Aim: To indirectly compare the efficacy and safety of elafibranor and seladelpar, as second-line treatments for primary biliary cholangitis. Materials & methods: Bayesian network meta-analyses compared data from randomized-controlled studies of elafibranor and seladelpar identified by a systematic literature review up to June 2024: (a) elafibranor (n = 108) versus placebo (n = 53; ELATIVE [NCT04526665]) and (b) seladelpar (n = 128) versus placebo (n = 65; RESPONSE [NCT03301506]). Patients from ELATIVE not meeting the RESPONSE upper limit of normal (ULN) criteria for alkaline phosphatase (ALP) and total bilirubin were excluded (n = 16); summary statistics for ELATIVE were recalculated using the new dataset. Randomeffects models assessed the outcomes of cholestasis response (ALP <1.67 × ULN, ALP reduction ≥15% from baseline and total bilirubin ≤ULN), ALP normalization, change from baseline in ALP and pruritus, pruritus as a treatment-emergent adverse event and all-cause discontinuation. Results: Elafibranortreated patients had greater odds of achieving cholestasis response than placebo- (median odds ratio [95% credible interval]: 84.79 [12.49, 2513.00]) or seladelpar-treated patients (13.02 [1.45, 420.20]), with posterior probabilities ≥99% that odds were higher with elafibranor than seladelpar or placebo. Among patients with ALP ≥350 U/l, the median odds ratio [95% credible interval] of cholestasis response for elafibranor-treated patients versus seladelpar-treated patients was 18.71 [0.65, 10,610.00], with a 95.2% posterior probability that odds were higher with elafibranor than seladelpar. For all other outcomes, there was no strong evidence of a difference between treatments. Conclusion: Bayesian network metaanalyses found strong probabilistic evidence supporting the treatment benefit of elafibranor compared with seladelpar for the achievement of cholestasis response at 52 weeks, while the treatment effect on other outcomes was uncertain. Head-to-head studies are needed to validate results of these indirect comparisons.

BACKGROUND & AIMS:We report 104-week placebo-controlled data and long-term open-label extension (OLE) data from the ongoing ELATIVE® phase III trial (NCT04526665) of elafibranor in primary biliary cholangitis (PBC). METHODS:161 patients were randomized 2:1 to elafibranor 80 mg or placebo. The double-blind period (DBP) consisted of 52-week common (Part 1) and variable (Part 2) periods. Patients completing Part 1 continued into Part 2 until all patients completed Part 1, or for a maximum of 104 weeks. All patients completing Part 1 could enter the OLE and receive elafibranor. RESULTS:At Week 104 in the DBP Part 2, 64.3% (18/28) and 10.7% (3/28) of elafibranor-treated patients achieved biochemical response and alkaline phosphatase (ALP) normalization, versus no placebo-treated patients. In patients with moderate-to-severe fatigue or pruritus at baseline, mean (SE) changes to Week 104 in PROMIS Fatigue Short Form 7a (PFSF 7a) and PBC Worst-Itch Numeric Rating Scale (PBC WI NRS) were -6.3 (2.2) versus -0.4 (1.2) and -4.1 (1.0) versus 0.3 (1.2) with elafibranor versus placebo. 138 patients entered the OLE (continuous elafibranor: n=93; crossover elafibranor: n=45). In continuous patients at Weeks 104 and 156, 58.8% (47/80) and 65.0% (13/20) achieved biochemical response, and 15.0% (12/80) and 25.0% (5/20) achieved ALP normalization. In crossover patients, 51.2% (21/41) and 22.0% (9/41) achieved biochemical response and ALP normalization after 52 weeks. In continuous patients with baseline moderate-to-severe symptoms, mean (SE) changes to Week 130 in PFSF 7a and PBC WI NRS were -4.8 (1.5) and -4.0 (0.7). There were no unexpected safety findings. CONCLUSIONS:Through three years of treatment, elafibranor led to sustained biochemical improvements and was generally well tolerated, with numerical improvements in fatigue and pruritus. TRIAL REGISTRATION:NCT04526665 (https://clinicaltrials.gov/study/NCT04526665); first registered 08/26/2020 IMPACT AND IMPLICATIONS: • Given the chronic, progressive nature of primary biliary cholangitis (PBC), the long-term efficacy and tolerability of treatments is important.• Here, we present two-year results from the double-blind period, and long-term data from the ongoing open-label extension of the phase III ELATIVE® trial, wherein elafibranor (a peroxisome proliferator-activated receptor-α/δ agonist) treatment led to sustained biochemical improvements, stable non-invasive tests of fibrosis, and numerical improvements in fatigue and pruritus, through three years.• Elafibranor demonstrated a favorable safety profile up to a maximum treatment exposure of 3.5 years, including in patients crossing over from placebo.• These findings support elafibranor's role as a durable long-term treatment for patients with PBC, and are particularly relevant for clinicians managing patients with inadequate response or intolerance to first-line treatments.

Background: Pruritus affects up to 80% of patients with primary biliary cholangitis (PBC) and reduces health-related quality of life (HRQoL). GLIMMER (NCT02966834) was a randomized, placebo-controlled phase IIb study of linerixibat in patients with PBC and pruritus. Using patient-reported outcome data from GLIMMER, we characterize the impact of pruritus in PBC. Methods: To objectively assess HRQoL impact, EQ-5D-5L data from GLIMMER (0–1 scale; 0 = death, 1 = perfect health) were analyzed post-hoc across pruritus severities. Inter-relationships between pruritus severity (0–10 numerical rating scale [NRS]), depression (Beck Depression Inventory-II, post-hoc), and sleep interference (0–10 NRS) and their impact on HRQoL were explored. Results: In patients with PBC (n = 147), severe pruritus was associated with worse HRQoL. EQ-5D-5L scores were lower in those with severe pruritus (≥7–10 NRS) versus mild/moderate pruritus (mean [SD]: 0.49 [0.28] and 0.75 [0.17]/0.76 [0.17], respectively). Among patients with severe pruritus, 31% had severe depression, versus 9/3% with mild/moderate pruritus. Patients with both severe pruritus and depression had a mean EQ-5D-5L score of 0.30. In those with severe pruritus, 54% reported severe sleep interference. Improvements in pruritus were accompanied by stepwise improvements in EQ-5D-5L scores. Conclusions: This analysis of patients in the largest investigational trial of cholestatic pruritus to date shows a clear association between pruritus and impaired HRQoL. Patients with severe pruritus had HRQoL comparable to patients with severe Parkinson’s disease. Severe pruritus alongside depression was associated with extremely poor HRQoL, indicating the importance of evaluating itch and managing depression. Sleep interference appears to be a major cofactor for reduced HRQoL. For each 1-point improvement in NRS HRQoL improved, clinicians should offer appropriate and timely intervention.

Background and aims Rare, pathogenic variants in multiple genes can cause severe liver disease, requiring transplantation in childhood, but it is unclear whether common variants in the same genes confer risk of liver disease in adults. Here, we aimed to establish whether 'monogenic' liver diseases are associated with a spectrum of liver phenotypes in adulthood. Methods We identified 99 genes where pathological mutations cause significant liver disease in children. For each, we used population-level data from over 1.5 million adults to identify associations with biomarkers of liver injury (e.g. ALT). These observations were validated using six external cohorts of adults with clinical liver disease and transcriptomics. Finally, we illustrated the importance of the JAG1-NOTCH pathway on the ductular reaction in adult liver disease using immunohistochemistry and transcriptomics. Results We identified 89 genome-wide (p<5x10-8) associations with biomarkers of liver injury in 46% (45/99) of genes. Variants in ABCC2, ADK, ASL, BCS1L, HFE, and SERPINA1 were also linked with presence of clinical liver disease in adults. For example, rs2862926C>T encoding p.Ile1324= in ABCC2 (which causes Dubin-Johnson syndrome) was associated with lower ALT (p=7.1x10-12) and lower risk of MASLD (p-FDR=0.03). Transcriptional expression of 30% of genes was associated with severity of MASLD. p.Pro871Arg in JAG1 causes a subtle form of Alagille syndrome with higher bilirubin (9.7x10-10) and hypertension (p=4.2x10-14). JAG1 and NOTCH2 were expressed in injured bile ducts but not adjacent unaffected ducts and transcriptional expression of JAG1 correlated with fibrosis stage in primary sclerosing cholangitis. Conclusions Pathways affected by severe childhood liver disease also influence risk and severity of liver disease in adulthood. ### Competing Interest Statement KZ is an employee of Gilead Sciences Inc. JX was an employee of Gilead Sciences Inc. at the time the research was conducted. ### Funding Statement AS, SPD, YHO, and JPM: NIHR BRC Birmingham. JPM is supported by grants from NIHR ACL (CL-2022-09-005), Royal Society (RG\R1\241312), BSPGHAN-Guts (BSPGHAN2023\_01), ESPGHAN, Royal College Physicians Dame Sheila Sherlock Bursary, and Little Princess Trust (CCLGA 2024 10 Mann). JM: Czech Science Foundation (25-15821S), PRIMUS/21/SCI/006 project funded by Charles University Grant Agency, MSCA Fellowships CZ - Charles University CZ.02.01.01/00/22\_010/0002902 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All liver tissue was obtained following informed consent, under the "Liver Inflammation" study (Research Ethics Committee approval reference - NHS Health Research Authority and Health and Care Research Wales (HCRW): 18/WA/0214; IRAS reference: 223072) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All raw data is publicly available and code used is available at: https://github.com/jmann01/MonogenicLiver.

BACKGROUND & AIMS:Both liver stiffness measurement (LSM) and biochemical response have prognostic significance in patients with primary biliary cholangitis (PBC). However, the frequency and clinical relevance of discordant biochemical and LSM changes remain unclear. We aim to determine the performance of the most recent or current LSM (LSMc) in predicting first hepatic decompensation (HD) in the setting of discordant biochemical and LSM responses. METHODS:In this international, multicenter study, we included patients with at least two reliable LSM performed at least 6 months apart. Patients with prior HD, liver transplantation or hepatocellular carcinoma were excluded. Biochemical response was based on the Paris-II criteria. LSM response was defined as stable or any reduction in LSM. The primary outcome was the occurrence of the first HD. Secondary outcomes were liver transplantation and liver-related death. The influence of LSM on HD was estimated using Cox regression analysis. RESULTS:A total of 1,793 patients with PBC were analyzed. Over a median follow-up of 22 (IQR 12-39) months, 3.3% developed HD. Up to 55% of patients with PBC exhibited discordance between LSM and biochemical response. Among patients with LSM response, achieving Paris-II criteria was associated with a lower risk of HD (hazard ratio [HR] 0.25, 95% CI 0.06-0.97, p <0.044). Among patients with biochemical response, LSM response did not influence the risk of developing HD (HR 0.64, 95% CI 0.21-1.96, p = 0.429). The LSMc >10 kPa strongly predicted HD (HR 14.5, 95% CI 6.9-30.6, p <0.001), irrespective of biochemical response and prior LSM trajectories. CONCLUSIONS:Discordance between LSM and biochemical response is frequent. Most recent or current LSM is the strongest predictor of first liver-related events in patients with PBC, irrespective of prior biochemical response or LSM trajectory. IMPACT AND IMPLICATIONS:Both liver stiffness measurement (LSM) and biochemical response have prognostic significance in patients with primary biliary cholangitis. However, the clinical relevance and how discordant biochemical and LSM changes should be best interpreted remain unclear. In this large international multicenter study, we demonstrated that once the current LSM is known, prior LSM trajectories and biochemical changes did not improve the prediction of liver-related events in patients with primary biliary cholangitis. Our finding addresses a common clinical dilemma in risk-stratifying PBC patients with discordant biochemical and LSM responses. Importantly, the use of the latest LSM value for risk prediction significantly simplifies the use of LSM in clinical decision-making for PBC patients with multiple LSM readings.