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ObjectivesObeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in PBC patients improve with OCA therapy.MethodsPatients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database.ResultsIn the RCT, the primary endpoint occurred in 28.6% of OCA (n=168) and 28.9% of placebo patients (n=166; intent-to-treat [ITT] analysis hazard ratio [HR]=1.01, 95% CI=0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting (IPCW) and as-treated analyses shifted the HR to favor OCA. In the EC (n=1051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR=0.39; 95% CI=0.22-0.69; P=0.001). No new safety signals were identified in the RCT.ConclusionsFunctional unblinding and treatment crossover, particularly in the placebo arm, confounded the ITT estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC.

Background and aimsENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).Approach and resultsPatients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events.ConclusionsPatients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

BackgroundPrimary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC.MethodsThis open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed.ResultsOf 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline.ConclusionsMaralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540.

Background & aimsPrimary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC.MethodsAESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin

Background: To our knowledge, no analysis of data from liver transplantation registries exists in Canada. We aimed to describe temporal trends in the number of liver transplantation procedures, patient characteristics and posttransplantation outcomes for autoimmune liver diseases (AILDs) in Canada. Methods: We used administrative data from the Canadian Organ Replacement Regis ter, which contains liver transplantation information from 6 centres in Canada. This study included transplantation information from 5 of the centres, as liver transplantation procedures in children were not included. We included adult (age [greater than or equal to] 18 yr) patients with a diagnosis of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH) or overlap syndrome (PBC-AIH or PSC-AIH) who received a liver transplant from 2000 to 2018. Results: Of 5722 primary liver transplantation procedures performed over the study period, 1070 (18.7%) were for an AILD: 489 (45.7%) for PSC, 341 (31.9%) for PBC, 220 (20.6%) for AIH and 20 (1.9%) for overlap syndrome. There was a significant increase in the absolute number of procedures for PSC, with a yearly increase of 0.6 (95% confidence interval 0.1 to 1.2), whereas the absolute number of procedures for PBC and AIH remained stable. The proportion of transplantation procedures decreased for PBC and AIH but remained stable for PSC. Recipient age at transplantation increased over time for males with PBC (median 53 yr in 2000-2005 to 57 yr in 2012-2018, p = 0.03); whereas the median age among patients with AIH decreased, from 53 years in 2000-2005 to 44 years in 2006-2011 (p = 0.03). The Model for Endstage Liver Disease score at the time of transplantation increased over time for all AILDs, particularly AIH (median 16 in 2000-2005 v. 24 in 2012-2018, p < 0.001). There was a trend toward improved survival in the PBC group, with a 5-year survival rate of 81% in 2000-2005 and 90% in 2012-2018 (p = 0.06). Conclusion: Between 2000 and 2018, the absolute number of liver transplantation procedures in Canada increased for PSC but remained stable for PBC and AIH; proportionally, PBC and AIH decreased as indications for transplantation. Posttransplantation survival improved only for the PBC group. An improved understanding of trends and outcomes on a national scale among patients with AILD undergoing liver transplantation can identify disparities and areas for potential health care improvement. Contexte : A notre connaissance, aucune analyse des donnees tirees des registres sur les transplantations hepatiques n'a ete effectuee au Canada. Nous avons cherche a decrire l'evolution dans le temps du nombre de transplantations hepatiques, des caracteristiques des patients et des issues post-transplantation pour les patients atteints de maladie auto-immune du foie (MAIF) au Canada. Methodes : Nous nous sommes servis des donnees administratives du Registre canadien des insuffsances et des transplantations d'organes, qui contient les renseignements concernant les transplantations hepatiques de 6 centres au Canada. Dans le cadre de cette etude, seuls les renseignements sur les transplantations de 5 centres ont ete utilises, puisque nous avons exclu les transplantations realisees chez des enfants. Nous y avons inclus les patients adultes (18 ans et plus) ayant recu un diagnostic de cholangite biliaire primitive (CBP), de cholangite sclerosante primitive (CSP), d'hepatite auto-immune (HAI) ou de formes frontieres (CBP-HAI ou CSP-HAI) ayant recu une transplantation hepatique entre 2000 et 2018. Resultats : Des 5722 transplantations realisees durant la periode de l'etude, 1070 (18,7 %) concernaient une MAIF : 489 (45,7 %) une CSP, 341 (31,9 %) une CBP, 220 (20,6 %) une HAI, et 20 (1,9 %) une forme frontiere. En valeurs absolues, le nombre de transplantations effectuees en raison d'une CSP a augmente significativement (augmentation annuelle de 0,6, intervalle de confance de 95 % 0,1-1,2), alors que pour les CBP et les HAI, il est reste stable. La proportion de transplantations effectuees en raison d'une CBP ou d'une HAI a connu une baisse, mais est demeuree stable pour la CSP. L'age median des receveurs lors de la transplantation a augmente chez les hommes atteints de CBP (53 ans entre 2000 et 2005, comparativement a 57 ans entre 2012 et 2018, p = 0,03), alors qu'il a diminue chez les patients atteints d'une HAI (53 ans entre 2000 et 2005, comparativement a 44 ans entre 2006 et 2011, p = 0,03). Le score MELD (Model for End-stage Liver Disease) lors de la transplantation a augmente avec le temps pour toutes les MAIF, particulierement pour les HAI (score median de 16 entre 2000 et 2005, comparativement a 24 entre 2012 et 2018, p < 0,001). Dans le groupe CBP, la survie a eu tendance a s'ameliorer, le taux de survie a 5 ans etant passe de 81 % entre 2000 et 2005 a 90 % entre 2012 et 2018 (p = 0,06). Conclusion : De 2000 a 2018, le nombre absolu de transplantations hepatiques a augmente au Canada pour les patients atteints de CSP, mais il est reste stable pour les personnes atteintes de CBP et de HAI; la proportion de transplantations hepatiques effectuees en raison d'une CBP ou d'une HAI a toutefois connu une baisse. Le taux de survie post-transplantation s'est ameliore seulement pour les patients du groupe CBP. En comprenant mieux les tendances et les resultats pour les patients atteints de MAIH qui ont subi une transplantation hepatique, on pourra mettre en evidence des disparites et des domaines potentiels d'amelioration dans les soins de sante., Autoimmune liver diseases (AILDs) consist of 3 major diseases: primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). The available pharmacologic treatment options differ for each AILD, [...]

Primary biliary cholangitis (PBC) is typically associated with elevated serum bile acid levels and pruritus, but pruritus is often refractory to treatment with existing therapies. This phase 2 study assessed the efficacy and safety of maralixibat, a selective, ileal, apical, sodium-dependent, bile acid transporter inhibitor, in adults with PBC and pruritus. Adults with PBC and pruritus who had received ursodeoxycholic acid (UDCA) for ≥6 months or were intolerant to UDCA were randomized 2:1 to maralixibat (10 or 20 mg/day) or placebo for 13 weeks in combination with UDCA (when tolerated). The primary outcome was change in Adult Itch Reported Outcome (ItchRO™) average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/early termination (ET). The study enrolled 66 patients (maralixibat [both doses combined], n = 42; placebo, n = 24). Mean ItchRO™ weekly sum scores decreased from baseline to week 13/ET with maralixibat (-26.5; 95% confidence interval [CI], -31.8, -21.2) and placebo (-23.4; 95% CI, -30.3, -16.4). The difference between groups was not significant (P = 0.48). In the maralixibat and placebo groups, adverse events (AEs) were reported in 97.6% and 70.8% of patients, respectively. Gastrointestinal disorders were the most frequently reported AEs (maralixibat, 78.6%; placebo, 50.0%). Conclusion: Reductions in pruritus did not differ significantly between maralixibat and placebo. However, a large placebo effect may have confounded assessment of pruritus. Lessons learned from this rigorously designed and executed trial are indispensable for understanding how to approach trials assessing pruritus as the primary endpoint and the therapeutic window of bile acid uptake inhibition as a therapeutic strategy in PBC.

ObjectivePrimary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.ResultsWe identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10-9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.ConclusionWe present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

Background & aimsPrimary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC.MethodsWe performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates.ResultsOf the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002).ConclusionsIn an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC.

Summary: Background: Imaging markers of biliary disease in primary sclerosing cholangitis (PSC) have potential for use in clinical and trial disease monitoring. Herein, we evaluate how quantitative magnetic resonance cholangiopancreatography (MRCP) metrics change over time, as per the natural history of disease. Methods: Individuals with PSC were prospectively scanned using non‐contrast MRCP. Quantitative metrics were calculated using MRCP+ post‐processing software to assess duct diameters and dilated and strictured regions. Additionally, a hepatopancreatobiliary radiologist (blinded to clinical details, biochemistry and quantitative biliary metrics) reported each scan, including ductal disease assessment according to the modified Amsterdam Cholangiographic Score (MAS). Results: At baseline, 14 quantitative MRCP+ metrics were found to be significantly different in patients with PSC (N = 55) compared to those with primary biliary cholangitis (N = 55), autoimmune hepatitis (N = 57) and healthy controls (N = 18). In PSC specifically, baseline metrics quantifying the number of strictures and the number and length of bile ducts correlated with the MAS, transient elastography and serum ALP values (p < 0.01 for all correlations). Over a median 371‐day follow‐up (range: 364–462), 29 patients with PSC underwent repeat MRCP, of whom 15 exhibited quantitative changes in MRCP+ metrics. Compared to baseline, quantitative MRCP+ identified an increasing number of strictures over time (p < 0.05). Comparatively, no significant differences in biochemistry, elastography or the MAS were observed between timepoints. Quantitative MRCP+ metrics remained stable in non‐PSC liver disease. Conclusion: Quantitative MRCP+ identifies changes in ductal disease over time in PSC, despite stability in biochemistry, liver stiffness and radiologist‐derived cholangiographic assessment (trial registration: ISRCTN39463479). [ABSTRACT FROM AUTHOR]

Background & aimsUsing high-density human recombinant protein microarrays, we identified two potential biomarkers, kelch-like 12 (KLHL12) and hexokinase-1 (HK1), in primary biliary cirrhosis (PBC). The objective of this study was to determine the diagnostic value of anti-KLHL12/HK1 autoantibodies in PBC. Initial discovery used sera from 22 patients with PBC and 62 non-PBC controls. KLHL12 and HK1 proteins were then analysed for immunoglobulin reactivity by immunoblot and enzyme-linked immunosorbent assay (ELISA) in two independent cohorts of PBC and disease/healthy control patients.MethodsSerum samples from 100 patients with PBC and 165 non-PBC disease controls were analysed by immunoblot and samples from 366 patients with PBC, 174 disease controls, and 80 healthy donors were tested by ELISA.ResultsAnti-KLHL12 and anti-HK1 antibodies were each detected more frequently in PBC compared with non-PBC disease controls (P