3.2.4. Antifibrotic Therapy

Despite fibrosis being central in the pathogenesis of the disease, very few antifibrotic drugs have been studied. Lysyl oxidase like-2 (LOXL2) is an enzyme that catalyzes the crosslinking of collagen and elastin fibers, thereby strengthening the extracellular matrix structure. Previous studies showed that LOXL2 levels in the serum and liver of PSC patients are correlated with disease severity [92]. Moreover, the administration of a LOXL2 inhibitor in rodents was shown to reduce the accumulation of hepatic and biliary fibrosis and also accelerate its reversal [93,94]. Unfortunately, no improvement in liver fibrosis was observed in a placebo-controlled, phase 2b trial testing Simtuzumab, a LOXL2 inhibitor. In the trial, a total of 234 patients with compensated PSC were randomized on a 1:1:1 basis to receive placebo, weekly subcutaneous injections of Simtuzumab 75 mg, or weekly subcutaneous injections of Simtuzumab 125 mg for 96 weeks. The study failed to demonstrate any effect of Simtuzumab on hepatic collagen content (measured by morphometry on liver biopsy) and fibrosis stage (measured by the Ishak fibrosis stage) [80].
