Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH)

References

• Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol. 2012;56(6):1384–1391.
   PubMed Web of Science ®Google Scholar
• Hester D, Golabi P, Paik J, et al. Among medicare patients with hepatocellular carcinoma, non-alcoholic fatty liver disease is the most common etiology and cause of mortality. J Clin Gastroenterol. 2019 Jan 21. doi: 10.1097/MCG.0000000000001172.
   PubMed Web of Science ®Google Scholar
• Rau M, Rehman A, Dittrich M, et al. Fecal scfas and scfa-producing bacteria in gut microbiome of human nafld as a putative link to systemic t-cell activation and advanced disease. United European Gastroenterol J. 2018;6(10):1496–1507.
   PubMed Web of Science ®Google Scholar
• Valenti L, Bugianesi E, Pajvani U, et al. Nonalcoholic fatty liver disease: cause or consequence of type 2 diabetes? Liver Int. 2016;36(11):1563–1579.
   PubMed Web of Science ®Google Scholar
• Kozakova M, Palombo C, Eng MP, et al. Fatty liver index, gamma-glutamyltransferase, and early carotid plaques. Hepatology. 2012;55(5):1406–1415.
   PubMed Web of Science ®Google Scholar
• Younossi ZM, Henry L, Bush H, et al. Clinical and economic burden of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Clin Liver Dis. 2018;22(1):1–10.
   PubMed Web of Science ®Google Scholar
• Adams LA, Anstee QM, Tilg H, et al. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66(6):1138–1153.
   PubMed Web of Science ®Google Scholar
• Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367–378.e365;quiz e314–365.
   Web of Science ®Google Scholar
• Patel NS, Doycheva I, Peterson MR, et al. Effect of weight loss on magnetic resonance imaging estimation of liver fat and volume in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2015;13(3):561–568.e561.
   PubMed Web of Science ®Google Scholar
• Easl-easd-easo clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–1402.
   PubMed Web of Science ®Google Scholar
• Chalasani N, Younossi Z, Lavine, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the american association for the study of liver diseases. Hepatology. 2018;67(1):328–357.
   PubMed Web of Science ®Google Scholar
• Stewart KE, Haller DL, Sargeant C, et al. Readiness for behaviour change in non-alcoholic fatty liver disease: implications for multidisciplinary care models. Liver Int. 2015;35(3):936–943.
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin e, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–1685.
   PubMed Web of Science ®Google Scholar
• Giles TD, Miller AB, Elkayam U, et al. Pioglitazone and heart failure: results from a controlled study in patients with type 2 diabetes mellitus and systolic dysfunction. J Card Fail. 2008;14(6):445–452.
   PubMed Web of Science ®Google Scholar
• Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: A meta-analysis of randomised clinical trials. Lancet. 2007;370(9593):1129–1136.
   PubMed Web of Science ®Google Scholar
• Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the proactive study (prospective pioglitazone clinical trial in macrovascular events): A randomised controlled trial. Lancet. 2005;366(9493):1279–1289.
   PubMed Web of Science ®Google Scholar
• Laursen TL, Hagemann CA, Wei C, et al. Bariatric surgery in patients with non-alcoholic fatty liver disease - from pathophysiology to clinical effects. World J Hepatol. 2019;11(2):138–149.
   PubMed Web of Science ®Google Scholar
• McCarty TR, Echouffo-Tcheugui JB, Lange A, et al. Impact of bariatric surgery on outcomes of patients with nonalcoholic fatty liver disease: A nationwide inpatient sample analysis, 2004–2012. Surg Obes Relat Dis. 2018;14(1):74–80.
   PubMed Web of Science ®Google Scholar
• Goh G-B-B, Schauer PR, McCullough AJ. Considerations for bariatric surgery in patients with cirrhosis. World J Gastroenterol. 2018;24(28):3112–3119.
   PubMed Web of Science ®Google Scholar
• Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–1321.
   PubMed Web of Science ®Google Scholar
• (CDER) CfDEaR: noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment guidance for industry draft guidance. (Ed). (FDA) FaDA; 2018. [cited 2019 Sep 23]. Available from: https://www.fda.gov/media/119044/download
   Google Scholar
• (CHMP) CfMPfHU: reflection paper on regulatory requirements for the development of medicinal products for chronic non infectious liver diseases (pbc, psc, nash). (Ed). Agency EM; 2018.[cited 2019 Sep 23]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-regulatory-requirements-development-medicinal-products-chronic-non-infectious-liver_en.pdf
   Google Scholar
• Caussy C, Reeder SB, Sirlin CB, et al. Noninvasive, quantitative assessment of liver fat by mri-pdff as an endpoint in nash trials. Hepatology. 2018;68(2):763–772.
   PubMed Web of Science ®Google Scholar
• Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (flirt) trial. Gastroenterology. 2008;135(1):100–110.
   PubMed Web of Science ®Google Scholar
• Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid x nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (flint): A multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–965.
   PubMed Web of Science ®Google Scholar
• Younossi Z, Ratziu V, Loomba R, et al. Gs-06-positive results from regenerate: A phase 3 international, randomized, placebo-controlled study evaluating obeticholic acid treatment for nash. J Hepatol. 2019;70(1):e5.
   PubMed Web of Science ®Google Scholar
• Gilead: gilead announces topline data from phase 3 stellar-3 study of selonsertib in bridging fibrosis (f3) due to nonalcoholic steatohepatitis (nash); 2019; p. 2. [cited 2019 Sep 23]. Available from: http://investors.gilead.com/news-releases/news-release-details/gilead-announces-topline-data-phase-3-stellar-3-study
   Google Scholar
• Gilead: gilead announces topline data from phase 3 stellar-4 study of selonsertib in compensated cirrhosis (f4) due to nonalcoholic steatohepatitis (nash); 2019;p. 2. [cited 2019 Sep 23]. Available from: 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
   Google Scholar
• Friedman SL, Ratziu V, Harrison SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2018;67(5):1754–1767.
   PubMed Web of Science ®Google Scholar
• Harrison S, Moussa S, Bashir M, et al. Mgl-3196, a selective thyroid hormone receptor-beta agonist significantly decreases hepatic fat in nash patients at 12 weeks, the primary endpoint in a 36 week serial liver biopsy study. J Hepatol. 2018;68(S38):S38.
   Google Scholar
• Ratziu V, Ladron-De-Guevara L, Safadi R, et al. 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. 2018;68(1 Supplement 1):1448A–1449A.
   PubMedGoogle Scholar
• Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (lean): A multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679–690.
   PubMed Web of Science ®Google Scholar
• Bougarne N, Weyers B, Desmet SJ, et al. Molecular actions of pparalpha in lipid metabolism and inflammation. Endocr Rev. 2018;39(5):760–802.
   PubMed Web of Science ®Google Scholar
• Palomer X, Barroso E, Pizarro-Delgado J, et al. Pparbeta/delta: a key therapeutic target in metabolic disorders. Int J Mol Sci. 2018;19(3):913.
   PubMed Web of Science ®Google Scholar
• Janani C, Ranjitha Kumari BD. Ppar gamma gene–a review. Diabetes Metab Syndr. 2015;9(1):46–50.
   PubMed Web of Science ®Google Scholar
• Cariou B, Hanf R, Lambert-Porcheron S, et al. Dual peroxisome proliferator-activated receptor alpha/delta agonist gft505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care. 2013;36(10):2923–2930.
   PubMed Web of Science ®Google Scholar
• Staels B, Rubenstrunk A, Noel B, et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, gft505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology. 2013;58(6):1941–1952.
   PubMed Web of Science ®Google Scholar
• Hanf R, Darteil R, Hum DW, et al.: Gft505 efficacy and safety in healthy volunteers and patients suffering from atherogenic dyslipidemia. Diabetes Conference: 70th Scientific Sessions of the American Diabetes Association Orlando, FL United States Conference Publication; 2010.
   Google Scholar
• Cariou B, Staels B. Gft505 for the treatment of nonalcoholic steatohepatitis and type 2 diabetes. Expert Opin Investig Drugs. 2014;23(10):1441–1448.
   PubMed Web of Science ®Google Scholar
• Hanf R, Millatt LJ, Cariou B, et al. The dual peroxisome proliferator-activated receptor alpha/delta agonist gft505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma-associated adverse cardiac effects. Diab Vasc Dis Res. 2014;11(6):440–447.
   PubMed Web of Science ®Google Scholar
• Arab JP, Karpen SJ, Dawson PA, et al. Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology. 2017;65(1):350–362.
   PubMed Web of Science ®Google Scholar
• Roth JD, Veidal SS, Fensholdt LKD, et al. Combined obeticholic acid and elafibranor treatment promotes additive liver histological improvements in a diet-induced ob/ob mouse model of biopsy-confirmed nash. Sci Rep. 2019;9(1):9046.
   PubMedGoogle Scholar
• Goedeke L, Bates J, Vatner DF, et al. Acetyl-coa carboxylase inhibition reverses nafld and hepatic insulin resistance but promotes hypertriglyceridemia in rodents. Hepatology. 2018;68(6):2197–2211.
   PubMed Web of Science ®Google Scholar
• Legry V, Descamps E, Noel B, et al. Fri-355-elafibranor, a drug candidate for first line nash monotherapy and a universal backbone for drug combination treatment. J Hepatol. 2019;70(1):e551.
   Web of Science ®Google Scholar
• Walczak R, Belanger C, Foucart C, et al. Identification of novel drug combinations with synergistic effects on hepatic fibrosis in vitro and in vivo. Hepatology. 2017;66(Supplement 1):217A–218A.
   Google Scholar
• Cariou B, Zair Y, Staels B, et al. Effects of the new dual ppar alpha/delta agonist gft505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care. 2011;34(9):2008–2014.
   PubMed Web of Science ®Google Scholar
• Eudract trial results, identifier 2010–021986-60: A pilot study to evaluate the efficacy and safety of gft505 (80mg) orally administered once daily for 12 weeks in patients with type 2 diabetes mellitus. A multicentre, randomised, double blind, placebo-controlled study. EU Clinical Trials Register. 2012. p. 10.
   Google Scholar
• Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(5):1147–1159.e1145.
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54(1):344–353.
   PubMedGoogle Scholar
• Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an american association for the study of liver diseases–u.S. Food and drug administration joint workshop. Hepatology. 2015;61(4):1392–1405.
   PubMed Web of Science ®Google Scholar
• Kleiner DE, Bedossa P. Liver histology and clinical trials for nonalcoholic steatohepatitis-perspectives from 2 pathologists. Gastroenterology. 2015;149(6):1305–1308.
   PubMed Web of Science ®Google Scholar
• Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (nafld). Metabolism. 2016;65(8):1038–1048.
   PubMed Web of Science ®Google Scholar
• Eudract trial results, identifier: 2007-003237-16: A pilot study to evaluate the efficacy and safety of gft505 (30 mg) orally administered for 28 days in patients with frederickson type iib dyslipidemia (mixed hyperlipidemia). A double blind, placebo-controlled and randomized study. EU Clinical Trials Register; 2008; p. 7.
   Google Scholar
• Genfit: the fda grants fast track designation to gft505 in nash. 2014. [cited 2019 Sep 23]. Available from: https://www.genfit.com/wp-content/uploads/2014/03/2014.02.17_PR-GENFIT_EN.pdf
   Google Scholar
• Sanyal AJ, Miller V. Regulatory science and drug approval for alcoholic and nonalcoholic steatohepatitis. Gastroenterology. 2016;150(8):1723–1727.
   PubMed Web of Science ®Google Scholar
• Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology. 2017;65(5):1557–1565.
   PubMed Web of Science ®Google Scholar