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.).

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.).

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.

The choleretic role of tauroursodeoxycholic acid exacerbates alpha-naphthylisothiocyanate induced cholestatic liver injury through the FXR/BSEP pathway.

The aim of this study was to determine the effect of tauroursodeoxycholic acid (TUDCA) on the alpha-naphthylisothiocyanate (ANIT)-induced model of cholestasis in mice. Wild-type and farnesoid X receptor (FXR)-deficient (Fxr-/- ) mice were used to generate cholestasis models by gavage with ANIT. Obeticholic acid (OCA) was used as a positive control. In wild-type mice, treatment with TUDCA for 7 days resulted in a dramatic increase in serum levels of alanine aminotransferase (ALT), with aggravation of bile infarcts and hepatocyte necrosis with ANIT-induction. TUDCA activated FXR to upregulate the expression of bile salt export pump (BSEP), increasing bile acids (BAs)-dependent bile flow, but aggravating cholestatic liver injury when bile ducts were obstructed resulting from ANIT. In contrast, TUDCA improved the liver pathology and decreased serum ALT and alkaline phosphatase (ALP) levels in ANIT-induced Fxr-/- mice. Furthermore, TUDCA inhibited the expression of cleaved caspase-3 and reduced the area of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining in the model mice. TUDCA also upregulated anion exchanger 2 (AE2) protein expression, protecting cholangiocytes against excessive toxic BAs. Our results showed that TUDCA aggravated cholestatic liver injury via the FXR/BSEP pathway when bile ducts were obstructed, although TUDCA inhibited apoptotic activity and protected cholangiocytes against excessive toxic BAs.

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.

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.

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.

Simplified 6-month prediction scores for primary biliary cholangitis patients treated with ursodeoxycholic acid.

OBJECTIVES: To develop a prognostic score evaluating treatment response at 6 months after ursodeoxycholic acid (UDCA) initiation in primary biliary cholangitis (PBC) patients. METHODS: Adult PBC patients who were newly prescribed UDCA at our institution (n = 292) were included. Significant determinants of liver-related adverse events in the multivariable Cox model were used for score development, weighted by ß-coefficients. Discrimination ability was assessed using Harrell's C-statistic. The performance of our model was compared to the previous models. RESULTS: Our model included the following variables evaluated at 6 months: (1) alkaline phosphatase decline of less than 50% from baseline and >upper limit normal (ULN) (2 points); (2) bilirubin >ULN (2 points); (3) albumin

Ursodeoxycholic acid and liver disease associated with cystic fibrosis: A multicenter cohort study.

BACKGROUND: The efficacy and safety of ursodeoxycholic acid (UDCA) for the treatment of liver disease associated with cystic fibrosis (CF) are under discussion, and clinical practice varies among centers. The study aimed at evaluating if the incidence of severe liver disease differs between CF centers routinely prescribing or not prescribing UDCA. METHODS: We carried out a retrospective multicenter cohort study including 1591 CF patients (1192 patients from UDCA-prescribing centers and 399 from non-prescribing centers) born between 1990 and 2007 and followed from birth up to 31 December 2016. We computed the crude cumulative incidence (CCI) of portal hypertension (PH) at the age of 20 years in the two groups and estimated the subdistribution hazard ratio (HR) through a Fine and Gray model. RESULTS: Over the observation period, 114 patients developed PH: 90 (7.6%) patients followed-up in UDCA prescribing centers and 24 (6.0%) in non-prescribing centers. The CCI of PH at 20 years was 10.1% (95% CI: 7.9-12.3) in UDCA-prescribing and 7.7% (95% CI: 4.6-10.7) in non-prescribing centers. The HR among patients followed in prescribing centers indicated no significant difference in the rate of PH either in the unadjusted model (HR: 1.21, 95% CI: 0.69-2.11) or in the model adjusted for pancreatic insufficiency (HR: 1.28, 95% CI: 0.77-2.12). CONCLUSIONS: CF patients followed-up in UDCA prescribing centers did not show a lower incidence of PH as compared to those followed in centers not prescribing UDCA. These results question the utility of UDCA in reducing the occurrence of severe liver disease in CF.

A randomized controlled trial comparing the effects of Vitamin E, Ursodeoxycholic acid and Pentoxifylline on Egyptian non-alcoholic steatohepatitis patients.

OBJECTIVE: Currently, no NASH-specific therapies are approved by the US Food and Drug Administration. This study aimed to compare the clinical effect of vitamin E (Vit. E), Ursodeoxycholic Acid (UDCA) and pentoxifylline (PTX) on Egyptian patients with NASH with exploration of their possible roles on inflammatory cytokines and chemokines mainly Interleukin 6 (IL6) and Monocyte Chemoattractant Protein-1 (CCL2/MCP-1). PATIENTS AND METHODS: We conducted a 3-month, randomized, single-blind study in 102 Egyptian NASH patients who were divided into three groups; group 1 received Vit. E 400 mg twice a day, group 2 received UDCA 250 mg twice a day and group 3 received PTX 400 mg twice daily. Liver aminotransferases (AST, ALT), IL6, CCL2/MCP-1, albumin, bilirubin, and lipid panel were measured both before and after intervention intake. RESULTS: A significant decrease was found in liver aminotransferases, serum cytokine and chemokine in participants after Vit. E, UDCA or PTX intake. Compared to the UDCA and PTX groups, liver aminotransferases, serum cytokine and chemokine showed a more statistically significant reduction after Vit. E administration (50%, 43%, 57% and 55% for ALT, AST, IL6 and CCL2/MCP-1, respectively). In contrast, other biochemical tests showed non-significant change after any drug intake. None of the tested drugs showed significant safety issues in this population. CONCLUSIONS: Treatment with Vit. E, UDCA and PTX was both safe and effective in improving hepatic aminotransferases and inflammatory markers in Egyptian NASH patients. The superior effect of Vit. E compared to UDCA and PTX may suggest that oxidative stress plays a key role in disease progression of NASH patients. Moreover, IL6 and CCL2/MCP-1 may be used with or without ALT for treatment evaluation of NASH people.

Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery (UPGRADE): a multicentre, double-blind, randomised, placebo-controlled superiority trial.

BACKGROUND: Rapid weight loss is a major risk factor for the formation of cholesterol gallstones. Consequently, patients with morbid obesity undergoing bariatric surgery frequently develop symptomatic gallstone disease. This trial assessed the efficacy of ursodeoxycholic acid versus placebo for the prevention of symptomatic gallstone disease after bariatric surgery. METHODS: This multicentre, double-blind, randomised, placebo-controlled superiority trial enrolled patients with an intact gallbladder scheduled for laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy in three hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module to receive 900 mg ursodeoxycholic acid daily for 6 months or matched placebo. Randomisation was stratified by the presence of asymptomatic gallstones at baseline and type of surgery. Patients, clinicians, and study staff were masked to treatment allocation. The primary endpoint was symptomatic gallstone disease within 24 months, assessed in the modified intention-to-treat population (all randomly assigned eligible patients with any post-randomisation measurement). Prespecified subgroup analyses were done based on the stratification groups. Safety was assessed in all patients who took at least one dose of the study drug. This trial is registered with the Netherlands Trial Register, NL5954. FINDINGS: Between Jan 11, 2017, and Oct 22, 2018, 985 patients were randomly assigned to receive either ursodeoxycholic acid (n=492) or placebo (n=493). 967 patients were included in the modified intention-to-treat population, of whom 959 had data available for primary endpoint assessment. 189 (20%) patients had asymptomatic gallstones at baseline and 78 (8%) received a sleeve gastrectomy. Symptomatic gallstone disease occurred in 31 (6·5%) of 475 patients in the ursodeoxycholic acid group and in 47 (9·7%) of 484 patients in the placebo group (relative risk 0·67, 95% CI 0·43-1·04, p=0·071). Logistic regression showed a significant interaction between ursodeoxycholic acid and the presence of asymptomatic gallstones at baseline (p=0·046), with an effect of ursodeoxycholic acid in patients without (0·47, 0·27-0·84, p=0·0081), and no effect in patients with asymptomatic gallstones at baseline (1·22, 0·61-2·47, p=0·57). The effect was stronger in patients without gallstones at baseline undergoing RYGB (0·37, 0·20-0·71, p=0·0016), whereas the subgroup of patients undergoing sleeve gastrectomy was too small to draw clear conclusions. Adverse events were rare. In the ursodeoxycholic acid group, diarrhoea occurred in four (0·9%) of 444 patients and skin rash in two (0·5%) patients. In the placebo group, diarrhoea occurred in two (0·4%) of 453 patients and skin rash in two (0·4%) patients. The total number of serious adverse events did not significantly differ between the trial groups (75 [17%] in 444 patients in the ursodeoxycholic acid group and 102 [23%] in 453 patients in the placebo group). The most common serious adverse events were abdominal pain and internal hernia. No serious adverse event was attributed to the study drug. INTERPRETATION: Ursodeoxycholic acid prophylaxis did not significantly reduce the occurrence of symptomatic gallstone disease in all patients after bariatric surgery. In patients without gallstones before RYGB surgery, ursodeoxycholic acid treatment reduced the occurrence of symptomatic gallstone disease compared with placebo. Further research is needed to assess the efficacy of ursodeoxycholic acid after sleeve gastrectomy. FUNDING: The Netherlands Organization for Health Research and Development, Zambon Netherlands BV, Foundation for Clinical Research of the Slotervaart Hospital, the Spaarne Gasthuis Academy, and Amsterdam Gastroenterology Endocrinology Metabolism.

Safety of fibrates in cholestatic liver diseases.

BACKGROUND AND AIM: Off-label use of fibrates in patients with cholestatic liver diseases results in improved biochemical parameters and pruritus; however, their safety in this population has been a concern. This study summarizes safety data for fibrates when used for treatment of cholestatic liver diseases. METHODS: A systematic review of published studies evaluating the use of fibrates for treatment of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) was performed. Electronic databases were searched up to December 2019 for published studies evaluating treatment outcomes associated to fibrates for these 2 diseases. RESULTS: A total of 37 studies were identified, including 31 for PBC and 6 for PSC, with a total of 1107 unique patients treated with fibrates ± ursodeoxycholic acid (UDCA). Most studies evaluated fenofibrate and bezafibrate, and only 1 study evaluated pemafibrate. There were no studies evaluating gemfibrozil or clofibrate. The most commonly reported adverse events (AEs) were gastrointestinal and musculoskeletal. Elevations of aminotransferases and serum creatinine were reported more commonly in patients treated with UDCA plus fibrates versus UDCA monotherapy. CONCLUSIONS: Fibrates appear to be safe and well tolerated in patients with PBC, with a low frequency of AEs. There are scarce data about the safety of these agents for treatment of PSC.

Efficacy and safety of injectable deoxycholic acid for submental fat reduction: a systematic review and meta-analysis of randomized controlled trials.

Objective: To investigate the efficacy and safety of deoxycholic acid (DOC) for SMF reduction.Methods: We conducted a systematic review and meta-analysis of randomized controlled trials. We searched PubMed/MEDLINE, EMBASE, and Cochrane databases until June 2020. Efficacy outcomes: Clinician-Reported Submental Fat Rating Scale; Patient-Reported Submental Fat Rating Scale; Subject Self-Rating Scale; SMF reduction measured using caliper and resonance magnetic imaging; Early therapeutic success. Safety outcomes: Withdrawals due to adverse events (AEs), Rates of AEs, Skin laxity.Results: Five studies were included, comprising 1,838 participants. DOC (1 or 2 mg/cm2) had greater improvement in all efficacy measures compared to placebo. No differences were seen between both doses of DOC. Withdrawals due to AEs were low with 1 and 2 mg/cm2 of DOC (6.8% vs. 9.9%, respectively), and there was no difference between the two doses (p = 0.22). AEs were usually associated with the injection site, were predominantly transient, and commonly resolved within the treatment session interval. Injection site pain, hematoma, anesthesia/numbness, erythema, and swelling/edema were the most common AEs. There was no difference in their prevalence between both doses of DOC.Conclusions: DOC is effective and safe for SMF reduction with no differences between doses of 1 and 2 mg/cm2.

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a secondary analysis of the PITCHES trial.

OBJECTIVE: To evaluate whether a particular group of women with intrahepatic cholestasis of pregnancy (ICP), based on their presenting characteristics, would benefit from treatment with ursodeoxycholic acid (UDCA). DESIGN: Secondary analysis of the PITCHES trial (ISRCTN91918806). SETTING: United Kingdom. POPULATION OR SAMPLE: 527 women with ICP. METHODS: Subgroup analyses were performed to determine whether baseline bile acid concentrations or baseline itch scores moderated a woman's response to treatment with UDCA. MAIN OUTCOME MEASURES: Bile acid concentration and itch score. RESULTS: In women with baseline bile acid concentrations less than 40 µmol/l, treatment with UDCA resulted in increased post-randomisation bile acid concentrations (geometric mean ratio 1.19, 95% CI 1.00-1.41, P = 0.048). A test of interaction showed no significance (P = 0.647). A small, clinically insignificant difference was seen in itch response in women with a high baseline itch score (-6.0 mm, 95% CI -11.80 to -0.21, P = 0.042), with a test of interaction not showing significance (P = 0.640). Further subgroup analyses showed no significance. Across all women there was a weak relationship between bile acid concentrations and itch severity. CONCLUSIONS: There was no subgroup of women with ICP in whom a beneficial effect of treatment with UDCA on bile acid concentration or itch score could be identified. This confirms that its routine use in women with this condition for improvement of bile acid concentration or itch score should be reconsidered. TWEETABLE ABSTRACT: PITCHES: No group of women with ICP has been found in whom UDCA reduces bile acid concentrations or pruritus.

Effectiveness and safety of obeticholic acid in a Southern European multicentre cohort of patients with primary biliary cholangitis and suboptimal response to ursodeoxycholic acid.

BACKGROUND: Obeticholic acid (OCA) was recently approved as the only on-label alternative for patients with primary biliary cholangitis (PBC) with intolerance or suboptimal response to ursodeoxycholic acid (UDCA). However, few data are available outside clinical trials. AIM: To assess the effectiveness and safety of OCA in a real-world cohort of patients with non-effective UDCA therapy. METHODS: Open-label, prospective, real-world, multicentre study, enrolling consecutive patients who did not meet Paris II criteria, from 18 institutions in Spain and Portugal. Effectiveness was assessed by the changes in GLOBE and UK-PBC scores from baseline. POISE and Paris II criteria were evaluated after 12 months of OCA . Liver fibrosis was evaluated by FIB-4 and AST to platelet ratio index (APRI). RESULTS: One hundred and twenty patients were eligible, median time since PBC diagnosis 9.3 (4.0-13.8) years, 21.7% had cirrhosis, and 26.7% received had previous or concomitant treatment with fibrates. Seventy-eight patients completed at least 1 year of OCA. The Globe-PBC score decreased to 0.17 (95% CI 0.05 to 0.28; P = 0.005) and the UK-PBC score decreased to 0.81 (95% CI -0.19 to 1.80; P = 0.11). There was a significant decrease in alkaline phosphatase of 81.3 U/L (95% CI 42.5 to 120; P < 0.001), ALT 22.1 U/L (95% CI 10.4 to 33.8; P < 0.001) and bilirubin 0.12 mg/dL (95% CI 0 to 0.24; P = 0.044). FIB-4 and APRI remained stable. According to the POISE criteria, 29.5% (23 out of 78) achieved response. The adverse events rate was 35%; 11.67% discontinued (8.3% due to pruritus). CONCLUSIONS: This study supports data from phase III trials with significant improvement of PBC-Globe continuous prognostic marker score among OCA-treated patients with good tolerability.

A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC. METHODS: AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3.0 mg, or OCA 5-10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety. RESULTS: The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5-3.0 mg (n = 25), and OCA 5-10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo (least-square [LS] mean difference = -83.4 [SE = 40.3] U/L; 95% CI -164.28 to -2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5-3.0 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L; 95% CI -162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5-3.0 mg 60%; OCA 5-10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged. CONCLUSIONS: Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event. REGISTRATION: ClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38. LAY SUMMARY: Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.

Improvement in Jowl Fat following ATX-101 Treatment: Results from a Single-Site Study.

BACKGROUND: Jowl fat overhang can reduce jawline definition. The most common treatment to reduce jowl fat is liposuction. ATX-101 (deoxycholic acid injection), a minimally invasive treatment approved for submental fat reduction, may also be an effective treatment for jowl fat. The current study evaluated the efficacy and safety of ATX-101 treatment for reducing jowl fat. METHODS: In this prospective single-site study, 66 adults were treated for excess jowl fat with ATX-101 (area-adjusted dose: 2 mg/cm). Eligible patients had pinchable fat on the jawline and relatively minimal skin laxity in the jowl. Depending on the size of the treatment area, ATX-101 injections of 0.2 ml spaced 1.0 cm apart or 0.1 ml spaced 0.50 to 0.75 cm apart were administered. Improvement in jowl appearance was assessed 6 months or more after the last treatment in person by the clinician. Improvement was also assessed by the patient and two independent plastic surgeons using blinded before/after treatment photographs. Safety was evaluated via adverse events. RESULTS: The mean number of ATX-101 treatments received was 1.8, with a mean injection volume of 0.8 ml per treatment per jowl. The majority of patients (98 percent) experienced an improvement in jowl appearance. Common adverse events were injection-site edema, numbness, tenderness, and bruising. Injection-site marginal mandibular nerve paresis and alopecia were experienced by three patients each; all events resolved without sequelae. CONCLUSIONS: ATX-101 effectively reduced jowl fat and was well tolerated in this small cohort. Care should be taken when injecting ATX-101 into jowl fat to avoid underlying anatomic structures such as the marginal mandibular nerve. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Efficacy and safety of ATX-101 as a treatment for submental fullness: A retrospective analysis of two aesthetic practices.

BACKGROUND: Submental fullness (SMF) is a common cosmetic concern that can have negative impact on one's self-esteem. ATX-101 has shown promise as a minimally invasive treatment for SMF correction in clinical trials. AIMS: To assess the safety and efficacy of ATX-101 for SMF correction. PATIENTS/METHODS: This was a retrospective review of 90 patients from two aesthetic practices who received ATX-101 injections for SMF (January 2016-August 2017). There were no exclusion criteria. Initial SMF severity was assigned using standardized photographs and a validated 5-point scale. Eighty one patients subsequently answered questionnaires regarding improvement, satisfaction, and adverse effects. Degree of SMF correction was also evaluated by the investigator and a blinded reviewer. RESULTS: Eighty one patients (mean initial submental fullness severity 1.6) received a mean of 1.84 ATX-101 treatment sessions using a median of 2.0 vials per treatment (mean 3.02, range 1-9). Mean Physician Global Aesthetic Improvement Scale scores were 2.73 and 2.25, after the first and second treatments, respectively (P = .04). Mean Subject Goal Aesthetic Improvement Scale scores were 2.7 and 2.25 after the first and second treatments, respectively (P = .01). Sixty-seven percentage of patients were "somewhat" or "very" satisfied. Adverse events were transient and limited to the treatment area. CONCLUSION: Patients achieved progressive improvement in SMF after the 1st and 2nd treatments, as judged by patients themselves, investigators, and blinded evaluators. These results of SMF correction suggest that significant benefit can be obtained with proper dosing at the initial visit. These data support the efficacy and safety profile of ATX-101 use for SMF correction.

Ursodeoxycholic acid in pregnancy?

The case of a 34-year-old woman with primary biliary cholangitis (PBC) before, during and after pregnancy is described. The use of ursodeoxycholic acid (UDCA) during and after pregnancy is discussed. UDCA has not been approved by the drug regulatory authorities as a pregnancy-safe drug; therefore, the reluctance of clinicians to prescribe UDCA during pregnancy is understandable. This Grand Round aims to provide a detailed analysis of the current evidence, safety data and clinical experience with UDCA (and alternative drugs) during pregnancy and lactation. Based on this analysis, advice for clinicians regarding the use of UDCA during pregnancy and lactation is given.