A Randomized, Controlled, Phase 2 Study of Maralixibat in the Treatment of Itching Associated With Primary Biliary Cholangitis.

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

Challenges and opportunities in the management of portal hypertension

PhD ThesisPortal hypertension and Gastro-Oesophageal varices (GOV) can occur in early stage Primary Biliary Cirrhosis (PBC) and are associated with a poor prognosis. Screening with endoscopy however, is only recommended in advanced disease. Transjugular-intrahepatic-portosystemic shunting (TIPS) is a life saving procedure in patients with decompensated portal hypertension. Serial TIPS patency checks using a venogram, in stable patients, offers a unique opportunity to sample portal venous blood, and in doing so to study the role of the human intestinal mucosa in bio-transforming essential nutrients. The aim of this work was to create a non invasive, inexpensive, externally validated screening tool to identify PBC patients with GOV and to use in-situ TIPS as a novel route of access to sample portal venous blood to define the exact site of bio-transformation of folates in humans. A cross-sectional retrospective study of 330 PBC patients who underwent an OGD at Newcastle was used to create a predictive tool that was externally validated in PBC patients from Cambridge and Toronto. 48% of the Newcastle, 31% of the Cambridge and 22% of the Toronto cohorts of PBC patients had GOV. 25% (95% CI 18–32%) of the Newcastle cohort had GOV diagnosed at an index variceal bleed. Of the others, 37% (95% CI 28–46%) bled after a median of 1.5 years (IQR 3.75). Transplant-free survival was significantly better in those without GOV vs. those with GOV (p <0.001), but similar in patients with GOV that bled and those that did not (p = 0.1). The NVP score (%Probability of GOV) = 1 / [1+exp ^ − (9.186 + 0.001 * alkaline phosphatase in IU − 0.178*albumin in g/L − 0.015*platelet×109) was validated in external cohorts ii (AUROC 0.86). Cost consequences analyses revealed the NVP score to be as accurate as, but more economical than using either OGD directly or other risk scores for screening. A prospective cross-over study of portal and peripheral venous labelled folate concentrations following oral dosing with physiological doses of stable-isotopelabelled folic acid (FA) or 5-formyltetrahydrofolic acid (5-FTHF) in six subjects with a TIPS in situ was set up. At 15 minutes, a median 86% [range 60-88%] of labelled folate in the hepatic portal vein following a dose of FA was unmodified FA. In contrast, following a dose of 5-FTHF, only a median 3% [range 2-6%] of labelled folate in the portal vein was unmodified 5-FTHF; the rest being methylated to 5-MTHF, suggesting limited gut wall dihydrofolate reductase capacity and suggesting that the liver in humans, rather than the intestinal mucosa as previously thought, is the organ responsible for this process.BBSRC project grant which funded the folic acid stud

UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis

Background &amp; aims: thirty-to-forty percent of patients with primary biliary cholangitis inadequately respond to ursodeoxycholic acid. Our aim was to assemble national, real-world data on the effectiveness of obeticholic acid (OCA) as a second-line treatment, alongside non-licensed therapy with fibric acid derivatives (bezafibrate or fenofibrate).Methods: this was a nationwide observational cohort study conducted from August 2017 until June 2021.Results: we accrued data from 457 patients; 349 treated with OCA and 108 with fibric acid derivatives. At baseline/pre-treatment, individuals in the OCA group manifest higher risk features compared with those taking fibric acid derivatives, evidenced by more elevated alkaline phosphatase values, and a larger proportion of individuals with cirrhosis, abnormal bilirubin, prior non-response to ursodeoxycholic acid, and elastography readings &gt;9.6kPa (P &lt; .05 for all). Overall, 259 patients (OCA) and 80 patients (fibric acid derivatives) completed 12 months of second-line therapy, yielding a dropout rate of 25.7% and 25.9%, respectively. At 12 months, the magnitude of alkaline phosphatase reduction was 29.5% and 56.7% in OCA and fibric acid groups (P &lt; .001). Conversely, 55.9% and 36.4% of patients normalized serum alanine transaminase and bilirubin in the OCA group (P &lt; .001). The proportion with normal alanine transaminase or bilirubin values in the fibric acid group was no different at 12 months compared with baseline. Twelve-month biochemical response rates were 70.6% with OCA and 80% under fibric acid treatment (P = .121). Response rates between treatment groups were no different on propensity-score matching or on sub-analysis of high-risk groups defined at baseline.Conclusion: across the population of patients with primary biliary cholangitis in the United Kingdom, rates of biochemical response and drug discontinuation appear similar under fibric acid and OCA treatment.</p

Characterizing low-sulfide instrumented waste-rock piles: image grain-size analysis and wind-induced gas transport

This study is part of the Diavik Waste-Rock Pile Project taking place at the Diavik Diamond Mine in the Northwest Territories, Canada. The project involves the construction of three 15m-scale low sulfide test waste-rock piles and monitoring of fluid flow, geochemical reactions, heat and gas transport within the waste-rock piles and characterization of the physical properties of the waste-rock piles. The focus of this thesis is characterizing grain-size distribution of the waste-rock and quantifying gas transport in the test waste-rock piles. Grain size of waste rock ranges from millimeters to meters. Sieve analysis typically only provides information of grain size 0.1 m and employs a region-growing algorithm for segmentation of waste-rock grains with pre- and post-processing techniques to improve the accuracy of segmentation. The program was applied to photographs of six different tip faces of the test waste-rock piles. For grain size <0.1 m, data from sieve analyses were attached to the grain-size curves generated from image grain-size analyses to obtain a full spectrum grain-size analyses ranging from boulders to fines. The results show that fine fractions are retained at the top of the tip faces and grain size increases non-linearly from top to bottom of a waste-rock pile. Calculations show that although the greatest mass is associated with the medium and coarse fractions, the greatest surface area is associated with the fine fractions. The results are consistent with field observation that the initial solute concentrations are greatest at the top of the pile and saturated hydraulic conductivity are lower at the top of the pile than in the pile interior. Statistical moments show that the test waste-rock piles have mean grain size of granules and are very poorly sorted, coarse skewed and leptokurtic. Permeability is calculated using empirical formulae and good agreement is obtained between calculated values and field measurements. The heterogeneity of grain size obtained from this study can provide a basis for future modeling efforts. Gas transport analysis focused on 1) substantiating the relationship between wind flow external to the waste-rock pile and gas pressures within the pile, 2) determining the gas flow regime in the pile, and 3) quantifying the temporal variation in wind speed and direction and determining the relevant time scales. Differential gas pressures were measured in 2008 at 49 locations within one of the three test waste-rock piles and 14 locations on the surface of the pile at one-minute intervals. Wind speed and direction were measured at 10-min intervals. Correlations between wind vectors and pressure measurements show that the wind influences pressure fluctuations in the test pile. The strength of the correlation is roughly inversely proportional to the distance between measurement ports and the atmospheric boundary. The linear relationship between internal pressure measurements and surface pressure measurements demonstrate that gas flow is Darcian within the test waste-rock pile. Spectral analysis of wind data and a one-dimensional analytical solution to the flow equations show that the persistence of wind in a certain direction has most pronounced effects on transient gas flow within the pile. The penetration depth of wind-induced gas pressure wave is a function of the periodicity of the wind and permeability of the waste-rock pile

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n1⁄42,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n1⁄43,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombinedo5108) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine–cytokine pathways, for which relevant therapies exist