Potent Suppression of Hydrophobic Bile Acids by Aldafermin, an FGF19 Analogue, Across Metabolic and Cholestatic Liver Diseases

Abstract Background & Aims Higher serum bile acid levels are associated with an increased risk of cirrhosis and liver-related morbidity and mortality. Here we report secondary analyses of aldafermin, an engineered analogue of the gut hormone FGF19, on circulating bile acid profile in prospective, phase 2 studies in patients with metabolic or cholestatic liver disease. Methods 176 patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) and fibrosis and elevated liver fat content (≥8% by MRI-PDFF) received 0.3 mg (n=23), 1 mg (n=49), 3 mg (n=49), 6 mg (n=28) aldafermin or placebo (n=27) for 12 weeks. 62 patients with primary sclerosing cholangitis (PSC) and elevated ALP (>1.5xULN) received 1 mg (n=21), 3 mg (n=21) aldafermin or placebo (n=20) for 12 weeks. Serum samples were collected on day 1 and week 12 for determination of bile acid profile and Pro-C3, a direct measure of fibrogenesis. Results Treatment with aldafermin resulted in significant, dose-dependent reductions in serum bile acids. In particular, bile acids with higher hydrophobicity indices, such as deoxycholic acid, lithocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid and glycocholic acid, were markedly lowered by aldafermin in both NASH and PSC populations. Moreover, aldafermin predominantly suppressed the glycine-conjugated bile acids, rather than the taurine-conjugated bile acids. Changes in levels of bile acids correlated with changes in the novel fibrogenesis marker Pro-C3, which detects a neo-epitope of the type III collagen during its formation, in the pooled NASH and PSC populations. Conclusion Aldafermin markedly reduced major hydrophobic bile acids that have greater detergent activity and cytotoxicity. Our data provide evidence that bile acids may contribute to sustaining a pro-fibrogenic microenvironment in the liver across metabolic and cholestatic liver diseases. Clinical trial number Clinicaltrials.gov NCT02443116 and NCT02704364.