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In a trial involving patients with primary biliary cholangitis, treatment with elafibranor, a dual PPAR-α and PPAR-δ agonist, led to greater improvements in biochemical indicators of cholestasis than placebo.

Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806. Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62–1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment. Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered. National Institute for Health Research Efficacy and Mechanism Evaluation Programme.

Cholestatic liver diseases are characterized by impaired bile flow, leading to inflammation and progression to cirrhosis and liver failure. Endoglin (ENG), a TGF-β co-receptor, regulates SMAD-dependent signalling and endothelial function. Carotuximab (TRC105) is an anti-ENG monoclonal antibody that binds to ENG. We hypothesized that treatment with TRC105 could prevent the upregulation of inflammatory biomarkers reflecting the activation of liver sinusoidal endothelial cells (LSECs) and hepatic inflammation during the progression of intrahepatic cholestasis (IC) in vivo by modulating the ENG and SMAD signaling pathways. IC was induced in male C57BL/6J mice by feeding with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 4 weeks. 18 mice were divided into three groups: a control group (chow diet), an IC group (DDC diet), and a rescue group (DDC diet + TRC105). The rescue group received TRC105 (15 mg/kg) twice weekly throughout the 4 weeks. We observed an inflammation in LSECs and the liver in IC animals characterized by overexpression of p65 NF-κB, ICAM-1, VCAM-1, endothelin-1, Galectin-3, CD11b, Ccl2, Ly6c, Il-1β, and Tnf-α, together with reduced expression of ENG and p-eNOS. TRC105 treatment prevented the downregulation of ENG and p-eNOS, the overexpression of inflammatory biomarkers, and the imbalance of SMAD signalling. We demonstrate for the first time that TRC105 prevents the upregulation of inflammatory biomarkers reflecting LSECs activation and hepatic inflammation, modulates ENG expression, and prevents the imbalance of the SMADs signalling during IC. These findings position ENG as a promising pharmacological target for alleviating inflammation in cholestatic liver disease, thereby opening a new avenue for translational research. Graphical abstract

Preliminary uncontrolled studies of photodynamic therapy (PDT) of bile duct cancer (BDC) have shown astonishingly good results in the reduction of cholestasis, improvement of life quality, and potential improvement of survival time. Therefore, we investigated the influence of PDT on survival time in advanced BDC in a randomized controlled study. Thirty-two patients with nonresectable BDC were randomized. In the PDT group 48 h after intravenous application of 2 mg/kg body weight of Photosan-3((R)), light activation was performed. In the control group, patients were treated with endoprostheses but no PDT. PDT group and the control group were comparable due to age, gender, performance status, bilirubin level, and BDC stage (Bismuth classification). The median survival time after randomization was 7 months for the control group and 21 months for the PDT group (p= 0.0109). In half of the initially percutaneously treated patients, we could change from percutaneous to transpapillary drainage after PDT. Four patients showed infectious complications after PDT versus one patient in the control group. PDT is minimally invasive but shows a considerable postinterventional cholangitis rate. PDT has the potential to result in a changeover of current palliative treatment of BDC.

•The efficacy of maralixibat versus odevixibat for children with progressive familial intrahepatic cholestasis was indirectly compared.•Maralixibat was associated with a significantly greater proportion of serum bile acid responders.•Maralixibat was associated with a greater change from baseline in serum bile acid concentration.•Maralixibat was associated with a greater change from baseline in total bilirubin.•Maralixibat and odevixibat had similar safety profiles, although maralixibat typically had milder AEs. Recent clinical trials provide evidence of the efficacy and safety of 2 ileal bile acid transporter inhibitors, maralixibat and odevixibat, for the treatment of children with progressive familial intrahepatic cholestasis (PFIC). However, no head-to-head trial currently exists assessing the efficacy of these 2 treatments. The objective of this study was to generate estimates of comparative efficacy and safety between maralixibat and odevixibat to inform optimal practices for the treatment of children with PFIC. Two phase 3 randomized placebo-controlled trials, MARCH-PFIC (maralixibat: n = 16; placebo: n = 19) and PEDFIC-1 (odevixibat: n = 42; placebo: n = 20), were included in an indirect treatment comparison (ITC) anchored by the placebo arms of each trial. Using patient-level data from MARCH-PFIC and published aggregate data from PEDFIC-1, we generated estimates of comparative efficacy for endpoints that were consistent between trials, including the proportion of patients achieving a serum bile acid (sBA) response and change from baseline in sBA concentration. Comparisons of the proportion of sBA responders indicated that maralixibat was significantly more efficacious than odevixibat (120 µg/kg), with an estimated treatment difference of 32.3% (95% CI, 1.1% to 63.4%, P = 0.043). In addition, point estimates for change from baseline in sBA concentration and total bilirubin trended in favor of maralixibat. These findings were robust to adjustments for imbalances in patient demographic characteristics between trials. No statistically significant differences were observed for alanine transaminase, aspartate transaminase, or gamma-glutamyl transferase. The safety profiles of maralixibat and odevixibat were comparable, although adverse events associated with maralixibat were typically milder than those with odevixibat (mild: 75% vs 45%; moderate: 25% vs 31%; severe: 0% vs 7%). These findings suggest that maralixibat provides additional clinical benefit for children with PFIC compared with odevixibat in terms of increasing the proportion of sBA responders. Further studies are needed to compare the ability of maralixibat and odevixibat to reduce pruritus and improve long-term outcomes, including patients’ quality of life.

Background Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. Methods We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. Discussion Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing “standard” UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. Trial identifiers Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018–004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

Background Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy and presents with maternal pruritus, raised concentrations of serum bile acids and abnormal liver function tests. ICP is associated with increased rates of spontaneous and iatrogenic preterm labour, fetal hypoxia, meconium-stained amniotic fluid and intrauterine death. Some clinicians treat ICP with ursodeoxycholic acid (UDCA) to improve maternal pruritus and biochemical abnormalities. However, there are currently no data to support the use of UDCA to improve pregnancy outcome as none of the trials performed to date have been powered to address this question. Methods The PITCHES trial is a triple-masked, placebo-controlled randomised trial, to evaluate UDCA versus placebo in women with ICP between 20 + 0 to 40 + 6 weeks’ gestation. The primary objective of the trial is to determine if UDCA treatment of women with ICP between 20 + 0 and 40 + 6 weeks’ gestation reduces the primary perinatal outcome: a composite of perinatal death (as defined by in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (less than 37 weeks’ gestation) or neonatal unit admission for at least 4 h (from infant delivery until hospital discharge). The secondary objectives of the trial are (1) to investigate the effect of UDCA on other short-term outcomes for both mother and infant and (2) to assess the impact of UDCA on health care resource use, in terms of the total number of nights for mother and infant, together with level of care. Discussion Current practice in the UK at the time of trial commencement for the treatment of ICP is inconsistent, with some units routinely prescribing UDCA, others prescribing very little and the remainder offering it variably. Our previous pilot trial of UDCA in women with ICP demonstrated that the trial would be feasible, and the research question remains active and unanswered. Results are highly likely to influence clinical practice, through direct management and impact on national and international guidelines. Trial registration ISRCTN registry, ID: ISRCTN91918806 . Prospectively registered on 27 August 2015.

Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) are ligand-activated transcriptional regulators of key metabolic processes including hepatic lipid and glucose metabolism, energy expenditure and bile acid (BA) homoeostasis, as well as inflammation, fibrosis and cellular proliferation. Dysregulation of these processes contributes to the pathogenesis and progression of cholestatic as well as fatty liver disease, placing NRs at the forefront of novel therapeutic approaches. This includes BA and fatty acid activated NRs such as farnesoid-X receptor (FXR) and peroxisome proliferator-activated receptors, respectively, for which high affinity therapeutic ligands targeting specific or multiple isoforms have been developed. Moreover, novel liver-specific ligands for thyroid hormone receptor beta 1 complete the spectrum of currently available NR-targeted drugs. Apart from FXR ligands, BA signalling can be targeted by mimetics of FXR-activated fibroblast growth factor 19, modulation of their enterohepatic circulation through uptake inhibitors in hepatocytes and enterocytes, as well as novel BA derivatives undergoing cholehepatic shunting (instead of enterohepatic circulation). Other therapeutic approaches more directly target inflammation and/or fibrosis as critical events of disease progression. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of these complex and multifactorial disorders.

Odevixibat (Bylvay™) is a small molecule inhibitor of the ileal bile acid transporter being developed by Albireo Pharma, Inc. for the treatment of various cholestatic diseases, including progressive familial intrahepatic cholestasis (PFIC). In July 2021, odevixibat received its first approval in the EU for the treatment of PFIC in patients aged ≥ 6 months, followed shortly by its approval in the USA for the treatment of pruritus in patients aged ≥ 3 months with PFIC. Odevixibat is also in clinical development for the treatment of other cholestatic diseases, including Alagille syndrome and biliary atresia, in various countries. This article summarizes the milestones in the development of odevixibat leading to this first approval for PFIC.

Objectives To test whether ursodeoxycholic acid reduces pruritus in women with intrahepatic cholestasis of pregnancy, whether early term delivery does not increase the incidence of caesarean section, and the feasibility of recruiting women with intrahepatic cholestasis of pregnancy to trials of these interventions.Design First phase of a semifactorial randomised controlled trial.Setting Nine consultant led maternity units, United Kingdom.Participants 125 women with intrahepatic cholestasis of pregnancy (pruritus and raised levels of serum bile acids) or pruritus and raised alanine transaminase levels (>100 IU/L) recruited after 24 weeks’ gestation and followed until delivery. 56 women were randomised to ursodeoxycholic acid, 55 to placebo, 30 to early term delivery, and 32 to expectant management.Interventions Ursodeoxycholic acid 500 mg twice daily or placebo increased as necessary for symptomatic or biochemical improvement until delivery; early term delivery (induction or delivery started between 37+0 and 37+6) or expectant management (spontaneous labour awaited until 40 weeks’ gestation or caesarean section undertaken by normal obstetric guidelines, usually after 39 weeks’ gestation).Main outcome measures The primary outcome for ursodeoxycholic acid was maternal itch (arithmetic mean of measures (100 mm visual analogue scale) of worst itch in past 24 hours) and for the timing of delivery was caesarean section. Secondary outcomes were other maternal and perinatal outcomes and recruitment rates.Results Ursodeoxycholic acid reduced itching by −16 mm (95% confidence interval −27 mm to −6 mm), less than the 30 mm difference prespecified by clinicians and women as clinically meaningful. 32% (14/44) of women randomised to ursodeoxycholic acid experienced a reduction in worst itching by at least 30 mm compared with 16% (6/37) randomised to placebo. The difference of 16% (95% confidence interval −3 to 34); this would represent a number needed to treat of 6, but it failed to reach significance. Early term delivery did not increase caesarean sections (7/30 (23%) in the early term delivery group versus 11/32 (33%) in the expectant management group (relative risk 0.70, 95% confidence interval 0.31 to 1.57). No serious harms were noted in either trial. 22% (73/325) of eligible women participated in the drug trial and 19% (39/209) in the timing of delivery trial; both groups had a similar spectrum of disease severity to non-participants.Conclusions Ursodeoxycholic acid significantly reduces pruritus, but the size of the benefit may be too small for most doctors to recommend it, or for most women to want to take it. Women are, however, likely to differ in whether they consider the benefit to be worthwhile. Planned early term delivery seems not to increase incidence of caesarean section, although a small increase cannot be excluded. A trial to test whether ursodeoxycholic acid reduces adverse perinatal outcomes would have to be large, but is feasible. A trial to test the effect of early term delivery on adverse fetal outcomes would have to be significantly larger and may not be feasible.Trial registration Current Controlled Trials ISRCTN37730443.