Investigational drugs in early phase development for primary biliary cholangitis

References

• Hirschfield GM, Beuers U, Corpechot C, et al. EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145–172.
   PubMed Web of Science ®Google Scholar
• Lindor KD, Bowlus CL, Boyer J, et al. Primary biliary cholangitis: 2018 practice guidance from the American association for the study of liver Diseases. Hepatology. 2019;69:394–419.
   PubMed Web of Science ®Google Scholar
• Cheung AC, LaRusso NF, Gores GJ, et al. Epigenetics in the primary biliary cholangitis and primary sclerosing cholangitis. Semin Liver Dis. 2017;37(02):159–174.
   PubMedGoogle Scholar
• Selmi C, Mayo MJ, Bach N, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology. 2004;127(2):485–492.
   PubMed Web of Science ®Google Scholar
• Lu M, Zhou Y, Haller IV, et al. Increasing prevalence of primary biliary cholangitis and reduced mortality with treatment. Clin gastroenterol hepatol. 2018 Aug;16(8):1342–1350.
   PubMed Web of Science ®Google Scholar
• Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid mechanisms of action and clinical use in hepatobiliary disorders. J Hepatol. 2001;35(1):134–146.
   PubMed Web of Science ®Google Scholar
• Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36(3):525–531.
   PubMed Web of Science ®Google Scholar
• Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology. 2009 Jul;50(1):291–308.
   PubMed Web of Science ®Google Scholar
• Angulo P, Jorgensen RA, Lindor KD. Incomplete response to ursodeoxycholic acid in primary biliary cirrhosis: is a double dosage worthwhile? Am J Gastroenterol. 2001 Nov;96(11):3152–3157.
   PubMed Web of Science ®Google Scholar
• Poupon RE, Poupon R, Balkau B, Ursodiol for the long-term treatment of primary biliary cirrhosis. the UDCA-PBC study group. N Engl J Med. 1994 May 12;330(19):1342–1347.
   PubMed Web of Science ®Google Scholar
• Poupon RE, Lindor KD, Cauch-Dudek K, et al. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997 Sep;113(3):884–890.
   PubMed Web of Science ®Google Scholar
• Lindor KD, Therneau TM, Jorgensen RA, et al. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology. 1996;110(5):1515–1518.
   PubMed Web of Science ®Google Scholar
• Harms MH, Buuren HRV, Corpechot C, et al. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis. J Hepatol. 2019;71(2):357–365.
   PubMed Web of Science ®Google Scholar
• Corpechot C, Carrat F, Bahr A, et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology. 2005 Feb;128(2):297–303.
   PubMed Web of Science ®Google Scholar
• Carbone M, Nardi A, Flack S, et al. Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA response score. Lancet Gastroenterol Hepatol. 2018;3(9):626–634.
   PubMed Web of Science ®Google Scholar
• Cheung AC, Lammers WJ, Murillo Perez CF, et al. Effects of age and sex of response to ursodeoxycholic acid and transplant-free survival in patients with primary biliary cholangitis. Clin Gastroenterol Hepatol. 2019;17(10):2076–84.e2.
   PubMed Web of Science ®Google Scholar
• Tang L, Zhong R, He X, et al. Evidence for the association between IgG-antimitochondrial antibody and biochemical response to ursodeoxycholic acid treatment in primary biliary cholangitis. J Gastroenterol Hepatol. 2017;32(3):659–666.
   PubMed Web of Science ®Google Scholar
• Goel A, Kim WR. Natural history of primary biliary cholangitis in the ursodeoxycholic acid era: role of scoring systems. Clin Liver Dis. 2018;22(3):563–578.
   PubMed Web of Science ®Google Scholar
• Carbone M, Sharp SJ, Flack S, et al. The UK-PBC risk scores: derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology. 2016;63(3):930–950.
   PubMed Web of Science ®Google Scholar
• Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology. 2015;149(7):1804–12.e4.
   PubMed Web of Science ®Google Scholar
• Bossen L, Gerussi A, Lygoura V, et al. Support of precision medicine through risk-stratification in autoimmune liver diseases - histology, scoring systems, and non-invasive markers. Autoimmun Rev. 2018;17(9):854–865.
   PubMed Web of Science ®Google Scholar
• Williams CN, Al-Knawy B, Blanchard W. Bioavailability of four ursodeoxycholic acid preparations. Aliment Pharmacol Ther. 2000;14(9):1133–1139.
   PubMed Web of Science ®Google Scholar
• Chazouillères O, Wendum D, Serfaty L, et al. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology. 1998;28(2):296–301.
   PubMed Web of Science ®Google Scholar
• To U, Silveira M. Overlap syndrome of autoimmune hepatitis and primary biliary cholangitis. Clin Liver Dis. 2018;22(3):603–611.
   PubMed Web of Science ®Google Scholar
• Boberg KM, Chapman RW, Hirschfield GM, et al. Overlap syndromes: the international autoimmune hepatitis group (IAIHG) position statement on a controversial issue. J Hepatol. 2011;54(2):374–385.
   PubMed Web of Science ®Google Scholar
• Efe C, Ozaslan E, Heurgué-Berlot A, et al. Sequential presentation of primary biliary cirrhosis and autoimmune hepatitis. Eur J Gastroenterol Hepatol. 2014;26(5):532–537.
   PubMed Web of Science ®Google Scholar
• Guo C, Zhang H, Yang J, et al. Combination therapy of ursodeoxycholic acid and budesonide for PBC-AIH overlap syndrome: a meta-analysis. Drug Des Devel Ther. 2015;9:567.
   PubMed Web of Science ®Google Scholar
• Pellicciari R, Fiorucci S, Camaioni E, et al. 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002;45(17):3569–3572.
   PubMed Web of Science ®Google Scholar
• Kliewer SA, Mangelsdorf DJ. Bile acids as hormones: the FXR-FGF15/19 pathway. Dig Dis. 2015;33(3):327–331.
   PubMed Web of Science ®Google Scholar
• Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015;148(4):751–61 e8.
   PubMed Web of Science ®Google Scholar
• Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016; 375(7): 631–643.
   PubMed Web of Science ®Google Scholar
• Trauner M, Nevens F, Shiffman ML, et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study. Lancet Gastroenterol Hepatol. 2019;4(6):445–453.
   PubMed Web of Science ®Google Scholar
• Kowdley KV, Luketic V, Chapman R, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology. 2018; 67(5): 1890–1902.
   PubMed Web of Science ®Google Scholar
• Bergasa NV. The pruritus of cholestasis: from bile acids to opiate agonists: relevant after all these years. Med Hypotheses. 2018;110:86–89.
   PubMed Web of Science ®Google Scholar
• Eaton JE, Vuppalanchi R, Reddy R, et al. Liver injury in patients with cholestatic liver disease treated with obeticholic acid. Hepatology. 2020;71(4):1511–1514.
   PubMed Web of Science ®Google Scholar
• Aschenbrenner DS. Excessive dosing of obeticholic acid may increase risk of liver damage. Am J Nurs. 2018 Feb;118(2): 46.
   Web of Science ®Google Scholar
• Food US, Administration D. FDA adds boxed warning to highlight correct dosing of ocaliva (obeticholic acid) for patients with a rare chronic liver disease. 2018. https://www.fda.gov/media/111167/download ( accessed2020Jan11).
   Google Scholar
• Hegade VS, Kendrick SFW, Dobbins RL, et al. Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Lancet. 2017; 389(10074): 1114–1123.
   PubMed Web of Science ®Google Scholar
• Liss KH, Finck BN. PPARs and nonalcoholic fatty liver disease. Biochimie. 2017;136:65–74.
   PubMed Web of Science ®Google Scholar
• Li T, Chiang JY. Regulation of bile acid and cholesterol metabolism by PPARs. PPAR Res. 2009;2009:501739.
   PubMed Web of Science ®Google Scholar
• Day AP, Feher MD, Chopra R, et al. The effect of bezafibrate treatment on serum alkaline phosphatase isoenzyme activities. Metabolism. 1993;42(7):839–842.
   PubMed Web of Science ®Google Scholar
• Kersten S, Stienstra R. The role and regulation of the peroxisome proliferator activated receptor alpha in human liver. Biochimie. 2017;136:75–84.
   PubMed Web of Science ®Google Scholar
• Xia X, Jung D, Webb P, et al. Liver X receptor β and peroxisome proliferator-activated receptor δ regulate cholesterol transport in murine cholangiocytes. Hepatology. 2012;56(6):2288–2296.
   PubMed Web of Science ®Google Scholar
• Mukundan L, Odegaard JI, Morel CR, et al. PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat Med. 2009;15(11):1266–1272.
   PubMed Web of Science ®Google Scholar
• Harada K, Isse K, Kamihira T, et al. Th1 cytokine-induced downregulation of PPARγ in human biliary cells relates to cholangitis in primary biliary cirrhosis. Hepatology. 2005;41(6):1329–1338.
   PubMed Web of Science ®Google Scholar
• Nozaki Y, Harada K, Sanzen T, et al. PPARγ ligand attenuates portal inflammation in the MRL-lpr mouse: a new strategy to restrain cholangiopathy in primary biliary cirrhosis. Med Mol Morphol. 2013;46(3):153–159.
   PubMed Web of Science ®Google Scholar
• Ghonem NS, Assis DN, Boyer JL. Fibrates and cholestasis. Hepatology. 2015;62(2):635–643.
   PubMed Web of Science ®Google Scholar
• Corpechot C, Chazouilleres O, Rousseau A, et al. A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med. 2018; 378(23): 2171–2181.
   PubMed Web of Science ®Google Scholar
• Honda A, Tanaka A, Kaneko T, et al. Bezafibrate improves GLOBE and UK-PBC scores and long-term outcomes in patients with primary biliary cholangitis. Hepatology. 2019 Dec;70(6):2035–2046.
   PubMed Web of Science ®Google Scholar
• Kanda T, Yokosuka O, Imazeki F, et al. Bezafibrate treatment: a new medical approach for PBC patients? J Gastroenterol. 2003;38(6):573–578.
   PubMed Web of Science ®Google Scholar
• Lens S, Leoz M, Nazal L, et al. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int. 2014;34(2):197–203.
   PubMed Web of Science ®Google Scholar
• Reig A, Sesé P, Parés A. Effects of bezafibrate on outcome and pruritus in primary biliary cholangitis with suboptimal ursodeoxycholic acid response. Am J Gastroenterol. 2018;113(1):49–55.
   PubMed Web of Science ®Google Scholar
• Hegade VS, Khanna A, Walker LJ, et al. Long-term fenofibrate treatment in primary biliary cholangitis improves biochemistry but not the UK-PBC risk score. Dig Dis Sci. 2016;61(10):3037–3044.
   PubMed Web of Science ®Google Scholar
• Grigorian AY, Mardini HE, Corpechot C, et al. Fenofibrate is effective adjunctive therapy in the treatment of primary biliary cirrhosis: a meta-analysis. Clin Res Hepatol Gastroenterol. 2015;39(3):96–306.
   Web of Science ®Google Scholar
• Jones D, Boudes PF, Swain MG, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of- concept study. Lancet Gastroenterol Hepatol. 2017; 2(10): 716–726.
   PubMed Web of Science ®Google Scholar
• Mayo M, Bowlus C, Galambos M, et al. Seladelpar for the treatment of primary biliary cholangitis: experience with 25 cirrhotic patients. European Association for the Study of the Liver International Liver Congress; Vienna, Austria; April 10–14, 2019.
   Google Scholar
• CymaBay Therapeutics, Inc. ENHANCE: seladelpar in subjects with primary biliary cholangitis (pbc) and an inadequate response to or an intolerance to ursodeoxycholic acid (UDCA). https://clinicaltrials.gov/ct2/show/NCT03602560. Accessed 2020Feb25.
   Google Scholar
• Genfit. Elafibranor in PBC. https://www.genfit.com/pipeline/elafibranor-in-pbc/( accessed 2020Feb25).
   Google Scholar
• Jain MR, Giri SR, Bhoi B, et al. Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int. 2018;38(6):1084–1094.
   PubMed Web of Science ®Google Scholar
• Mayo MJ, Wigg AJ, Leggett BA, et al. NGM 282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Commun. 2018; 2(9): 1037–1050.
   PubMed Web of Science ®Google Scholar
• Schramm C, Hirschfield G, Mason AL, et al. Early assessment of safety and efficacy of tropifexor, a potent non-bile acid FXR agonist, in patients with primary biliary cholangitis: an interim analysis of an ongoing phase 2 study. European Association for the Study of the Liver International Liver Congress; Paris, France; 2018Apr11–15.
   Google Scholar
• Trauner M, Gulamhusein A, Hameed B, et al. The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis. Hepatology. 2019;70(3):788–801.
   PubMed Web of Science ®Google Scholar
• Kowdley KV, Minuk GY, Pagadala MR, et al. The nonsteroidal farnesoid x receptor (fxr) agonist cilfexor improves liver biochemistry in patients with primary biliary cholangitis (pbc): a phase 2, randomized, placebo-controlled trial. American Association for the Study of Liver Diseases Liver Meeting; Boston, Massachusetts; 2019Nov8–12.
   Google Scholar
• Erstad DJ, Farrar CT, Ghoshal S, et al. Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP-305, a novel farnesoid X receptor agonist. Hepatol Commun. 2018;2(7):821–835.
   PubMed Web of Science ®Google Scholar
• Asuri S, McIntosh S, Taylor V, et al. Primary biliary cholangitis in British Columbia first nations: clinical features and discovery of novel genetic susceptibility loci. Liver Int. 2018;38(5):940–948.
   PubMed Web of Science ®Google Scholar
• Liaskou E, Patel SR, Webb G, et al. Increased sensitivity of treg cells from patients with PBC to low dose IL-12 drives their differentiation into IFN-γ secreting cells. J Autoimmun. 2018;94:143–155.
   PubMed Web of Science ®Google Scholar
• Eli Lilly and Company. https://clinicaltrials.gov/ct2/show/NCT03742973. Accessed 2020Mar4.
   Google Scholar
• Fabregat I, Caballero-Díaz D. Transforming growth factor-β-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front Oncol. 2018;8:357.
   PubMed Web of Science ®Google Scholar
• Baglieri J, Brenner D, Kisseleva T. The role of fibrosis and liver-associated fibroblasts in the pathogenesis of hepatocellular carcinoma. Int J Mol Sci. 2019;20(7):1723.
   Web of Science ®Google Scholar
• Genkyotex SA. https://clinicaltrials.gov/ct2/show/NCT03226067. Accessed 2020Mar4.
   Google Scholar
• Studer E, Zhou X, Zhao R, et al. Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes. Hepatology. 2012;55(1):267–276.
   PubMed Web of Science ®Google Scholar
• Moritoki Y, Tsuneyama K, Nakamura Y, et al. Anti-drug antibodies against a novel humanized anti-CD20 antibody impair its therapeutic effect on primary biliary cholangitis in human CD20- and FcγR-expressing mice. Front Immunol. 2018;9:2534.
   PubMed Web of Science ®Google Scholar
• Al-Shamma H, Lehmann-Bruinsma K, Carroll C, et al. The selective sphingosine 1-phosphate receptor modulator etrasimod regulates lymphocyte trafficking and alleviates experimental colitis. J Pharmacol Exp Ther. 2019;369(3):311–317.
   PubMed Web of Science ®Google Scholar
• Cederbaum AI. Hepatoprotective effects of S-adenosyl-L-methionine against alcohol- and cytochrome P450 2E1-induced liver injury. World J Gastroenterol. 2010;16(11):1366–1376.
   PubMed Web of Science ®Google Scholar
• Milkiewicz P, Roma MG, Cardenas R, et al. Effect of tauroursodeoxycholate and S-adenosyl-L-methionine on 17beta-estradiol glucuronide-induced cholestasis. J Hepatol. 2001;34(2):184–191.
   PubMed Web of Science ®Google Scholar
• Wunsch E, Raszeja-Wyszomirska J, Barbier O, et al. Effect of S-adenosyl-L-methionine on liver biochemistry and quality of life in patients with primary biliary cholangitis treated with ursodeoxycholic acid. A prospective, open label pilot study. J Gastrointest Liver Dis. 2018;27(3):273–279.
   PubMed Web of Science ®Google Scholar
• Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353(12):1261–1273.
   PubMed Web of Science ®Google Scholar
• Long SL, Gahan CGM, Joyce SA. Interactions between gut bacteria and bile in health and disease. Mol Aspects Med. 2017;56:54–65.
   PubMed Web of Science ®Google Scholar
• Degirolamo C, Rainaldi S, Bovenga F, et al. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep. 2014;7(1):12–18.
   PubMed Web of Science ®Google Scholar
• Fukui H. Increased intestinal permeability and decreased barrier function: does it really influence the risk of inflammation? Inflamm Intest Dis. 2016;1(3):135–145.
   PubMedGoogle Scholar
• Sun Yat-sen University. https://clinicaltrials.gov/ct2/show/NCT03521297. Accessed 2020Apr30.
   Google Scholar
• Wang L, Li J, Liu H, et al. A pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis. J Gastroenterol Hepatol. 2013;28(suppl 1):85–92.
   PubMed Web of Science ®Google Scholar
• Xijing Hospital of Digestive Diseases. https://clinicaltrials.gov/ct2/show/NCT03668145. Accessed 2020 Apr30.
   Google Scholar
• Sasaki M, Miyakoshi M, Sato Y, et al. Chemokine-chemokine receptor CCL2-CCR2 and CX3CL1-CX3CR1 axis may play a role in the aggravated inflammation in primary biliary cirrhosis. Dig Dis Sci. 2014;59(2):358–364.
   PubMed Web of Science ®Google Scholar
• Harada K, Kakuda Y, Nakamura M, et al. Clinicopathological significance of serum fractalkine in primary biliary cirrhosis. Dig Dis Sci. 2013;58(10):3037–3043.
   PubMed Web of Science ®Google Scholar
• EA Pharma Co., Ltd. https://clinicaltrials.gov/ct2/show/NCT03092765. Accessed 2020Mar4.
   Google Scholar
• de Graaf KL, Lapeyre G, Guilhot F, et al. NI-0801, an anti-chemokine (C-X-C motif) ligand 10 antibody, in patients with primary biliary cholangitis and an incomplete response to ursodeoxycholic acid. Hepatol Commun. 2018;2(5):492–503.
   PubMed Web of Science ®Google Scholar
• Singal AK, Guturu P, Hmoud B, et al. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation. 2013;95(5):755–760.
   PubMed Web of Science ®Google Scholar
• Montano-Loza AJ, Hansen BE, Corpechot C, et al. Factors associated with recurrence of primary biliary cholangitis after liver transplantation and effects on graft and patient survival. Gastroenterology. 2019;156(1):96–107.e1.
   PubMed Web of Science ®Google Scholar
• Corpechot C, Chazouilleres O, Montano-Loza A, et al. Preventive administration of ursodeoxycholic acid after liver transplantation for primary biliary cholangitis prevents disease recurrence and prolongs graft survival. European Association for the Study of the Liver International Liver Congress; Vienna, Austria; 2019Apr10–14
   Google Scholar