3.2.5. Immunomodulators

Although PSC is an immune-mediated disease, traditional immunosuppressive approaches so far failed to demonstrate a clinical benefit in PSC [95]. Timolumab (BTT1023), a human monoclonal anti-VAP-1 antibody, was shown to prevent fibrosis in murine models of liver injury [96]. A phase 2 clinical trial (BUTEO trial) evaluating the effect of Timolumab in PSC over a 78-day treatment (primary endpoint: reduction of ALP levels by >25% from baseline) is still ongoing (NCT02239211) [97]. Cenicriviroc, a CCR2/CCR5 antagonist, was tested in a phase 2 trial (PERSEUS trial), and it was proven to cause a modest reduction in ALP (median 18%) after 24 weeks among 24 patients [98]. Moreover, it was shown to have anti-inflammatory and antifibrotic effects in NASH animal models and in Abcb4 (Mdr2−/−) mice [99].

Vedolizumab is a monoclonal antibody directed against the α4β7 integrin, which is used in the treatment of inflammatory bowel disease. MADCAM-1 is the ligand for α4β7 integrin and is normally expressed in the gut. Since MADCAM-1 is also found in the liver, administration of vedolizumab is thought to reduce MADCAM-1-induced leucocyte migration between the gut and the liver [100]. Despite these promising premises, in a retrospective analysis, Vedolizumab treatment did not show any improvement in liver biochemistry in patients affected by IBD and PSC who received at least three doses of vedolizumab. About 20% of patients experienced a reduction of at least 20% in ALP levels; however, this outcome was independently associated only with the presence of cirrhosis [81]. Similar results were reported in a previous retrospective study in 34 patients with PSC and IBD (16 patients affected by Crohn's disease and 18 patients by ulcerative colitis) treated with vedolizumab [101].

Vidofludimus is an inhibitor of the dihydroorotate dehydrogenase that blocks the replication of activated T- and B-cells and interferes with the JAK/signal transducer [45]. A phase 2, open-label clinical trial evaluating the safety and the efficacy of vidofludimus in patients with PSC will start in 2020 (NCT03722576).

#### 3.2.6. Modulation of the Gut Microbiome

Recent research focused on the gut microbiome as a potential element in the pathogenesis of PSC. One of the hypothesis is that gut microbiome activates innate immunity within the liver, resulting in inflammation and fibrosis in the bile duct [102]. Moreover, studies on the microbiome and PSC demonstrated that the microbiome of PSC patients is different from healthy controls and IBD-patients [103]. Thus, changing the composition of the gut microbiome might reduce inflammation and fibrosis in the bile ducts.

Vancomycin is a glycopeptide antibiotic that also has an immunomodulatory effect due to the decrease in T cell cytokine production [104]. Vancomycin was compared to metronidazole [105] and to placebo [106] in two randomized trials in PSC patients with or without IBD, and a significant reduction in ALP levels and the Mayo score was reported. A phase 2, multicenter clinical trial aiming to recruit 102 adult participants with PSC and evaluating ALP levels at 6, 12, and 18 months is still ongoing (NCT03710122).

Other interesting antibiotics are rifaximin and minocycline. Rifaximin had no effect in decreasing cholestatic markers and the Mayo score in 16 PSC patients [82]. In contrast, minocycline was shown to cause an improvement in ALP levels and the Mayo score in 16 patients [83].

Fecal Microbiome Transplantation (FMT) is a promising treatment for PSC patients. In one small pilot study, patients with PSC underwent FMT, and three of them experienced a ≥50% decrease in ALP levels. Its effect may be correlated with the bacterial diversity and donor engraftment [84].

#### 3.2.7. Other Treatments

Anti-inflammatory drugs such as sulfasalazine and curcumin were tested in PSC patients. A multicenter, randomized, double-blinded, placebo-controlled trial to assess the benefit and the safety of sulfasalazine in the treatment of PSC just ended, and results are

not available (NCT03561584). No significant improvements in cholestasis or symptoms were seen in patients treated with Curcumin [85].

Various minor drugs with different mechanisms of action could have a role in the treatment of PSC, and they were evaluated in different clinical trials. HTD1801 was studied in two phase 2 ongoing trials due to its action on lipid metabolism (NCT03333928, NCT03678480). DUR-928 is an endogenous epigenetic regulator that was studied in a phase 2 study on PSC patients due to its anti-inflammatory properties and its role in lipid metabolism and cell survival (NCT03394781) [3]. Docosahexaenoicacid supplementation, increasing PPAR signaling, was associated with a drop in ALP levels in patients with PSC, in a 12-month, open-label, pilot study on 23 PSC patients [86]. Another ongoing phase 1/2 trial is evaluating the potential effect of Hymecromone, a hyaluronic acid synthesis inhibitor (NCT02780752). Additionally, selected mesenchymal stromal cells (Orbcel-C) are in an ongoing phase 2 trial on PSC patients (NCT02997878) [3].
