Time for the dawn of multimodal therapies and the dusk for mono- therapeutic trials for cholestatic liver diseases?

1 | INTRODUCTION

Cholestatic liver diseases comprise a complex spectrum of hereditary and acquired hepatobiliary disorders, which at some later time- point will manifest with jaundice, elevated bile acids and in some cases impaired bile flow, the hallmarks of clinically overt cholestasis. However, as variable as aetiology, as variable is their disease course. At a given time- point chronic cholestatic liver diseases will show various aspects of earlier or current immune- mediated, later bile- acid and inflammation- induced toxic injury as well as late adaptive responses and fibrotic repair. From this point of view, it may appear rather simplistic to target such complex diseases with a “one- pill- that- fits- all” phases and stages strategy. Rather, more complex therapeutic concepts, which take disease stages (ie disease progression) and phases (ie time- course) as well as spatiotemporal variability within the liver into account, may be favourable.
Recently, Peter Jansen and co- workers proposed a thought- provoking pathophysiological concept of spatiotemporal disease development for chronic cholestatic liver disease, which may particularly apply for primary biliary cholangitis (PBC) and (primary) sclerosing cholangitis (PSC).1 In this model, cholestatic disease development follows an “ascending” pattern, which starts which an immune- modulated necro- inflammation in some large (in PSC) or small (in PBC) bile ducts. This early non- or poor- symptomatic cholangitic phase may precede clinically overt cholestasis with jaundice by years, but eventually bile leakage and bile acid- mediated inflammatory response result in local toxic injury. Adaptive anti- cholestatic events on the level of the biliary tree, the canalicular network and the hepatocytes may successfully compensate for parenchymal injury and further mitigate symptoms. This may be one reason for the long symptom- poor natural course of this type of diseases before finally overt cholestasis, cirrhosis and portal hypertension develops in more progressed and end- stage disease.1 Multimodal anticholestatic strategies therefore should include ideally immune- modulating, anti- inflammatory, bile acid toxicity- reducing and antifibrotic properties, with emphasis on immunogenic objectives earlier and antitoxic and antifibrotic targets later in disease course. However, since spatiotemporal progression will likely vary even in different areas of the liver and cannot clinically be distinguished by currently established biomarkers, combination therapies will be required.

2 | WHY DOES UDCA WORK IN CHOLESTATIC LIVER DISEASES?

Ursodeoxycholic acid (UDCA) monotherapy is the primary anticholestatic drug for several cholestatic liver diseases including PBC, intrahepatic cholestasis of pregnancy and liver involvement in cystic fibrosis, while for other cholestatic entities UDCA alone does not work, particular not for PSC.2,3 UDCA has multiple sites of action to counteract cholestasis. It shows immunomodulatory effects by interfering with MHC class I/II presentation as well as anti- inflammatory effects on macrophages, although the latter effects are questionable to occur within the typical pharmacological dose range.2,3 UDCA reduces bile acid- mediated toxicity because of its anti- apoptotic and ER- stress relieving properties and by induction of a bicarbonate- rich biliary choleresis which lowers toxic bile acid concentrations and counteracts biliary stasis. Moreover, UDCA enhances hepatocellular adaptation by upregulating bile acid- transporting systems and reducing bile acid synthesis.2,3 Overall, UDCA shows anticholestatic qualities at different disease stages and phases on hepatocyte and bile duct level and is therefore the basic main stay in anticholestatic therapy.

3 | WHY DO WE NEED ADDITIONAL THERAPY?

In PSC, UDCA has no survival- or transplantation- free- survival benefit. In PBC, complete responders to UDCA therapy have normal life expectancy4 but 25%- 50% of the patients do not satisfactory respond to UDCA treatment and 15% may develop cirrhosis- associated non- neoplastic complications.5 It remains unclear why some PBC patients only respond incompletely to UDCA therapy and there has been no biomarker identified that distinguishes potential UDCA responders from non- responders. Thus, currently we cannot stratify for more targeted and individualised therapy with novel immune- modulatory, anti- inflammatory, bile- acid reducing, choleretic or antifibrotic interventions.
Several novel mono- therapeutic treatments options are currently being intensively tested for various cholestatic disorders, including PSC. Some of these drugs show, similar to UDCA, multiple sites for anticholestatic action. Obeticholic acid (OCA), an agonist to the bile acid receptor FXR, has already been approved as second line therapy for PBC patients, who inadequately respond to UDCA therapy.6 Also, phase II studies for OCA in PSC (AESOP trial NCT02177136) are underway. FXR agonists primarily act on hepatocytes and ileocytes to suppress de novo bile acid synthesis and to support cell- protective adaptive transporter responses.7 Thus, the main action of FXR agonists is later in disease course and presumes that bile acid synthesis is not reduced. In addition, FXR agonists also inherit some anti- inflammatory, choleretic and potentially also anti- fibrotic effects,7 which similar to UDCA- broaden the overall anticholestatic properties of this class of compounds. However, approx. 40% of OCA- treated UDCA nonresponders do not adequately respond to OCA, underpinning the need for even more powerful anticholestatic concepts. PPARα agonists are another veritable approved option in PBC for UDCA nonresponders and are also investigated for PSC (trial NCT01142323). Also PPARα agonists have at least a dual anticholestatic mode of action. PPARα agonists induce biliary phospholipid secretion, supposedly protecting the bile ducts and have anti- inflammatory action.7 However, long- term treatment with bezafibrate did not increase survival in PBC.8 PPARδ agonists, currently tested for PBC (trial NCT03301506 and NCT02609048), reduce bile acid synthesis, are anti- inflammatory and anti- fibrotic, and are another promising future multi- action tool for cholestatic disorders.9 All together, these compounds have multiple beneficial anticholestatic effects but it remains doubtful if these single- drug effects are powerful enough for the treatment of challenging cholestatic diseases such as PSC.
There exist more anticholestatic compounds, which in contrast to the aforementioned drugs, do not possess multiple anticholestatic properties but show a single very potent anticholestatic feature. NorUDCA is the most powerful inducer of bicarbonate- rich biliary hypercholeresis to protect bile ducts, and has shown promising effects in a phase II clinical PSC trial.10 FGF19 mimetics potently reduce bile acid synthesis (trial NCT02704364 and NCT02135536).11 ASBT (CLARITY trial NCT01904058 and NCT02061540) and NTCP inhibitors effectively reduce intestinal and hepatocellular bile acid re- uptake and significantly lower bile acid pools.12 Lysyloxidase inhibitors are antifibrotic and should act at late disease stages (trial NCT01672853). Finally, there are several strategies to selectively modulate immunogenic functions which may act earlier during disease development. This includes the CCR2/CCR5 antagonist cenicriviroc (PERSEUS trial NCT02653625), the anti- VAP1 antibody timolumab (trial NCT02239211), the integrin blocker vedolizumab (trial NCT03035058), the CD40 blocker FFP104 (trial NCT02193360), the interleukin 12 and 23 antagonist ustekinumab (trial NCT01389973), the anti- CD 20 antibody rituximab (trial NCT00364819) and abatacept as an inhibitor of the antigen presentencing cells and T cell activation (trial NCT02078882) (list not complete). In addition, attempts to target the gut microbiome such as faecal microbiota transplantation (trial NCT02424175) or gut selective antibiotic eradication with vancomycin (eg trial NCT01802073 or NCT01085760) or rifaximin (trial NCT01695174) also may finally contribute to immunomodulatory effects.

4 | WHY DO WE NEED MULTIMODAL COMBINATION THERAPY?

Chronic cholestatic liver diseases such as PBC and particular PSC show spatiotemporal features of an immunogenic, inflammatory, bile- acid toxic and fibrotic injury along with cellular and ductular adaptations. Selectively targeting only one of these features may result in negative short- term results in clinical trials, use of single multi- acting compounds may result in too weak anticholestatic effects for beneficial long- term results on overall- or transplant- free survival. In this issue of Liver International Dongke Yu from Jim Boyer’s group nicely supports the above raised theoretical considerations.13 They studied anticholestatic drug combinations in two different rodent models of cholestasis, ie common bile duct ligated rats as an extreme model for acute biliary obstruction and Mdr2 (Abcb4) knockout mice, which phenotypically resemble human PSC and are the preferred animal model for preclinical drug testing.14 Animals were fed either all- trans retinoic acid, which activates FXR and repress bile acid synthesis or cenicriviroc, an antagonist to both chemokine receptors CCR2 & CCR5 that are expressed in many inflammatory cells including neutrophils, T- cells and monocytes or a animals were treated with combination of both. Interestingly, while the effects of the single compounds were moderate, the most prominent results on liver injury, inflammation, fibrosis and bile acid levels were seen when both drugs were administered synergistically. Consequently, the authors concluded that “multi- targeted therapy is an important paradigm for treating cholestatic liver injury” and that this combination therapy may warrant further clinical testing. Along with these interesting preclinical data we also suggest for future clinical trials in PSC or PBC combining immunomodulatory drugs with bile acid pool- reducing agents or choleretic substances, or, if disease stage is more advanced, with anti- fibrotic strategies (Figure 1). Particularly, since several of the drugs have already been safely used for different diseases (eg vedolizumab) or passed phase II trials safely, but did not meet primary endpoints as single compound (eg simtuzumab),15 combinatory efforts appear to be plausible from a clinical perspective.
The biggest success story in Hepatology in the last decades is the treatment of hepatitis C. Hepatitis C has been treated with modest success for many years with interferon alpha which has multiple effects on the immune system and virus replication. Combination with ribavirin almost doubled the efficacy to moderate 35% response rates. However, only development and combination of specific antiviral polymerase, protease and additional viral target inhibitors allowed almost 100% virus eradication. Advances in understanding the pathogenesis of cholestatic liver diseases have shown us several attractive and specific therapeutic targets, which now need to be addressed synergistically.

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