Domenico Alvaro, MD
Sapienza University of Rome, Division of Gastroenterology, Department of Internal Medicine and Medical Specialties, Viale del Policlinico 151, 000161 ROME, ITALY.

Q. WHY IS THE ACTIVATION OF FXR GAINING INTEREST AS A THERAPEUTIC TARGET IN CHRONIC CHOLESTATIC LIVER DISEASES?

FXR signaling protects hepatocytes against bile salt (BS) toxicity by inhibiting their synthesis (via the inhibition of CYP7A1 and CYP8A1), increasing their excretion, and reducing liver uptake and intestinal reabsorption [1]. In addition, FXR regulates other pathways with direct anti-inflammatory and anti-fibrotic effects. For years, we have treated primary biliary cholangitis (PBC) by using an approach (ursodeoxycholic acid, UDCA) which aimed to qualitatively change (by decreasing hydrophobicity) the BS pool composition [1]. Now, we are approaching a strategy which is directed at quantitatively decreasing the BS pool size and the intrahepatic BS concentration [1]. This should help in counteracting the apoptotic, pro-inflammatory, and pro-fibrogenic activities of BS accumulating in the liver in cholestatic pathologies. This new approach, which began with FXR agonists, is now extending further, with investigations into fibroblast growth factor 19 (FGF19) analogues and mimetics [2] as well as apical ileal bile salt transporter inhibitors [3]. However, it is important to state that also with this new approach we are not triggering the cause of cholestasis (virtually unknown for PBC), but only the detrimental consequences of retained BS. Nevertheless, given the promising experimental and clinical results, a number of FXR agonists are under development.

Q. COULD FXR AGONISTS EXERT BENEFICIAL EFFECTS ON PBC BY ACTING ON THE GUT-LIVER AXIS?

FXR is a central transcriptional sensor of bile acid metabolism, and one of its key target genes is intestinal FGF19 which encodes an enterokine released into portal circulation following BS activation of FXR [1]. FGF19 inhibits BS synthesis in the liver while exerting a number of effects on cell proliferation and inflammation. In addition to this mechanism, we cannot neglect the role of intestinal FXR on the gut microbioma and intestinal barrier integrity [4]. The biliary tree, as part of the enterohepatic circulation, is exposed to a huge number of enterotoxins at its luminal pole where the physico-chemical and immune tolerance of the biliary epithelium is fundamental to avoid damage. There are new insights that in PBC the composition of the intestinal and biliary microbiota and their mutual interactions with the host are altered as a consequence of the decreased BS concentration in the intestinal lumen [5]. In addition, the expansion of individual microbes leads to altered integrity of epithelial layers, promoting microbial translocation. FXR activation preserves the integrity of the intestinal epithelial barrier, counteracts NF-kB-mediated immune responses, inhibits inflammatory signaling in various primary human immune cell types and, finally, results in the enhanced synthesis of antimicrobial proteins (AMPs) on epithelial surfaces which directly kill or inhibit the growth of microorganisms favored by a lower BS concentration in the gut lumen [4].

Q. WHY SHOULD FXR AGONISTS WORK IN PBC PATIENTS UNRESPONSIVE TO UDCA?

PBC is a heterogeneous disease, both at the histological as well as the clinical level. At diagnosis, a number of variables have been considered as negative predictors of UDCA non response including ductopenia, advanced fibrosis stages, and interface hepatitis [6]. We don’t know why approximately 40% of PBC patients are unresponsive to UDCA, and the lack of adequate histological information doesn’t help in this setting. It is likely that in these patients FXR agonists add more effective mechanisms to UDCA, including counteraction of the pro-inflammatory and pro-fibrogenic activities of retained BS, as well as other more recently discovered mechanisms such as the capability of activated FXR to inhibit the activation of inflammasome components in macrophages and to reduce endotoxemia in cholestasis [7].

Q. DO WE HAVE EVIDENCE THAT FXR AGONISTS COULD HALT THE PROGRESSION OF THE DISEASE AND IMPROVE CLINICAL OUTCOMES IN UDCA NON-RESPONDER PBC PATIENTS?

Unfortunately, we have only indirect evidence based on the measurement of surrogate markers during treatment with obeticholic acid (OCA) in PBC patients unresponsive to UDCA. In pivotal studies and in particular in the POISE trial [8] a composite primary endpoint was based on alkaline phosphatase (ALP) <1.67 upper limit of normal (ULN), ALP reduction of at least by 15% from baseline and total bilirubin lower than or equal to ULN, at 12 months. The primary endpoint was reached by 47% of patients taking OCA. In the extension open-label phase the composite end point was reached, after 12-month, in approximately 50% of patients. In addition, when the UK-PBC prognostic score [9] was applied to these patients, those who crossed over from placebo to OCA experienced a significant reduction in the predicted risk of developing end stage liver disease (ESLD). Specifically, while the predicted relative risk of ESLD increased by approximately 15% after 5, 10 and 15 years in patients remaining in the placebo arm for 12 months, this risk decreased by approximately 20% after 12 and 24 months of OCA treatment [10]. A limitation of this analysis is that the UK-PBC score was developed based on response to UDCA and has not been validated for use with OCA. Apart from this limitation, although based on robust data, the prognostic score takes into account surrogate markers of disease progression including ALP, bilirubin, albumin, transaminases, and platelet count. Therefore, it is a well-founded hope that OCA may improve relevant clinical outcomes, but this needs to be definitively demonstrated. To this regard, a multicenter study aimed at assessing the effects of OCA on clinical outcomes (all-cause mortality, liver transplant, MELD > 15, uncontrolled ascitis, bleeding, encephalopathy, spontaneous bacterial peritonitis) in patients with more advanced disease (compared to patients in the POISE trial) is currently enrolling patients. The study period, determined by the time required to accrue 121 primary endpoint events, is estimated to be around 8 years. Therefore, we will have to wait approximately a decade before being able to confirm the effectiveness of OCA on PBC clinical outcomes. In addition, we need information on the effects of FXR agonists on advanced stages of the disease since pivotal studies only enrolled patients with mild disease. In the meantime, a number of unmet needs have to be explored, including the validation of surrogates at interim time points for non-responders, which may assist in an earlier identification of progressive disease, as well as the additive predictive value of histological features, noninvasive surrogates (AST to platelet ratio index, enhanced liver fibrosis (ELF) score, transient elastography) and genetic biomarkers of disease severity. In substance, what we are looking for in PBC is a robust surrogate comparable to SVR in chronic viral hepatitis. However, despite the evolving landscape in PBC and the progress reached with the use of FXR agonists, the main challenge still remains the long-term effects of novel therapies on the clinical outcomes.

References

[1] Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol. 2015; 62(1 Suppl): S25-37.

[2] Walters JR, Appleby RN. A variant of FGF19 for treatment of disorders of cholestasis and bile acid metabolism. Ann Transl Med 2015; 3(S1): S7.

[3] Miethke AG, Zhang W, Simmons J, et al. Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice. Hepatology 2016; 63(2): 512-523.

[4] Gadaleta RM, van Erpecum KJ, Oldenburg B, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 2011; 60: 463-472.

[5] Tang R, Wei Y, Li Y et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut. 2017; 17. pii: gutjnl-2016-313332.

[6] European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. Journal of Hepatology 2017; http://dx.doi.org/10.1016/j.jhep.2017.03.022.

[7] Hao H, Cao L, Jiang C, et al. Farnesoid X Receptor Regulation of the NLRP3 Inflammasome Underlies Cholestasis-Associated Sepsis. Cell Metab. 2017; 4; 25(4): 856-867.

[8] Nevens F, Andreone P, Mazzella G, et al. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. The New England journal of medicine 2016; 375: 631-643.

[9] Carbone M, Sharp SJ, Flack S, et al. The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology 2016; 63: 930-950.

[10] Carbone M. et al. AASLD 2016, 67th Annual meeting, Poster # 361.