BackgroundObeticholic acid (OCA) stands as the sole approved second-line treatment for primary biliary cholangitis (PBC) patients unresponsive to ursodeoxycholic acid (UDCA). Preliminary studies suggested OCA's efficacy in reducing PBC decompensation and increasing survival. However, these studies face limitations, either due to heterogeneous cohorts (OCA registrative trial Vs real-world controls) or reliance on administrative data.AimTo compare transplant-free and liver-related event (LRE)-free survival between two large real-world cohorts of OCA-treated and untreated PBC patients.MethodsThe Italian RECAPITULATE is a multicenter real-world cohort of OCA-treated PBC patients enrolled from across Italy. An external control cohort of OCA-untreated PBC patients was derived from the GLOBAL-PBC dataset. Controls met OCA prescription criteria in Italy (ALP≥1.5/ULN and/or 1<bilirubin<2 mg/dl after ≥1 year of UDCA treatment), and a random visit in which eligibility criteria were met represented the index date. LRE (ascites with-/-out spontaneous bacterial peritonitis, hepatic encephalopathy, and upper gastrointestinal bleeding), liver transplant and liver-related death were tracked during follow-up. Weighted Cox regression method (using propensity scores) was applied for the external control group, incorporating age, ALP, AST, bilirubin, UDCA duration, cirrhosis and age at OCA start as baseline confounders.ResultsThe study included 437 RECAPITULATE patients (female: 88%; cirrhotics: 34%; on UDCA: 98%), and 831 GLOBAL-PBC controls (female: 91%; cirrhotics: 15%; on UDCA: 74%). RECAPITULATE's median follow-up was 30 months, and time was censored accordingly in the control cohort. Liver transplant/liver-related death and LRE were 4 and 16 in the RECAPITULATE cohort, and 58 and 107 in GLOBAL-PBC controls, respectively. In the weighted Cox regression analyses, patients in the RECAPITULATE cohort showed reduced risk of liver transplant/liver-related death [HR 0.318 (0.153-0.660); p<0.0001] and LRE [HR 0.327 (0.196-0.543); p<0.001] with respect to GLOBAL-PBC controls (Figure 1).ConclusionIn the comparison between two real-world cohorts, OCA-treated PBC patients show a longer transplant-free and LRE-free survival with respect to propensity-matched untreated controls.

Abstract Background Obeticholic acid (OCA), a potent farnesoid X receptor agonist, is approved as second-line treatment for primary biliary cholangitis (PBC) in patients with an incomplete response or intolerance to ursodeoxycholic acid. Aims We evaluated the effect of OCA in PBC patients enrolled in the POISE trial, comparing those who did or did not achieve the POISE response criteria. Methods The phase 3, randomized, double-blind, 1-year POISE trial evaluated the efficacy and safety of OCA 5 and 10 mg vs placebo in patients with PBC; a 5-year open-label extension followed in which all patients received OCA. This analysis evaluated longer-term efficacy and safety in patients who achieved the POISE primary endpoint of alkaline phosphatase (ALP) <1.67 × upper limit of normal (ULN), total bilirubin 15% from baseline after 1 year of OCA and in patients who were incomplete responders. Results The analysis included 86 patients who achieved the POISE primary endpoint at year 1 of OCA treatment and 107 incomplete responders (mean baseline ALP, 268 vs 356 U/L, respectively; P<0.0001). Mean change from baseline in ALP at year 5 was –101 U/L for responders and –121 U/L for incomplete responders (P<0.0001; Figure). Median (Q1, Q3) baseline GLOBE 10-year risk of event scores were 16 (11, 23) for responders and 25 (15, 43) for incomplete responders. Change from baseline in median (Q1, Q3) GLOBE 10-year risk of event at year 1, which includes age and thus increases with time, was –2 (–4, 2) for responders and –2 (–6, 4) for incomplete responders; at year 5, these changes were 2 (–2, 7) and 4 (–4, 11), respectively. Median (Q1, Q3) baseline UK-PBC 10-year risk of event scores were 5 (3, 8) for responders and 8 (4, 16) for incomplete responders. Change from baseline in median (Q1, Q3) UK-PBC 10-year risk of event at year 1 was –1 (–3, 0.2) for responders and –1 (–3, 1) for incomplete responders; at year 5, these changes were –0.8 (–2, 0.2) and –0.05 (–2, 2), respectively. The most frequently reported AEs among responders and incomplete responders were pruritus (67%, 86%) and fatigue (35%, 31%). Conclusions OCA treatment improved key biochemical markers of PBC, regardless of achieving the POISE primary endpoint after 1 year of OCA treatment. Changes in biochemical parameters over time were often similar between groups. Funding Agencies Intercept Pharmaceuticals

R. J. de Knegt has received speaker's honoraria from Roche and Gilead, received grants from Roche and BMS and is consultant for BMS and Gilead. H. L. A. Janssen has received grants from and is consultant for Abbott, Anadys, Bristol-Myers Squibb, Gilead Sciences, Innogenetics, Merck, Novartis, Roche, Santaris, Tibotec and Janssen. B. E. Hansen has received grants from and is consultant for Intercept Pharmaceuticals. H. Chi, A. Japhary and R. A. de Man have nothing to disclose. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment-naive CHB patients at one tertiary care centre were scored by a single hepato-pathologist. Laboratory values at liver biopsy were used to calculate the PAGE-B, REACH-B, GAG-HCC, CU-HCC and FIB-4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow-up of 10.1 (IQR 5.7-15.9) years. The PAGE-B score predicted any clinical event (C-statistic.86, 95% CI: 0.80-0.92), HCC development (C-statistic .91) and reduced transplant-free survival (C-statistic .83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C-statistics (95% CI) of the REACH-B, GAG-HCC, CU-HCC and FIB-4 scores for any event were .70 (0.59-0.81), .82 (0.75-0.89), .73 (0.63-0.84) and.79 (0.69-0.89), respectively. The PAGE-B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C-statistic .87, 95% CI: 0.82-0.93). The PAGE-B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15 years of follow-up. Additional liver histological characteristics did not appear to provide a clinically significant improvement.

Introduction: The Global PBC Study Group have developed and validated the GLOBE score: a prognostic algorithm (calculated from: age, ALP, total bilirubin, platelets and albumin) to predict risk of liver transplantation and all-cause mortality (http://www.globalpbc.com). A GLOBE score ≤0.3 is associated with a liver transplant-free survival similar to that of a sex and age matched normal population, whereas a GLOBE score >0.3 is associated with significantly diminished liver transplant-free survival. POISE was a placebo-controlled, double-blind, 12-month Phase 3 study which assessed the efficacy of daily 5-10 mg obeticholic acid (OCA) in patients with PBC. The aim of this analysis was to use data from POISE trial to assess if OCA treatment had an effect on categorical shifts in the GLOBE score. Methods: POISE inclusion criteria: PBC diagnosis, ALP ≥1.67x ULN and/or total bilirubin >ULN to < 2x ULN, stable UDCA dose or unable to tolerate UDCA. 216 patients were randomized and dosed with Placebo (PBO, n=73), OCA 5-10 mg (n=70; titration from daily 5 mg to 10 mg at month 6 based on response or tolerability), or OCA 10 mg (n=73). The GLOBE score was calculated at baseline and month 12 to assess disease progression. Results: At baseline there were a similar number of patients across treatment groups who had a GLOBE score above or below 0.3. After 12 months of treatment, patients receiving OCA 5-10 mg (27%, p < 0.05) were significantly more likely to shift from above to below a GLOBE score of 0.3, as compared to PBO (6%). Additionally, after 12 months of treatment, more PBO patients (33%) compared to OCA-treated patients (OCA 5-10 mg: 13%, p= 0.06; OCA 10 mg: 3%, p < 0.01) progressed from a baseline GLOBE score below 0.3 to a GLOBE score above 0.3. Conclusion: OCA treatment resulted in a significantly greater number of patients achieving a GLOBE score ≤0.3, associated with survival that is similar to age and sex matched individuals as compared to PBO treatment. Also, fewer patients progressed to a GLOBE score >0.3, associated with diminished survival. These changes indicate a potential effect of OCA after only 12 months of treatment to delay disease progression in PBC patients who are insufficiently responding to UDCA; however, further evaluation is required. A Phase 3 study evaluating clinical outcomes with OCA in patients with PBC (COBALT) is ongoing to confirm the clinical benefit of OCA and may be used to test the utility of the GLOBE score with OCA.Figure