Investigational drugs in phase II clinical trials for primary biliary cholangitis

References

• Silveira MG, Brunt EM, Heathcote J, et al. American association for the study of liver diseases endpoints conference: design and endpoints for clinical trials in primary biliary cirrhosis. Hepatology. 2010 Jul;52(1):349–359.
   PubMed Web of Science ®Google Scholar
• Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012 May;56(5):1181–1188.
   PubMed Web of Science ®Google Scholar
• Liaskou E, Hirschfield GM, Gershwin ME. Mechanisms of tissue injury in autoimmune liver diseases. Semin Immunopathol. 2014 Sep;36(5):553–568.
   PubMed Web of Science ®Google Scholar
• Kita H, Matsumura S, He XS, et al. Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest. 2002 May;109(9):1231–1240.
   PubMed Web of Science ®Google Scholar
• Poupon R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. Clin Res Hepatol Gastroenterol. 2012 Sep;36(Suppl 1):S3–S12.
   PubMed Web of Science ®Google Scholar
• Dyson JK, Hirschfield GM, Adams DH, et al. Novel therapeutic targets in primary biliary cirrhosis. Nat Rev Gastroenterol Hepatol. 2015 Mar;12(3):147–158.
   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
• European Association for the Study of the Liver. Electronic address eee, European association for the study of the L. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017 Jul;67(1):145–172.
   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, Dickson ER, Baldus WP, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology. 1994 May;106(5):1284–1290.
   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 May;110(5):1515–1518.
   PubMed Web of Science ®Google Scholar
• Angulo P, Lindor KD, Therneau TM, et al. Utilization of the Mayo risk score in patients with primary biliary cirrhosis receiving ursodeoxycholic acid. Liver. 1999 Apr;19(2):115–121.
   PubMedGoogle Scholar
• Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology. 2006 Mar;130(3):715–720.
   PubMed Web of Science ®Google Scholar
• Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008 Sep;48(3):871–877.
   PubMed Web of Science ®Google Scholar
• Momah N, Silveira MG, Jorgensen R, et al. Optimizing biochemical markers as endpoints for clinical trials in primary biliary cirrhosis. Liver Int. 2012 May;32(5):790–795.
   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 Dec;149(7):1804–1812.e4.
   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 Mar;63(3):930–950.
   PubMed Web of Science ®Google Scholar
• Carbone M, Mells GF, Pells G, et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology. 2013 Mar;144(3):560–569e7. quiz e13-4.
   PubMed Web of Science ®Google Scholar
• Kowdley KV, Jones D, Luketic V, et al. An international study evaluating the farnesoid X receptor agonist obeticholic acid as monotherapy in PBC. J Hepatol. 2011;54(Suppl 1):S28.
   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 Aug 18;375(7):631–643.
   PubMed Web of Science ®Google Scholar
• Ananthanarayanan M, Balasubramanian N, Makishima M, et al. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem. 2001 Aug 3;276(31):28857–28865.
   PubMed Web of Science ®Google Scholar
• Fiorucci S, Rizzo G, Antonelli E, et al. A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther. 2005 Aug;314(2):584–595.
   PubMed Web of Science ®Google Scholar
• Fiorucci S, Rizzo G, Antonelli E, et al. Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. J Pharmacol Exp Ther. 2005 Oct;315(1):58–68.
   PubMed Web of Science ®Google Scholar
• Fiorucci S, Antonelli E, Rizzo G, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology. 2004 Nov;127(5):1497–1512.
   PubMed Web of Science ®Google Scholar
• Liles JT, Karnik S, Hambruch E, et al. FXR agonism by GS-9674 decreases steatosis and fibrosis in a murine model of NASH. J Hepatol. 2016;64(Suppl):S169.
   Google Scholar
• Schwabl P, Hambruch E, Supper P, et al. The non-steroidal FXR agonist GS-9674 reduces liver fibrosis and ameliorates portal hypertension in a rat NASH model. J Hepatol. 2016;64(Suppl):S165.
   Google Scholar
• Kirby B, Djedjos CS, Birkebak J, et al. Evaluation of the safety and pharmacokinetic effects of the oral, non-steroidal Farnesoid X receptor agonist GS-9674 in healthy volunteers. Hepatology. 2016;64(1(Suppl)):574–5A.
   Google Scholar
• Djedjos CS, Kirby B, Billin A, et al. Pharmacodynamic effects of the oral, non-steroidal Farnesoid X receptor agonist GS-9674 in healthy volunteers. Hepatology. 2016;64(1(Suppl)):543A.
   Google Scholar
• Badman MK, Desai S, Laffitte B, et al. First-in-Human experience with LJN452, an orally available non-bile acid FXR agonist, demonstrates potent activation of FXR in healthy subjects. Hepatology. 2016;64(1(Suppl)):16A–17A.
   PubMed Web of Science ®Google Scholar
• Inagaki T, Choi M, Moschetta A, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005 Oct;2(4):217–225.
   PubMed Web of Science ®Google Scholar
• Zhou M, Learned RM, Rossi SJ, et al. Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice. Hepatology. 2016 Mar;63(3):914–929.
   PubMed Web of Science ®Google Scholar
• Luo J, Ko B, Elliott M, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med. 2014 Jul 30;6(247):247ra100.
   PubMed Web of Science ®Google Scholar
• Mayo MJ, Wigg AJ, Roberts SK, et al. NGM282, a novel variant of FGF-19, demonstrates biologic activity in primary biliary cirrhosis patients with an incomplete response to ursodeoxycholic acid: results of a phase 2 multicenter, randomized, double blinded, placebo controlled trial. Hepatology. 2016;62(Suppl1):263A–64A.
   Google Scholar
• Craddock AL, Love MW, Daniel RW, et al. Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am J Physiol. 1998 Jan;274(1 Pt 1):G157–G169.
   PubMed Web of Science ®Google Scholar
• Miethke AG, Zhang W, Simmons J, et al. Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice. Hepatology. 2016 Feb;63(2):512–523.
   PubMed Web of Science ®Google Scholar
• Pares A. Novel treatment strategies for primary biliary cholangitis. Semin Liver Dis. 2017 Feb;37(1):60–72.
   PubMed Web of Science ®Google Scholar
• Baghdasaryan A, Fuchs CD, Osterreicher CH, et al. Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis. J Hepatol. 2016 Mar;64(3):674–681.
   PubMed Web of Science ®Google Scholar
• Graffner H, Gillberg PG, Rikner L, et al. The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation. Aliment Pharmacol Ther. 2016 Jan;43(2):303–310.
   PubMed Web of Science ®Google Scholar
• Mayo MJ, Pockros P, Jones D, et al. Clarity: A phase 2, randomized, double-blind, placebo-controlled study of lopixibat chloride (formerly LUM001), a novel apical sodium-dependent bile acid transporter inhibitor, in the treatment of primary biliary cirrhosis associated with itching. J Hepatol. 2016;64(Suppl):S197.
   Google Scholar
• Bays HE, Schwartz S, Littlejohn T 3rd, et al. MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J Clin Endocrinol Metab. 2011 Sep;96(9):2889–2897.
   PubMed Web of Science ®Google Scholar
• Delerive P, Gervois P, Fruchart JC, et al. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem. 2000 Nov 24;275(47):36703–36707.
   PubMed Web of Science ®Google Scholar
• Kleemann R, Gervois PP, Verschuren L, et al. Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation. Blood. 2003 Jan 15;101(2):545–551.
   PubMed Web of Science ®Google Scholar
• Moffit JS, Aleksunes LM, Maher JM, et al. Induction of hepatic transporters multidrug resistance-associated proteins (Mrp) 3 and 4 by clofibrate is regulated by peroxisome proliferator-activated receptor alpha. J Pharmacol Exp Ther. 2006 May;317(2):537–545.
   PubMed Web of Science ®Google Scholar
• Levy C, Peter JA, Nelson DR, et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther. 2011 Jan;33(2):235–242.
   PubMed Web of Science ®Google Scholar
• Honda A, Ikegami T, Nakamuta M, et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology. 2013 May;57(5):1931–1941.
   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 Feb;34(2):197–203.
   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 Jun;39(3):296–306.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Li S, He L, et al. Combination therapy of fenofibrate and ursodeoxycholic acid in patients with primary biliary cirrhosis who respond incompletely to UDCA monotherapy: a meta-analysis. Drug Des Devel Ther. 2015;9:2757–2766.
   PubMed Web of Science ®Google Scholar
• Yin Q, Li J, Xia Y, et al. Systematic review and meta-analysis: bezafibrate in patients with primary biliary cirrhosis. Drug Des Devel Ther. 2015;9:5407–5419.
   PubMed Web of Science ®Google Scholar
• Corpechot C, Chazouilleres O, Rousseau A, et al. A 2-year multicenter, double-blind, randomized, placebo-controlled study of bezafibrate for the treatment of primary biliary cholangitis in patients with inadequate biochemical response to ursodeoxycholic acid therapy (Bezurso). J Hepatol. 2017;66:S89.
   Web of Science ®Google Scholar
• Wallace JM, Schwarz M, Coward P, et al. Effects of peroxisome proliferator-activated receptor alpha/delta agonists on HDL-cholesterol in vervet monkeys. J Lipid Res. 2005 May;46(5):1009–1016.
   PubMed Web of Science ®Google Scholar
• Briand F, Naik SU, Fuki I, et al. Both the peroxisome proliferator-activated receptor delta agonist, GW0742, and ezetimibe promote reverse cholesterol transport in mice by reducing intestinal reabsorption of HDL-derived cholesterol. Clin Transl Sci. 2009 Apr;2(2):127–133.
   PubMed Web of Science ®Google Scholar
• Choi YJ, Roberts BK, Wang X, et al. Effects of the PPAR-delta agonist MBX-8025 on atherogenic dyslipidemia. Atherosclerosis. 2012 Feb;220(2):470–476.
   PubMed Web of Science ®Google Scholar
• Jones D, Galambos MR, Swain M, et al. A phase 2 proof of concept study of MBX-8025 in patients with primary biliary cholangitis (PBC) who are inadequate responders to ursodeoxycholic acid (UDCA). Hepatology. 2016;64(6(Suppl)):1123A–1124A.
   Web of Science ®Google Scholar
• Bergasa NV, Alling DW, Talbot TL, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med. 1995 Aug 1;123(3):161–167.
   PubMed Web of Science ®Google Scholar
• Borchers AT, Shimoda S, Bowlus C, et al. Lymphocyte recruitment and homing to the liver in primary biliary cirrhosis and primary sclerosing cholangitis. Semin Immunopathol. 2009 Sep;31(3):309–322.
   PubMed Web of Science ®Google Scholar
• Chuang YH, Lian ZX, Cheng CM, et al. Increased levels of chemokine receptor CXCR3 and chemokines IP-10 and MIG in patients with primary biliary cirrhosis and their first degree relatives. J Autoimmun. 2005 Sep;25(2):126–132.
   PubMed Web of Science ®Google Scholar
• Balan V, Dickson ER, Jorgensen RA, et al. Effect of ursodeoxycholic acid on serum lipids of patients with primary biliary cirrhosis. Mayo Clin Proc. 1994 Oct;69(10):923–929.
   PubMed Web of Science ®Google Scholar
• Carbone M, Invernizzi P. Novel treatments targeting immune-related mechanisms in primary biliary cholangitis. Clin Liver Dis. 2016;8(5):127–131.
   Google Scholar
• Gulamhusein AF, Juran BD, Lazaridis KN. Genome-wide association studies in primary biliary cirrhosis. Semin Liver Dis. 2015 Nov;35(4):392–401.
   PubMed Web of Science ®Google Scholar
• Lleo A, Gershwin ME, Mantovani A, et al. Towards common denominators in primary biliary cirrhosis: the role of IL-12. J Hepatol. 2012 Mar;56(3):731–733.
   PubMed Web of Science ®Google Scholar
• Hirschfield GM, Liu X, Xu C, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med. 2009 Jun 11;360(24):2544–2555.
   PubMed Web of Science ®Google Scholar
• Yoshida K, Yang GX, Zhang W, et al. Deletion of Interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice. Hepatology. 2009 Nov;50(5):1494–1500.
   PubMed Web of Science ®Google Scholar
• Hirschfield GM, Gershwin ME, Strauss R, et al. Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: a proof-of-concept study. Hepatology. 2016 Jul;64(1):189–199.
   PubMed Web of Science ®Google Scholar
• Tanaka H, Yang GX, Iwakoshi N, et al. Anti-CD40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis. Clin Exp Immunol. 2013 Dec;174(3):364–371.
   PubMed Web of Science ®Google Scholar
• Carayanniotis G, Masters SR, Noelle RJ. Suppression of murine thyroiditis via blockade of the CD40-CD40L interaction. Immunology. 1997 Mar;90(3):421–426.
   PubMed Web of Science ®Google Scholar
• Balasa B, Krahl T, Patstone G, et al. CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice. J Immunology. 1997 Nov 01;159(9):4620–4627.
   PubMed Web of Science ®Google Scholar
• Danese S, Sans M, Fiocchi C. The CD40/CD40L costimulatory pathway in inflammatory bowel disease. Gut. 2004 Jul;53(7):1035–1043.
   PubMed Web of Science ®Google Scholar
• Afford SC, Ahmed-Choudhury J, Randhawa S, et al. CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells. Faseb J. 2001 Nov;15(13):2345–2354.
   PubMed Web of Science ®Google Scholar
• Lleo A, Liao J, Invernizzi P, et al. Immunoglobulin M levels inversely correlate with CD40 ligand promoter methylation in patients with primary biliary cirrhosis. Hepatology. 2012 Jan;55(1):153–160.
   PubMed Web of Science ®Google Scholar
• Wang D, Zhang H, Liang J, et al. Effect of allogeneic bone marrow-derived mesenchymal stem cells transplantation in a polyI:C-induced primary biliary cirrhosis mouse model. Clin Exp Med. 2011 Mar;11(1):25–32.
   PubMed Web of Science ®Google Scholar
• Wang L, Han Q, Chen H, et al. Allogeneic bone marrow mesenchymal stem cell transplantation in patients with UDCA-resistant primary biliary cirrhosis. Stem Cells Dev. 2014 Oct 15;23(20):2482–2489.
   PubMed Web of Science ®Google Scholar
• Levy C. Primary biliary cholangitis: treatment options finally expand. Hepatology. 2017 Apr;65(4):1405–1407.
   PubMedGoogle Scholar