhawan A, et al. Addressing liver disease in the UK: a blueprint for attaining excellence in healthcare and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity and viral hepatitis. Lancet 2014;384(9958):1953–1997 BSG Liver Section Training information 2014. http://www.bsg.org.uk/sections/liver-training/index.html