Autoimmune Liver Diseases Dig Dis 2014;32:631–636 DOI: 10.1159/000360517
Therapeutic Role of Bile Acids and Nuclear Receptor Agonists in Fibrosing Cholangiopathies Michael Trauner Emina Halilbasic Lili Kazemi-Shirazi Christian Kienbacher Katharina Staufer Stefan Traussnigg Harald Hofer Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
Abstract Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) result in progressive fibrosis of the biliary tract and ultimately cirrhosis of the liver. Since the etiology and pathogenesis of these fibrosing cholangiopathies are still poorly understood, therapeutic options are rather limited at present. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and established standard treatment for PBC, but its role for medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid, a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g. obeticholic acid) which currently undergo clinical development for fibrosing cholangiopathies such as PBC and PSC. Other nuclear receptors such as vitamin D receptor and fatty acid-activated peroxisome proliferator-activated receptors are also of considerable interest. This review article
© 2014 S. Karger AG, Basel 0257–2753/14/0325–0631$39.50/0 E-Mail [email protected] www.karger.com/ddi
is a summary of an overview talk given at Falk Symposium 191 on Advances in Pathogenesis and Treatment of Liver Diseases held in London, October 3–4, 2013, and summarizes the recent progress with novel therapeutic bile acids and bile acid derivatives as novel therapies for fibrosing cholangiopathies such as PBC and PSC. © 2014 S. Karger AG, Basel
Introduction
Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) result in progressive fibrosis of the biliary tract and ultimately cirrhosis of the liver [1]. As a result of the considerable limitations in understanding the etiology and pathogenesis of PBC and PSC [2–7], no causal Please note that the references had to be largely limited to reviews for reasons of space constraint. We wish to apologize to the authors of several important original contributions which could not be primarily referenced and have to refer to other more extensive recent reviews from our group (e.g. [4, 5, 11–13]) listing these important original references.
Michael Trauner, MD Division of Gastroenterology and Hepatology Department of Internal Medicine III, Medical University of Vienna Waehringer Guertel 18–20, AT–1090 Vienna (Austria) E-Mail michael.trauner @ meduniwien.ac.at
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Key Words Bile acids · Nuclear receptor agonists · Fibrosing cholangiopathies · 24-norUrsodeoxycholic acid · Primary biliary cirrhosis · Primary sclerosing cholangitis
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Limitations for UDCA as Baseline Therapy in Fibrosing Cholangiopathies
The hydrophilic bile acid ursodeoxycholic acid (UDCA) has multiple mechanisms of action including stimulation of expression and function of hepatobiliary transporters and enzymes involved in bile acid synthesis and detoxification at transcriptional and post-transcriptional levels counteracting cholestatic liver injury [17–19]. As such, UDCA may target bile toxicity and also possess some immunomodulatory and anti-inflammatory effects [17–19]. Although UDCA appears to act largely at a post-transcriptional level (e.g. through activation of protein kinase C) [19], several beneficial mechanisms of UDCA may be mediated at least in part by NRs (e.g. GR, PXR) while UDCA is only a very weak agonist for the bile acid receptors FXR and TGR5 [13]. UDCA is the paradigm therapeutic bile acid which improves biochemical serum markers of cholestasis nearly regardless of the cause and may delay disease progression in many cholestatic disorders [17]. As such, UDCA is the mainstay for treatment of fibrosing cholangiopathies such as PBC and so far the only FDA-approved drug for the treatment of cholestatic disorders. While UDCA is an established treatment option for PBC (with the drawback of incomplete responders in about one third of cases) [18, 20], no established medical treatment for PSC is available [5–10]. Current evidence indicates: (i) the role of UDCA in slowing PSC progression has not been demonstrated; (ii) conventional-dose UDCA is safe, but the efficacy is unclear; (iii) high-dose UDCA (28–30 mg/kg/day) in PSC may be even harmful [reviewed in 21]. Moreover, there is limited information to support UDCA as a chemopreventive drug against colorectal or cholangiocellular cancer [21, 22]. As such, the American Association for the Study of Liver Disease (AASLD) recommendations advise against the use of UDCA in PSC [10], while the European Association for the Study of the Liver (EASL) recommendations are open for its use (especially in early-stage disease) [9], while emphasizing that the limited data do not allow a specific recommendation for the general use of UDCA in PSC [reviewed in 21]. Of note, in daily clinical practice, UDCA is combined with endoscopic therapy of dominant strictures – an approach shown to improve predicted patient survival in retrospective trials [9, 10, 22, 23]. Therefore, there is an urgent need for novel therapeutic approaches in cholangiopathies such as PSC [22].
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therapy is available and current therapeutic options are limited to drugs attenuating the disease course or liver transplantation for end-stage liver disease [5–10]. In addition to PSC, secondary (sometimes potentially treatable) causes such as recurrent bacterial cholangitis, IgG4associated cholangitis, critical illness/ischemia, portal biliopathy, AIDS cholangiopathy, cystic fibrosis-associated liver disease or other even rarer causes (e.g. eosinophilic cholangitis, systemic mastocytosis and histiocytosis X, etc.) can also lead to sclerosing cholangitis [5–9]. To handle potentially toxic cholephils under physiological and pathological conditions, the liver possesses a complex network of bile acid-activated nuclear receptor (NR)-regulated pathways that coordinate bile homeostasis and bile secretion to limit their concentrations and prevent hepatic as well as systemic accumulation [11–13]. The most relevant bile salt-activated NRs for regulation of hepatobiliary homeostasis, bile secretion and thereby understanding and treating cholestasis, include the farnesoid X receptor (FXR, NR1H4), pregnane X receptor (PXR, NR1I2) and vitamin D receptor (VDR, NR1I1). Apart from bile salts, other biliary constituents such as bilirubin can also activate NRs including the constitutive androstane receptor (CAR, NR1I3). Furthermore, other NRs like glucocorticoid receptor (GR, NR3C1) and fatty acid-activated peroxisome proliferator-activated receptors (PPARs), in particular PPARα (NR1C1) and PPARγ (NR1C3) as regulators of inflammation, fibrosis and energy homeostasis, may also impact on biliary homeostasis and cholestatic liver injury. Due to their capability to control hepatic bile acid metabolism, hepatic inflammation and fibrosis, NRs in general and bile acid-activated NRs in particular have emerged as promising therapeutic targets in many liver diseases including cholestatic disorders and fibrosing cholangiopathies [13]. This review article is focused on PSC as paradigm fibrosing cholangiopathy lacking an established or effective drug therapy frequently leading to end-stage liver disease and requiring liver transplantation [5–10]. Moreover, PSC is typically associated with a peculiar presentation of inflammatory bowel disease (IBD, now often referred to as PSC-IBD) and characterized by a significantly increased risk for malignancy within the hepatobiliary tract and large intestine [5–10, 14]. Overall, PSC carries a poor prognosis (medium survival free of liver transplantation of 12 years; 10-year survival approx. 65%) [5–10, 15, 16] and – according to Michael Manns (Hannover Medical School) – represents one of the last remaining black boxes of hepatology [M. Manns, Vienna, January 31 2011, pers. commun.] [16].
enroll 160 patients in 30 centers in 11 countries across Europe. The primary objectives are (i) to evaluate the efficacy of three doses of norUDCA (500, 1,000 and 1,500 mg/day) versus placebo for the treatment of PSC over 12 weeks and (ii) to identify the optimum dose of norUDCA for the treatment of PSC. Additionally, secondary objectives include (i) to study safety and tolerability (adverse events, laboratory parameters) of norUDCA, (ii) to assess patient-reported outcomes, and (iii) quality of life. The results of this study are eagerly awaited by the medical and patient community.
24-norUrsodeoxycholic acid (norUDCA) is a side chain-shortened derivate of UDCA which lacks a methylene group in its side chain [24]. This side chain shortening results in relative resistance to amidation with taurine or glycine compared with UDCA [25]. As such, norUDCA undergoes cholehepatic shunting with profound hepatic enrichment and ‘ductular targeting’ of bile ducts/ductules which stimulates bicarbonate-rich hypercholeresis [26–29]. Increased biliary secretion of bicarbonate counteracts bile acid toxicity by reinforcing the biliary ‘bicarbonate umbrella’ [30, 31]. Apart from these properties, norUDCA is even more hydrophilic and thereby even less toxic than its mother compound UDCA which may further help to counteract (intrinsic) biliary toxicity [24–26, 29], while UDCA even aggravates bile infarcts in (partial) biliary obstruction [26, 29, 32]. norUDCA (but not ‘conventional’ UDCA) reverses sclerosing cholangitis in the experimental Mdr2/Abcb4 knockout mouse (Mdr2/Abcb4–/–) cholangiopathy model for sclerosing cholangitis when administered over 4 weeks [26–28]. Notably, taurin-conjugated norUDCA lacks cholehepatic shunting with loss of its therapeutic efficacy [27]. A more detailed gene expression and metabolomic profiling of norUDCA effects has revealed antilipotoxic, antiproliferative, antifibrotic as well as antiinflammatory mechanisms [28] which complement mechanisms involved in stimulation of bile acid detoxification and alternative export via overflow systems at the basolateral membrane [26]. In addition, norUDCA has potent anti-inflammatory properties which target the cross-talk between reactive cholangiocytes with components of the innate immune system and inhibits mammalian target of rapamycin (mTOR) signaling, alleviates endoplasmatic reticulum (ER) stress and restores abnormal cell cycle regulation [26–28]. These properties could also be beneficial by contributing to potential antiproliferative and antifibrotic effects in non-cholestatic conditions. As a result of these encouraging experimental data in preclinical models, norUDCA is currently undergoing further clinical development in humans. Phase I clinical trials have been successfully completed and a doubleblind, randomized, multicenter, placebo-controlled, comparative, exploratory phase II dose-finding trial sponsored by Dr. Falk Pharma GmbH comparing three different doses of norUDCA with placebo in the treatment of PSC has been initiated. This phase II study will
Other interesting opportunities for targeted therapy in cholangiopathies are agents directed at the bile acid receptors TGR5 and FXR [13, 33, 34]. While FXR is a nuclear (hormone) receptor, TGR5 is a G-protein-coupled bile acid receptor at the plasma membrane; both receptors mediate the effects of bile acids in the regulation of glucose and lipid metabolism and inflammation [33, 34]. Notably, some TGR5 polymorphisms have recently been associated with the pathogenesis of PSC and ulcerative colitis [35, 36], while FXR also appears to be involved in the pathogenesis of IBD [37–40]. Selective TGR5 and FXR agonists as well as dual TGR5/FXR ligands are now available [34]. Notably, neither UDCA nor norUDCA are FXR or TGR5 ligands [28]. A 6α-ethyl derivative of CDCA [also known as 6-ECDCA or INT-747 or obeticholic acid (OCA)] had beneficial effects in mouse models of chemically-induced liver injury or in bile duct ligation as model of cholestasis [reviewed in 33, 34]. In recent phase II clinical trials in PBC patients with suboptimal biochemical response to UDCA, addition of OCA showed substantial reduction of biochemical cholestasis parameters. Moreover, OCA also improves biochemical cholestasis parameters when applied as monotherapy in PBC. Dosedependent itching was the most common adverse event in patients receiving higher doses of OCA, limiting its tolerability profile. A multicenter, placebo-controlled, randomized phase III clinical trial testing OCA in PBC patients with inadequate biochemical response to standard UDCA has recently been completed [reviewed in 13, 33, 34]. FXR ligands have not yet been tested in patients with PSC. In the Mdr2 (Abcb4)–/– cholangiopathy model a dual ligand with high affinity to FXR (INT-767, but not the clinical lead compound INT-747/OCA) was able to
Therapeutic Role of Bile Acids and NR Agonists in Fibrosing Cholangiopathies
Dig Dis 2014;32:631–636 DOI: 10.1159/000360517
Novel Bile Acid Receptor Ligands Targeting FXR and TGR5
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Mechanisms of Action and Clinical Potential of norUDCA
Table 1. Nuclear receptor agonists in fibrosing cholangiopathies: status for PSC as paradigm example [reviewed in 13 and 44]
Nuclear receptor Ligand
Rationale, mechanism
Status
FXR [41]
INT-747 (obeticholic acid), INT-767
BA homeostasis, HCO3– umbrella, inflammation (IBD?)
Preclinical (Mdr2–/–) Phase II planned? (phase III in PBC)
PPARα [45]
Fibrates
BA/PC homeostasis, inflammation (IBD?) (déjà vu – PBC)
Single cases/small series phase II completed (similar observations in PBC)
PPARγ [46]
Curcumin
Fibrosis, inflammation
Preclinical (Mdr2–/–) (dosage issue for human application)
VDR [47]
Vitamin D
Fibrosis, inflammation (cathelicidin?)
Preclinical (Mdr2–/–)
RAR [48]
Retinoic acid (atRA)
BA homeostasis, fibrosis
Preclinical (CBDL) Open-label study currently recruiting
BA = Bile acid; CBDL = common bile duct ligation; PC = phosphatidylcholine.
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Summary and Outlook
While UDCA prolongs survival in PBC patients showing a sufficient biochemical response, so far no established drug therapy for those with suboptimal biochemical response or PSC patients is available. Therefore, an urgent medical need for novel therapies targeting fibrosing cholangiopathies exists. norUDCA appears to be one of the most promising novel treatment approaches targeting the bile duct system at a multifactorial and multicellular level and is currently undergoing a multicenter phase II clinical trial for PSC in Europe. Alternative approaches may target NRs for bile acids such as FXR which could combine the treatment of the liver disease and associated IBD. In addition to FXR, other NRs such as VDR and PPAR also represent interesting therapeutic targets in fibrosing cholangiopathies [13, 44]. In view of the possibility that biliary infection or composition of the gut microbiota may contribute to PSC pathogenesis, the role of antibiotics (and pre-/probiotics) deserves re-evaluation, especially since antibiotics may also exert direct anti-inflammatory, antiapoptotic, and immunomodulatory actions [reviewed in 5–7]. Although therapeutic strategies against tumor necrosis factor (e.g. infliximab, pentoxifylline) have been ineffective in PSC, the potential of newer biologic agents targeting the gut deserves further evaluation. These include ustekinumab (anti-interleukin-12 and -23), vedolizumab (a gut-specific α4β7-integrin-neutralising monoclonal antibody), and CCX282B (a small-molecule inhibitor of chemokine receptor 9) [5–7]. The tyrosine kinase/janus kinase inhibitor tofacitinib has been shown to have beneficial effects in ulcerTrauner et al.
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cure bile duct injury [41]. Subsequent studies in FXR knockout mice revealed that these effects were mediated exclusively by FXR and not by TGR5. The therapeutic mechanisms involved suppression of bile acid synthesis and anti-inflammatory as well as antifibrotic effects [41]. Whether stimulation of FXR has direct antifibrotic effects is still a matter of debate, but the virtual absence of FXR in myofibroblasts and hepatic stellate cells suggests that the observed antifibrotic effects may rather be secondary to improvement of cholestasis and inflammation [42]. Notably, similar to norUDCA, this therapeutic effect was also linked to generation of a bicarbonate-rich choleresis [41] which appears to be a common denominator for successful treatment of cholangiopathies in general [29, 30]. However, a recent study revealed that intestinal overexpression of FXR was also able to cure biliary injury in various models of cholestasis including Mdr2 (Abcb4)–/– mice, effects which may be linked to FGF15/19-mediated suppression of bile acid synthesis [43] independent of bicarbonate-rich choleresis. In addition to FXR, other (bile acid-activated) NRs such as PPAR, VDR and retinoic acid receptor (RAR) may also hold some promise for treatment of fibrosing cholangiopathies such as PSC (table 1) [reviewed in 13, 44]. The role of fibrates (liganding PPARα) in PBC has recently been reviewed elsewhere [13, 44] and also holds some promise in PSC [45]. Besides its role in regulation of fatty acid metabolism, PPARα is involved in the regulation of bile acid homeostasis and has anti-inflammatory properties, making PPARα an attractive therapeutic target in cholestatic liver diseases including fibrosing cholangiopathies [13, 14].
ative colitis and to be associated with decreases in proinflammatory cytokine signaling, T-cell differentiation, and lipopolysaccaride-induced innate immune responses (pathways which are also involved in PSC pathogenesis). Directly inhibiting progressive fibrosis remains an attractive target in PSC as paradigm fibrosing cholangiopathy, and simtuzumab, a monoclonal antibody against lysyl oxidase homolog 2 (an extracellular matrix protein/enzyme), is currently under evaluation in clinical studies. Finally, tyrosine kinase inhibitors may also have antifibrotic actions [5–7]. Collectively, the translation of the expanding knowledge from animal experimental models should result in optimization of the currently available therapies for chronic inflammatory bile duct diseases/fibrosing cholangiopathies such as PSC.
Acknowledgement This work was supported by grants F3008-B05 and F3517-B20 from the Austrian Science Foundation (to M.T.). The final results of a phase III clinical trial on OCA in PBC have recently been reported at the EASL International Liver Congress in London, April 2014 (Nevens et al., late breaking oral presentation).
Disclosure Statement The Medical University of Graz has filed a patent on the medical use of norUDCA and M.T. is listed as coinventor.
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Therapeutic Role of Bile Acids and NR Agonists in Fibrosing Cholangiopathies
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27 Halilbasic E, Fiorotto R, Fickert P, Marschall HU, Moustafa T, Spirli C, Fuchsbichler A, Gumhold J, Silbert D, Zatloukal K, Langner C, Maitra U, Denk H, Hofmann AF, Strazzabosco M, Trauner M: Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2–/– mice. Hepatology 2009; 49: 1972– 1981. 28 Moustafa T, Fickert P, Magnes C, Guelly C, Thueringer A, Frank S, Kratky D, Sattler W, Reicher H, Sinner F, Gumhold J, Silbert D, Fauler G, Höfler G, Lass A, Zechner R, Trauner M: Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology 2012;142:140–151. 29 Fickert P, Pollheimer MJ, Silbert D, Moustafa T, Halilbasic E, Krones E, Durchschein F, Thüringer A, Zollner G, Denk H, Trauner M: Differential effects of norUDCA and UDCA in obstructive cholestasis in mice. J Hepatol 2013;58:1201–1208. 30 Beuers U, Hohenester S, de Buy Wenniger LJ, Kremer AE, Jansen PL, Elferink RP: The biliary HCO3– umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology 2010; 52:1489–1496. 31 Beuers U, Maroni L, Elferink RO: The biliary HCO3– umbrella: experimental evidence revisited. Curr Opin Gastroenterol 2012; 28: 253–257. 32 Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Weiglein AH, Lammert F, Marschall HU, Tsybrovskyy O, Zatloukal K, Denk H, Trauner M: Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology 2002;123:1238–1251. 33 Trauner M, Halilbasic E: Nuclear receptors as new perspective for the management of liver diseases. Gastroenterology 2011; 140: 1120– 1125. 34 Schaap FG, Trauner M, Jansen PL: Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 2014; 11: 55– 67.
Therapeutic Role of Bile Acids and Nuclear Receptor Agonists in Fibrosing Cholangiopathies Michael Trauner Emina Halilbasic Lili Kazemi-Shirazi Christian Kienbacher Katharina Staufer Stefan Traussnigg Harald Hofer Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
Abstract Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) result in progressive fibrosis of the biliary tract and ultimately cirrhosis of the liver. Since the etiology and pathogenesis of these fibrosing cholangiopathies are still poorly understood, therapeutic options are rather limited at present. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and established standard treatment for PBC, but its role for medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid, a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g. obeticholic acid) which currently undergo clinical development for fibrosing cholangiopathies such as PBC and PSC. Other nuclear receptors such as vitamin D receptor and fatty acid-activated peroxisome proliferator-activated receptors are also of considerable interest. This review article
© 2014 S. Karger AG, Basel 0257–2753/14/0325–0631$39.50/0 E-Mail [email protected] www.karger.com/ddi
is a summary of an overview talk given at Falk Symposium 191 on Advances in Pathogenesis and Treatment of Liver Diseases held in London, October 3–4, 2013, and summarizes the recent progress with novel therapeutic bile acids and bile acid derivatives as novel therapies for fibrosing cholangiopathies such as PBC and PSC. © 2014 S. Karger AG, Basel
Introduction
Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) result in progressive fibrosis of the biliary tract and ultimately cirrhosis of the liver [1]. As a result of the considerable limitations in understanding the etiology and pathogenesis of PBC and PSC [2–7], no causal Please note that the references had to be largely limited to reviews for reasons of space constraint. We wish to apologize to the authors of several important original contributions which could not be primarily referenced and have to refer to other more extensive recent reviews from our group (e.g. [4, 5, 11–13]) listing these important original references.
Michael Trauner, MD Division of Gastroenterology and Hepatology Department of Internal Medicine III, Medical University of Vienna Waehringer Guertel 18–20, AT–1090 Vienna (Austria) E-Mail michael.trauner @ meduniwien.ac.at
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Key Words Bile acids · Nuclear receptor agonists · Fibrosing cholangiopathies · 24-norUrsodeoxycholic acid · Primary biliary cirrhosis · Primary sclerosing cholangitis
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Limitations for UDCA as Baseline Therapy in Fibrosing Cholangiopathies
The hydrophilic bile acid ursodeoxycholic acid (UDCA) has multiple mechanisms of action including stimulation of expression and function of hepatobiliary transporters and enzymes involved in bile acid synthesis and detoxification at transcriptional and post-transcriptional levels counteracting cholestatic liver injury [17–19]. As such, UDCA may target bile toxicity and also possess some immunomodulatory and anti-inflammatory effects [17–19]. Although UDCA appears to act largely at a post-transcriptional level (e.g. through activation of protein kinase C) [19], several beneficial mechanisms of UDCA may be mediated at least in part by NRs (e.g. GR, PXR) while UDCA is only a very weak agonist for the bile acid receptors FXR and TGR5 [13]. UDCA is the paradigm therapeutic bile acid which improves biochemical serum markers of cholestasis nearly regardless of the cause and may delay disease progression in many cholestatic disorders [17]. As such, UDCA is the mainstay for treatment of fibrosing cholangiopathies such as PBC and so far the only FDA-approved drug for the treatment of cholestatic disorders. While UDCA is an established treatment option for PBC (with the drawback of incomplete responders in about one third of cases) [18, 20], no established medical treatment for PSC is available [5–10]. Current evidence indicates: (i) the role of UDCA in slowing PSC progression has not been demonstrated; (ii) conventional-dose UDCA is safe, but the efficacy is unclear; (iii) high-dose UDCA (28–30 mg/kg/day) in PSC may be even harmful [reviewed in 21]. Moreover, there is limited information to support UDCA as a chemopreventive drug against colorectal or cholangiocellular cancer [21, 22]. As such, the American Association for the Study of Liver Disease (AASLD) recommendations advise against the use of UDCA in PSC [10], while the European Association for the Study of the Liver (EASL) recommendations are open for its use (especially in early-stage disease) [9], while emphasizing that the limited data do not allow a specific recommendation for the general use of UDCA in PSC [reviewed in 21]. Of note, in daily clinical practice, UDCA is combined with endoscopic therapy of dominant strictures – an approach shown to improve predicted patient survival in retrospective trials [9, 10, 22, 23]. Therefore, there is an urgent need for novel therapeutic approaches in cholangiopathies such as PSC [22].
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therapy is available and current therapeutic options are limited to drugs attenuating the disease course or liver transplantation for end-stage liver disease [5–10]. In addition to PSC, secondary (sometimes potentially treatable) causes such as recurrent bacterial cholangitis, IgG4associated cholangitis, critical illness/ischemia, portal biliopathy, AIDS cholangiopathy, cystic fibrosis-associated liver disease or other even rarer causes (e.g. eosinophilic cholangitis, systemic mastocytosis and histiocytosis X, etc.) can also lead to sclerosing cholangitis [5–9]. To handle potentially toxic cholephils under physiological and pathological conditions, the liver possesses a complex network of bile acid-activated nuclear receptor (NR)-regulated pathways that coordinate bile homeostasis and bile secretion to limit their concentrations and prevent hepatic as well as systemic accumulation [11–13]. The most relevant bile salt-activated NRs for regulation of hepatobiliary homeostasis, bile secretion and thereby understanding and treating cholestasis, include the farnesoid X receptor (FXR, NR1H4), pregnane X receptor (PXR, NR1I2) and vitamin D receptor (VDR, NR1I1). Apart from bile salts, other biliary constituents such as bilirubin can also activate NRs including the constitutive androstane receptor (CAR, NR1I3). Furthermore, other NRs like glucocorticoid receptor (GR, NR3C1) and fatty acid-activated peroxisome proliferator-activated receptors (PPARs), in particular PPARα (NR1C1) and PPARγ (NR1C3) as regulators of inflammation, fibrosis and energy homeostasis, may also impact on biliary homeostasis and cholestatic liver injury. Due to their capability to control hepatic bile acid metabolism, hepatic inflammation and fibrosis, NRs in general and bile acid-activated NRs in particular have emerged as promising therapeutic targets in many liver diseases including cholestatic disorders and fibrosing cholangiopathies [13]. This review article is focused on PSC as paradigm fibrosing cholangiopathy lacking an established or effective drug therapy frequently leading to end-stage liver disease and requiring liver transplantation [5–10]. Moreover, PSC is typically associated with a peculiar presentation of inflammatory bowel disease (IBD, now often referred to as PSC-IBD) and characterized by a significantly increased risk for malignancy within the hepatobiliary tract and large intestine [5–10, 14]. Overall, PSC carries a poor prognosis (medium survival free of liver transplantation of 12 years; 10-year survival approx. 65%) [5–10, 15, 16] and – according to Michael Manns (Hannover Medical School) – represents one of the last remaining black boxes of hepatology [M. Manns, Vienna, January 31 2011, pers. commun.] [16].
enroll 160 patients in 30 centers in 11 countries across Europe. The primary objectives are (i) to evaluate the efficacy of three doses of norUDCA (500, 1,000 and 1,500 mg/day) versus placebo for the treatment of PSC over 12 weeks and (ii) to identify the optimum dose of norUDCA for the treatment of PSC. Additionally, secondary objectives include (i) to study safety and tolerability (adverse events, laboratory parameters) of norUDCA, (ii) to assess patient-reported outcomes, and (iii) quality of life. The results of this study are eagerly awaited by the medical and patient community.
24-norUrsodeoxycholic acid (norUDCA) is a side chain-shortened derivate of UDCA which lacks a methylene group in its side chain [24]. This side chain shortening results in relative resistance to amidation with taurine or glycine compared with UDCA [25]. As such, norUDCA undergoes cholehepatic shunting with profound hepatic enrichment and ‘ductular targeting’ of bile ducts/ductules which stimulates bicarbonate-rich hypercholeresis [26–29]. Increased biliary secretion of bicarbonate counteracts bile acid toxicity by reinforcing the biliary ‘bicarbonate umbrella’ [30, 31]. Apart from these properties, norUDCA is even more hydrophilic and thereby even less toxic than its mother compound UDCA which may further help to counteract (intrinsic) biliary toxicity [24–26, 29], while UDCA even aggravates bile infarcts in (partial) biliary obstruction [26, 29, 32]. norUDCA (but not ‘conventional’ UDCA) reverses sclerosing cholangitis in the experimental Mdr2/Abcb4 knockout mouse (Mdr2/Abcb4–/–) cholangiopathy model for sclerosing cholangitis when administered over 4 weeks [26–28]. Notably, taurin-conjugated norUDCA lacks cholehepatic shunting with loss of its therapeutic efficacy [27]. A more detailed gene expression and metabolomic profiling of norUDCA effects has revealed antilipotoxic, antiproliferative, antifibrotic as well as antiinflammatory mechanisms [28] which complement mechanisms involved in stimulation of bile acid detoxification and alternative export via overflow systems at the basolateral membrane [26]. In addition, norUDCA has potent anti-inflammatory properties which target the cross-talk between reactive cholangiocytes with components of the innate immune system and inhibits mammalian target of rapamycin (mTOR) signaling, alleviates endoplasmatic reticulum (ER) stress and restores abnormal cell cycle regulation [26–28]. These properties could also be beneficial by contributing to potential antiproliferative and antifibrotic effects in non-cholestatic conditions. As a result of these encouraging experimental data in preclinical models, norUDCA is currently undergoing further clinical development in humans. Phase I clinical trials have been successfully completed and a doubleblind, randomized, multicenter, placebo-controlled, comparative, exploratory phase II dose-finding trial sponsored by Dr. Falk Pharma GmbH comparing three different doses of norUDCA with placebo in the treatment of PSC has been initiated. This phase II study will
Other interesting opportunities for targeted therapy in cholangiopathies are agents directed at the bile acid receptors TGR5 and FXR [13, 33, 34]. While FXR is a nuclear (hormone) receptor, TGR5 is a G-protein-coupled bile acid receptor at the plasma membrane; both receptors mediate the effects of bile acids in the regulation of glucose and lipid metabolism and inflammation [33, 34]. Notably, some TGR5 polymorphisms have recently been associated with the pathogenesis of PSC and ulcerative colitis [35, 36], while FXR also appears to be involved in the pathogenesis of IBD [37–40]. Selective TGR5 and FXR agonists as well as dual TGR5/FXR ligands are now available [34]. Notably, neither UDCA nor norUDCA are FXR or TGR5 ligands [28]. A 6α-ethyl derivative of CDCA [also known as 6-ECDCA or INT-747 or obeticholic acid (OCA)] had beneficial effects in mouse models of chemically-induced liver injury or in bile duct ligation as model of cholestasis [reviewed in 33, 34]. In recent phase II clinical trials in PBC patients with suboptimal biochemical response to UDCA, addition of OCA showed substantial reduction of biochemical cholestasis parameters. Moreover, OCA also improves biochemical cholestasis parameters when applied as monotherapy in PBC. Dosedependent itching was the most common adverse event in patients receiving higher doses of OCA, limiting its tolerability profile. A multicenter, placebo-controlled, randomized phase III clinical trial testing OCA in PBC patients with inadequate biochemical response to standard UDCA has recently been completed [reviewed in 13, 33, 34]. FXR ligands have not yet been tested in patients with PSC. In the Mdr2 (Abcb4)–/– cholangiopathy model a dual ligand with high affinity to FXR (INT-767, but not the clinical lead compound INT-747/OCA) was able to
Therapeutic Role of Bile Acids and NR Agonists in Fibrosing Cholangiopathies
Dig Dis 2014;32:631–636 DOI: 10.1159/000360517
Novel Bile Acid Receptor Ligands Targeting FXR and TGR5
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Mechanisms of Action and Clinical Potential of norUDCA
Table 1. Nuclear receptor agonists in fibrosing cholangiopathies: status for PSC as paradigm example [reviewed in 13 and 44]
Nuclear receptor Ligand
Rationale, mechanism
Status
FXR [41]
INT-747 (obeticholic acid), INT-767
BA homeostasis, HCO3– umbrella, inflammation (IBD?)
Preclinical (Mdr2–/–) Phase II planned? (phase III in PBC)
PPARα [45]
Fibrates
BA/PC homeostasis, inflammation (IBD?) (déjà vu – PBC)
Single cases/small series phase II completed (similar observations in PBC)
PPARγ [46]
Curcumin
Fibrosis, inflammation
Preclinical (Mdr2–/–) (dosage issue for human application)
VDR [47]
Vitamin D
Fibrosis, inflammation (cathelicidin?)
Preclinical (Mdr2–/–)
RAR [48]
Retinoic acid (atRA)
BA homeostasis, fibrosis
Preclinical (CBDL) Open-label study currently recruiting
BA = Bile acid; CBDL = common bile duct ligation; PC = phosphatidylcholine.
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Summary and Outlook
While UDCA prolongs survival in PBC patients showing a sufficient biochemical response, so far no established drug therapy for those with suboptimal biochemical response or PSC patients is available. Therefore, an urgent medical need for novel therapies targeting fibrosing cholangiopathies exists. norUDCA appears to be one of the most promising novel treatment approaches targeting the bile duct system at a multifactorial and multicellular level and is currently undergoing a multicenter phase II clinical trial for PSC in Europe. Alternative approaches may target NRs for bile acids such as FXR which could combine the treatment of the liver disease and associated IBD. In addition to FXR, other NRs such as VDR and PPAR also represent interesting therapeutic targets in fibrosing cholangiopathies [13, 44]. In view of the possibility that biliary infection or composition of the gut microbiota may contribute to PSC pathogenesis, the role of antibiotics (and pre-/probiotics) deserves re-evaluation, especially since antibiotics may also exert direct anti-inflammatory, antiapoptotic, and immunomodulatory actions [reviewed in 5–7]. Although therapeutic strategies against tumor necrosis factor (e.g. infliximab, pentoxifylline) have been ineffective in PSC, the potential of newer biologic agents targeting the gut deserves further evaluation. These include ustekinumab (anti-interleukin-12 and -23), vedolizumab (a gut-specific α4β7-integrin-neutralising monoclonal antibody), and CCX282B (a small-molecule inhibitor of chemokine receptor 9) [5–7]. The tyrosine kinase/janus kinase inhibitor tofacitinib has been shown to have beneficial effects in ulcerTrauner et al.
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cure bile duct injury [41]. Subsequent studies in FXR knockout mice revealed that these effects were mediated exclusively by FXR and not by TGR5. The therapeutic mechanisms involved suppression of bile acid synthesis and anti-inflammatory as well as antifibrotic effects [41]. Whether stimulation of FXR has direct antifibrotic effects is still a matter of debate, but the virtual absence of FXR in myofibroblasts and hepatic stellate cells suggests that the observed antifibrotic effects may rather be secondary to improvement of cholestasis and inflammation [42]. Notably, similar to norUDCA, this therapeutic effect was also linked to generation of a bicarbonate-rich choleresis [41] which appears to be a common denominator for successful treatment of cholangiopathies in general [29, 30]. However, a recent study revealed that intestinal overexpression of FXR was also able to cure biliary injury in various models of cholestasis including Mdr2 (Abcb4)–/– mice, effects which may be linked to FGF15/19-mediated suppression of bile acid synthesis [43] independent of bicarbonate-rich choleresis. In addition to FXR, other (bile acid-activated) NRs such as PPAR, VDR and retinoic acid receptor (RAR) may also hold some promise for treatment of fibrosing cholangiopathies such as PSC (table 1) [reviewed in 13, 44]. The role of fibrates (liganding PPARα) in PBC has recently been reviewed elsewhere [13, 44] and also holds some promise in PSC [45]. Besides its role in regulation of fatty acid metabolism, PPARα is involved in the regulation of bile acid homeostasis and has anti-inflammatory properties, making PPARα an attractive therapeutic target in cholestatic liver diseases including fibrosing cholangiopathies [13, 14].
ative colitis and to be associated with decreases in proinflammatory cytokine signaling, T-cell differentiation, and lipopolysaccaride-induced innate immune responses (pathways which are also involved in PSC pathogenesis). Directly inhibiting progressive fibrosis remains an attractive target in PSC as paradigm fibrosing cholangiopathy, and simtuzumab, a monoclonal antibody against lysyl oxidase homolog 2 (an extracellular matrix protein/enzyme), is currently under evaluation in clinical studies. Finally, tyrosine kinase inhibitors may also have antifibrotic actions [5–7]. Collectively, the translation of the expanding knowledge from animal experimental models should result in optimization of the currently available therapies for chronic inflammatory bile duct diseases/fibrosing cholangiopathies such as PSC.
Acknowledgement This work was supported by grants F3008-B05 and F3517-B20 from the Austrian Science Foundation (to M.T.). The final results of a phase III clinical trial on OCA in PBC have recently been reported at the EASL International Liver Congress in London, April 2014 (Nevens et al., late breaking oral presentation).
Disclosure Statement The Medical University of Graz has filed a patent on the medical use of norUDCA and M.T. is listed as coinventor.
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Therapeutic Role of Bile Acids and NR Agonists in Fibrosing Cholangiopathies
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