Potent suppression of hydrophobic bile acids by aldafermin, an FGF19 analogue, across metabolic and cholestatic liver diseases

Arun J Sanyal, Lei Ling, Ulrich Beuers, Alex M DePaoli, Hsiao D Lieu, Stephen A Harrison, Gideon M Hirschfield, Arun J Sanyal, Lei Ling, Ulrich Beuers, Alex M DePaoli, Hsiao D Lieu, Stephen A Harrison, Gideon M Hirschfield

Abstract

Background & aims: Higher serum bile acid levels are associated with an increased risk of cirrhosis and liver-related morbidity and mortality. Herein, we report secondary analyses of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19, on the circulating bile acid profile in prospective, phase II studies in patients with metabolic or cholestatic liver disease.

Methods: One hundred and seventy-six patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH) and fibrosis and elevated liver fat content (≥8% by magnetic resonance imaging-proton density fat fraction) 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. Sixty-two patients with primary sclerosing cholangitis (PSC) and elevated alkaline phosphatase (>1.5× upper limit of normal) 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 neoepitope-specific N-terminal pro-peptide of type III collagen (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.

Conclusions: 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.

Lay summary: Aldafermin is an analogue of a gut hormone, which is in development as a treatment for patients with chronic liver disease. Herein, we show that aldafermin can potently and robustly suppress the toxic, hydrophobic bile acids irrespective of disease aetiology. The therapeutic strategy utilising aldafermin may be broadly applicable to other chronic gastrointestinal and liver disorders.

Clinical trials registration: The study is registered at Clinicaltrials.govNCT02443116 and NCT02704364.

Keywords: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BAAT, bile acid-CoA:amino acid N-acyltransferase; Bile acid synthesis; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; ELF test, Enhanced Liver Fibrosis test; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; Fibroblast growth factor; Fibrogenesis; G/T ratio, ratio of glycine to taurine conjugates of bile acids; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; GLCA, glycolithocholic acid; LCA, lithocholic acid; MRI-PDFF, magnetic resonance imaging-proton density fat fraction; NAFLD, non-alcoholic fatty liver disease; NAS, non-alcoholic fatty liver disease activity score; NASH CRN, NASH Clinical Research Network; NASH, non-alcoholic steatohepatitis; Non-alcoholic steatohepatitis; PSC, primary sclerosing cholangitis; Primary sclerosing cholangitis; Pro-C3; Pro-C3, neoepitope-specific N-terminal pro-peptide of type III collagen; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; TLCA, taurolithocholic acid; UDCA, ursodeoxycholic acid.

Conflict of interest statement

A.J.S. reports serving as an unpaid consultant to Intercept, Zydus, Echosense, Immuron, Madrigal, Galectin, Blade, Pliant, Albireo, and AMRA; is a consultant to Gilead, Allergan, Bristol-Myers Squibb, Pfizer, Merck, Galmed, Novartis, Novo Nordisk, Lilly, Siemens, Genentech, Boehringer Ingelhiem, Glympse Bio, Genfit, Coherus, Surrozen, Poxel, 89 Bio, Perspectum, AstraZeneca, Medimmune, and Lipocine; owns stock options in Indalo, Durect, Tiziana, Exhalenz, and Northsea; and is president of Sanyal Bio. L.L., A.M.D., and H.D.L. are employees and stockholders of NGM Biopharmaceuticals. U.B. reports consulting for Novartis, Intercept; grant/research support from Norwegian, American, and South African PSC patient foundations and German DCCV; received lecture fees from Abbvie, Falk Foundation, Gilead, Intercept, Novartis, Roche, Shire, and Zambon; and received research support for investigator-initiated studies from Dr. Falk Pharma and Intercept. S.A.H. reports research support from Conatus, Galectin, Galmed, Genfit, Gilead, Intercept, Madrigal, NGM, Akero, Axcella, Metacrine, Sagimet, Enyo, NorthSea, Genentech, Hepion, Cymabay, and Hightide; and is a consulting adviser for the Chronic Liver Disease Foundation, Cirius, Echosens, Akero, Galectin, Galmed, Genfit, Gilead, Intercept, Madrigal, NGM, Novartis, Perspectum, Metacrine, Medpace, Sagimet, Blade, Viking, Poxel, Axcella, Terns, HistoIndex, Hightide, Hepion, Ridgeline Therapeutics, CiVi, and Prometic. G.M.H. reports consulting for Cymabay, Genfit, Falk, Intercept, GSK, Mirum, Roche, and Pliant. Please refer to the accompanying ICMJE disclosure forms for further details.

© 2021 The Author(s).

Figures

Graphical abstract
Graphical abstract
Fig. 1
Fig. 1
Aldafermin reduces the toxic, hydrophobic, glycine-conjugated bile acids in patients with NASH. (A) A total of 176 patients with biopsy-proven NASH 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 in this phase II trial of aldafermin. Serum samples were collected at baseline (day 1) and week 12 (end of treatment) for bile acid profiling. (B) Change from baseline at week 12 in primary bile acids and conjugates. Note that aldafermin preferentially reduced levels of the more toxic, hydrophobic, glycine-conjugated primary bile acids. (C) Change from baseline at week 12 in secondary bile acids and conjugates. Similarly, aldafermin preferentially reduced levels of the more toxic, hydrophobic, glycine-conjugated secondary bile acids. ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001 vs. baseline (Wilcoxon test). CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; GLCA, glycolithocholic acid; LCA, lithocholic acid; NASH, non-alcoholic steatohepatitis; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; TLCA, taurolithocholic acid.
Fig. 2
Fig. 2
Aldafermin lowers the G/T ratio and the ratio of 12α-hydroxylated to non-12α-hydroxylated bile acids in patients with NASH. A total of 176 patients with biopsy-proven NASH 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. Serum samples were collected at baseline (day 1) and week 12 (end of treatment) for bile acid profiling. (A) Aldafermin reduced total primary and secondary bile acids. (B) Aldafermin reduced total glycine-conjugated, but not total taurine-conjugated bile acids. (C) Aldafermin lowered the G/T ratio in a dose-dependent manner. (D) Aldafermin lowered (CA + DCA)/(CDCA + LCA) ratio in a dose-dependent manner. ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001; n.s., not significant (Wilcoxon test). CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; G/T ratio, ratio of glycine to taurine conjugates of bile acids; LCA, lithocholic acid; NASH, non-alcoholic steatohepatitis.
Fig. 3
Fig. 3
Aldafermin reduces the toxic, hydrophobic, glycine-conjugated bile acids in patients with PSC. (A) Sixty-two patients with PSC diagnosed according to EASL criteria received 1 mg (n = 21), 3 mg (n = 21) aldafermin or placebo (n = 20) for 12 weeks. Serum samples were collected at baseline (day 1) and week 12 (end of treatment) for bile acid profiling. (B) Concentrations of the primary bile acids and their conjugates. Note that aldafermin preferentially reduced levels of the more toxic, hydrophobic, glycine-conjugated primary bile acids. (C) Concentrations of the secondary bile acids and their conjugates. Similarly, aldafermin preferentially reduced levels of the more toxic, hydrophobic, glycine-conjugated secondary bile acids. ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001; n.s., not significant (Wilcoxon test). CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; GLCA, glycolithocholic acid; G/T ratio, ratio of glycine to taurine conjugates of bile acids; LCA, lithocholic acid; PSC, primary sclerosing cholangitis; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; TLCA, taurolithocholic acid.
Fig. 4
Fig. 4
Aldafermin lowers the G/T ratio and the ratio of 12α-hydroxylated to non-12α-hydroxylated bile acids in patients with PSC. Sixty-two patients with PSC diagnosed according to EASL criteria received 1 mg (n = 21), 3 mg (n = 21) aldafermin or placebo (n = 20) for 12 weeks. Serum samples were collected at baseline (day 1) and week 12 (end of treatment) for bile acid profiling. (A) Aldafermin reduced total secondary bile acids. (B) Aldafermin reduced total glycine-conjugated, but not total taurine-conjugated bile acids. (C) Aldafermin lowered the G/T ratio. (D) Aldafermin lowered (CA + DCA)/(CDCA + LCA) ratio. ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001; n.s., not significant (Wilcoxon test). CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; G/T ratio, ratio of glycine to taurine conjugates of bile acids; LCA, lithocholic acid; PSC, primary sclerosing cholangitis.
Fig. 5
Fig. 5
Serum bile acids correlate with the novel fibrogenesis biomarker Pro-C3. (A) Serum Pro-C3 concentrations increase with fibrosis stage in patients with NASH. A total of 176 patients had liver biopsies evaluated according to the NASH CRN criteria at baseline. Patients with stage 1 fibrosis (F1) had the lowest Pro-C3 levels, whereas those with stage 3 fibrosis (F3, advanced fibrosis) had the highest Pro-C3 levels. ∗∗p <0.01, ∗∗∗p <0.001 vs. F1 (Kruskal–Wallis test with Dunn’s multiple comparison correction). (B) No significant differences in Pro-C3 concentrations by histological grade of steatosis, inflammation, or ballooning. (C) Change from baseline to week 12 in Pro-C3 in NASH and PSC populations.∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001 (Wilcoxon test). (D) GCA and GCDCA levels correlate with Pro-C3 at baseline in the pooled NASH and PSC populations. A total of 238 patients (176 patients with NASH and 62 patients with PSC) were included in the analysis. The Spearman’s correlation coefficients and p values are labelled on the graphs. (E) GCA and GCDCA levels correlate with Pro-C3 at week 12 (end of treatment) in the pooled NASH and PSC populations. A total of 238 patients were included in the analysis. (F) Percent change in the major, toxic, hydrophobic bile acids in patients who achieved >25% reduction in Pro-C3 vs. those who did not. DCA, deoxycholic acid; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; GDCA, glycodeoxycholic acid; NASH, non-alcoholic steatohepatitis; NASH CRN, NASH Clinical Research Network; Pro-C3, neoepitope-specific N-terminal pro-peptide of type III collagen; PSC, primary sclerosing cholangitis.

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