A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis.

BACKGROUND: Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. METHODS: In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus). RESULTS: Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively. CONCLUSIONS: In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).

Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis.

BACKGROUND: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects. AIMS: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC. METHODS: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years. RESULTS: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2. CONCLUSIONS: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. CLINICALTRIALS: gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16.

Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).

Obeticholic acid as a second-line treatment for low phospholipid-associated cholelithiasis syndrome.

BACKGROUND: Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare genetic cause of hepatolithiasis. A pathogenic variant of the ABCB4 gene is reported in half of all patients. Ursodeoxycholic acid (UDCA) is the only drug approved. However, in some patients, UDCA fails to prevent recurrence of symptoms and complications. Experimental evidence suggests that agonists of the farnesoid-X receptor (FXR), the main transcription factor regulating ABCB4, may be beneficial in this context. AIM: To study the efficacy of obeticholic acid (OCA) in patients with LPAC syndrome with an inadequate response or intolerance to UDCA. METHODS: This was a retrospective study of patients with LPAC syndrome treated with OCA, a selective FXR agonist. RESULTS: We reviewed the records of five OCA-treated patients (4 women; median age 29; ABCB4 variant in 4; no hepatic fibrosis). All patients received OCA at an initial dose of 5 mg daily and then 10 mg daily for a median period of 36 months in combination with UDCA (4 patients) or as a monotherapy (one patient). There were no adverse effects reported. Four patients had improvement in their symptoms - three completely and one partially. One patient had no clinical benefit. Abnormalities of blood liver tests persisted in one patient despite resolution of symptoms. Radiological signs of hepatolithiasis persisted in three of the four patients who responded clinically to OCA. CONCLUSIONS: These preliminary observations suggest that OCA may have the potential to effectively treat LPAC syndrome in patients with inadequate response or intolerance to UDCA. Larger studies are needed to confirm these data.

Evaluation of therapeutic effect of oral Ursodeoxycholic Acid on indirect hyperbilirubinemia in term neonates undergoing phototherapy: A randomized controlled clinical trial.

INTRODUCTION AND AIMS: Phototherapy is the most common treatment modality of neonatal hyperbilirubinemia. We aimed to evaluate the therapeutic effect of oral Ursodeoxycholic Acid (UDCA) on indirect hyperbilirubinemia in term neonates undergoing phototherapy. MATERIALS AND METHODS: This randomized controlled clinical trial was performed on 106 full-term neonates with jaundice who were admitted to the neonatal ward of 17 Shahrivar Hospital in Rasht, Iran. The neonates were randomly assigned to two groups of intervention (10 mg/kg UDCA+phototherapy) and control (phototherapy alone). Total serum bilirubin (TSB) was measured at the time of admission, during first 12, 24, and 48 hours after admission and at the time of discharge. The duration of hospitalization and side effects were also assessed in both groups. IBM SPSS Statistics for Windows, version 20 was used to analyze the data. RESULTS: Results showed that in the intervention group, 28 (52.8%) of neonates were boys with the mean age of 5.1±1.25 days. While, in the control group 29 (54.7%) of them were boys with the mean age of 5.19±2.26 days. Bilirubin levels in both groups decreased significantly after hospitalization (at 12, 24 and 48 hours) (P <0.001). The mean of bilirubin at 12, 24 and 48 hours in the intervention and control groups were 17.1, 13.2, 10.2 mg / dl and 17.1, 14.2 and 11.3 mg / dl, respectively. At the time of discharge, TSB in the former compared to the latter group was significantly reduced (7.74± 1.39 vs. 8.67±1.35) (P = 0.001). In addition, the duration of hospitalization was considerably shorter in the intervention compared to the control group (P = 0.038) and no side effects were observed. CONCLUSIONS: Administering UDCA plus phototherapy reduced TSB and length of hospital stay with proper safety and efficacy. Therefore, it seems that this combination can be an appropriate treatment modality in neonatal hyperbilirubinemia.

High neutrophil-lymphocyte ratio indicates a worse response to ursodeoxycholic acid in primary biliary cholangitis: a retrospective cohort study.

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by inflammation of the interlobular bile ducts. Ursodeoxycholic acid (UDCA) is the only FDA approved first-line therapy for PBC, but up to 40% of patients with PBC have an incomplete response to UDCA. Neutrophil-to-lymphocyte (NLR) has been used to predict prognosis in various liver diseases. There is limited evidence on the treatment response to UDCA in PBC patients. Our study aimed to evaluate the relationship between NRL and the response to UDCA treatment in PBC patients. METHODS: A total of 257 primary biliary cholangitis (PBC) patients treated with UDCA (13-15 mg/kg/d) were enrolled in this retrospective study. The response to treatment was evaluated based on alkaline phosphatase levels ≤1.67 times the upper limit of the normal value after 12 months of UDCA treatment. Multivariable logistic regression analysis was performed to investigate the association between NLR at baseline and the response to 12 months of UDCA treatment after adjusting for important confounding variables. The stability of the results was evaluated by unadjusted and adjusted models. RESULTS: The results of multiple regression analysis showed that NLR at baseline was positively associated with the nonresponse to UDCA treatment after adjustments for potential confounders (age, sex, BMI, hypertension, arterial plaque, thyroid disease, jaundice, albumin, globulin, total bile acid, ALP, GGT, LDLC, total cholesterol, hemoglobin, and APTT) (OR = 1.370, 95% CI 1.066-1.761). These results reveal that NLR is an independent risk factor for UDCA treatment nonresponse. CONCLUSIONS: Our results suggest that PBC patients with a high NLR had a worse response to UDCA therapy.

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

BACKGROUND AND AIMS: ENHANCE 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 RESULTS: Patients 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. CONCLUSIONS: Patients 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.

[Therapeutic effect of ursodeoxycholic acid-berberine supramolecular nanoparticles on ulcerative colitis based on supramolecular system induced by weak bond].

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.

Efficacy and safety of ursodeoxycholic acid in children with cholestasis: A systematic review and meta-analysis.

OBJECTIVES: Ursodeoxycholic acid (UDCA) is the main therapeutic drug for cholestasis, but its use in children is controversial. We conducted this study to evaluate the efficacy and safety of ursodeoxycholic acid in children with cholestasis. METHODS: We searched Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, WanFang Data and VIP from the establishment of databases to July 2022. Eligible studies included Chinese or English randomized controlled trials (RCTs) comparing the efficacy and safety of no UDCA (placebo or blank control) and UDCA in children with cholestasis. This study had been registered with PROSPERO (CRD42022354052). RESULTS: A total of 32 RCTs proved eligible, which included 2153 patients. The results of meta-analysis showed that UDCA could improve symptoms of children with cholestasis (risk ratio 1.24, 95% CI 1.18 to 1.29; moderate quality of evidence), and serum levels of alanine aminotransferase, total bilirubin, direct bilirubin and total bile acid (low quality of evidence). For some children with specific cholestasis, UDCA could also effectively drop serum levels of aspartate aminotransferase (parenteral nutrition-associated cholestasis) and γ-glutamyl transferase (infantile hepatitis syndrome, parenteral nutrition-associated cholestasis). The most common adverse drug reactions (ADRs) of UDCA in children were gastrointestinal adverse reactions, with an incidence of 10.63% (67/630). There was no significant difference in the incidence of ADRs between UDCA and placebo/blank control groups (risk difference 0.03, 95%CI -0.01 to 0.06; moderate quality of evidence), and among children taking different UDCA doses (P = 0.27). CONCLUSION: The available short-term evidence showed that UDCA was effective and safe for children with cholestasis. Clinicians should use UDCA with caution (start with a low dose) until the long-term effect is further explored in future larger RCTs.

Efficacy and Safety of Bezafibrate Alone or in Combination with Ursodeoxycholic Acid in Primary Biliary Cholangitis: Systematic Review and Meta-Analysis.

BACKGROUND: Bezafibrate (BZF) alone or in combination with ursodeoxycholic acid (UDCA) has been used to slow disease progression in patients with primary biliary cholangitis (PBC). We performed a systematic review and meta-analysis to assess the efficacy and harms of BZF monotherapy or combination therapy. METHODS: We performed a systematic search of PubMed, EMBASE, Cochrane Library, Scopus, ClinicalTrials.gov, and WHO ICTRP from inception until January 2020, for randomized controlled clinical trials assessing BZF + UDCA versus UDCA monotherapy or BZF monotherapy versus UDCA monotherapy in PBC patients. Additionally, we systematically evaluated data on harms using seven observational studies. Pooled effect estimates were calculated for the outcomes of interest. The certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: We identified 7 randomized controlled trials with a total of 279 participants. Comparing BZF + UDCA to UDCA alone, a clinically significant improvement was observed in serum ALP with a mean difference (MD) of - 159.04 U/L (95% CI - 186.45 to - 131.62) and a reduction in gamma-glutamyltransferase (GGT) (MD - 106.94 IU/L; 95% CI - 151.99 to - 61.89), but not in total bilirubin (TB) or IgM levels. A statistically significant reduction in ALP levels was also noticed with BZF monotherapy compared to UDCA monotherapy. The effect of BZF + UDCA versus UDCA on mortality remains unclear. Across 5 observational studies including 106 patients, one death was reported due to advanced liver disease in an incomplete responder getting treatment with BZF + UDCA. Analysis of observational studies demonstrated improvement in pruritus intensity with BZF. CONCLUSIONS: Use of BZF alone or in combination with UDCA improved liver biochemistries in patients with PBC, but its effect on mortality, liver-related complications or quality of life remains unknown.

Therapeutic role of ursodeoxycholic acid in colitis-associated cancer via gut microbiota modulation.

Inflammatory bowel disease (IBD) is a predisposing factor for colitis-associated cancer (CAC). The association between bile acids and the gut microbiota has been demonstrated in colon neoplasia; however, the effect of ursodeoxycholic acid (UDCA) on gut microbiota alteration in development of colitis and CAC is unknown. Our analysis of publicly available datasets demonstrated the association of UDCA treatment and accumulation of Akkermansia. UDCA-mediated alleviation of DSS-induced colitis was microbially dependent. UDCA treatment significantly upregulated Akkermansia colonization in a mouse model. Colonization of Akkermansia was associated with enhancement of the mucus layer upon UDCA treatment as well as activation of bile acid receptors in macrophages. UDCA played a role in CAC prevention and treatment in the AOM-DSS and ApcMin/+-DSS models through downregulation of inflammation and accumulation of Akkermansia. This study suggests that UDCA intervention could reshape intestinal gut homeostasis, facilitating colonization of Akkermansia and preventing and treating colitis and CAC.

Therapeutic effect of ursodeoxycholic acid-berberine supramolecular nanoparticles on ulcerative colitis based on supramolecular system induced by weak bond / 中国中药杂志

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.

Incomplete response to ursodeoxycholic acid in primary biliary cholangitis: criteria, epidemiology, and possible mechanisms.

INTRODUCTION: As a common autoimmune disease with the characteristic of early complication, primary biliary cholangitis (PBC) leads to an increasing number of mortalities among people with end-stage liver disease (ESLD) waiting for liver transplantation. Ursodeoxycholic acid (UDCA) is the only approved first-line medicine for PBC, and a good response to treatment could acquire an ideal prognosis. Patients with poor UDCA response usually have more adverse outcomes and worse survival, therefore, the management of this group become a major consideration. AREAS COVERED: Due to the complexity of race and environment for PBC, different criteria for UDCA response exhibit various predictive performances. Factors affecting UDCA response conditions include gender, age, ethnicity, serum indicators, auto-antibodies, and autoimmune comorbidities, while no agreement has been reached. In this review, we mainly focus on cellular senescence, immune-mediated damage, and vitamin D deficiency as possible mechanisms for UDCA non-responders. EXPERT OPINION: The pathogenesis of PBC has yet to be clarified. Immunology-related mechanisms and therapy targets ought to be the main effort made for further study. Irrespective of the response condition, UDCA is recommended for routine administration in all PBC patients without contraindication. Ongoing clinical trials of second-line and additional therapy exhibit promising prospects.

Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls.

BACKGROUND & AIMS: The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA-treated external controls. METHODS: Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis. RESULTS: During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10-0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12-0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03-1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09-1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21-0.85) including hepatic decompensation. CONCLUSIONS: Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients.

Therapeutic Management of Idiosyncratic Drug-Induced Liver Injury and Acetaminophen Hepatotoxicity in the Paediatric Population: A Systematic Review.

INTRODUCTION: Drug-induced liver injury (DILI) is a rare but serious adverse event that can progress to acute liver failure (ALF). The evidence for treatment of DILI in children is scarce. OBJECTIVE: We aimed to comprehensively review the available literature on the therapies for both acetaminophen overdose (APAP) and idiosyncratic DILI in the paediatric population. METHODS: We included original articles conducted in a paediatric population (< 18 years) in which a therapeutic intervention was described to manage APAP or idiosyncratic DILI. Findings were summarized based on age groups (preterm newborn neonates, term and post-term neonates, infants, children and adolescents). RESULTS: Overall, 25 publications (fifteen case reports, six case series and four retrospective cohort studies) were included, including a total of 140 paediatric DILI cases, from preterm newborn neonates to adolescents. N-acetylcysteine was used to treat 19 APAP cases. N-acetylcysteine (n = 14), ursodeoxycholic acid (n = 3), corticosteroids (n = 31), carnitine (n = 16) and the combination of glycyrrhizin, reduced glutathione, polyene phosphatidylcholine and S-adenosylmethionine (n = 31) were the therapeutic options for treating idiosyncratic DILI. The molecular adsorbent recirculating system was used in the management of either APAP (n = 4) or idiosyncratic DILI (n = 2), while 20 paediatric ALF cases received continuous renal replacement therapy. CONCLUSIONS: This systematic review identified DILI in the paediatric population who have received specific treatment. These interventions appear to be mainly extrapolated from low-quality evidence from the adult population. Thus, there is a need for high-quality studies to test the efficacy of known and novel therapies to treat DILI specifically addressed to the paediatric population. PROSPERO registration number CRD42021214702.

Fenofibrate in primary sclerosing cholangitis; a randomized, double-blind, placebo-controlled trial.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with no medical treatment proven to improve survival and postpone liver transplantation. Previous studies have shown the effectiveness of fibrates in primary biliary cholangitis. The current study prospectively evaluated the effect of fenofibrate on PSC patients. We administered 200 mg of fenofibrate to PSC patients in the intervention arm and a placebo in the control arm once per day for 6 months and evaluated liver biochemistries (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin, and albumin) and the Mayo Risk Score at the start and end of the study. The primary endpoint was defined as a reduction greater than 50% or normalization of ALP levels. Secondary endpoints were an improvement in the Mayo Risk Score and serum bilirubin levels. Thirty patients were included (19 female, 11 male, 40.2 ± 9.2 years old), all under treatment with Ursodeoxycholic acid prior to this study. ALP and ALT levels significantly decreased in the fenofibrate group, by 64.7% (mean difference = 557, p = 0.004, 95% CI = 208.72, 905.27) and 52.78%, (p = 0.006), respectively. The primary endpoint was achieved in 66.7% of patients (10 in 15) in the fenofibrate group versus 20% of patients (3 in 15) in the placebo group (p = 0.009). Other endpoints were not met. As studies have demonstrated lower levels of ALP may improve outcomes for PSC, our study resulted in significantly lower levels of ALP in the fenofibrate group, which could translate into better disease prognosis in PSC.

A multi-centered trial investigating gestational treatment with ursodeoxycholic acid compared to metformin to reduce effects of diabetes mellitus (GUARD): a randomized controlled trial protocol.

BACKGROUND: Each year in the UK, approximately 35,000 women develop gestational diabetes mellitus (GDM). The condition increases the risk of obstetric and neonatal complications for mother and child, including preeclampsia, preterm birth, and large for gestational age babies. Biochemical consequences include maternal hyperglycemia, neonatal hypoglycemia, and dyslipidemia. Metformin is the most commonly used firstline pharmacological treatment. However, there are concerns about its widespread use during pregnancy, due to its limited efficacy and potential safety concerns. Therefore, there is a need for additional therapies that improve both maternal-fetal glucose and lipid metabolism. Ursodeoxycholic acid (UDCA) is not currently used for treatment for GDM. However, it can improve glucose control in type 2 diabetes, and it improves fetal lipid profiles in gestational cholestasis. Consequentially, it is hypothesized that treatment with UDCA for women with GDM may improve both maternal metabolism and neonatal outcomes. The primary outcome of this trial is to assess the efficacy of UDCA compared with metformin to improve glucose levels in women with GDM. METHODS: The trial is a two-armed, open-label, multi-center, randomized controlled trial. Women are eligible if they have been diagnosed with GDM by an oral glucose tolerance test between 24 + 0 and 30 + 6 weeks' gestation, and if they require pharmacological intervention. In total, 158 pregnant women will be recruited across seven NHS Trusts in England and Wales. Women who consent will be recruited and randomized to either metformin or UDCA, which will be taken daily until the birth of their baby. Maternal and neonatal blood samples will be taken to evaluate the impact of the treatments on maternal glucose control, and maternal and neonatal lipid metabolism. Maternal and fetal outcomes will be evaluated, and acceptability of UDCA compared with metformin will be assessed. DISCUSSION: This trial has the potential to identify a potential new treatment for women with GDM. If successful, a future large multi-center trial will be designed to investigate where decisions can be personalized to identify which women will respond more effectively to UDCA than alternatives to improve maternal and baby outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04407650.

Intrahepatic cholestasis of pregnancy: from an obstetrician point of view.

Intrahepatic cholestasis of pregnancy (ICP) is the commonest among the specific dermatoses of pregnancy. The disease is characterised by intense pruritus and specifically by elevated bile acid levels and owing to the rarity of data published in this context, the disease carries a great challenge in both diagnosis and management. The disease is associated with significant maternal as well as perinatal adverse effects, hence, this article aims at improving the knowledge of the women's health carers with the up-to-date and evidence-based, whenever possible, recommendations while managing patients with ICP.

Efficiency of ursodeoxycholic acid for the treatment of nonalcoholic steatohepatitis: A systematic review and meta-analysis.

BACKGROUND: Previous studies have demonstrated that ursodeoxycholic acid (UDCA) possesses anti-inflammatory, antioxidant, and anti-fibrotic properties, and it may reduce the degree of liver damage caused by nonalcoholic steatohepatitis (NASH). However, the effectiveness of UDCA in improving liver function and histology in cases of NASH remains unclear. Therefore, we performed a meta-analysis to assess the efficacy of UDCA in the treatment of NASH. METHODS: PubMed, Web of Science, Embase, Cochrane, and other databases were searched for randomized controlled trials (RCTs) published before 1 January 2022, in which UDCA was used to treat patients with NASH. RESULTS: A total of 8 studies with 655 participantsmet the criteria for inclusion in this meta-analysis. The forest plot displayed that UDCA treatment significantly reduced blood concentrations of alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT). However, the pooled effect size results did not suggest any significant effect of UDCA on anthropometric characteristics or hepatic histology. CONCLUSION: UDCA therapy can effectively reduce serum levels of ALT and GGT in patients with NASH but has no significant effects on physical characteristics or liver histology. Further large-scale and dose-response clinical studies are needed to evaluate the clinical potential of UDCA in treating NASH.