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2022 | OriginalPaper | Buchkapitel

21. Spezifische Therapie – neue Medikamente

verfasst von : Naomi F. Lange, Jean-François Dufour

Erschienen in: Nicht-alkoholische Fettlebererkrankung

Verlag: Springer Berlin Heidelberg

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Zusammenfassung

Der Bedarf an effektiven Medikamenten zur Therapie der nicht-alkoholischen Steatohepatitis (NASH) auf dem Boden einer nicht-alkoholischen Fettlebererkrankung (NAFLD) steigt mit der zunehmenden Anzahl betroffener Patienten stetig. Dabei gibt es aktuell keine zugelassenen Wirkstoffe für die Behandlung der NASH, zahlreiche Präparate werden derzeit jedoch in klinischen Studien der Phasen 2 und 3 erprobt. Einige dieser Studien zeigen vielversprechende Ergebnisse mit relevanten Verbesserungen von Steatose, Fibrose und entzündlicher Aktivität. Aufgrund der komplexen und multifokalen Pathogenese der Grunderkrankung bietet sich eine Vielzahl an Substanzklassen mit diversen pharmakologischen Ansätzen und Wirkprinzipien an. Während bekannte antidiabetische Therapien auf ihre Wirksamkeit bei NASH hin untersucht werden, werden auch zahlreiche neue, spezifische Therapien entwickelt.

Abdelmalek MF, Freilich BL, Harrison SA, Powell EE, McCarthy ME, Rinella NT, Peres D, Kanellos J, Lalazar G, Sanyal AJ (2018) Imm-124E improves metabolic endotoxemia and markers of liver injury in nonalcoholic steatohepatitis. Hepatology 68(October):68A-69A

Ali AH, Carey EJ, Lindor KD (2015) Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med 3(1). https://doi.org/10.3978/j.issn.2305-5839.2014.12.06

Amin N, Carvajal-Gonzalez S, Aggarwal N, Tuthill T, Inglot M, Bergman A, Esler W (2019) PF-05221304 (PF’1304), a liver-targeted acetyl-coa carboxylase inhibitor (Acci), in adults with nonalcoholic fatty liver disease (Nafld) demonstrates robust reductions in liver fat and alt – phase 2a, dose-ranging study. Hepatology 70(October):21A-22A

Anstee QM, Neuschwander-Tetri BA, Wong VW-S, Abdelmalek MF, Younossi ZM, Yuan J, Pecoraro ML et al (2020) Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA phase 3 study design. Contemp Clin Trials 89(February):105922. https://doi.org/10.1016/j.cct.2019.105922CrossRefPubMed

Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM et al (2016) Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387(10019):679–690. https://doi.org/10.1016/S0140-6736(15)00803-XCrossRefPubMed

Bifari F, Manfrini R, Cas MD, Berra C, Siano M, Zuin M, Paroni R, Folli F (2018) Multiple target tissue effects of GLP-1 analogues on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Pharmacol Res 137:219–229. https://doi.org/10.1016/j.phrs.2018.09.025CrossRefPubMed

Bojic LA, Huff MW (2013) Peroxisome proliferator-activated receptor δ: a multifaceted metabolic player. Curr Opin Lipidol 24(2):171–177. https://doi.org/10.1097/MOL.0b013e32835cc949CrossRefPubMed

Businesswire (2020) Press Release – HighTide Therapeutics Announces Positive Topline Results From Phase 2a Study of HTD1801 in NASH Patients. 7 May 2020. https://www.businesswire.com/news/home/20200507005019/en/HighTide-Therapeutics-Announces-Positive-Topline-Results-Phase

Calle R, Cappon G, Somayaji V, Esler W, Bergman A (2019) Co-Administration of the acc inhibitor Pf-05221304 and the Dgat2 Inhibitor Pf-06865571 is safe and well tolerated in short-term studies in non-human primates and humans with no clinically meaningful pharmacokinetic interaction. Hepatology 70(October):1273A-1273A

Can-Fite BioPharma Ltd (2020a) Press Release – Can-Fite Reports Positive Top LineResults from Its Phase II NASH Study WithNamodenoson. 7 April 2020. https://ir.canfite.com/press-releases/detail/900/can-fite-reports-positive-top-line-results-from-its-phase-ii-nash-study-with-namodenoson

Can-Fite BioPharma Ltd (2020b) Press Release – Can-Fite Reports Additional Findings FromSuccessful Phase II NASH Study: 25 MgDose of Namodenoson SignificantlyReduced Liver Fat and Fibrosis. 18 May 2020. https://ir.canfite.com/press-releases/detail/904/can-fite-reports-additional-findings-from-successful-phase-ii-nash-study-25-mg-dose-of-namodenoson-significantly-reduced-liver-fat-and-fibrosis

Chalasani N, Garcia-Tsao G, Goodman Z, Lawitz E, Abdelmalek M, Rinella M, Ryan M, Noureddin M, et al (2019) A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Galectin-3 Inhibitor (GR-MD-02) for One Year in Patients with NASH Cirrhosis and Portal Hypertension The NASH-CX Trial, 19

Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ (2018) The Diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the american association for the study of liver diseases. Hepatology 67(1):328–357. https://doi.org/10.1002/hep.29367CrossRefPubMed

Charles ED, Neuschwander-Tetri BA, Pablo Frias J, Kundu S, Luo Y, Tirucherai GS, Christian R (2019) Pegbelfermin (BMS-986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: results from a randomized phase 2 study. Obesity (Silver Spring, Md.) 27(1): 41–49. https://doi.org/10.1002/oby.22344

Chen Z, Vigueira PA, Chambers KT, Hall AM, Mitra MS, Qi N, McDonald WG, Colca JR, Kletzien RF, Finck BN (2012) Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor γ-sparing thiazolidinedione. J Biol Chem 287(28):23537–23548. https://doi.org/10.1074/jbc.M112.363960CrossRefPubMedPubMedCentral

Colca JR, McDonald WG, Cavey GS, Cole SL, Holewa DD, Brightwell-Conrad AS, Wolfe CL et al (2013) Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (MTOT)–relationship to newly identified mitochondrial pyruvate carrier proteins. PLoS ONE 8(5):e61551. https://doi.org/10.1371/journal.pone.0061551CrossRefPubMedPubMedCentral

CymaBay (2019) Press Release – CymaBay Therapeutics Halts Clinical Development of Seladelpar. 25 November 2019. https://ir.cymabay.com/press-releases/detail/476/cymabay-therapeutics-halts-clinical-development-of-seladelpar

Diehl AM, Harrison S, Caldwell S, Rinella M, Paredes A, Moylan C, Guy C et al (2018) JKB-121 in patients with nonalcoholic steatohepatitis: a phase 2 double blind randomized placebo control study. J Hepatol 68(April):S103. https://doi.org/10.1016/S0168-8278(18)30425-2CrossRef

EASL–EASD–EASO. (2016) EASL–EASD–EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 64(6):1388–1402. https://doi.org/10.1016/j.jhep.2015.11.004CrossRef

Enanta Pharmaceuticals (2019) Enanta Announces Positive Results of ARGON-1 Study of Its Lead FXR Agonist, EDP-305, for the Treatment of NASH. 25 September 2019. https://www.enanta.com/investors/news-releases/press-release/2019/Enanta-Announces-Positive-Results-of-ARGON-1-Study-of-its-lead-FXR-Agonist-EDP-305-for-the-Treatment-of-NASH/default.aspx

Estes C, Anstee QM, Arias-Loste MT, Bantel H, Bellentani S, Caballeria J, Colombo M et al (2018) Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the Period 2016–2030. J Hepatol 69(4):896–904. https://doi.org/10.1016/j.jhep.2018.05.036CrossRefPubMed

FDA (2017) Drug Safety and Availability – FDA Adds Boxed Warning to Highlight Correct Dosing of Ocaliva (Obeticholic Acid) for Patients with a Rare Chronic Liver Disease. WebContent. Drug Safety Communication. 21 September 2017. https://www.fda.gov/Drugs/DrugSafety/ucm594941.htm

Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, Francque S, et al (2018) A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology (Baltimore, Md.) 67(5): 1754–67. https://doi.org/10.1002/hep.29477

Friedman S, Sanyal A, Goodman Z, Lefebvre E, Gottwald M, Fischer L, Ratziu V (2016) Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR phase 2b study design. Contemp Clin Trials 47(March):356–365. https://doi.org/10.1016/j.cct.2016.02.012CrossRefPubMed

Galectin Therapeutics Inc (2020) Press Release -Galectin Therapeutics Reports Fiscal 2019 Financial Results and Provides Business Update. GlobeNewswire News Room. 16 March 2020. https://www.globenewswire.com/news-release/2020/03/16/2000999/0/en/Galectin-Therapeutics-Reports-Fiscal-2019-Financial-Results-and-Provides-Business-Update.html

Garcia-Tsao G, Bosch J, Kayali Z, Harrison S, Abdelmalek M, Lawitz E, Satapathy S, et al (2019) Multicenter, double-blind, placebo-controlled, randomized trial of emricasan in subjects with NASH cirrhosis and severe portal hypertension. Presented at the late-breaking oral presentation at EASL, April

Garcia-Tsao G, Fuchs M, Shiffman M, Borg BB, Pyrsopoulos N, Shetty K, Gallegos-Orozco JF et al (2019) Emricasan (IDN-6556) lowers portal pressure in patients with compensated cirrhosis and severe portal hypertension. Hepatology 69(2):717–728. https://doi.org/10.1002/hep.30199CrossRefPubMed

Gawrieh S, Noureddin M, Loo NM, Mohseni R, Awasty VR, Cusi K, Kowdley KV et al (2019) A phase 2, prospective, multicenter, double-blind, randomized study of saroglitazar magnesium 1 Mg, 2 Mg or 4 Mg versus placebo in patients with nonalcoholic fatty liver disease and/or nonalcoholic steatohepatitis (Evidences Iv). Hepatology 70(6):1484A-1485A

GENFIT (2020) GENFIT: Announces Results from Interim Analysis of RESOLVE-IT Phase 3 Trial of Elafibranor in Adults with NASH and Fibrosis. GlobeNewswire News Room. 5 November 2020. https://www.globenewswire.com/news-release/2020/05/11/2031418/0/en/GENFIT-Announces-Results-from-Interim-Analysis-of-RESOLVE-IT-Phase-3-Trial-of-Elafibranor-in-Adults-with-NASH-and-Fibrosis.html

Gilead Sciences (2019) Gilead Announces Topline Data From Phase 3 STELLAR-4 Study of Selonsertib in Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH). 11 February 2019. https://www.gilead.com/news-and-press/press-room/press-releases/2019/2/gilead-announces-topline-data-from-phase-3-stellar4-study-of-selonsertib-in-compensated-cirrhosis-f4-due-to-nonalcoholic-steatohepatitis-nash

Gilead Sciences (2020) Gilead Announces Topline Results From Phase 2 ATLAS Study in Patients With Bridging Fibrosis (F3) and Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH). 1 July 2020. https://www.gilead.com/news-and-press/press-room/press-releases/2019/12/gilead-announces-topline-results-from-phase-2-atlas-study-in-patients-with-bridging-fibrosis-f3-and-compensated-cirrhosis-f4-due-to-nonalcoholic-s

Grover GJ, Mellström K, Ye L, Malm J, Li Y-L, Bladh L-G, Sleph PG et al (2003) Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. PNAS 100(17):10067–10072. https://doi.org/10.1073/pnas.1633737100CrossRefPubMedPubMedCentral

Harrison SA, Alkhouri N, Davison BA, Sanyal A, Edwards C, Colca JR, Lee BH et al (2020) Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study. J Hepatol 72(4):613–626. https://doi.org/10.1016/j.jhep.2019.10.023CrossRefPubMed

Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, Alkhouri N et al (2019) Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 394(10213):2012–2024. https://doi.org/10.1016/S0140-6736(19)32517-6CrossRefPubMed

Harrison SA, Goodman Z, Jabbar A, Vemulapalli R, Younes ZH, Freilich B, Sheikh MY et al (2020) A randomized, placebo-controlled trial of emricasan in patients with NASH and F1–F3 fibrosis. J Hepatol 72(5):816–827. https://doi.org/10.1016/j.jhep.2019.11.024CrossRefPubMed

Harrison SA, Manghi FP, Smith WB, Alpenidze D, Aizenberg D, Burggraaf K, Chen C-Y et al (2019) LIK066 (LICOGLIFLOZIN), AN SGLT1/2 inhibitor, robustly decreases alt and improves markers of hepatic and metabolic health in patients with non-alcoholic fatty liver disease: interim analysis of a 12-week, randomized, placebo-controlled, phase 2a study. Hepatology 70(6):1482A-1483A

Harrison SA, Rinella ME, Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, Kugelmas M et al (2018) NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 391(10126):1174–1185. https://doi.org/10.1016/S0140-6736(18)30474-4CrossRefPubMed

Harrison SA, Rossi SJ, Paredes AH, Trotter JF, Bashir MR, Guy CD, Banerjee R, et al (2019) NGM282 Improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology 0(0). https://doi.org/10.1002/hep.30590

Harrison SA, Wong V-S, Okanoue T, Bzowej N, Vuppalanchi R, Younes Z, Kohli A et al (2019) Safety and efficacy of selonsertib for the treatment of bridging fibrosis or compensated cirrhosis due to nonalcoholic steatohepatitis (Nash): results of the phase 3 stellar studies. Hepatology 70(October):45A-46A

He Y-L, Haynes W, Meyers CD, Amer A, Zhang Y, Mahling P, Mendonza AE, Ma S, Chutkow W, Bachman E (2019) The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes. Diab Obes Metab 21(6):1311–1321. https://doi.org/10.1111/dom.13654CrossRef

Ikenaga N, Peng Z-W, Vaid KA, Liu SB, Yoshida S, Sverdlov DY, Mikels-Vigdal A, Smith V, Schuppan D, Popov YV (2017) Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut 66(9):1697–1708. https://doi.org/10.1136/gutjnl-2016-312473CrossRefPubMed

Inventiva (2020) Lanifibranor Meets Efficacy, Safety Endpoints in Phase 2b NASH Trial. 24 June 2020. https://www.healio.com/news/hepatology/20200624/lanifibranor-meets-efficacy-safety-endpoints-in-phase-2b-nash-trial

Ishibashi S, Arai H, Yokote K, Araki E, Suganami H, Yamashita S (2018) Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia: results from a 24-week, randomized, double blind, active-controlled, phase 3 trial. J Clin Lipidol 12(1):173–184. https://doi.org/10.1016/j.jacl.2017.10.006CrossRefPubMed

Issa D, Wattacheril J, Sanyal AJ (2017) Treatment options for nonalcoholic steatohepatitis – a safety evaluation. Expert Opin Drug Saf 16(8):903–913. https://doi.org/10.1080/14740338.2017.1343299CrossRefPubMed

Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, Merad M, Luedde T, Trautwein C, Tacke F (2009) Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50(1):261–274. https://doi.org/10.1002/hep.22950CrossRefPubMed

Kawarazaki Y, Ichijo H, Naguro I (2014) Apoptosis signal-regulating kinase 1 as a therapeutic target. Expert Opin Ther Targets 18(6):651–664. https://doi.org/10.1517/14728222.2014.896903CrossRefPubMed

Kelly K, Reagan WJ, Sonnenberg G, Bergman A, Clasquin M, Amor P, Carvajal-Gonzalez S et al (2019) De novo lipogenesis is critical for platelet production; the liver directed ACC inhibitor pf-05221304 for the treatment of NASH shows improved platelet safety profile over systemic acc inhibition. Hepatology 70(October):1272A-1272A

Kelly MJ, Sherrie Pietranico-Cole J, Larigan D, Haynes N-E, Reynolds CH, Scott N, Vermeulen J et al (2014) Discovery of 2-[3,5-Dichloro-4-(5-Isopropyl-6-Oxo-1,6-Dihydropyridazin-3-Yloxy)Phenyl]-3,5-Dioxo-2,3,4,5-Tetrahydro[1,2,4]Triazine-6-Carbonitrile (MGL-3196), a highly selective thyroid hormone receptor β agonist in clinical trials for the treatment of dyslipidemia. J Med Chem 57(10):3912–3923. https://doi.org/10.1021/jm4019299CrossRefPubMed

Klein EA, Thompson IM, Tangen CM, Crowley JJ, Scott Lucia M, Goodman PJ, Minasian LM et al (2011) Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT). JAMA 306(14):1549–1556. https://doi.org/10.1001/jama.2011.1437CrossRefPubMedPubMedCentral

Lawitz E, Gane E, Ruane P, Herring JR, Younes ZH, Kwo P, Zhang J et al (2019) A combination of the ACC inhibitor GS-0976 and the nonsteroidal FXR Agonist GS-9674 improves hepatic steatosis, biochemistry, and stiffness in patients with non-alcoholic steatohepatitis. J Hepatol 70(1):E794–E794CrossRef

Lech ML, Ross TR, Jelinsky S, Shipstone A, Monetti M, Breitkopf S, Xue L, Esler W, Martinez R (2019) Acetyl-co-enzyme a carboxylase (ACC) inhibition is anti-fibrotic in both human in vitro and rat in vivo models of hepatic fibrosis. Hepatology 70(October):886A-886A

Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, Wang L et al (2018) GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology 155(5):1463-1473.e6. https://doi.org/10.1053/j.gastro.2018.07.027CrossRefPubMed

Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, Diehl AM, et al (2018) The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology (Baltimore, Md.) 67(2): 549–59. https://doi.org/10.1002/hep.29514

Loomba R, Neutel J, Mohseni R, Bernard D, Severance R, Dao M, Saini S et al (2019) VK2809, a novel liver-directed thyroid receptor beta agonist, significantly reduces liver fat with both low and high doses in patients with non-alcoholic fatty liver disease: a phase 2 randomized, placebo-controlled trial. J Hepatol 70(1):E150–E151. https://doi.org/10.1016/S0618-8278(19)30266-XCrossRef

Lucas KJ, Lopez P, Lawitz EJ, Sheikh A, Aizenberg D, Hsia S, Goh GBB et al (2019) Tropifexor, a highly potent FXR agonist, produces robust and dose-dependent reductions in hepatic fat and serum alanine aminotransferase in patients with fibrotic NASH After 12 weeks of therapy: FLIGHT-FXR Part C interim results. Hepatology 70(6):1479A-1480A

Makishima M, Okamoto AY, Repa JJ, Hua Tu, Marc Learned R, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B (1999) Identification of a nuclear receptor for bile acids. Science 284(5418):1362–1365. https://doi.org/10.1126/science.284.5418.1362CrossRefPubMed

Matsuda K, Gutierrez J, Hassanein T, Iwaki Y (2018) The anti-fibrotic agent, tipelukast (MN-001) reduces serum triglyceride significantly in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease patients with hypertriglyceridemia after 4 weeks of treatment, an interim analysis of ongoing clinical trial, MN-001-NATG-201. J Hepatol 68(April):S586–S586. https://doi.org/10.1016/S0168-8278(18)31433-8CrossRef

Matsuda K, Iwaki Y (2014) MN-001 (Tipelukast), a novel, orally bioavailable drug, reduces fibrosis and inflammation and down-regulates TIMP-1, collagen type 1 and LOXL2 MRNA overexpression in an advanced NASH (nonalcoholic steatohepatitis) Model. Hepatology 60(6):1283A-1284A

McCommis KS, Finck BN (2015) Mitochondrial pyruvate transport: a historical perspective and future research directions. Biochem J 466(3):443–454. https://doi.org/10.1042/BJ20141171CrossRefPubMed

McCommis KS, Hodges WT, Brunt EM, Nalbantoglu I, McDonald WG, Holley C, Fujiwara H, Schaffer JE, Colca JR, Finck BN (2017) Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology (Baltimore, Md.) 65(5): 1543–56. https://doi.org/10.1002/hep.29025

Mello T, Materozzi M, Galli A (2016) PPARs and Mitochondrial Metabolism: From NAFLD to HCC. PPAR Res 2016. https://doi.org/10.1155/2016/7403230

Merk D, Gellrich L (2017) Therapeutic potential of peroxisome proliferator-activated receptor modulation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Nuclear Receptor Research 4 (December). https://doi.org/10.11131/2017/101310

Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E (2012) Hepatic Recruitment of Macrophages Promotes Nonalcoholic Steatohepatitis through CCR2. Am J Physiol-Gastrointest Liver Physiol 302(11): G1310–G1321. https://doi.org/10.1152/ajpgi.00365.2011

Mizrahi M, Shabat Y, Ya’acov AB, Lalazar G, Adar T, Wong V, Muller B, Rawlin G, Ilan Y (2012) Alleviation of insulin resistance and liver damage by oral administration of imm124-E is mediated by increased tregs and associated with increased serum GLP-1 and adiponectin: results of a phase I/II clinical trial in NASH. J Inflamm Res 5(December): 141–50. https://doi.org/10.2147/JIR.S35227

Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall H-U, Kipnes M, Adorini L et al (2013) Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145(3):574-582.e1. https://doi.org/10.1053/j.gastro.2013.05.042CrossRefPubMed

Musso G, Gambino R, Cassader M, Pagano G (2010) A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.) 52(1): 79–104. https://doi.org/10.1002/hep.23623

Nahra R, Wang T, Oscarsson J, Repetto E, Gadde K, Stumvoll M, Jermutus L, Hirshberg B, Ambery P (2019) Effects of cotadutide (MEDI0382) on biomarkers of nonalcoholic steatohepatitis (NASH) in overweight or obese subjects with type 2 diabetes mellitus (T2DM): a 26-week analysis of a randomized phase 2b study. Hepatology 70(October):24A-25A

Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N et al (2015) Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385(9972):956–965. https://doi.org/10.1016/S0140-6736(14)61933-4CrossRefPubMed

Newsome PN, Palmer M, Freilich B, Sheikh MY, Sheikh A, Sarles H, Herring R, et al (2020) Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study. J Hepatol March. https://doi.org/10.1016/j.jhep.2020.03.024

Novartis (2019) Press Release – Novartis Provides Update on Phase 2b ENCORE-LF Trial in NASH Cirrhosis. Novartis. 24 June 2019. https://www.novartis.com/news/media-releases/novartis-provides-update-phase-2b-encore-lf-trial-nash-cirrhosis

Novo Nordisk (2020) Financial Report for the Period 1 January 2020 to 31 March 2020

Patel K, Harrison SA, Elkashab M, Trotter JF, Herring R, Rojter S, Kayali Z, et al (2020) Cilofexor, a Nonsteroidal FXR Agonist, in Non-Cirrhotic Patients with Nonalcoholic Steatohepatitis: A Phase 2 Randomized Controlled Trial. Hepatology (Baltimore, Md.), March. https://doi.org/10.1002/hep.31205

Pawlak M, Lefebvre P, Staels B (2015) Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol 62(3):720–733. https://doi.org/10.1016/j.jhep.2014.10.039CrossRefPubMed

Pedrosa M, Seyedkazemi S, Francque S, Sanyal A, Rinella M, Charlton M, Loomba R et al (2020) A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: study design of the TANDEM trial. Contemp Clin Trials 88(January):105889. https://doi.org/10.1016/j.cct.2019.105889CrossRefPubMed

Petit J-M, Cercueil J-P, Loffroy R, Denimal D, Bouillet B, Fourmont C, Chevallier O, Duvillard L, Vergès B (2017) Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes: the Lira-NAFLD study. J Clin Endocrinol Metab 102(2):407–415. https://doi.org/10.1210/jc.2016-2775CrossRefPubMed

Radreau P, Joly S, Dubos C, Vonderscher J, Scalfaro P, Meldrum E, Darteil R (2019) Vitro and in vivo characterization of EYP001 a novel, potent and selective FXR agonist now in a phase 2 clinical trial in NASH. Hepatology 70(October):1267A-1267A

Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, Romero-Gomez M et al (2016) Elafibranor, an Agonist of the Peroxisome Proliferator−Activated Receptor−α and −δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology 150(5):1147-1159.e5. https://doi.org/10.1053/j.gastro.2016.01.038CrossRefPubMed

Ratziu V, Ladron-De-Guevara L, Safadi R, Poordad F, Fuster F, Flores-Figueroa J, Harrison SA, et al (2018) One-year results of the global phase 2b randomized placebo-controlled arrest trial of aramchol, a stearoyl CoA desaturase inhibitor, in patients with NASH. Hepatology 68(6): 1448A–1449A

Ratziu V, Sanyal A, Harrison SA, Wong VW-S, Francque S, Goodman Z, Aithal GP, et al (2020) Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study. Hepatology (Baltimore, Md.), January. https://doi.org/10.1002/hep.31108

Roeb, E, Steffen HM, Bantel H, Baumann U, Canbay A, Demir M, Drebber U, et al (2015) S2k Leitlinie Nicht-alkoholische Fettlebererkrankungen. S2k Leitlinie, S2k Leitlinie, no 1. (January). https://www.awmf.org/leitlinien/detail/ll/021-025.html

Ross T, Kelly K, Rinaldi A, Lech M, Martinez R, Crowley C, Gonzalez SC et al (2019) The Acetyl-CoA carboxylase inhibitor PF-05221304 exerts direct effects on hepatic inflammation and fibrosis independent of benefits on steatosis. J Hepatol 70(1):E86–E86. https://doi.org/10.1016/S0618-8278(19)30150-1CrossRef

Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, Oren R et al (2014) The fatty acid-bile acid conjugate aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 12(12):2085-2091.e1. https://doi.org/10.1016/j.cgh.2014.04.038CrossRefPubMed

Sanyal A, Abdelmalek MF, Diehl AM, Caldwell S, Shiffman ML, Ghalib R, Lawitz E et al (2017) Efficacy and safety of simtuzumab for the treatment of nonalcoholic steatohepatitis with bridging fibrosis or cirrhosis: results of two phase 2b, dose-ranging, randomized, placebo-controlled trials. J Hepatol 66(1):S54. https://doi.org/10.1016/S0168-8278(17)30370-7CrossRef

Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF, Lawitz EJ et al (2018) Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 392(10165):2705–2717. https://doi.org/10.1016/S0140-6736(18)31785-9CrossRefPubMed

Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA et al (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. New England J Med 362(18):1675–1685. https://doi.org/10.1056/NEJMoa0907929CrossRef

Sanyal AJ, Lopez PM, Lawitz E, Kim W, Huang J-F, Andreone P, Goh BBG et al (2018) Tropifexor (TXR), an FXR agonist for the treatment of NASH – interim results from first two parts of phase 2b study flight-FXR. Hepatology 68(6):1461A-1462A

Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, Schwabe RF, Brenner DA (2009) CCR2 promotes hepatic fibrosis in mice. Hepatology 50(1):185–197. https://doi.org/10.1002/hep.22952CrossRefPubMed

Seko Y, Nishikawa T, Umemura A, Yamaguchi K, Moriguchi M, Yasui K, Kimura M et al (2018) Efficacy and safety of canagliflozin in type 2 diabetes mellitus patients with biopsy-proven nonalcoholic steatohepatitis classified as stage 1–3 fibrosis. Diab Metab Syndr Obes: Targets Ther 11(November):835–843. https://doi.org/10.2147/DMSO.S184767CrossRef

Shiffman M, Freilich B, Vuppalanchi R, Watt K, Chan JL, Spada Al, Hagerty DT, Schiff E (2019) Randomised clinical trial: emricasan versus placebo significantly decreases ALT and caspase 3/7 activation in subjects with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 49(1):64–73. https://doi.org/10.1111/apt.15030CrossRefPubMed

Softic S, Cohen DE, Ronald Kahn C (2016) Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease. Dig Dis Sci 61(5):1282–1293. https://doi.org/10.1007/s10620-016-4054-0CrossRefPubMedPubMedCentral

TaiwanJ Pharmaceuticals (2019) TaiwanJ Pharmaceuticals Reports Positive Data from Trial of JKB-122. Clinical Trials Arena. 22 January 2019. https://www.clinicaltrialsarena.com/news/taiwanj-reports-positive-data/

Thompson M, Saag M, DeJesus E, Gathe J, Lalezari J, Landay AL, Cade J, Enejosa J, Lefebvre E, Feinberg J (2016) A 48-week randomized phase 2b study evaluating cenicriviroc versus efavirenz in treatment-naive HIV-infected adults with C-C chemokine receptor type 5-tropic virus. AIDS (london, England) 30(6):869–878. https://doi.org/10.1097/QAD.0000000000000988CrossRef

Traber PG, Chou H, Zomer E, Hong F, Klyosov A, Fiel M-I, Friedman SL (2013) Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS ONE 8(10):e75361. https://doi.org/10.1371/journal.pone.0075361CrossRefPubMedPubMedCentral

Trauner M, Nevens F, Shiffman ML, Drenth JPH, Bowlus CL, Vargas V, Andreone P et al (2019) 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 4(6):445–453. https://doi.org/10.1016/S2468-1253(19)30094-9CrossRefPubMed

Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda K, Ide T et al (2001) The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem 276(44):41245–41254. https://doi.org/10.1074/jbc.M103241200CrossRefPubMed

Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, Bedossa P et al (2019) Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 394(10215):2184–2196. https://doi.org/10.1016/S0140-6736(19)33041-7CrossRefPubMed

Titel: Spezifische Therapie – neue Medikamente
verfasst von: Naomi F. Lange
Jean-François Dufour
Verlag: Springer Berlin Heidelberg
Buch: Nicht-alkoholische Fettlebererkrankung
Print ISBN: 978-3-662-62483-8

Electronic ISBN: 978-3-662-62484-5

Copyright-Jahr: 2022
DOI: https://doi.org/10.1007/978-3-662-62484-5_21

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