Pandora's box opens for cholestatic liver disease
Authors: Peter L.M. Jansen, Frank G. Schaap
Journal: Hepatology (2015)

Potential conflict of interest: Prof. Jansen advises Shire. See Article On Page 914 Fibroblast growth factor 19 (FGF19) is produced in the ileum upon activation of the farnesoid X receptor (FXR) by bile salts and FXR agonists/bile salt analogs. FGF19 has its main action in the liver, where it binds to FGF receptor (FGFR) 4/β‐Klotho and causes the down‐regulation of CYP7A1, coding for the first committed enzyme in the conversion of cholesterol to bile salts. The importance of the FGF19/Fgf15 (the rodent analog) pathway is apparent upon bile duct ligation in the mouse.1 This interrupts the enterohepatic circulation and Fgf15 is no longer produced because of lack of FXR‐activating bile salts in the ileum. In the absence of Fgf15, Cyp7a1 expression is not repressed with, as a consequence, continued synthesis of bile salts that contributes to ongoing liver damage. In contrast to mice, the human liver can synthesize FGF19, but only does so under cholestatic conditions.2 Thus, CYP7A1 is strongly down‐regulated in human extrahepatic cholestasis, and this, to an extent, protects the liver. Other metabolic actions of FGF19/Fgf15 (e.g., inhibition of hepatic gluconeogenesis) are also mediated by FGFR4/βKlotho, whereas FGFR1c/β‐Klotho is implicated in pharmacological effects of FGF19 and physiological actions of FGF21 in adipose tissue.3 Bile salt analogs and FGF19 have potential as pharmacological agents in a number of liver diseases in that they down‐regulate bile salt synthesis and inhibit lipo‐ and gluconeogenesis. However, the downside is that FGF19 induces hepatocyte proliferation and, on prolonged exposure, can cause hepatocellular carcinoma (HCC), as has been shown in mice.4 FGF19 also stimulates growth and invasiveness in prostate and colon carcinoma cell lines.3 These neoplastic actions are mediated by FGFR4, the same receptor that mediates repression of CYP7A1 in the liver.5 Arguably, in transgenic animals, the neoplastic effect occurs upon prolonged exposure to supraphysiological doses of ectopically produced FGF19. Nevertheless, there is concern that the potential tumorigenic actions of FGF19 will negatively impact on its development as a drug. The role of FGF19/Fgf15 in established human HCC and in animal HCC models contribute to this notion.6 Human HCCs can express FGFR4 and FGF19, and, in these tumors, FGF19 is seen as a driver of tumor proliferation and migration. In line with this, FGFR4 inhibitors and blocking antibodies are developed for treatment of HCC.5 It is ironic that FXR agonists, that stimulate the synthesis of FGF19, are developed for treatment of nonalcoholic steatohepatitis (NASH) and cholestatic liver disease, whereas inhibitors of the FGF19/FGFR4 pathway are in development for treatment of HCC. This seems contradictory. Against this background, FGF19 variants have been engineered that lack affinity for FGFR4 while retaining affinity for FGFR1c.7 This product (FGF19‐7) lacks mitogenic actions, but has also lost the capability to down‐regulate Cyp7a1 and therefore may be more useful for NASH than for treatment of cholestatic liver disease (Fig. 1). As reported in this issue of Hepatology, a group of researchers has succeeded in modifying FGF19 so that it still acts through FGFR4/β‐Klotho with suppression of CYP7A1, but is devoid of neoplastic activity (Fig. 1).8 The mechanism for this selectivity (biased FGFR4 agonist) is not known.Figure 1: Effect of FGF19 and variants on metabolism and hepatocyte proliferation. FGF19 and the FGF19 variant M70 down‐regulate CYP7A1 in the liver whereas only wild‐type FGF19 stimulates hepatocyte proliferation.8 Both also have an effect on triglyceride and glucose metabolism in hepatocytes and adipocytes. FGF19‐7 (Amgen product) has lost affinity for FGFR4 and, as with FGF21, affects triglyceride and glucose metabolism in adipocytes.7Engineered FGF19 (M70) was tested in Mdr2−/− mice. These mice lack a transporter needed for hepatobiliary secretion of phospholipids and develop a disease that, in many aspects, resembles human primary sclerosing cholangitis (PSC). These features are probably owing to the unopposed detergent actions of bile salts in and around the bile ducts. As with PSC, bile ducts of these mice show a beaded pattern, and, on microscopy, there is onion skin‐like periductular fibrosis and ductular proliferation. Cholestatic parameters, such as serum bilirubin, bile salts, and alkaline phosphatase, are elevated, and at 10‐12 months of age, these mice develop carcinoma of the liver, resembling HCC. Using adeno‐associated virus (AAV)‐mediated delivery of wild‐type or modified FGF19 (M70), Zhou et al. show that a single AAV injection resulted in high serum levels of FGF19 or M70 for up to 24 weeks.8 Serum levels of FGF19 were approximately 10‐ to 20‐fold the levels observed in humans with obstructive cholestasis.2 Both FGF19 and M70 suppressed Cyp7a1 and reduced circulating and hepatic bile salt levels. In Mdr2−/− mice, this was accompanied by improvement of cholestasis, inflammation, and periductular fibrosis. Thus, repression of bile salt synthesis by FGF19/M70 prevented cholangiopathy in these mice. FGF19 and M70 treatment also corrected anomalies in cholesterol and triglyceride metabolism (including cholecystolithiasis) abnormalities that are also observed in patients with mutations of the orthologous MDR3 gene. The article also shows that prolonged exposure to FGF19 resulted in hepatocarcinogenesis, whereas no tumors were observed in mock‐ or M70‐treated animals at 44 weeks of age.8 Intriguingly, M70 reduced ductular expansion and hepatocellular proliferation in Mdr2−/− mice. This may be owing to competition with endogenous Fgf15 for binding to Fgfr4. M70 has potential in the treatment of cholestatic liver diseases, notably primary biliary cholangitis (PBC), PSC, and pediatric cholestasis and perhaps also in HCC. A phase 2b trial in PBC is being conducted (NCT02135536), and a trial in PSC is being organized. What are the pitfalls? First of all, although their disease resembles PSC, Mdr2−/− mice do not have PSC. The etiology of PSC in humans most probably is related to events in the gut given that 70% of patients with PSC have concomitant inflammatory bowel disease. Mdr2−/− mice do not have inflammatory bowel disease. Moreover, the cholangiopathy in human PSC is more severe than in Mdr2−/− mice. Therefore, it is difficult to predict whether patients with PSC will respond as favorably as Mdr2−/− mice. Second, serum FGF19 is already elevated in patients with extrahepatic cholestasis and in PBC patients with a high Mayo risk score.2 Therefore, one may question whether administration of FGF19/M70 will elicit a further biological response. One can also argue that high‐dose FGF19 therapy in PSC is not the way to go because of the already increased risk for hepatobiliary and colorectal malignancies in PSC. Here, M70 comes in as an agent not only lacking tumorigenic properties, but by competing with endogenous FGF19 it may also exert antitumor activity.8 Whether M70 also lacks tumorigenic effects in prostate and colon needs to be evaluated. The downside is that M70 needs to be injected subcutaneously, and because of a short half‐life, one probably needs multiple injections per day. In this regard, the AAV platform, mainly used in gene therapy applications, may be an attractive alternative. Some years ago, we only had ursodeoxycholic acid for treatment of cholestatic liver disease. Now, Pandora's box has opened with FXR agonists, engineered FGF19 variants, intestinal bile salt uptake inhibitors, stimulators of cholangiocyte bicarbonate secretion, as well as pregnane X receptor and dual peroxisome proliferator‐activated receptor alpha/delta agonists, for treatment of cholestatic liver disease and some of them also for NASH. Many of these are in clinical trials, and this is good news for our patients. Some of the new drugs have potential for cholestatic liver disease, a condition that is relatively rare, and for NASH, a condition that is fairly common. This extended field of indications paves the way for rapid drug development by taking advantage of the orphan status, eventually leading to big pharma applications. Author names in bold designate shared co‐first authorship.