ObjectiveXT1061 is a newly developed oral small-molecule agent designed to promote the assembly of empty capsids devoid of pregenomic RNA, representing a potential therapeutic approach for chronic hepatitis B (CHB). This first-in-human trial aimed to assess the pharmacokinetic profile and tolerability of single ascending doses and multiple doses of XT1061 in healthy Chinese individuals.MethodsThe Phase Ia clinical study consisted of two components: a double-blind, randomized, placebo-controlled, single-ascending-dose assessment conducted under fasting conditions across dose levels ranging from 12.5 mg to 600 mg—including a food-effect evaluation at 62.5 mg—followed by a multiple-dose regimen at 250 mg administered under fasting conditions.ResultsXT1061 demonstrated good tolerability in healthy Chinese participants, with no notable difference in the incidence of adverse events between the XT1061 and placebo groups. Following administration, the median time to peak concentration ranged from 1.0 to 2.5 h, while the mean elimination half-life varied between 2.864 and 11.478 h. Systemic exposure exhibited an approximately dose-proportional increase. Steady-state concentrations were achieved within approximately 2 days of repeated dosing, with mean accumulation indices ranging from 1.043 to 1.333. Additionally, concomitant food intake reduced the peak plasma concentration by approximately 50%, although it had no significant impact on total systemic exposure, as measured by the area under the curve.ConclusionThese findings indicate that XT1061 possesses a favorable safety profile and predictable pharmacokinetics, providing a solid foundation for advancing into further clinical investigations to evaluate its efficacy and safety in patients with CHB.Clinical Trial Registration[http://www.chinadrugtrials.org.cn/index.html], identifier [CTR20232071].

ObjectiveTo evaluate the effects of mild and moderate hepatic impairment on the pharmacokinetics and safety of SHR0302.MethodsThis open-label, parallel-group study enrolled 24 Chinese subjects, including subjects with normal hepatic function and those with mild or moderate hepatic impairment (8 per group). All subjects received a single oral dose of SHR0302 (8 mg). Plasma PK parameters of SHR0302 and its metabolite, SHR161279, were assessed and compared across groups. Safety was evaluated throughout the study.ResultsMild hepatic impairment had minimal effect on the exposure of SHR0302. In subjects with moderate hepatic impairment, the Cmax of SHR0302 was approximately 17% lower than that in subjects with normal hepatic function, whereas AUC0-t and AUC0‐∞ remained generally unchanged. Meanwhile, exposure to SHR161279 decreased in both hepatic impairment groups, with reductions of approximately 21%–38%. SHR0302 was generally safe after single-dose administration. Eight subjects (8/24, 33.3%) experienced treatment-emergent adverse events (TEAEs). No serious adverse events were reported.ConclusionMild and moderate hepatic impairment had minimal effect on SHR0302 exposure. Based on the single-dose pharmacokinetic and safety data, dose adjustment of SHR0302 may not be necessary in patients with mild or moderate hepatic impairment.Clinical Trial Registrationhttps://clinicaltrials.gov/, identifier NCT04293029.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by cholestasis-driven bile duct injury and fibrosis. Biliary epithelial cells (BECs) play a central role in both bile homeostasis and immune regulation, and their metabolic and immune dysfunction is critical in PBC pathogenesis. Furthermore, systemic metabolic disturbances, such as gut dysbiosis, contribute to disease progression. This paper systematically examines the interplay between BEC metabolism-including bile acid imbalance and lipotoxicity-and immune dysregulation, such as autoantigen exposure and Th1/Th17 responses, highlighting how these interactions fuel a self-sustaining "metabolo-immune-fibrosis" cycle in PBC. Current and emerging therapies are also reviewed, emphasizing that future management should move beyond single-pathway targeting and pursue combination strategies capable of simultaneously modulating metabolic, inflammatory, and immune networks.

BACKGROUND:Cholestatic pruritus is common and undertreated in primary biliary cholangitis (PBC) and negatively affects patients' lives. We aimed to evaluate the safety and efficacy of linerixibat, an ileal bile acid transporter inhibitor, as a specific antipruritic therapy in patients with PBC. METHODS:We conducted a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Patients with PBC and moderate-to-severe pruritus (Worst Itch Numerical Rating Scale [WI-NRS] ≥4) were recruited at 115 centres in 19 countries. Patients were randomly assigned to receive either oral linerixibat 40 mg twice a day or a matching placebo through an interactive online response system, with pruritus severity (moderate or severe) and concomitant pruritus treatment (bile acid binding resins, other treatments, or none) as stratification factors. The primary endpoint was change in pruritus over 24 weeks assessed using the WI-NRS, ranging from 0 (no itching) to 10 (worst imaginable itching). Efficacy analyses included all randomly allocated patients; safety analyses included all randomly allocated patients who received one dose of study treatment or more. This study is registered with ClinicalTrials.gov, number NCT04950127. FINDINGS:From Dec 1, 2021, to May 13, 2024, a total of 238 patients were randomly assigned to receive either linerixibat (n=119) or placebo (n=119). One (<1%) of 119 patients randomly allocated to receive placebo withdrew before receiving treatment. Patients receiving linerixibat experienced significant improvement in pruritus over 24 weeks compared with placebo (least-squares mean change from baseline -2·86 [95% CI -3·23 to -2·50] for linerixibat vs -2·15 [-2·51 to -1·78] for placebo; adjusted mean difference -0·72 [95% CI -1·15 to -0·28]; p=0·0013). Gastrointestinal adverse events were more frequent in patients treated with linerixibat than with placebo (72 [61%] of 119 vs 21 [18%] of 118 had diarrhoea; 22 [18%] vs four [3%] had abdominal pain). Treatment discontinuations due to gastrointestinal adverse events occurred in eight (7%) of 119 patients in the linerixibat group (of which five were due to diarrhoea) and one (<1%) of 118 in the placebo group. Serious adverse events were reported in 14 (12%) of 119 patients receiving linerixibat and four (3%) of 118 receiving placebo. No deaths were reported during the study. INTERPRETATION:Linerixibat significantly improved pruritus versus placebo, supporting its potential to address a major symptom of PBC. An expected increase in diarrhoea in linerixibat-treated patients was observed. FUNDING:GSK.

Recombinant human serum albumin (rHA) is a promising alternative to human serum albumin (HSA) for managing ascites in cirrhotic patients. This phase Ib study aims to assess the safety, tolerability, and pharmacokinetics/pharmacodynamics (PK/PD) profiles of rHA in this population. This randomized, open-label, phase Ib trial was conducted between December 2019 and September 2020 at 3 medical centers in China. Patients with cirrhotic ascites were randomly assigned to receive rHA or HSA at 10 g/day, 20 g/day, or 30 g/day. Each group had 12 participants (nine receiving rHA and three receiving HSA as positive control). Treatment lasted up to 14 days or until serum albumin levels reached 35 g/L, followed by a 28-day follow-up. Adverse events monitored assessed safety and tolerability, while PK/PD was evaluated by tracking serum albumin levels and plasma colloid osmotic pressure (PCOP) before and after each dose (ClinicalTrials.gov No. NCT04701697). Thirty-six Chinese participants were enrolled, with 32 completing the study. The incidence of adverse events was similar between the rHA and HSA groups (44.4

ABSTRACT GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C-like (3CL) protease inhibitor that was recently approved for treating mild to moderate coronavirus disease 2019 patients in China. Since cytochrome P450 (CYP) enzymes, primarily CYP3A, are the main metabolic enzymes of GST-HG171, hepatic impairment may affect its pharmacokinetic (PK) profile. Aiming to guide clinical dosing for patients with hepatic impairment, this study, using a non-randomized, open-label, single-dose design, assessed the impact of hepatic impairment on the PK, safety, and tolerability of GST-HG171. Patients with mild and moderate hepatic impairment along with healthy subjects were enrolled ( n = 8 each), receiving a single oral dose of 150 mg GST-HG171, with concurrent administration of 100 mg ritonavir to sustain CYP3A inhibition before and after GST-HG171 administration (−12, 0, 12, and 24 hours). Compared to subjects with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for GST-HG171’s maximum plasma concentration ( C max ), area under the concentration-time curve up to the last quantifiable time (AUC 0- t ), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC 0-∞ ) in subjects with mild hepatic impairment were 1.14 (0.99, 1.31), 1.07 (0.88, 1.30), and 1.07 (0.88, 1.29), respectively. For moderate hepatic impairment, the ratios were 0.87 (0.70, 1.07), 0.82 (0.61, 1.10), and 0.82 (0.61, 1.10), respectively. Hepatic impairment did not significantly alter GST-HG171’s peak time ( T max ) and elimination half-life ( T 1/2 ). GST-HG171 exhibited good safety and tolerability in the study. Taken together, mild to moderate hepatic impairment minimally impacted GST-HG171 exposure, suggesting no need to adjust GST-HG171 dosage for patients with mild to moderate hepatic impairment in the clinic. Clinical Trials Registered at ClinicalTrials.gov ( NCT06106113 ).

ObjectiveTo investigate the effect of Compound Lingdan Capsule on serum biochemical parameters and liver fibrosis degree in a mouse model of liver fibrosis. MethodsA total of 125 specific pathogen-free male C57BL/6 mice were randomly divided into normal control group with 5 mice, CCl4 model group with 15 mice, low-, middle-, and high-dose CCl4 groups (0.8, 1.6, and 3.2 mg·g-1·d-1) with 15 mice in each group, DDC model group with 15 mice, and low-, middle-, and high-dose DDC groups (0.8, 1.6, and 3.2 mg·g-1·d-1) with 15 mice in each group. After successful modeling, the mice in the administration groups were given Compound Lingdan Capsule suspension at the respective doses by gavage, and those in the normal control group and the model group were given an equal volume of normal saline by gavage, for 4 consecutive weeks. Blood samples were collected from the eyeballs, and serum was used to measure aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and bilirubin. Liver tissue samples were collected at the same site of the right lobe of the liver for pathological observation, Sirius Red staining, α-SMA antibody staining, and COL1A1 antibody staining. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the Bonferroni method was used for further comparison between two groups. ResultsCompared with the model group, each dose group had significant reductions in the serum level of ALT and a significant increase in the serum level of albumin after the administration of Compound Lingdan Capsule (all P＜0.05), the levels of AST and bilirubin in the middle and high dose groups were lower (all P＜0.05), and the difference of each index in the high dose group was more significant than that in the low dose group (all P＜0.05). Each dose group had varying degrees of improvement in the pathological changes of the liver and a significant reduction in the number of Sirius Red staining-positive cells, as well as varying degrees of reduction in the protein expression of α-SMA and COL1A1. ConclusionCompound Lingdan Capsule can improve liver function and reduce liver fibrosis degree in mice with liver fibrosis.

Introduction The aim of this study was to develop a noninvasive prediction model for histological stages in PBC that is simple, easy to implement, and highly accurate. Methods A total of 114 patients with PBC were included in this study. Demographic, laboratory data and histological assessments were collected. The independent predictors of histological stages were selected to establish a noninvasive serological model. The scores of 22 noninvasive models were calculated and compared with the established model. Results This study included 99 females (86.8%) and 15 males (13.2%). The number of patients in Scheuer’s stage 1, 2, 3 and 4 was 33 (29.0%), 34 (29.8%), 16 (14.0%), and 31 (27.2%), respectively. TBA and RDW are independent predictors of PBC histological stages. The above indexes were used to establish a noninvasive model-TR score. When predicting early histological change (S1) or liver fibrosis and cirrhosis (S3-S4), the AUROC of TR score were 0.887 (95% CI, 0.809-0.965) and 0.893 (95% CI, 0.816-0.969), higher than all of the other 22 models included in this study. When predicting cirrhosis (S4), its AUROC is still as high as 0.921 (95% CI, 0.837-1.000). Conclusion TR score is an easy, cheap and stable noninvasive model, without complex calculation formulas and tools, and shows good accuracy in diagnosing the histological stages of PBC.

Background: Although several prognostic scores have been reported to correlate with the prognosis of primary biliary cholangitis (PBC) patients, there are limited tools to predict the prognosis of PBC with compensated cirrhosis. This study aimed to evaluate the prognostic performance of the albumin-bilirubin (ALBI) score in PBC patients with compensated cirrhosis. Methods: We conducted a retrospective longitudinal study of 219 patients with compensated PBC cirrhosis to evaluate the prognostic performance of the ALBI using Cox regression model, receiver operating characteristic (ROC) curve, and Kaplan-Meier method. Results: During follow-up, a total of 19 subjects (8.7%) met the primary endpoint of liver-related death or liver transplantation (LT). Patients who died/underwent LT have higher ALBI score (−1.06 vs. −2.06, p < 0.001) at baseline than those who survived. ALBI score (hazard ratio: 15.011, 95% confidence interval [CI]: 5.045–44.665, p < 0.001) was associated with an increase in liver-related mortality or LT. ALBI score had the best discriminative capacity to predict the 5-year liver-related mortality (area under the ROC curve: 0.871, 95% CI [0.820, 0.913]) compared with other prognostic scores. The ROC curve showed that the best cut-off value of ALBI score was −1.47, with 90.0% sensitivity and 76.6% specificity. Also, the probability of transplant-free survival decreased with increasing ALBI grade (log-rank p = 0.003). The 5-year transplant-free survival rates of patients in grade 1, grade 2, and grade 3 were 100.0%, 96.4%, and 89.4%, respectively. Conclusion: ALBI score is a simple and effective predictive factor estimating the clinical outcome of patients with compensated PBC cirrhosis and provides better prognostic performance compared with other prognostic scores.