*3.1. Therapies in Clinical Use* UDCA

The use of UDCA in PSC patients remains controversial to date. Previous small and uncontrolled studies of short duration consistently reported an improvement in liver tests in PSC treated with UDCA [65,66]. The first randomized controlled trial of UDCA (13 to 15 mg/kg) in PSC patients appeared in 1992. Beuers et al. showed a significant improvement of biochemical parameters, such as bilirubin, ALP, GGT, and transaminases, in six PSC patients treated for one year as compared to placebo [67]. A number of subsequent studies evaluated the effect of UDCA at different dosages in PSC. Despite the amelioration of biochemical parameters that appears to be relatively constant in all studies, definite proof for an improvement in "hard endpoints" such as survival, liver transplantation, or progression to CCA is still lacking. In a small cohort of 26 PSC patients, Mitchell et al. reported beneficial effects of UDCA (20 mg/kg) not only on liver tests but also on the cholagiographic appearance of the biliary tree evaluated by ERCP and liver fibrosis [68]. A subsequent randomized controlled trial in 219 PSC patients treated with UDCA (17 to 23 mg/kg) or placebo failed to show a significant improvement in the combined endpoint "death or liver transplantation", despite a trend to a reduction in both (31% and 34% reduction, respectively) [69]. Moreover, high doses of UDCA in the range of 28–30 mg/kg were shown to be associated with an increased risk of disease progression to cirrhosis, development of varices, CCA, liver transplantation, or death [70]. Unfortunately, three meta-analyses also failed to show an effect of UDCA on mortality or liver transplantation [71–73]. To date, the most recent guidelines by the British Society of Gastroenterology recommend not to treat newly diagnosed PSC patients with UDCA routinely [74].

#### *3.2. Therapies Evaluated in Clinical Trials*

The principal characteristics of the clinical trials are described in Table 2.

**Note**


**Table 2.** Principal characteristics of the study of the drugs in clinical trials.


**Table 2.** *Cont.*


**Table 2.** *Cont.*

\* estimated.

#### 3.2.1. 24-Norursodeoxycholic Acid (norUDCA)

24-norursodeoxycholic acid (norUDCA) has a molecular structure similar to UDCA, except for the lack of a methylene group, resulting in a resistance to conjugation. NorUDCA is therefore passively absorbed from cholangiocytes and goes through cholehepatic shunt, which leads to the stimulation of a bicarbonate-rich choleresis. Moreover, norUDCA has anti-lipotoxic, anti-proliferative, anti-fibrotic, and anti-inflammatory effects, and, in vitro, it is less toxic than UDCA for hepatocytes and cholangiocytes due to its hydrophilicity [2]. A phase 2 clinical trial on 161 PSC patients without concomitant UDCA therapy, evaluating the efficacy of three doses of oral norUDCA, showed a significant dose-dependent reduction in ALP values after 12 weeks, without significant adverse events. The authors showed a significant reduction in ALP levels of 12.3%, 17.3%, and 26.0% in patients treated with 500 mg, 1000 mg, and 1500 mg per day of norUDCA, respectively; placebo-treated patients had a minor increase in ALP levels (1.2%) [61]. Despite some concerns of possible worsening of the disease due to the choleretic effects of norUDCA (especially in PSC patients with dominant strictures), these effects need to be clarified in longer studies; the association of UDCA and norUDCA has the potential to offer additive beneficial effects for PSC patients [87]. A phase 3 double-blind, randomized clinical trial is actively recruiting patients across several worldwide centers (NCT03872921).

### 3.2.2. FXR Agonists

FXR agonists are evaluated in PSC because of their inhibition in bile acid synthesis in the liver, as previous explained [45].

OCA was tested in PSC patients in the AESOP trial (a randomized, double-blind, placebo-controlled phase II study). Seventy-seven PSC patients were recruited, and they were treated for 24 weeks with titrating doses of 1.5–3 mg/day and 5–10 mg/day OCA, or placebo, after 12 weeks. At the end of the study, serum ALP was significantly reduced with OCA 5–10 mg compared with the placebo arm (least-square mean difference of −83.4 U/L; *p* = 0.043). Interestingly, the effective dose of OCA is already in use for PBC therapy. The effect of OCA 5–10 mg was independent of administration of UDCA, despite a greater reduction in ALP that was registered in patients without UDCA at baseline (25–30% ALP reduction in patients without UDCA at baseline vs. 14–16% ALP reduction in patients with UDCA at baseline). The main side effect was dose-dependent pruritus, which occurred in 67% of patients in the OCA 5–10 mg group, in 60% of patients in the OCA 1.5–3 mg group, and in 45% of patients in the placebo arm. Discontinuation due to pruritus occurred only in one patient in the OCA 1.5–3.0 mg group and in three patients in the OCA 5–10 mg group [75]. A phase 3 trial is actively recruiting patients (NCT02177136).

Cilofexor (GS-9674), a non-steroidal FXR agonist, was tested in a phase 2, randomized, double-blind, placebo-controlled trial of 52 non-cirrhotic PSC patients with ALP levels

greater than 1.67 ULN. Patients treated with Cilofexor 100 mg had a significant drop in ALP, gamma-GT, ALT, and primary bile acids (ALP mean reduction of −13.8%, *p* = 0.005; gamma-GT mean reduction of 47.7%, *p* < 0.001; ALT mean reduction of −17.8%, *p* = 0.08; primary bile acids reduction of −30.5%, *p* = 0.0008). The main limitations of this trial were the inclusion of only large-duct PSC cases without cirrhosis and the low prevalence of IBD [76].

NGM282, a FGF19 analogue, was recently studied in a phase 2, randomized, doubleblind, placebo-controlled trial in PSC patients with ALP levels greater than 1.5 × ULN. Despite that no significant changes in ALP from baseline were observed, fibrosis biomarkers (Enhanced Liver Fibrosis test score and Pro-C3) were significantly improved in the treatment group [77]. This trial has stimulated discussion about the most appropriated target in PSC [88]. There are no established endpoints in PSC. A recent consensus of the International Primary Sclerosing Cholangitis Study Group, reviewing available literature, concluded that the only few candidates as surrogate endpoints in PSC may be ALP, transient elastography, histology, or the combination of ALP and histology and bilirubin; however, no one exceeds level 3 validation [89].

All-trans retinoic acid (ATRA), currently used in acne and in acute promyelocytic leukemia, represses bile acid synthesis through the FXR/RXR nuclear receptor complex pathway [90]. The efficacy of the combination of UDCA (15–23 mg/kg/day) and ATRA (45 mg/m2/day) was tested in 15 PSC patients. Despite ATRA, admiration did not reach the primary endpoint of the study (30% reduction in serum ALP), and a decrease in ALT and C4 levels were observed [78]. An open-label phase 2 trial evaluating efficacy and the safety of a lower dose of ATRA is currently ongoing (NCT03359174).
