Future Therapies for Primary Sclerosing Cholangitis



Fig. 12.1
A schematic overview of possible therapeutic targets, underlying mechanistic pathways, and pathogenesis of PSC: bile acid composition, detoxification, gut microbiota, hepatic fibrosis, adaptive and innate immune system activation, and immune cell trafficking represent areas in which a number study compounds and available drugs may exert therapeutic potential in the disease course. FXR farnesoid X receptor, PPARa peroxisome proliferator-activated receptor alpha, VDR vitamin D receptor, RAR/RXR retinoic acid receptor and retinoid X receptor, LOXL2 lysyl oxidase-like 2, ASBT apical sodium-dependent bile acid transporter, FMT fecal microbiota transplantation, FGF fibroblast growth factor, MAdCAM-1 mucosal vascular addressin cell adhesion molecule 1, VAP vascular adhesion protein, CCR5 chemokine receptor type 5, CCR9 chemokine receptor type 9





Gut-Liver Axis in PSC and IBD


The liver plays a critical role in the immune surveillance against bacterial translocation or absorption of bacterial endotoxins into the portal circulation. Since the intestinal and biliary epithelia are continuous, any alterations in gut mucosal immunity (“leaky gut”) or microbiome (dysbiosis) may, therefore, lead to heightened innate immune activation (liver-gut crosstalk) resulting in hepatobiliary injury (Fig. 12.1).

One of the hypotheses for the pathogenesis of PSC is the cross-reactive immunity to an antigen leading to immune-mediated gut and biliary inflammation from the enterohepatic circulation of gut-activated T lymphocytes. During intestinal inflammation, naive lymphocytes are imprinted with gut tropism by intestinal dendritic cells localized in the intestinal mucosa via integrin ligand, mucosal vascular addressin cell addressin molecule 1 (MAdCAM-1) and gut-specific chemokine, and CCL25-dependent mechanisms. Normally, these molecules are highly restricted to the gut, where they drive selective recruitment of gut-specific T and B cells and the expression the CCL25, chemokine receptor CCR9, and the integrin combination, α4β7, which binds to MAdCAM-1. It is suggested that in a genetically predisposed individual, gut dysbiosis and intestinal inflammation with translocation of enteric pathogens beyond the mucosal barrier lead to activation of endogenous molecules termed damage-associated molecular patterns (DAMPS) [1921]. Due to aberrant gut tropism seen in PSC, DAMP-associated activation of innate immunity and hepatic expression CCL25 and MAdCAM-1 result in the recruitment of mucosal effector lymphocytes bearing a “gut-trophic” phenotype. Additionally, the adhesion molecule and ectoenzyme vascular adhesion protein (VAP-1) are upregulated during chronic inflammation and support both lymphocyte adhesion through upregulation of several endothelial adhesion molecules, including MAdCAM-1, on sinusoidal endothelium [22, 23]. Also, it catabolizes amine substrates secreted by gut bacteria and contributes to reactive oxygen species generation. After entering the liver, effector cells use chemokine receptors such as CCR9 to respond to chemokines secreted by epithelial target cells resulting in cell-mediated immunological attack and bile duct destruction (Fig. 12.1). Hepatobiliary damage is likely enhanced by the action of toxic bile acids and heightened DAMP activation resulting in cellular production of inflammatory cytokines that act as ligands for chemokine receptors leading to downstream processes such as autophagy, apoptosis, and fibrosis [19, 2426].


Therapeutic Targeting of the Gut-Liver Axis



Gut Microbiome


The importance of the commensal microbiota and its metabolites in protecting against biliary injury was recently highlighted in an animal model [27]. The critical role of gut dysbiosis is increasingly being recognized in IBD and liver disease pathogenesis through alterations in the mucosal immune system and activation of DAMPs. Gut dysbiosis represents a modifiable therapeutic target through the use of antibiotics, probiotics, or fecal microbiota transplantation. Initial positive reports with improvement in liver biochemistries after oral administration of antibiotics in combination with ursodiol have led to three prospective studies to date. In the first study, 80 patients with PSC were randomized to 3 years of UDCA (15 mg/kg per day) plus metronidazole or UDCA alone [28]. This study showed the superiority of combination therapy in the improvement in alkaline phosphatase, Mayo PSC risk score, and histology. One of the well-conducted double-blind, randomized pilot study randomized, 35 adult PSC patients to low-dose vancomycin (125 mg four times a day), high-dose vancomycin (250 mg four times a day), low-dose metronidazole (250 mg three times a day), or high-dose metronidazole (500 mg three times a day) [29]. Low-dose and high-dose vancomycin were superior to metronidazole and achieved significant decreases in serum alkaline phosphatase levels at 12 weeks [29]. In another pilot study, 16 adult patients with PSC were treated with minocycline, 100 mg orally twice daily, for a year. A modest improvement in serum alkaline phosphatase levels and Mayo risk score was observed with treatment but there was no improvement in serum bilirubin and albumin [30]. However, a recent pilot study of 16 patients PSC and UC with oral rifaximin (550 mg twice a day) has failed to show any biochemical improvement [31]. Future studies are therefore needed to understand how the antimicrobial spectra and other properties of antibiotics might determine their utility in treating PSC. Studies with oral vancomycin and fecal microbiota transplantation are currently planned (Table 12.1).


Table 12.1
List of novel therapeutic agents that are currently under evaluation for treatment of PSC. Brief overview of mechanism of action, route of administration, and details of the study design with primary efficacy endpoints are listed in the following table








































































































































Investigational drug (ClinicalTrials.gov identifier)

Mechanism of action

Administration

Clinical research phase

Sample size and study duration

Elevated alkaline phosphatase (AlkP) as inclusion criteria

Primary efficacy endpoint

Status

Estimated study completion date

Company

Simtuzumab (NCT01672853)

Monoclonal antibody against lysyl oxidase-like 2 (LOXL2)

Subcutaneous inj weekly

Phase 2b

N = 225,

96 weeks

Not required

Change from baseline in morphometric quantitative collagen on liver biopsy

Active, not recruiting

July 2016

Gilead Sciences

LUM001 (NCT02061540)

apical sodium-dependent bile acid transporter inhibitor (ASBTi)

Oral, once daily

Phase 2

N = 20,

14 weeks

Not required

Change from baseline in liver biochemistries, bile acids, and pruritus

Active, not recruiting

December 2015

Shire

norUDCA (NCT01755507)

Improve bicarbonate umbrella

Oral, once daily

Phase 2

N = 160,

12 weeks

Not required

Decrease in AlkP levels

Unknown

March 2014

Dr. Falk Pharma GmbH

Obeticholic acid (NCT02177136)

FXR agonism

Oral, once daily

Phase 2

N = 75,

24 weeks

AlkP at baseline ≥2xULN

Decrease in AlkP levels

Recruiting

June 2019

Intercept Pharmaceuticals

BTT1023 (NCT02239211)

Human monoclonal antibody (BTT1023) which targets the vascular adhesion protein (VAP-1)

IV infusion, every 14 days

Phase 2

N = 41,

120 days

AlkP at baseline >2xULN

Decrease in AlkP levels

Recruiting

March 2017

Biotie Therapies Corp

Mitomycin C (NCT01688024)

Nucleic acid synthesis inhibitors, antineoplastic agent

Delivery into biliary tree via ERCP, as needed

Phase 2

N = 130,

2 years

Not required

Improvement in Mayo Risk Score

Recruiting

September 2017

Investigator initiated

Vancomycin (NCT02605213)

Improve gut dysbiosis

Oral, every 6 h

Phase 4

N = 30,

12 weeks

Not required

Decrease in AlkP levels

Recruiting

February 2016

Investigator initiated

Fecal Microbiota Transplantation (NCT02424175)

Improve gut dysbiosis

Single FMT

Phase 1, Phase 2

N = 5,

12 weeks

AlkP at baseline >1.5xULN

>50 % improvement in liver biochemistries 3 months after intervention

Not yet recruiting

June 2017

Investigator initiated, OpenBiome

Cenicriviroc (NCT02653625)

Dual CCR2 and CCR5 receptor inhibitor

Oral, once daily

Phase 2

N = 25,

24 weeks

AlkP at baseline >1.5xULN

Decrease in AlkP levels

Not yet recruiting

June 2017

Tobira Therapeutics

All-trans retinoic acid (ATRA) (NCT01456468)

Active metabolite of vitamin A

Oral, twice daily

Phase 1

N = 30,

3 months

AlkP at baseline elevated

Reduction in AlkP by at least 30 %

Ongoing, but not recruiting

December 2015

Investigator initiated


Gut Adhesion Molecules and Enterohepatic Circulation


Gut adhesion molecules are very attractive targets for pharmaceutical intervention, and given their enterohepatic expression in PSC, there is a possibility that agents that block the α4β7 – MAdCAM-1 – is expected to result in amelioration of ongoing chronic inflammation. Vedolizumab is a recombinant humanized IgG1 antibody constructed from the murine antibody Act-1, previously developed for use in patients with IBD. It inhibits adhesion and migration of leukocytes into the gastrointestinal tract by preventing the α4β7 integrin subunit from binding to MAdCAM-1. Therefore, the safety and efficacy of vedolizumab for the treatment of PSC in patients with underlying IBD is a matter of interest. Similarly, the VAP-1-blocking agent, BTT1023, is currently under investigation in phase 2 clinical trial in PSC patients with stable IBD (Table 12.1).


Bicarbonate Umbrella and Toxic Bile Acids in PSC


Bile acids are cholanic acid derivatives that act as detergents and are responsible for facilitating the absorption of dietary lipids, fat-soluble vitamins and for maintaining cholesterol homeostasis. The formation of bile acids is initiated in hepatocytes and mediated by cholesterol 7 α-hydroxylase (CYP7A1) [32]. Bile composed primarily of water, various ions, and solutes and is released into bile canaliculi on the apical side of hepatocytes. The bile acids flow through the canals of Hering before continuing through the biliary epithelium [32]. Despite continuous exposure to millimolar levels of hydrophobic bile salt monomers, the cholangiocytes are protected from damage due to a biliary HCO3- umbrella [3337]. The formation of bicarbonate umbrella is mediated through transmembrane G-protein couple receptor (TGR5) [38]. Bile acids are stored in the gallbladder, and are then secreted into the duodenum where they are metabolized by enteric bacteria. Approximately, 95 % of these bile acids are absorbed in the terminal ileum and are then transported back to the liver via the portal vein for recycling [32]. These conjugated bile acids will be secreted back into the bile pool. This process is known as the enterohepatic shunt [32]. However, unconjugated bile acids are absorbed by the cholangiocytes and returned to the hepatocytes via the peribiliary vascular plexus in a process known as the cholehepatic shunt [32]. After synthesis, bile acids are conjugated with either glycine or taurine, which decreases the toxicity of bile and makes it more soluble [32]. In the liver, bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that results in inhibition of CYP7A1 [32]. In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 19 (FGF19), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit bile acid synthesis resulting in decreased levels of 7ahydroxy-4-cholesten-3-one (C4) and endogenous bile acids (Fig. 12.1) [32].


Therapeutic Targeting of Toxic Bile


Because of the important processes that bile acids regulate through activation of receptors, bile acid derivatives and drugs that target these receptors are under development for the treatment of several diseases, including cholestatic liver disease and metabolic syndrome [3941].


UDCA Derivative


24-norursodeoxycholic acid (norUDCA) is a derivative of UDCA and is formed after removal of a methylene side group. This small alteration of the native compound establishes novel bile acid properties, enabling norUDCA to overcome previous functional limitations of UDCA. norUDCA is passively absorbed by cholangiocytes and subsequently undergoes extensive cholehepatic shunting [42, 43]. The physiologic result is increased cholangiocyte bicarbonate secretion and the creation of a possibly therapeutic “bicarbonate umbrella” in the biliary tree (Fig. 12.1). In fact, norUDCA resists taurine amidation, a property that increases its function in cholehepatic function compared to UDCA. norUDCA has other unique features beyond UDCA, as it is more hydrophilic and thus less toxic to cholangiocytes and hepatocytes [44], but contains anti-lipotoxic, antiproliferative, antifibrotic, and anti-inflammatory effects [42, 45, 46]. Thus, norUDCA has genuine potential to mitigate a number of steps in the pathogenesis of PSC and even complement mechanisms of bile acid detoxification and various overflow systems at the basolateral membrane [42, 46]. norUDCA has mediated sclerosing cholangitis reversal in an experimental Mdr2/Abcb4 knockout mouse model over a short study period, whereas the parent compound (UDCA) did not [45]. Human studies with norUDCA are underway, and results of phase 2 dose finding study (160 patients among 30 centers in Europe) are anticipated soon (Table 12.1). This study includes a primary outcome measure of change in serum alkaline phosphatase (AP) during the 12-week study, as well as secondary measures of the proportion of patients with at least 50 % reduction in AP and rates of adverse events (NCT017555078).


Suppression of Bile Acid Biosynthesis


Bile acids, specifically those targeting the nuclear hormone receptor, FXR and the membrane associated G-protein couple receptor, TGR5 with high affinity, represent viable opportunities in the treatment of PSC [47]. Historically speaking, both targets (FXR and TGR5) have a rich history among autoimmune diseases. Specifically, TGR5 genetic polymorphisms have been associated with PSC and ulcerative colitis [48, 49], and FXR polymorphisms have been linked to inflammation and epithelial permeability in inflammatory bowel disease [50, 51]. FXR activation controls a number of downstream effects that enable cellular mechanisms to counteract biliary cholestasis via modulation of bile acid composition and inflammation. Activation of FXR not only leads to increased bile acid conjugation and excretion of bile from the hepatocyte into the canaliculi (also a bicarbonate rich choleresis) but contributes an additive role in the promotion of both phase I and phase II detoxification pathways [5254]. UDCA and norUDCA are not ligands for FXR; however, 6-ethylchenodeoxcyholic acid (obeticholic acid (OCA) or INT-747) has strong receptor binding and activation profile [55, 56].

FXR agonist investigation in the Mdr2/Abcb4 knockout mouse model has revealed significant mitigation of bile duct injury via diminished bile acid synthesis but also anti-inflammatory effects via FXR agonists (INT-767, similar FXR affinity as INT-747) [57]. Furthermore, overexpression of FXR in this model induced fibroblast growth factor 15 (or FGF19 in human) and suppressed the rate limiting enzyme-converting cholesterol to bile acids resulting in the cure of biliary injury [58]. OCA use is currently under investigation in a phase 2, blinded and randomized, placebo-controlled trial of the efficacy and safety in patients with PSC (NCT02177136). This study, estimated completion in June 2019, seeks to recruit a total of 75 subjects at 1:1:1 ratio into one of three treatment arms (Table 12.1). Two active compound groups include a daily OCA dose of 1.5 mg titrated to 3 mg and daily OCA dose of 5 mg titrated to 10 mg. The primary outcome measures include the effect of the compound on serum alkaline phosphatase as well as safety profile.

TGR5 and FGF19 also represent theoretic PSC therapeutic targets via roles in modulation of biliary composition and inflammation [59, 60]. TGR5, once activated, inhibits inflammation in part by suppression of NF-kb signaling [59] but also has a role in bile composition via cholangiocyte sensing bile sensing and bicarbonate secretion via cystic fibrosis transmembrane conductance regulator (CTFR) and anion exchange 2 (AE2) [61]. TGR5 has no current trials underway but a dual agonist of FXR, and TGR5 (INT-767) is currently undergoing preclinical evaluation. In the future, when targeted TGR5 compounds are available for treatment of cholangiopathies, off-target effects will have to be considered [62]. FGF19 expression is increased after FXR activation, resulting in a multitude of metabolic effects including suppression of bile acid synthesis and anti-inflammatory activity [63, 64]. Currently, NGM282, a recombinant protein with an amino acid sequence of 95.4 % identical to that of human FGF19, is currently under evaluation for PBC and PSC based on robust efficacy with no evidence of proliferative activity in a preclinical model (Table 12.1) [60].

Only gold members can continue reading. Log In or Register to continue

Oct 9, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Future Therapies for Primary Sclerosing Cholangitis
Premium Wordpress Themes by UFO Themes