Future Medical Treatment of PSC

Abstract

Purpose of Review Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder characterized by inflammation of intrahepatic and/or extrahepatic bile ducts leading to stricturing, biliary fibrosis, cirrhosis, and liver failure. PSC is highly associated with inflammatory bowel diseases (IBD) and bears significant risk for cholangiocellular and colorectal cancer. To date, no medical treatment has been proven in randomized controlled trials to improve transplant-free and overall patient survival. However, numerous innovative therapeutic concepts are currently tested in phase 2 to phase 3 clinical trials. Based on currently suggested pathogenetic mechanisms of PSC, such drugs target its immunopathogenesis and nuclear and membrane receptors regulating bile acid transport and metabolism, gut microbiota, and liver fibrosis. The purpose of this review is to discuss recent advances in targeted medical treatment options for PSC. Recent Findings While a large carefully designed phase 2b trial targeting fibrosis development in PSC failed (simtuzumab), another compound was promoted from phase 2a to phase 3 trial based on significant improvements of alkaline phosphatase (AP) and excellent safety profile (norursodeoxycholic acid, norUDCA). Summary Ongoing trials evaluate numerous different targets considered to be involved in PSC pathogenesis, with so far, no clear advantage of either compound. This must be attributed to the still unknown cause of PSC. It may turn out that only combination therapy may reach a breakthrough. The fact that numerous studies isochronally test the same drug or therapeutic concept like in the case of vancomycin or faecal microbiota transplantation (FMT) demands improved and coordinated international strategies for study design to develop more effective drug pipelines, which is one major target of the International PSC Study Group (IPSCSG).

An Overview on Primary Sclerosing Cholangitis

“…This leads to the secretion of antibodies such as antinuclear antibodies (ANA), smooth muscle antibodies (SMA) (13-20%), and atypical perinuclear antineutrophil cytoplasmatic antibodies (ANCA) (65-88%) [1,8]. Recent studies have identified novel target molecules involved in the pathogenesis of PSC-vascular adhesion protein 1 (VAP-1) and lysyl oxidase like-2 (LOXL2)-and are important in dysbiosis in gut microbiota [9].…”

“…ERCP is the go-to strategy in different situations such as cholangitis, contraindication for MRCP, early PSC, AMA-negative PBC, equivocal biopsy, and dominant strictures. Due to the expansion in the therapeutic opportunities in ERCP, a large number of investigations were possible such as endoscopic sphincterotomy (in difficult cannulation, cholelithiasis), hydrostatic balloon dilatation, nasobiliary tube drainage and saline irrigation (used to prevent recurrent biliary obstruction), biliary stent placement, and ductal sampling (brush cytology and endobiliary biopsies with spyglass) [9]. A dominant stricture was described in 36-50% of cases with PSC [22].…”

“…Obethicolic acid, an acid-derived farnesoid X receptor (FXR) agonist, is still in clinical studies to observe its efficacy in PSC. Phase 2a studies show great promise in decreasing alkaline phosphatase values, though pruritus is a major side effect [9,24]. Non-bile acid-derived FXR agonists and FGF19 analogues are also in clinical studies, showing not only the FXR agonistic effect but also lower levels of drug toxicity and adverse reactions (pruritus) [9].…”

“…Even though the BEZURSO trial shows the efficacy of bezafibrate UDCA (pan peroxisome proliferator-activated receptor (PPAR) agonist) associated with as second-line treatment in PSC, if UDCA fails, there are no randomized controlled trials to ensure these results. Fenofibrate (PPAR-α agonist), seladelpar (orally PPAR-δ agonist), and elabibranor (dual PPAR-α and PAPR-γ agonist) are currently tested in PSC [9,25].…”

“…Norursodeoxycholic acid (norUDCA) presents a great safety profile, and a phase 3 trial is in progress to establish its efficacy, since norUDCA presents not only anti-cholestatic effects but also anti-inflammatory and anti-fibrotic properties [9].…”