2.2.3. Fibroblast Growth Factor 19 (FGF19) Analogues

FGF19 acts as a hormone on a cell surface receptor complex in hepatocytes, decreasing bile acid synthesis, gluconeogenesis, and lipogenesis. FGF19 expression is induced by bile-acid-mediated activation of FXR in the gut [49], and it reaches the liver through portal circulation. In the liver, FGF19 suppresses bile acid synthesis due to the inhibition of cholesterol 7-α-hydroxylase (CYP7A1) and sterol 12-α-hydroxylase (CYP8B1). Moreover, FXR decreases hepatic fibrogenesis by reducing collagen and by increasing matrix metalloprotease activity in hepatic stellate cells [50].

NGM282 (Aldafermin), an engineered analogue of FGF19, was tested in a 28-day, double-blind, placebo-controlled phase 2 trial. Forty-five PBC patients with an inadequate response to UDCA were treated with subcutaneous daily doses of NGM282 at 0.3 mg (n = 14), 3 mg (n = 16), or placebo (n = 15). ALP level had a significant drop in the treatment group, as well as transaminase levels and markers of cholestasis, hepatocellular injury, and inflammation (IgM levels). The reduction in complement component 4 (C4) levels suggests that NGM282 acts with a direct inhibition in the de-novo bile acid synthesis through the classical pathway. The main adverse effect was diarrhea. No effect on itch was detected [37]. In contrast to FGF19, no increase in liver cancer risk was observed in animal models treated with NGM282 [51]. Longer studies are needed to evaluate the long-term efficacy and safety of this molecule.

#### 2.2.4. Antifibrotic Agent

Setanaxib (GKT137831) is an inhibitor of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidases isoforms 1 and 4. NADPH oxidase enzymes, generating reactive species of oxygen, play a central role in inflammation and stellate cell-mediated fibrogenesis [52]. It was demonstrated in animal models of acute biliary injury and steatohepatitis that GKT137831 reduces hepatocyte apoptosis and liver fibrosis [53]. Thus, a multicenter, randomized, double-blind, placebo-controlled phase 2 study evaluating the safety and the efficacy of GKT137831 OD or BID in 111 patients with PBC and incomplete response to UDCA was performed (NCT03226067). Interim analysis showed a reduction in GGT and ALP level in six weeks, without a significant concomitant adverse event. A decrease in GGT of 7%, 12%, and 23% were observed in the placebo, 400 mg OD, and 400 mg BID groups, respectively (*p* < 0.01 for 400 mg BID vs. placebo). A greater GGT reduction was reached in patients with more advanced disease (GGT ≥ 2.5 X ULN at baseline). Changes in ALP were statistically significant in the 400 mg BID versus placebo [38].
