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Primary biliary cholangitis as a roadmap for the development of novel treatments for cholestatic liver diseases

Published:October 19, 2022DOI:https://doi.org/10.1016/j.jhep.2022.10.007

      Summary

      The discovery of nuclear receptors and transporters has contributed to the development of new drugs for the treatment of cholestatic liver diseases. Particular progress has been made in the development of second-line therapies for PBC. These new drugs can be separated into compounds primarily targeting cholestasis, molecules targeting fibrogenesis and molecules with immune-mediated action. Finally, drugs aimed at symptom relief (pruritus and fatigue) are also under investigation. Obeticholic acid is currently the only approved second-line therapy for PBC. Drugs in the late phase of clinical development include peroxisome proliferator-activated receptor agonists, norursodeoxycholic acid and NADPH oxidase 1/4 inhibitors.

      Keywords

      Abbreviations:

      PBC (primary biliary cholangitis), PSC (primary sclerosing cholangitis), FXR (farnesoid X receptor), OCA (obeticholic acid), PPAR (peroxisome proliferator -activated receptors)

      Introduction

      Among the wide spectrum of chronic cholestatic liver diseases, primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most frequent. Although these immune-mediated cholestatic liver diseases are rare and the number of liver transplants for PBC has fallen in recent years, cholestatic liver disease still represents a major indication for liver transplantation, which points to the need for more effective medical therapies.
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      Despite shortcomings in our current understanding of the pathogenesis of these diseases, several genetic and environmental factors have recently been identified both for PBC and PSC.
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      One of the reasons for the remarkable progress in the development of new drugs for PBC is the availability of well-validated risk scores and endpoints that are utilised in clinical trials. For instance, serum alkaline phosphatase (ALP) and bilirubin have been extensively validated for this purpose in large international cohorts of patients. A continuous relationship exists between ALP/bilirubin and long-term outcomes.
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      Since most studies have used the same inclusion and exclusion criteria as well as endpoints (POISE criteria), it is also easier to compare the effect of different drugs. The primary end point in the POISE trial was an ALP level of <1.67x the upper limit of normal (ULN) range, with a reduction of at least 15% from baseline, and a normal total bilirubin level.
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      However, as discussed later in this review, we probably need to move to more stringent composite biochemical endpoints in trials. The most recent tools to select patients in need of second-line therapy are the Globe and the UK-PBC scores, which are continuous scoring systems.
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      All of these scores (GLOBE, UK-PBC and also the Mayo risk score) demonstrated comparable discriminative performance with regards to liver transplantation or death, as well as high accuracy.
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      For decades liver biopsy was the gold standard for diagnosis, and to assess disease stage and the effect of treatment. However, a biopsy is no longer required for these purposes.
      EASL clinical practice guidelines
      The diagnosis and management of patients with primary biliary cholangitis.
      Indeed, PBC is the first cholestatic liver disease in which the value of elastography has been extensively investigated. Liver stiffness measurement by vibration-controlled transient elastography appeared to be a major predictor of PBC outcome that should be combined with biochemical response, as surrogate composite endpoints, for future clinical trials.
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      Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis.
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      Liver stiffness measured by either magnetic resonance or transient elastography is associated with liver fibrosis and is an independent predictor of outcomes among patients with primary biliary cholangitis.
      Unfortunately, the situation is different in PSC. There is still no approved medical therapy and the endpoints for clinical trials are still under debate. However, irrespective of the drug used in PSC, survival is better in patients with an ALP value <1.5x ULN.
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      An expert panel recently concluded that no sufficiently validated endpoints have been defined for use in clinical trials for PSC. Histology, ALP and elastography are the most promising surrogate endpoints but require further validation and combining multiple endpoints seems advisable.
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      • Individuals with PBC with an incomplete biochemical response to ursodeoxycholic acid are at risk of major complications within 10 years.
      • One of the reasons for the remarkable progress in the successful development of new drugs for PBC is the availability of well-validated risk scores and endpoints for clinical trials, which unfortunately are not yet well validated for PSC.
      • Most drugs in development exert an anti-cholestatic effect. Preliminary data suggest that drugs with an antifibrotic profile might also be effective. Drugs targeting the underlying immune-mediated pathogenesis of cholestatic diseases have generated disappointing results and will most likely only be effective in the early stages of the disease.
      • The most promising drugs in later stage development for PBC are PPAR agonists which also have a beneficial effect on pruritus.
      • Combinations of bezafibrates and obeticholic acid, in addition to ursodesoxycholic acid, enable complete normalisation of the markers of cholestasis in a substantial number of patients.

      New therapeutic targets for cholestatic liver diseases (preclinical data)

      Further progress in the treatment of PBC has occurred since the discovery of nuclear (hormone) receptors. The nuclear receptor superfamily is the largest group of transcriptional regulators and consists of 48 members in humans. Nuclear receptors act as ligand-activated transcription factors which control a broad spectrum of genes involved in BA homeostasis, lipid and glucose metabolism, inflammation, cell proliferation, tissue repair and fibrosis and are widely expressed in hepatocytes, cholangiocytes, hepatic stellate cells, macrophages and other immune cells, which makes them attractive targets for the treatment of cholestatic disorders.
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      Natural ligands include both endogenous and exogenous molecules such as hormones, fatty acids, BAs, other intermediary products of metabolism, drugs and toxins. Nuclear receptors offer a feedback mechanism to maintain cellular homoeostasis.
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      Other nuclear receptors of importance for cholestatic liver diseases are the peroxisome proliferator-activated receptors (PPARs), pregnane X receptor and glucocorticoid receptor.
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      Nuclear receptors not only influence hepatobiliary homoeostasis but also gut inflammation and microbiota, making them interesting targets for the treatment of PSC. The interactions between BAs, intestinal microbiota and changes in gut microbiota (dysbiosis) may play a role in the pathogenesis of cholestasis in PSC.
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      Specific gut pathobionts may disrupt the intestinal epithelial barrier and initiate a hepatic T helper 17 cell immune response.
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      Vancomycin is one of the most promising agents but its mode of action may be complex and include direct immunoregulatory effects.
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      In addition, faecal microbiota transplantation from lean donors has shown promising early results in PSC.
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      Importantly, as well as serving as a trigger of liver injury, gut microbiota may also have protective effects. As such, total elimination of the intestinal microbiome in germ-free mice has been shown to aggravate liver injury in mouse models of liver fibrosis and PSC.
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      Overall, drug therapy in cholestatic disorders is based on disease pathogenesis. Drug targets can be separated into molecules primarily targeting
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      PBC-transplantation and disease recurrence.
      cholestasis (the hepatocellular retention of endogenous BAs),
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      fibrogenesis and
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      Liver transplantation in PBC and PSC: indications and disease recurrence.
      immune processes. On the other hand, there are also
      • Folseraas T.
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      • Franke A.
      • Karlsen T.H.
      Genetics in primary sclerosing cholangitis.
      drugs aimed at symptom relief. Indeed pruritus, fatigue and cognitive dysfunction are the most common complaints in individuals with cholestatic liver disease. Pruritus appears to be particularly frequent in individuals with PBC but may also become a significant problem in those with PSC and other cholestatic conditions.
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      Current guidelines provide a treatment algorithm for the management of pruritus, but response rates of less than 50% are common for most of the recommended drugs.
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      Central fatigue with cognitive dysfunction is currently untreatable.
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      Disease stage influences the efficacy of some of the drugs used to treat cholestatic liver diseases. In this regard, Peter L.M. Jansen et al. developed the concept that cholestatic liver diseases, particularly PBC and PSC, have an ascending pathophysiology.
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      Knowledge of this concept might allow one to use these drugs in a more appropriate way. Indeed, the early lesions caused by immunological injury are in the “downstream” biliary tree which can lead to cholestasis. This causes BA-mediated toxic injury of the “upstream” liver parenchyma. High concentrations of BAs are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis by reducing uptake systems and BA synthesis while inducing (alternative) efflux systems (adaptation phase). According to this concept, ileal BA transporter (IBAT) inhibitors that reduce intestinal bile salt absorption and lower the BA load may be most efficient in this stage. The effectiveness of BA synthesis-suppressing drugs, such as FXR agonists, is greatest when adaptation is not yet established. Anti-inflammatory agents are probably most effective in early disease. Finally, drugs that antagonise BA toxicity, such as ursodeoxycholic acid and norursodeoxycholic acid (norUDCA), might be effective at all disease stages.
      An overview of the mechanism of action of anticholestatic drugs is provided in Fig. 1.
      Figure thumbnail gr1
      Fig. 1Mechanism of action of anticholestatic drugs.
      In hepatocytes, activation of FXR downregulates BA uptake via NTCP (SLC10A1) and BA synthesis (via CYP7A1), while inducing activation of BSEP (ABCB11), thus limiting hepatocellular BA load. CYP7A1 is also inhibited by FGF19 (produced in the intestine) as well as PPARα and δ. Both FXR and PPARα stimulate phospholipid secretion (via MDR3 [ABCB4]), thus counteracting intrinsic BA toxicity. At the basolateral membrane, OSTα (SLC51A)/OSTβ (SLC51B), MRP3 (ABCC3) and MRP4 (ABCC4) facilitate an alternative hepatic BA pump which is also in part induced by FXR. Drugs such as norUDCA undergo a cholehepatic shunting resulting in ductular HCO3 secretion (‘HCO3 umbrella’) which protects cholangiocytes against BA toxicity. In the intestine, BAs are normally taken up by IBAT, followed by efflux via OSTα/OSTβ. Intestinal FXR induces FGF19, which circulates via portal blood back to the liver and binds to its receptor FGFR4, subsequently inhibiting BA synthesis. IBAT inhibitors interfere with BA uptake in the terminal ileum, while FGF19 mimetics have metabolic effects but lack the pro-proliferative, potentially pro-carcinogenic, effects of intrinsic FGF19. Moreover, therapies targeting FXR and PPARs and novel BA derivatives, such as norUDCA, also have direct and indirect anti-inflammatory, immunomodulatory and anti-fibrotic effects in immune cells and hepatic stellate cells (lower right panel, see text for further details). Other therapeutic approaches directly target underlying immune pathogenesis and fibrogenesis (not shown, see text for details). BA, bile acid; BSEP, bile salt export pump; FGF, fibroblast growth factor; FXR, farnesoid X receptor; IBAT, ileal BA transporter; norUDCA, norursodeoxycholic acid; OA, organic anion; PPAR, peroxisome proliferator-activated receptor.

      Improvement of cholestasis

      Targeting the nuclear BA receptor FXR

      As an intracellular BA receptor and key regulator of BA homoeostasis, FXR has become a central therapeutic target for cholestatic liver diseases.
      • Halilbasic E.
      • Claudel T.
      • Trauner M.
      Bile acid transporters and regulatory nuclear receptors in the liver and beyond.
      • Beuers U.
      • Trauner M.
      • Jansen P.
      • Poupon R.
      New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond.
      • Trauner M.
      • Fuchs C.D.
      Novel therapeutic targets for cholestatic and fatty liver disease.
      Moreover, FXR also modulates liver regeneration and inflammation.
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      Pharmacological activation of FXR reduces hepatocellular BA levels by stimulating BA export while repressing BA uptake and synthesis.
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      In addition, FXR has anti-inflammatory effects, mainly due to the antagonising effects of NF-κB.
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      The steroidal FXR agonists

      Obeticholic acid (OCA) was the first-in-class steroidal FXR agonist (still maintaining its BA structure) and is a synthetic BA derivative from the natural BA chenodeoxycholic acid.
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      6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity.
      OCA improves hepatic BA excretion and reduces exposure of hepatocytes to cytotoxic BAs in humans.
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      In addition to restoration of BA homeostasis, activation of FXR also promotes HCO3 secretion in mice, which in humans may reinforce the HCO3 umbrella.
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      Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO-3 output.
      FXR stimulation also reduces inflammation in the liver and has antifibrotic effects through inhibition of fibrosis progression, promotion of fibrosis resolution and inhibition of hepatic stellate cell activity.
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      In addition, OCA acts as a local nitric oxide donor in the liver, lowering portal hypertension in animals.
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      • Covens K.
      • Vanuytsel T.
      • Verhaegen J.
      • et al.
      The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.
      • Ceulemans L.J.
      • Verbeke L.
      • Decuypere J.P.
      • Farré R.
      • De Hertogh G.
      • Lenaerts K.
      • et al.
      Farnesoid X receptor activation attenuates intestinal ischemia reperfusion injury in rats.
      • Sorribas M.
      • Jakob M.O.
      • Yilmaz B.
      • Li H.
      • Stutz D.
      • Noser Y.
      • et al.
      FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis.

      Non-steroidal FXR agonists

      An increasing number of non-steroidal FXR ligands with higher affinity for FXR have been developed.
      • Gege C.
      • Hambruch E.
      • Hambruch N.
      • Kinzel O.
      • Kremoser C.
      Nonsteroidal FXR ligands: current status and clinical applications.
      In contrast to steroidal FXR agonists, non-steroidal FXR ligands no longer have a BA structure and therefore have different pharmacokinetic, efficacy and safety profiles. Some of these agonists may operate as gut-preferential FXR ligands and have limited systemic exposure. However, side effects such as dyslipidaemia and pruritus are still encountered and appear to be dose-dependent class effects of FXR-targeted strategies.
      • Verbeke L.
      • Nevens F.
      • Laleman W.
      Steroidal or non-steroidal FXR agonists - is that the question?.
      ,
      • Kremoser C.
      FXR agonists for NASH: how are they different and what difference do they make?.
      Two compounds are in phase II clinical development: cilofexor and tropifexor.

      The FXR downstream target: fibroblast growth factor 19

      FXR stimulates the production of intestinal fibroblast growth factor 19 (FGF19) in the terminal ileum, which after reaching the liver via the portal circulation and binding to the FGFR4/ß-klotho receptor complex, inhibits hepatic BA synthesis through repression of the rate-limiting enzyme CYP7A1.
      • Degirolamo C.
      • Sabbà C.
      • Moschetta A.
      Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23.
      In addition to its role in regulating BA homeostasis, FGF19 also stimulates cell proliferation in the liver, raising concerns about potential hepatocarcinogenesis. FGF19 overstimulation by FXR ligands and aberrant FGF19-FGFR4 signalling has been identified in HCC.
      • Raja A.
      • Park I.
      • Haq F.
      • Ahn S.M.
      FGF19-FGFR4 signaling in hepatocellular carcinoma.
      However, the non-tumorigenic FGF19 mimetic aldafermin (NGM282) improved liver injury in the Mdr2/Abcb4–/– mouse model of sclerosing cholangitis and protected Mdr2/Abcb4–/– and Fxr–/– mice from spontaneous hepatic fibrosis, cellular proliferation and HCC formation.
      • Zhou M.
      • Learned R.M.
      • Rossi S.J.
      • DePaoli A.M.
      • Tian H.
      • Ling L.
      Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice.
      ,
      • Gadaleta R.M.
      • Scialpi N.
      • Peres C.
      • Cariello M.
      • Ko B.
      • Luo J.
      • et al.
      Suppression of hepatic bile acid synthesis by a non-tumorigenic FGF19 analogue protects mice from fibrosis and hepatocarcinogenesis.
      Aldafermin is an engineered analogue of human FGF19 and is 95.4% identical to FGF19. Aldafermin differs from wild-type FGF19 in the amino terminus, a key region of the protein involved in receptor interactions and signalling modulation. In aldafermin, a five-amino acid deletion (P24–S28) coupled with the substitution of three amino acids at critical positions (A30S, G31S, H33L) enable biased FGFR4 signalling so that aldafermin retains the ability to potently repress CYP7A1 expression but no longer triggers activation of signal transducer and activator of transcription 3, a signalling pathway essential for FGF19-mediated hepatocarcinogenesis.
      • Zhou M.
      • Wang X.
      • Phung V.
      • Lindhout D.A.
      • Mondal K.
      • Hsu J.Y.
      • et al.
      Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19.
      • Luo J.
      • Ko B.
      • Elliott M.
      • Zhou M.
      • Lindhout D.A.
      • Phung V.
      • et al.
      A nontumorigenic variant of FGF19 treats cholestatic liver diseases.
      • Zhou M.
      • Yang H.
      • Learned R.M.
      • Tian H.
      • Ling L.
      Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis.
      By engaging both FGFR4 and FGFR1c pathways to reduce BA toxicity, aldafermin has demonstrated anti-inflammatory, and anti-fibrotic activities in multiple animal models.

      Targeting PPARs

      PPARs belong to the same nuclear receptor family as FXR. PPARs act as transcriptional modifiers of bile formation and regulate inflammation and fibrosis.
      • Beuers U.
      • Trauner M.
      • Jansen P.
      • Poupon R.
      New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond.
      There are three isoforms: PPARα/γ/δ. PPARα is the predominant isoform in the liver. FXR and PPAR are also involved in crosstalk with other nuclear receptors. The three isoforms are expressed in different parenchymal and non-parenchymal liver cell compartments, making them highly attractive targets for the treatment of cholestatic liver diseases.
      Fibrates such as bezafibrate and fenofibrate act as PPAR agonists and have been licensed for the treatment of dyslipidaemia for decades. Fibrates suppress BA synthesis (CYP7A1) in the liver, increase phospholipid excretion (via MDR3 which is also known as ABCB4) into the bile and have anti-inflammatory effects (via suppression of NF-κB signalling).
      • Ghonem N.S.
      • Assis D.N.
      • Boyer J.L.
      Fibrates and cholestasis.
      Bezafibrate is a potent pan-PPAR agonist
      • Dubois V.
      • Eeckhoute J.
      • Lefebvre P.
      • Staels B.
      Distinct but complementary contributions of PPAR isotypes to energy homeostasis.
      while fenofibrate is a more selective PPARα agonist.
      • Staels B.
      • Dallongeville J.
      • Auwerx J.
      • Schoonjans K.
      • Leitersdorf E.
      • Fruchart J.C.
      Mechanism of action of fibrates on lipid and lipoprotein metabolism.
      Seladelpar is an oral, once-daily selective PPARδ agonist. PPARδ is expressed not only in hepatocytes but also in cholangiocytes, Kupffer cells and hepatic stellate cells. PPARδ profoundly influences BA levels and has effects on inflammation and fibrosis. PPARδ-triggered mechanisms could promote cancer cell survival and cancer progression, which has raised concerns regarding their clinical development.
      • Liu Y.
      • Colby J.K.
      • Zuo X.
      • Jaoude J.
      • Wei D.
      • Shureiqi I.
      The role of PPAR-δ in metabolism, inflammation, and cancer: many characters of a critical transcription factor.
      Seladelpar decreases BA synthesis and prevents toxic BA accumulation in hepatocytes. Seladelpar also decreases the synthesis of cholesterol and inhibits its dietary absorption, which decreases the levels of cholesterol available for BA synthesis. In addition, seladelpar has anti-inflammatory effects. In contrast to the other PPARs, a direct role for PPARγ in the regulation of BA metabolism has not yet been reported.
      Elafibranor, a PPAR agonist with affinity for the α/δ isoforms, and saroglitazar, a PPAR agonist with affinity for the α/γ isoforms, are under investigation. It must be kept in mind that cardiovascular and renal side effects have been reported for some compounds in this drug class.
      • Rubenstrunk A.
      • Hanf R.
      • Hum D.W.
      • Fruchart J.C.
      • Staels B.
      Safety issues and prospects for future generations of PPAR modulators.

      Targeting the glucocorticoid receptor

      The anti-inflammatory and immunosuppressive effects of budesonide are well known and the drug is mainly used in the context of overlap syndromes and non-cirrhotic autoimmune hepatitis. However, budesonide is a glucocorticoid receptor ligand and recent data indicate that it may also control BA detoxification (via PXR) and HCO3 secretion.
      • Arenas F.
      • Hervias I.
      • Uriz M.
      • Joplin R.
      • Prieto J.
      • Medina J.F.
      Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells.

      Other anti-cholestatic agents beyond nuclear receptors

      NorUDCA, recently assigned the new international non-proprietary name norucholic acid, is a side-chain-shortened derivate of UDCA and is resistant to side-chain conjugation with glycine and taurine.
      • Yoon Y.B.
      • Hagey L.R.
      • Hofmann A.F.
      • Gurantz D.
      • Michelotti E.L.
      • Steinbach J.H.
      Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents.
      In contrast to UDCA, norUDCA undergoes cholehepatic shunting between cholangiocytes and hepatocytes, which leads to HCO3–rich hypercholeresis and high intrahepatic enrichment.
      • Halilbasic E.
      • Fiorotto R.
      • Fickert P.
      • Marschall H.U.
      • Moustafa T.
      • Spirli C.
      Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2-/- mice.
      NorUDCA has shown anti-cholestatic, anti-inflammatory, immunomodulatory and anti-fibrotic actions in animal models and improves cholestatic liver and bile duct injury in the Mdr2/Abcb4–/– mouse model of sclerosing cholangitis.
      • Fickert P.
      • Wagner M.
      • Marschall H.U.
      • Fuchsbichler A.
      • Zollner G.
      • Tsybrovskyy O.
      • et al.
      24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in mdr2 (ABCB4)knockout mice.
      • Moustafa T.
      • Fickert P.
      • Magnes C.
      • Guelly C.
      • Thueringer A.
      • Frank S.
      • et al.
      Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury.
      • Zhu C.
      • Boucheron N.
      • Müller A.C.
      • Májek P.
      • Claudel T.
      • Halilbasic E.
      • et al.
      24-Norursodeoxycholic acid reshapes immunometabolism in CD8+ T cells and alleviates hepatic inflammation.
      Since norUDCA reinforces the HCO3 umbrella, it may be a therapeutic approach for several cholangiopathies characterised by defective HCO3 secretion, such as PBC. Notably, norUDCA does not act via FXR or other nuclear receptors, making it an attractive combination partner for drugs targeting nuclear receptors.

      Fibrogenesis

      Lysyl oxidase-like 2 (LOXL2) contributes to fibrogenesis by cross-linking collagen and regulates bile duct permeability. Simtuzumab is a humanised monoclonal antibody against LOXL2. In individuals with PSC, increased serum levels of LOXL2 correlate with more advanced fibrosis and more severe portal hypertension.
      • Chen W.
      • Yang A.
      • Jia J.
      • Popov Y.V.
      • Schuppan D.
      • You H.
      Lysyl oxidase (LOX) family members: rationale and their potential as therapeutic targets for liver fibrosis.
      ,
      • Pollheimer M.J.
      • Racedo S.
      • Mikels-Vigdal A.
      • Marshall D.
      • Bowlus C.
      • Lackner C.
      • et al.
      Lysyl oxidase-like protein 2 (LOXL2) modulates barrier function in cholangiocytes in cholestasis.
      Setanaxib is an oral small molecule and a first-in-class selective inhibitor of the NADPH oxidase 1 and 4 isoforms (NOX inhibitor). Activation of NOX enzymes is key in many multifactorial diseases and the drug has been studied in phase II trials in kidney fibrosis and idiopathic fibrosis. The compound has demonstrated the potential to downregulate markers of oxidative stress (anti-inflammatory effect) and prevent progression to liver fibrosis in in vitro and animal studies.
      • Jiang J.X.
      • Chen X.
      • Serizawa N.
      • Szyndralewiez C.
      • Page P.
      • Schröder K.
      • et al.
      Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo.
      ,
      • Aoyama T.
      • Paik Y.H.
      • Watanabe S.
      • Laleu B.
      • Gaggini F.
      • Fioraso-Cartier L.
      • et al.
      Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent.

      Targeting underlying (immune-mediated) pathogenesis

      Examples of these latter compounds are: rituximab, a B-cell depleting monoclonal antibody targeting the CD20 antigen; RhuDex, a novel, orally bioavailable, low molecular weight modulator of T-lymphocyte co-stimulation; cenicriviroc, a dual CCR2/CCR5 chemokine receptor antagonist; and the CCL24 monoclonal antibody CM-101. No convincing clinical data have yet been reported, but these agents are most likely to be effective in the early stages of the disease.

      Symptom relief

      Pruritus

      The mechanisms underlying cholestatic pruritus are still not clear. Retention of toxic hydrophobic BAs is postulated to play a key pathogenetic role. In this regard, cholestyramine is the current first-line treatment option for cholestatic pruritus. However, in the past, colesevelam – an anion-exchange resin associated with a 7-fold higher BA-binding capacity and fewer side effects than cholestyramine – decreased serum BA levels but did not appear to be more effective than placebo in alleviating the severity of pruritus of cholestasis.
      • Kuiper E.M.
      • van Erpecum K.J.
      • Beuers U.
      • Hansen B.E.
      • Thio H.B.
      • de Man R.A.
      • et al.
      The potent bile acid sequestrant colesevelam is not effective in cholestatic pruritus: results of a double-blind, randomized, placebo-controlled trial.
      IBAT is an integral brush border membrane glycoprotein mainly expressed in the distal ileum. In cholestatic liver disease, ileal BA absorption is increased and inhibiting IBAT may prevent inappropriate conservation of BAs and improve pruritus.
      • Hofmann A.F.
      Inappropriate ileal conservation of bile acids in cholestatic liver disease: homeostasis gone awry.
      MRGPRX4 (Mas-related G protein-coupled receptor X4) is a newly identified receptor for BAs and bilirubin, which is likely to play a role in cholestatic itch. Its discovery provides a promising target for novel anti-itch treatments.
      • Meixiong J.
      • Vasavda C.
      • Snyder S.H.
      • Dong X.
      MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus.
      • Yu H.
      • Zhao T.
      • Liu S.
      • Wu Q.
      • Johnson O.
      • Wu Z.
      • et al.
      MRGPRX4 is a bile acid receptor for human cholestatic itch.
      • Yu H.
      • Wangensteen K.
      • Deng T.
      • Li Y.
      • Luo W.
      MRGPRX4 in cholestatic pruritus.

      Fatigue

      Over-activation of GABA-A receptors by neurosteroids plays a role in cognitive dysfunction and fatigue.
      • Johansson M.
      • Stromberg J.
      • Ragagnin G.
      • Doverskog M.
      • Backstrom T.
      GABAA receptor modulating steroid antagonists (GAMSA) are functional in vivo.
      Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders. It restores spatial learning and motor coordination in animal models of hepatic encephalopathy and has been investigated for hepatic encephalopathy.
      • Montagnese S.
      • Lauridsen M.
      • Vilstrup H.
      • Zarantonello L.
      • Lakner G.
      • Fitilev S.
      • et al.
      A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy.

      Medical treatment: established drugs and drugs in the late phase of clinical development in PBC and PSC

      PBC experience

      The first-line drug for PBC is UDCA, which is effective in the majority of individuals with PBC (60-80% are biochemical responders). UDCA is relatively cheap and is well tolerated at a standard dose of 13-15 mg/kg/day.
      • Angulo P.
      • Batts K.P.
      • Therneau T.M.
      • Jorgensen R.A.
      • Dickson E.R.
      • Lindor K.D.
      Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.
      Discontinuation due to digestive adverse events occurs in less than 5% of patients.
      • Hempfling W.
      • Dilger K.
      • Beuers U.
      Systematic review: ursodeoxycholic acid–adverse effects and drug interactions.
      The earlier patients are treated, the higher the chances of achieving a response.
      • Carbone M.
      • Nardi A.
      • Flack S.
      • Carpino G.
      • Varvaropoulou N.
      • Gavrila C.
      • et al.
      Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score.
      UDCA improves cholestasis and underlying liver histology and delays the development of oesophageal varices. The drug reduces the risk of hepatocellular carcinoma and based on open label extension studies it is accepted that it improves survival and reduces the need for liver transplantation.
      • Poupon R.E.
      • Balkau B.
      • Eschwège E.
      • Poupon R.
      A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.
      • Harms M.H.
      • de Veer R.C.
      • Lammers W.J.
      • Corpechot C.
      • Thorburn D.
      • Janssen H.L.A.
      • et al.
      Number needed to treat with ursodeoxycholic acid therapy to prevent liver transplantation or death in primary biliary cholangitis.
      • Jackson H.
      • Solaymani-Dodaran M.
      • Card T.R.
      • Aithal G.P.
      • Logan R.
      • West J.
      Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: a population-based cohort study.
      • Parés A.
      • Caballería L.
      • Rodés J.
      Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid.
      Since the wide implementation of UDCA, the need for liver transplantation for PBC in Europe has declined, despite there being no decrease in the prevalence of PBC.
      • Webb G.J.
      • Rana A.
      • Hodson J.
      • Akhtar M.Z.
      • Ferguson J.W.
      • Neuberger J.M.
      • et al.
      Twenty-Year comparative analysis of patients with autoimmune liver diseases on transplant Waitlists.
      UDCA also has a place after liver transplantation. Recurrence of PBC following liver transplantation is reported in up to 46% of transplant recipients and can be prevented by UDCA when treatment is started early.
      • Corpechot C.
      • Chazouillères O.
      • Belnou P.
      • Montano-Loza A.J.
      • Mason A.
      • Ebadi M.
      • et al.
      Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis.
      Around 30-40% of individuals with PBC have an incomplete response to UDCA, which may result in disease progression over long-term follow-up.
      • Harms M.H.
      • Lammers W.J.
      • Thorburn D.
      • Corpechot C.
      • Invernizzi P.
      • Janssen H.L.A.
      • et al.
      Major hepatic complications in ursodeoxycholic acid-treated patients with primary biliary cholangitis: risk factors and time trends in incidence and outcome.
      The strongest risk factor for an incomplete response to UDCA therapy is early age at diagnosis (<45 years) and advanced stage at presentation.
      • Carbone M.
      • Mells G.F.
      • Pells G.
      • Dawwas M.F.
      • Newton J.L.
      • Heneghan M.A.
      • et al.
      Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid.
      ,
      • Cheung A.C.
      • Lammers W.J.
      • Murillo Perez C.F.
      • van Buuren H.R.
      • Gulamhusein A.
      • Trivedi P.J.
      • et al.
      Effects of age and sex of response to ursodeoxycholic acid and transplant-free survival in patients with primary biliary cholangitis.
      This observation provides the rationale for second-line therapies in combination with UDCA. EASL clinical practice guidelines recommend an ALP level >1.5x ULN or abnormal levels of bilirubin as biochemical thresholds at which to initiate second-line therapy.
      EASL clinical practice guidelines
      The diagnosis and management of patients with primary biliary cholangitis.
      Before considering the introduction of second-line therapies, it remains important to exclude other reasons for a suboptimal response to UDCA such as: adherence, inappropriate UDCA dosage and co-administration of BA sequestrants inhibiting uptake of UDCA.
      An overview of the established drugs approved for PBC therapy and those in advanced stages of clinical development is provided in Table 1. It is important to note that none of these drugs have been investigated in patients with advanced disease.
      Table 1An overview of the established drugs approved for PBC and those in advanced stages of clinical development for PBC and PSC and their major side effects.
      CompoundPBCPSC
      Steroidal FXR agonists:
       Obeticholic acidPOISE trial (ref 16): On the market (conditional approval)Phase II (ref 148): reduction in ALP after 24 weeks, maintained for 2 years/pruritus
      Non-steroidal FXR agonists:
       CilofexorPhase II (abstract): improved cholestasis after 12 weeks/pruritusPhase II (ref 149): improvement of cholestasis and non-invasive markers of fibrosis

      Phase III in progress
       TropifexorPhase II (abstract): improvement of GGT after 4 weeks/pruritus
      PPAR agonists:
       BezafibrateBEZURSO trial (ref 117):

      Off label in Europe/myalgia
      Small retrospective study (ref 151): improvement of cholestasis and decrease in pruritus

      Phase III in progress
       SeladelparPhase II (ref 126, abstract): improvement of cholestasis maintained for 52 weeks

      Phase III ongoing
      Phase II ongoing
       ElafibranorPhase II (ref 128): improvement of cholestasis after 12 weeks

      Phase III ongoing
       SaroglitazarOpen label (ref 129):

      Improvement of cholestasis after 16 weeks
      FGF 19 mimetic:
       AldaferminPhase II (ref 130): improvement of cholestasis after 28 days/gastrointestinal side effectsPhase II (ref 150): reduction in markers of fibrosis after 12 weeks/gastrointestinal side effects
      NorUDCAPhase II initiatedPhase II (ref 152): dose-dependent improvement of ALP after 12 weeks

      Phase III ongoing
      CCR2/CCR agonist:
       CenicrivivocSingle arm open label study (ref 153): modest reduction of ALP after 24 weeks/rash, fatigue and dizziness
      LOXL2 inhibitor:
       SimtuzumabPhase II (ref 154): no clinical benefit
      NOX1 & 4 inhibitor:
       SenataxibPhase II: improvement of cholestasis

      Phase III initiated
      BudenosideInvestigator driven (ref 135): improvement of cholestasis/no improvement of histology/high dropout rate
      ALP, alkaline phosphatase; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.
      NR ligands, which were the first second-line drugs for PBC, have also been widely investigated for the treatment of non-alcoholic steatohepatitis. This valuable experience offers crucial information about dose and safety that can be extrapolated to the PBC population.
      • Trauner M.
      • Fuchs C.D.
      Novel therapeutic targets for cholestatic and fatty liver disease.
      A treatment algorithm for PBC is provided in Fig. 2.
      Figure thumbnail gr2
      Fig. 2Algorithm for the treatment of PBC.
      ∗Currently based on ALP ≥1,67 x ULN and total bilirubin ≤2 x ULN. ∗∗Patients with cirrhosis are excluded. PBC, primary biliary cholangitis; PPAR, peroxisome proliferator-activated receptor.

      FXR agonists

      OCA is currently the only approved second-line therapy for PBC. The starting dose is 5 mg with adjustment to 10 mg after 3-6 months if tolerable. Long-term clinical data have confirmed preclinical observations. Two prospective studies demonstrated that OCA in patients with an incomplete response to UDCA or intolerance to UDCA improves cholestasis in a dose-dependent manner.
      • Hirschfield G.M.
      • Mason A.
      • Luketic V.
      • Lindor K.
      • Gordon S.C.
      • Mayo M.
      • et al.
      Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid.
      In the POISE trial comparing OCA to placebo, a significant reduction of ALP and bilirubin after 1 year was observed in 35% of those receiving OCA and 8% of those receiving placebo, respectively.
      • Nevens F.
      • Andreone P.
      • Mazzella G.
      • Strasser S.I.
      • Bowlus C.
      • Invernizzi P.
      • et al.
      POISE study group. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis.
      OCA treatment also significantly reduced serum levels of gamma glutamyltransferase. The rate of serious adverse events was 16% in the 5–10 mg group vs. 4% in the placebo group. Pruritus is the most common adverse event; it is dose related and occurs more frequently in patients with pre-existing pruritus. There was no effect on non-invasive measures of liver fibrosis (liver stiffness and enhanced liver fibrosis score) after 1 year. Paired biopsies in a small group of 17 patients included in the POISE trial showed improvements or stabilisation of histological disease features, including ductular injury, fibrosis, and collagen morphometry, following OCA treatment.
      • Bowlus C.L.
      • Pockros P.J.
      • Kremer A.E.
      • Parés A.
      • Forman L.M.
      • Drenth J.P.H.
      Long-term obeticholic acid therapy improves histological endpoints in patients with primary biliary cholangitis.
      The effect of the drug on biochemical markers is sustained for at least 3 years.
      • Trauner M.
      • Nevens F.
      • Shiffman M.L.
      • Drenth J.P.H.
      • Bowlus C.L.
      • Vargas V.
      • et al.
      Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study.
      Real-world data demonstrated a discontinuation rate of between 12% and 17%, mainly due to pruritus, and confirmed the efficacy of the drug on the biochemical surrogate markers of outcome.
      • Roberts S.B.
      • Ismail M.
      • Kanagalingam G.
      • Mason A.L.
      • Swain M.G.
      • Vincent C.
      • et al.
      Real-world effectiveness of obeticholic acid in patients with primary biliary cholangitis.
      • Gomez E.
      • Garcia Buey L.
      • Molina E.
      • Casado M.
      • Conde I.
      • Berenguer M.
      • et al.
      Effectiveness and safety of obeticholic acid in a Southern European multicentre cohort of patients with primary biliary cholangitis and suboptimal response to ursodeoxycholic acid.
      • D'Amato D.
      • De Vincentis A.
      • Malinverno F.
      • Viganò M.
      • Alvaro D.
      • Pompili M.
      • et al.
      Real-world experience with obeticholic acid in patients with primary biliary cholangitis.
      The effect of OCA on ‘hard’ clinical endpoints still needs to be demonstrated. Meanwhile, the use of OCA has been associated with an increase in hepatic decompensation in individuals with advanced liver disease. This led to a label change, with its use contraindicated in individuals with decompensated cirrhosis, a history of prior decompensation and in those with compensated cirrhosis and evidence of portal hypertension.
      • John B.V.
      • Schwartz K.
      • Levy C.
      • Dahman B.
      • Deng Y.
      • Martin P.
      • et al.
      Impact of obeticholic acid exposure on decompensation and mortality in primary biliary cholangitis and cirrhosis.
      ,
      • Lindor K.D.
      • Bowlus C.L.
      • Boyer J.
      • Levy C.
      • Mayo M.
      Primary biliary cholangitis: 2021 practice guidance update from the American Association for the Study of Liver Diseases.
      Two non-OCA FXR agonists are being investigated. In a phase II study, which was only published as an abstract (Kowdley KV et al. 2019), cilofexor for 12 weeks improved biochemical parameters of cholestasis, with pruritus as a side effect. In another phase II study, also only published in abstract form thus far (Schramm C et al. 2018), tropifexor led to a dose-dependent decrease in gamma glutamyltransferase but had no effect on ALP after 4 weeks of therapy, again with pruritus as a side effect.

      PPAR agonists

      Ten randomised clinical trials including the BEZURSO trial reported a positive effect of fibrates on cholestasis.
      • Agrawal R.
      • Majeed M.
      • Attar B.M.
      • Omar Y.A.
      • Mbachi C.
      • Wang Y.
      • et al.
      Effectiveness of bezafibrate and ursodeoxycholic acid in patients with primary biliary cholangitis: a meta-analysis of randomized controlled trials.
      In the BEZURSO trial, bezafibrate at a dose of 400 mg/day improved ALP and bilirubin during a follow-up of 2 years, with normalisation of ALP and bilirubin achieved in 31% of patients vs. 0% in the placebo group.
      • Corpechot C.
      • Chazouillères O.
      • Rousseau A.
      • Le Gruyer A.
      • Habersetzer F.
      • Mathurin P.
      • et al.
      A placebo-controlled trial of bezafibrate in primary biliary cholangitis.
      There was also an improvement of non-invasive markers of liver fibrosis (liver stiffness values and enhanced liver fibrosis score). The drug was well tolerated and myalgia was the most common side effect, occurring in 20% of the active group vs. 10% of the placebo group. Serum creatinine increased in 5% of patients at 2 years, a well-known class effect of fibrates with no long-term influence on renal function.
      • Ting R.D.
      • Keech A.C.
      • Drury P.L.
      • Donoghoe M.W.
      • Hedley J.
      • Jenkins A.J.
      • et al.
      Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment: the FIELD Study.
      ,
      • Hosonuma K.
      • Sato K.
      • Yamazaki Y.
      • Yanagisawa M.
      • Hashizume H.
      • Horiguchi N.
      • et al.
      A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia.
      Overall, a recent systematic review concluded that fibrates are safe and well tolerated in individuals with PBC.
      • Carrion A.F.
      • Lindor K.D.
      • Levy C.
      Safety of fibrates in cholestatic liver diseases.
      In favour of the use of bezafibrates is the improvement of pruritus in some patients.
      • de Vries E.
      • Bolier R.
      • Goet J.
      • Parés A.
      • Verbeek J.
      • de Vree M.
      • et al.
      Fibrates for itch (FITCH) in fibrosing cholangiopathies: a double-blind, randomized, placebo-controlled trial.
      In a large Japanese retrospective cohort study, the combination of bezafibrate and UDCA improved transplant-free survival.
      • Tanaka A.
      • Hirohara J.
      • Nakano T.
      • Matsumoto K.
      • Chazouillères O.
      • Takikawa H.
      • et al.
      Association of bezafibrate with transplant-free survival in patients with primary biliary cholangitis.
      There are no data on safety in individuals with advanced liver disease. Evaluation of paired liver biopsies in 31 patients after 5 years showed a significant decrease in liver damage as reflected by Ludwig and Ishak scores. Overall, regression of fibrosis was attained in 48% of patients.
      • Sorda J.A.
      • González Ballerga E.
      • Barreyro F.J.
      • Avagnina A.
      • Carballo P.
      • Paes de Lima A.
      • et al.
      Bezafibrate therapy in primary biliary cholangitis refractory to ursodeoxycholic acid: a longitudinal study of paired liver biopsies at 5 years of follow up.
      Bezafibrate is currently not approved for the treatment of cholestatic liver diseases and thus is used off-label when prescribed to individuals with PBC.
      • Wilde A.B.
      • Lieb C.
      • Leicht E.
      • Greverath L.M.
      • Steinhagen L.M.
      • Wald de Chamorro N.
      • et al.
      Real-world clinical management of patients with primary biliary cholangitis-A retrospective multicenter study from Germany.
      Moreover, bezafibrate is not available in the USA, where fenofibrate with a narrower PPARα spectrum is available and has also demonstrated beneficial effects in smaller studies.
      • Cheung A.C.
      • Lapointe-Shaw L.
      • Kowgier M.
      • Meza-Cardona J.
      • Hirschfield G.M.
      • Janssen H.L.
      • et al.
      Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes.
      An update from the AASLD in 2021 mentioned that fibrates can be considered as off-label alternatives for individuals with PBC and incomplete response to UDCA but are discouraged in those with decompensated liver disease.
      • Lindor K.D.
      • Bowlus C.L.
      • Boyer J.
      • Levy C.
      • Mayo M.
      Primary biliary cholangitis: 2021 practice guidance update from the American Association for the Study of Liver Diseases.
      Seladelpar has been explored in 4 clinical studies. The first phase II study which used dosages of 50 mg and 200 mg/day was terminated early after 41 participants were enrolled, as three developed grade 3 elevations in alanine aminotransferase (ALT) levels that were reversible after cessation of the drug.
      • Jones D.
      • Boudes P.F.
      • Swain M.G.
      • Bowlus C.L.
      • Galambos M.R.
      • Bacon B.R.
      • et al.
      Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study.
      The next phase II study, which has only been published as an abstract (Levy C et al. 2020), used lower doses and showed that 5 mg and 10 mg consistently lowered ALP, with the effect maintained over 52 weeks. Interestingly, 31% of patients in the 10 mg dose group achieved normalisation of ALP by week 12. In this study, a decrease in ALT levels was seen over 12 weeks. The study also confirmed that ALT elevations are a dose-related phenomenon. In a subsequent phase III study, seladelpar was well tolerated at doses of 5 mg and 10 mg/day. However, this study was prematurely terminated shortly after completing enrolment (n = 265) owing to histological observations suggestive of drug-induced liver injury in a separate study for a different indication, namely individuals with non-alcoholic steatohepatitis. Finally, this observation was not confirmed. The data from this phase III study were consistent with those in phase II. After 3 months of therapy, reductions in ALP were highly significant and seladelpar 10 mg led to normalisation of ALP in 27.3% of treated patients. Seladelpar improved pruritus and fatigue in a dose-dependent manner; no cases of severe myalgia were observed.
      • Kremer A.E.
      • Mayo M.J.
      • Hirschfield G.
      • Levy C.
      • Bowlus C.L.
      • Jones D.E.
      • et al.
      Seladelpar improved measures of pruritus, sleep, and fatigue and decreased serum bile acids in patients with primary biliary cholangitis.
      A phase III confirmation trial using 10 mg/day is ongoing.
      In a placebo-controlled phase II study, elafibranor improved cholestasis after 12 weeks and improved pruritus.
      • Schattenberg J.M.
      • Pares A.
      • Kowdley K.V.
      • Heneghan M.A.
      • Caldwell S.
      • Pratt D.
      • et al.
      A randomized placebo-controlled Trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA.
      A phase III study assessing a dose of 80 mg/day is ongoing.
      In an open-label study, saroglitazar improved biochemical markers of cholestasis after 16 weeks of therapy.
      • Vuppalanchi R.
      • Caldwell S.H.
      • Pyrsopoulos N.
      • deLemos A.S.
      • Rossi S.
      • Levy C.
      • et al.
      Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis.

      Other drugs

      Aldafermin improved ALP after 28 days. Gastrointestinal side effects such as diarrhoea, abdominal pain and nausea were seen, but pruritus was not reported.
      • Mayo M.J.
      • Wigg A.J.
      • Leggett B.A.
      • Arnold H.
      • Thompson A.J.
      • Weltman M.
      • et al.
      NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial.
      Interestingly, aldafermin improved cholestatic liver enzymes in PBC but not in PSC.
      • Hirschfield G.M.
      • Chazouillères O.
      • Drenth J.P.
      • Thorburn D.
      • Harrison S.A.
      • Landis C.S.
      • et al.
      Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial.
      However, an improvement of non-invasive fibrosis markers was observed.
      Several small studies in the past showed promising results with budenoside.
      • Leuschner M.
      • Maier K.P.
      • Schlichting J.
      • Strahl S.
      • Herrmann G.
      • Dahm H.H.
      • et al.
      Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial.
      • Angulo P.
      • Jorgensen R.A.
      • Keach J.C.
      • Dickson E.R.
      • Smith C.
      • Lindor K.D.
      Budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.
      • Hempfling W.
      • Grunhage F.
      • Dilger K.
      • Reichel C.
      • Beuers U.
      • Sauerbruch T.
      Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis.
      In the most recent study, in patients at high risk of disease progression, budenoside at a dose of 9 mg with a reduction to 3 mg in case of normalisation of ALP values, in combination with UDCA, was associated with improved biochemical markers of cholestasis and improvement of the POISE score. However, this combination did not improve liver histology and was associated with a high dropout rate. Adverse events leading to premature discontinuation occurred in 23% of individuals in the budenoside arm vs. 9% in the placebo arm.
      • Hirschfield G.M.
      • Beuers U.
      • Kupcinskas L.
      • Ott P.
      • Bergquist A.
      • Färkkilä M.
      • et al.
      A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA.
      A large, 24-week phase II trial was carried out to explore the possible effect of setanaxib on cholestasis, fibrogenesis and quality of life. Based on the positive results obtained in the study, a phase II/III study is in progress focusing on individuals with PBC and fibrosis.
      Several trials investigating orally administered, small-molecule IBAT inhibitors have been conducted in paediatric cholestasis, with a few studies in adults with PBC.
      • Karpen S.J.
      • Kelly D.
      • Mack C.
      • Stein P.
      Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders.
      ,
      • Kamath B.M.
      • Stein P.
      • Houwen R.H.J.
      • Verkade H.J.
      Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis.
      Linerixibat is an oral agent that is minimally absorbed and a selective inhibitor of human IBAT.
      • Wu Y.
      • Aquino C.J.
      • Cowan D.J.
      • Anderson D.L.
      • Ambroso J.L.
      • Bishop M.J.
      • et al.
      Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes.
      In a 14-day trial in 21 individuals with PBC, linerixibat (GSK2330672) reduced pruritus and total serum BA concentrations compared with placebo and was generally well tolerated.
      • Hegade V.S.
      • Kendrick S.F.
      • Dobbins R.L.
      • Miller S.R.
      • Thompson D.
      • Richards D.
      • et al.
      Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study.
      Maralixabat (also known as lopixibat/LUM001/SHP625) and odevixibat (A4250) have been successfully developed for the treatment of paediatric cholestatic liver diseases such as progressive familial intrahepatic cholestasis, Alagille syndrome and biliary atresia and have already received approval for some of these indications.
      • Gonzales E.
      • Hardikar W.
      • Stormon M.
      • Baker A.
      • Hierro L.
      • Gliwicz D.
      • et al.
      Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study.
      ,
      • Al-Dury S.
      • Wahlström A.
      • Wahlin S.
      • Langedijk J.
      • Elferink R.O.
      • Ståhlman M.
      • et al.
      Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis.
      In children with cholestatic diseases, orally administered odevixibat was well tolerated, reduced serum BAs, and improved pruritus and sleep disturbance.
      • Baumann U.
      • Sturm E.
      • Lacaille F.
      • Gonzalès E.
      • Arnell H.
      • Fischler B.
      • et al.
      Effects of odevixibat on pruritus and bile acids in children with cholestatic liver disease: phase 2 study.
      In a phase II randomised-controlled trial, rituximab over the 12-month study period showed no evidence of effectiveness for the treatment of fatigue in PBC.
      • Khanna A.
      • Jopson L.
      • Howel D.
      • Bryant A.
      • Blamire A.
      • Newton J.L.
      • et al.
      Rituximab is ineffective for treatment of fatigue in primary biliary cholangitis: a phase 2 randomized controlled trial.
      Based on the findings that golexanolone was well tolerated and improved cognitive performance in individuals with hepatic encephalopathy, a phase II clinical trial was initiated to explore the effect of the drug in individuals with PBC suffering from central fatigue and cognitive dysfunction.
      • Montagnese S.
      • Lauridsen M.
      • Vilstrup H.
      • Zarantonello L.
      • Lakner G.
      • Fitilev S.
      • et al.
      A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy.

      Experience in PSC

      An overview of drugs in advanced development for PSC is provided in Table 1.
      The value of UDCA has been extensively investigated. Based on published evidence, the ability of UDCA (at moderate/medium doses) to slow the progression of PSC-related liver disease is still unclear, while high doses of UDCA are harmful and should be avoided.
      • Lindor K.D.
      • Kowdley K.V.
      • Luketic V.A.
      • Harrison M.E.
      • McCashland T.
      • Befeler A.S.
      • et al.
      High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis.
      • Cullen S.N.
      • Rust C.
      • Fleming K.
      • Edwards C.
      • Beuers U.
      • Chapman R.W.
      High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective.
      • Eaton J.E.
      • Silveira M.G.
      • Pardi D.S.
      • Sinakos E.
      • Kowdley K.V.
      • Luketic V.A.
      • et al.
      High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis.
      EASL clinical practice guidelines on sclerosing cholangitis.
      OCA was investigated in a phase II, randomised, double-blind, placebo-controlled, dose-finding study. In this AESOP study, treatment with OCA 5-10 mg reduced ALP during an initial 24-week treatment period. The result was sustained during a long-term (2-year) extension of the study. The most common side effect of OCA was again pruritus.
      • Kowdley K.V.
      • Vuppalanchi R.
      • Levy C.
      • Floreani A.
      • Andreone P.
      • LaRusso N.F.
      • et al.
      A randomized, placebo-controlled phase II study of obeticholic acid for primary sclerosing cholangitis.
      In a 12-week, randomised, placebo-controlled study, cilofexor was well tolerated and led to significant improvements in liver biochemistries, markers of cholestasis and non-invasive markers of liver fibrosis without aggravating pruritus.
      • Trauner M.
      • Gulamhusein A.
      • Hameed B.
      • Caldwell S.
      • Shiffman M.L.
      • Landis C.
      • et al.
      The nonsteroidal farnesoid X receptor agonist Cilofexor (GS-9674) improves markers of cholestasisand liver injury in patients with primary sclerosing cholangitis.
      The risk of progression of fibrosis in individuals without cirrhosis is currently being investigated in a phase III study.
      In a 12-week double-blind, placebo-controlled phase II trial, aldafermin potently inhibited BA synthesis and decreased fibrosis markers, without significantly affecting ALP levels; gastrointestinal symptoms were more frequent in the aldafermin treatment groups, possibly reflecting the direct anti-inflammatory and antifibrotic action of the compound.
      • Hirschfield G.M.
      • Chazouillères O.
      • Drenth J.P.
      • Thorburn D.
      • Harrison S.A.
      • Landis C.S.
      • et al.
      Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial.
      In a small retrospective study, the combination of UDCA with bezafibrate resulted in a significant biochemical improvement and decrease in pruritus in individuals with PSC and an incomplete response to UDCA; the drug is currently being further investigated in ongoing investigator-initiated trials.
      • Lemoinne S.
      • Pares A.
      • Reig A.
      • Ben Belkacem K.
      • Kemgang Fankem A.D.
      • Gaouar F.
      • et al.
      Primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid: French-Spanish experience.
      Another PPAR agonist, seladelpar, is being investigated in an ongoing phase II trial.
      A randomised-controlled trial, including 38 centres from 12 European countries, evaluated the safety and efficacy of 3 doses of oral norUDCA (500 mg/day, 1,000 mg/day or 1,500 mg/day) compared with placebo for 12 weeks. NorUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile was excellent and comparable to placebo.
      • Fickert P.
      • Hirschfield G.M.
      • Denk G.
      • Marschall H.U.
      • Altorjay I.
      • Färkkilä M.
      • et al.
      norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis.
      A phase III trial is ongoing.
      Cenicriviroc, a dual antagonist of CCR2 and CCR5, was investigated in a single-arm, open-label, exploratory study. After 24 weeks, adults achieved a modest reduction (median 18%) in the surrogate endpoint of ALP. The most frequent events were rash, fatigue, and dizziness.
      • Eksteen B.
      • Bowlus C.L.
      • Montano-Loza A.J.
      • Lefebvre E.
      • Fischer L.
      • Vig P.
      • et al.
      Efficacy and safety of Cenicriviroc in patients with primary sclerosing cholangitis: PERSEUS study.
      Simtuzumab (a monoclonal antibody directed against LOXL2) was investigated in a large placebo-controlled trial in 234 patients. The primary efficacy endpoint was mean change in hepatic collagen content assessed by morphometry between baseline and week 96. Additional endpoints included change in Ishak fibrosis stage. Treatment with the LOXL2 inhibitor simtuzumab did not provide clinical benefit in individuals with PSC.
      • Muir A.J.
      • Levy C.
      • Janssen H.L.A.
      • Montano-Loza A.J.
      • Shiffman M.L.
      • Caldwell S.
      • et al.
      Simtuzumab for primary sclerosing cholangitis: phase 2 study results with insights on the natural history of the disease.

      Conclusions and future perspectives

      UDCA at a dose of 13-15 mg/kg is still the cornerstone of treatment for PBC (Fig. 2). In case of an incomplete response or intolerance, which is rare, second-line therapy should be initiated. Incomplete response can occur and is more likely in patients with an early age at diagnosis (<45 years) or in those diagnosed at advanced stages. An incomplete response is currently defined as an ALP level >1.5x ULN or abnormal levels of bilirubin when a correct dose of UDCA (13–15 mg/kg) is given for at least 6 months. It is expected that in the near future, when several second-line drugs become available and combination therapy is possible, that complete normalisation of markers of cholestasis including ALP will be achieved.
      • Smets L.
      • Verbeek J.
      • Korf H.
      • van der Merwe S.
      • Nevens F.
      Improved markers of cholestatic liver injury in patients with primary biliary cholangitis treated with obeticholic acid and bezafibrate.
      ,
      • Soret P.A.
      • Lam L.
      • Carrat F.
      • Smets L.
      • Berg T.
      • Carbone M.
      • et al.
      Combination of fibrates with obeticholic acid is able to normalise biochemical liver tests in patients with difficult-to-treat primary biliary cholangitis.
      In this regard, any decrease in bilirubin (even within the normal range) is associated with an improvement in outcome.
      • Murillo Perez C.F.
      • Harms M.H.
      • Lindor K.D.
      • van Buuren H.R.
      • Hirschfield G.M.
      • Corpechot C.
      • et al.
      Goals of treatment for improved survival in primary biliary cholangitis: treatment target should Be bilirubin within the normal range and normalization of alkaline phosphatase.
      These parameters are therapeutic goals in an ongoing phase II combination study of OCA with bezafibrate.
      The identification of nuclear receptors has accelerated the development of second-line therapies for PBC. The only approved second-line therapy today is OCA, a steroidal nuclear receptor FXR agonist, whose dosage is limited by the occurrence of pruritus. It was hoped that treatment with non-steroidal FXR agonists, such as cilofexor and tropifexor, would induce less pruritus. However, this does not seem to be the case. In Europe, the pan-PPAR agonist bezafibrate is frequently used off label as a second-line therapy for PBC. Bezafibrate has the advantage that it also improves pruritus; however, it can cause myalgia. Pruritus and fatigue are frequent and important symptoms experienced by individuals with PBC. In this regard, seladelpar and elafibronar, which are both PPAR agonists, improved pruritus with no cases of severe myalgia observed to date.
      In the near future, the availability of several second-line drugs will allow for a more individualised approach using a personalised combination of drugs based on whether the patient is in an early disease stage, whether there is fibrosis or if the patient suffers from pruritus or severe fatigue.
      PBC is a rare disease and with the introduction of second-line therapies in clinical practice, the recruitment of participants for future clinical trials will be a challenge. Placebo-controlled trials will no longer be possible for this indication.
      In the case of PSC, there is no approved treatment yet. The design of clinical trials is hampered by the absence of well-defined and validated endpoints. Several new drugs are being explored, including nuclear receptor agonists and norUDCA.
      Finally, medical treatment for individuals with advanced stages of both PBC and PSC is not available. This remains a major unmet need.

      Abbreviations

      ALP, alkaline phosphatase; BA, bile acid; FGF, fibroblast growth factor; FXR, farnesoid X receptor; IBAT, ileal BA transporter; LOXL2, lysyl oxidase-like 2; norUDCA, norursodeoxycholic acid; NOX, NADPH oxidase; OCA, obeticholic acid; PBC, primary biliary cholangitis; PPAR, peroxisome proliferator-activated receptor; PSC, primary sclerosing cholangitis; UDCA, ursodesoxycholic acid.

      Financial support

      The authors did not receive any financial support for writing this review.

      Conflict of interest

      F Nevens received grants from Gilead, Promethera Therapeutics and Ipsen; Consulting fees from Gilead Science, Abbvie, W.L. Gore, Cook Medical, TwinPharma, Intercept, Genkyotex, Camurus, Chemomab Therapeutics, Agomab Therapeutics, Novartis Pharma, Mayoly Spindler, Calliditas Therapeutics, Norgine, Takeda, Dynacure. M Trauner received grants from Albireo, Cymabay, Falk Pharma, Gilead, Intercept, MSD, Takeda, Alnylam and Ultragenyx; Consulting fees from Albireo, BiomX, Boehringer Ingelheim, Falk Pharma, Genfit, Intercept, Janssen, MSD, Gilead, Novartis, Shire, Phenex, Regulus and Hightide; he has a co-inventor Patent on medical use of norUDCA. MP Manns received grants from Falk Pharma, Intercept and Gilead; Consulting fee from Falk Pharma, Novartis, Intercept and Gilead.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      FN: writing the review and coordinator. MT: writing the review. MM: writing the review.

      Supplementary data

      The following are the supplementary data to this article:

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