Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design

Contemporary Clinical Trials

Volumn 47, Issue , 2016, Pages 356-365

  Friedman, Scott ^a   Sanyal, Arun ^b   Goodman, Zachary ^c   Lefebvre, Eric ^d   Gottwald, Mildred ^d   Fischer, Laurent ^d   Ratziu, Vlad ^e  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^b VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

^c INOVA FAIRFAX HOSPITAL   (United States)

^d Tobira Therapeutics Inc   (United States)

^e SORBONNE UNIVERSITÉ   (France)

Author keywords

Cenicriviroc; Liver fibrosis; Metabolic syndrome; Non alcoholic fatty liver; Non alcoholic steatohepatitis; Type 2 diabetes mellitus

Indexed keywords

CENICRIVIROC; PLACEBO; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; IMIDAZOLE DERIVATIVE; TAK-652;

ADULT; AGED; ARTICLE; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG SAFETY; FEMALE; HUMAN; LIVER BIOPSY; LIVER CIRRHOSIS; LIVER FIBROSIS; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; NONALCOHOLIC FATTY LIVER; NONALCOHOLIC FATTY LIVER DISEASE ACTIVITY SCORE; PHASE 2 CLINICAL TRIAL; PROSPECTIVE STUDY; RANDOMIZED CONTROLLED TRIAL; STUDY DESIGN; ADOLESCENT; CLINICAL PROTOCOL; CLINICAL TRIAL; COMPLICATION; DRUG ADMINISTRATION; FOLLOW UP; METHODOLOGY; MIDDLE AGED; NON-ALCOHOLIC FATTY LIVER DISEASE; ORAL DRUG ADMINISTRATION; TREATMENT OUTCOME; YOUNG ADULT;

ADMINISTRATION, ORAL; ADOLESCENT; ADULT; AGED; CCR5 RECEPTOR ANTAGONISTS; CLINICAL PROTOCOLS; DOUBLE-BLIND METHOD; DRUG ADMINISTRATION SCHEDULE; FEMALE; FOLLOW-UP STUDIES; HUMANS; IMIDAZOLES; LIVER CIRRHOSIS; MALE; MIDDLE AGED; NON-ALCOHOLIC FATTY LIVER DISEASE; PROSPECTIVE STUDIES; RESEARCH DESIGN; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84960110717     PISSN: 15517144     EISSN: 15592030     Source Type: Journal    
DOI: 10.1016/j.cct.2016.02.012     Document Type: Article

References (45)

1. Chalasani N., Younossi Z., Lavine J.E., Diehl A.M., Brunt E.M., Cusi K., et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am. J. Gastroenterol. 2012, 107:811-826.
2. McCullough A.J. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin. Liver Dis. 2004, 8:521-533.
3. Wanless I.R., Lentz J.S. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990, 12:1106-1110.
4. Cortez-Pinto H., Camilo M.E., Baptista A., De Oliveira A.G., De Moura M.C. Non-alcoholic fatty liver: another feature of the metabolic syndrome?. Clin. Nutr. 1999, 18:353-358.
5. Targher G., Bertolini L., Padovani R., Rodella S., Tessari R., Zenari L., et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007, 30:1212-1218.
6. World Gastroenterology Organisation (WGO) WGO global guidelines. nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (Accessed 11 November 2015). http://www.worldgastroenterology.org/UserFiles/file/guidelines/nafld-nash-english-2012.pdf.
7. Matteoni C.A., Younossi Z.M., Gramlich T., Boparai N., Liu Y.C., McCullough A.J. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999, 116:1413-1419.
8. Charlton M., Kasparova P., Weston S., Lindor K., Maor-Kendler Y., Wiesner R.H., et al. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Liver Transpl. 2001, 7:608-614.
9. Bugianesi E., Leone N., Vanni E., Marchesini G., Brunello F., Carucci P., et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002, 123:134-140.
10. Angulo P., Kleiner D.E., Dam-Larsen S., Adams L.A., Bjornsson E.S., Charatcharoenwitthaya P., et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015, 149:389-397.
11. Vernon G., Baranova A., Younossi Z.M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Ther. 2011, 34:274-285.
12. Loomba R., Sanyal A.J. The global NAFLD epidemic. Nat. Rev. Gastroenterol. Hepatol. 2013, 10:686-690.
13. Saiman Y., Friedman S.L. The role of chemokines in acute liver injury. Front. Physiol. 2012, 3:213.
14. Schwabe R.F., Bataller R., Brenner D.A. Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. Am. J. Physiol. Gastrointest. Liver Physiol. 2003, 285:G949-G958.
15. Seki E., De Minicis S., Gwak G.Y., Kluwe J., Inokuchi S., Bursill C.A., et al. CCR1 and CCR5 promote hepatic fibrosis in mice. J. Clin. Invest. 2009, 119:1858-1870.
16. Seki E., De Minicis S., Inokuchi S., Taura K., Miyai K., van Rooijen N., et al. CCR2 promotes hepatic fibrosis in mice. Hepatology 2009, 50:185-197.
17. Mitchell C., Couton D., Couty J.P., Anson M., Crain A.M., Bizet V., et al. Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice. Am. J. Pathol. 2009, 174:1766-1775.
18. Berres M.L., Koenen R.R., Rueland A., Zaldivar M.M., Heinrichs D., Sahin H., et al. Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. J. Clin. Invest. 2010, 120:4129-4140.
19. Karlmark K.R., Weiskirchen R., Zimmermann H.W., Gassler N., Ginhoux F., Weber C., et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 2009, 50:261-274.
20. Miura K., Yang L., van Rooijen N., Ohnishi H., Seki E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 302:G1310-G1321.
21. Rivera C.A., Bradford B.U., Hunt K.J., Adachi Y., Schrum L.W., Koop D.R., et al. Attenuation of CCl(4)-induced hepatic fibrosis by GdCl(3) treatment or dietary glycine. Am. J. Physiol. Gastrointest. Liver Physiol. 2001, 281:G200-G207.
22. Duffield J.S., Forbes S.J., Constandinou C.M., Clay S., Partolina M., Vuthoori S., et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 2005, 115:56-65.
23. De Minicis S., Seki E., Uchinami H., Kluwe J., Zhang Y., Brenner D.A., et al. Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology 2007, 132:1937-1946.
24. Pradere J.P., Kluwe J., De Minicis S., Jiao J.J., Gwak G.Y., Dapito D.H., et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 2013, 58:1461-1473.
25. Bertola A., Bonnafous S., Anty R., Patouraux S., Saint-Paul M.C., Iannelli A., et al. Hepatic expression patterns of inflammatory and immune response genes associated with obesity and NASH in morbidly obese patients. PLoS One 2010, 5.
26. Marier J.F., Trinh M., Pheng L.H., Palleja S.M., Martin D.E. Pharmacokinetics and pharmacodynamics of TBR-652, a novel CCR5 antagonist, in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve patients. Antimicrob. Agents Chemother. 2011, 55:2768-2774.
27. Thompson M., Saag M., Dejesus E., Gathe J., Lalezari J., Landay A.L., et al. A 48-week randomized Phase 2b study evaluating cenicriviroc vs. efavirenz in treatment-naive HIV-infected adults with CCR5-tropic virus. AIDS 2015, 30:869-878.
28. Lefebvre E., Hashiguchi T., Jenkins H., Nabhan A., Yoneyama H., Friedman S.L., et al. Anti-fibrotic and anti-inflammatory activity of the dual CCR2 and CCR5 antagonist cenicriviroc in a mouse model of NASH. Hepatology 2013, 58:221A-222A.
29. Hong F., Chou H., Friedman S.L. Significant anti-fibrotic activity of cenicriviroc, a dual CCR2/CCR5 antagonist, in a rat model of thioacetamide-induced liver fibrosis and cirrhosis. Hepatology 2013, 58:1381A-1382A.
30. Thompson M., Chang W., Jenkins H., Flynt A., Gottwald M., Lefebvre E. Improvements in APRI and FIB-4 fibrosis scores correlate with decreases in sCD14 in HIV-1 infected adults receiving cenicriviroc over 48 weeks. Hepatology 2014, 60:424A.
31. Sherman K.E., Abdel-Hameed E., Rouster S.D. CCR2/CCR5 antagonism with cenicriviroc decreases fibrosis scores in HIV-infected patients. Presented at HEP DART. Frontiers in Drug Development for Viral Hepatitis, 2015, Hawaii, USA. Abstract 2015.
32. Thompson M., Chang W., Jenkins H., Flynt A., Gottwald M., Lefebvre E. Improvements in APRI and FIB-4 fibrosis scores correlate with decreases in sCD14 in HIV-1-infected adults receiving cenicriviroc (CVC) over 48 weeks 2014, Presented at the American Association for the Study of Liver Diseases (AASLD), Boston, MA, USA. Poster 455.
33. Lefebvre E., Smith P., Willett M.S., Lasseter K.C., Chang W., Gottwald M.D. Pharmacokinetics and safety of multiple-dose cenicriviroc, a novel, oral, once-daily CCR2 and CCR5 antagonist, in adults with mild or moderate hepatic impairment. Hepatology 2014, 60:23-24.
34. Bataller R., Brenner D.A. Liver fibrosis. J. Clin. Invest. 2005, 115:209-218.
35. Sanyal A.J., Brunt E.M., Kleiner D.E., Kowdley K.V., Chalasani N., Lavine J.E., et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011, 54:344-353.
36. Sanyal A.J., Friedman S.L., McCullough A.J., Dimick-Santos L. 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, 61:1392-1405.
37. Neuschwander-Tetri B.A., Loomba R., Sanyal A.J., Lavine J.E., Van Natta M.L., Abdelmalek M.F., et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015, 385:956-965.
38. Sanyal A.J., Harrison S.A., Francque S.M., Bedossa P., Lawrence S., Romero-Gomez M., et al. The hepatic and extra-hepatic profile of resolution of steatohepatitis induced by GFT-505. Hepatology 2015, 62:1252A.
39. Sanyal A.J., Chalasani N., Kowdley K.V., McCullough A., Diehl A.M., Bass N.M., et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 2010, 362:1675-1685.
40. Lefebvre E., Enejosa J., Chang W., Jenkins H., Martínez A., Willett M. Pharmacokinetic interactions between cenicriviroc and dolutegravir. Presented at 14th European AIDS Conference (EACS) 2013, Brussels, Belgium Poster PE10/8.
41. Gottwald M., Galloway C., Willett M., Chang W., Lefebvre E. Cenicriviroc and pioglitazone co-administration shows favorable pharmacokinetics and safety in healthy subjects. Hepatology 2015, 62:1301A.
42. Menning M.M., Dalziel S.M. Fumaric acid microenvironment tablet formulation and process development for crystalline cenicriviroc mesylate, a BCS IV compound. Mol. Pharm. 2013, 10:4005-4015.
43. National Cancer Institute Common terminology criteria for adverse events (CTCAE) version 4.03 (Accessed 13 November 2015). http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference:5x7.pdf.
44. Ratziu V., Harrison S., Francque S., Bedossa P., Lehert P., Serfaty L., et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016, (Epub ahead of print).
45. Angulo P., Keach J.C., Batts K.P., Lindor K.D. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999, 30:1356-1362.