Hepatology. Expert Opin Investig Drugs. 2018;67(5):17541767. Part II will include 800 newly randomized participants with histological evidence of NASH and stage F3 fibrosis plus the 1200 participants from part I. If all goes . This Phase 3 study is designed to assess the safety and efficacy of an investigational drug, cenicriviroc (CVC), compared to placebo in treating liver fibrosis in adult patients who have nonalcoholic steatohepatitis (NASH). Alkhouri N, Scott A. Web Design by Adhesion. . However, CVC was associated with a statistically significant improvement in the secondary endpoint of liver fibrosis of 1 stage or greater without worsening SH, which was achieved in 2010% of patients treated with CVC and placebo, respectively (p=0.02). Asses the efficacy and durability of short and prolonged CVC therapy in a diet induced mouse model of NASH, Mice received 4 or 14 weeks of standard chow or the choline deficient, L-amino acid-defined high fat diet (CDAHFD). Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Register your specific details and specific drugs of interest and we will match the information you provide to articles from our extensive database and email PDF copies to you promptly. Abbreviations: CCR2/CCR5, CC-motif chemokine receptors 2 and 5; CVC, cenicriviroc; NASH, non-alcoholic steatohepatitis; NAFLD, non-alcoholic fatty liver disease; CCL4, carbon tetrachloride; MoMF, monocyte-derived macrophages; CDAHFD, L-amino acid-defined high fat diet; PK, pharmacokinetics; HI, hepatic insufficiency; NAS, NAFLD activity score; HS, hepatic steatosis; TXR, tropifexor; qd, daily. To receive information about our clinical trials, including how to participate as an investigator, please contact us via one of the ways below. Hepatology. The primary objective of the phase 2b TANDEM trial is to evaluate the safety and tolerability of a TXR plus CVC combination regimen compared with TXR and CVC monotherapy in 200 patients with NASH and liver fibrosis stage F2/F3 over 48 weeks. PMC We do not sell or distribute actual drugs. Table 1 Pre-Clinical Studies and Clinical Trials Evaluating Cenicriviroc for NASH Treatment, Table 2 Other Therapies in Phase 3 Clinical Trials for NASH (Clinicaltrials.gov). The full terms of this license are available at, cenicriviroc, fatty liver, non-alcoholic steatohepatitis, liver fibrosis, antifibrotic therapy, clinical trials, {"type":"clinical-trial","attrs":{"text":"NCT02217475","term_id":"NCT02217475"}}. PLoS Pathog. CVC is now under evaluation in the phase 3 clinical trial AURORA.32 The AURORA trial was designed on the basis of findings from the CENTAUR trial, showing that those participants who are more likely to benefit from CVC are those with advanced disease. Tsuchida T, Friedman SL. Furthermore, patients treated with CVC in Arm B (placebo for 1 year followed by CVC 150 mg for 1 year) demonstrated a trend towards greater fibrosis progression of 1stage versus Arm C (placebo for 2 years) (24.4% vs 17.1%, p=0.37). Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet-induced mouse model of nonalcoholic steatohepatitis. Am J Gastroenterol. The primary objective of part 2 is to compare CVC vs placebo on the composite endpoint of histopathologic progression to cirrhosis, liver-related outcomes and all-cause mortality. Moreno Traspas R, Teoh TS, Wong PM, Maier M, Chia CY, Lay K, Ali NA, Larson A, Al Mutairi F, Al-Sannaa NA, Faqeih EA, Alfadhel M, Cheema HA, Dupont J, Bzieau S, Isidor B, Low DY, Wang Y, Tan G, Lai PS, Piloquet H, Joubert M, Kayserili H, Kripps KA, Nahas SA, Wartchow EP, Warren M, Bhavani GS, Dasouki M, Sandoval R, Carvalho E, Ramos L, Porta G, Wu B, Lashkari HP, AlSaleem B, BaAbbad RM, Abreu Ferro AN, Karageorgou V, Ordonez-Herrera N, Khan S, Bauer P, Cogne B, Bertoli-Avella AM, Vincent M, Girisha KM, Reversade B. Nat Genet. drug (8) Funder Type. Cenicriviroc Terminated Phase 3 Trials for Non Alcoholic Steatohepatitis (NASH) Treatment. Cenicriviroc (CVC) is a novel, orally administered, potent chemokine 2 and 5 receptor antagonist currently in development for the treatment of liver fibrosis in adults with NASH. The investigators additionally observed that 53% of patients who experienced worse liver fibrosis at the end of year 1 experienced fibrosis improvement at the end of year 2, which may represent natural fluctuation and/or variability in the natural history of NASH fibrosis, particularly in individuals with less severe liver disease. Headache and gastrointestinal complaints were reported in two participants, and one patient experienced an increase in serum transaminases. Key exclusion criteria include presence of cirrhosis or hepatic decompensation, other known causes of chronic liver disease, prior or planned liver transplantation, HIV, alcohol consumption >21 units/week, >5 upper limit of normal for liver function tests, total bilirubin >1.3mg/dL, INR >1.3, MELD score >12 and HbA1c >9%. Cenicriviroc (CVC) is a CCR2/5 dual antagonist under evaluation for treating liver fibrosis in adults with nonalcoholic steatohepatitis (NASH). Nasr P, Ignatova S, Kechagias S, Ekstedt M. Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies. Ju C, Tacke F. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease, Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. FOIA Efficacy and safety of CVC will be comprehensively evaluated in a global, Phase 3, multicenter, randomized, double-blind, placebo-controlled study (AURORA, NCT03028740) of subjects with NASH and Stage F2 or F3 fibrosis. A member of the Allergan Clinical Operations Team will contact you via email soon. The 1-year results of a 2-year phase IIb study showed that CVC treatment for nonalcoholic steatohepatitis (NASH) in patients with fibrosis appears to be safe and effective in reducing fibrosis: Twice as many patients on CVC had 1-stage improvement in fibrosis than those . Lefere S, Tacke F. Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism. Improvement of fibrosis has been observed in the phase II trial for NASH . Hepatology. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. Please enter a work/business email address. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. doi:10.1016/j.jhepr.2019.02.004, 13. Files DC, Tacke F, O'Sullivan A, Dorr P, Ferguson WG, Powderly WG. Back to Journals Hepatic Medicine: Evidence and Research Volume 12, Evaluating the Therapeutic Potential of Cenicriviroc in the Treatment of Nonalcoholic Steatohepatitis with Fibrosis: A Brief Report on Emerging Data, Published 13 August 2020 Ali AH, Carey EJ, Lindor KD. Cenicriviroc, a dual CC chemokine receptor 2 and 5 antagonist aimed at preventing liver fibrosis via inhibition of inflammatory signaling immune infiltration and stellate cell proliferation, was recently tested in the CENTAUR trial (Efficacy and Safety Study of Cenicriviroc for the Treatment of Nonalcoholic Steatohepatitis [NASH] in Adult Subjects with Liver Fibrosis; NCT02217475). Accessibility Cenicriviroc is a dual antagonist for CC-chemokine receptor 2 (CCR2) and CCR5 (ref. You can learn about our use of cookies by reading our Privacy Policy. ET government site. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis, Cenicriviroc Treatment for Adults with Nonalcoholic Steatohepatitis and Fibrosis: final Analysis of the Phase 2b CENTAUR Study. Ratziu V, Sanyal A, Harrison SA, et al. CVC showed promising results in various preclinical models. Schwabe RF, Bataller R, Brenner DA. Burden of illness and economic model for patients with nonalcoholic steatohepatitis in the United States. Abbreviations: FXR, farnesoid X receptor; NASH, non-alcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; SCD, stearoyl-CoA desaturase 1. PMC legacy view 2019;69(3):11051121. doi:10.1053/j.gastro.2014.06.043, 19. Neither NP-135 or Cenicriviroc (CVC), both a positive control and comparator arm in the study, and currently in Phase III trials for NASH, showed any significant negative effect on any important . This helps our clients to analyze the disruptive potential of start-ups for early alliances, investments, and acquisition prospects to develop future-proof strategic roadmaps for a competitive advantage. Primary: 2-point improvement in NAS and no worsening of fibrosis at year 1. Has Results. Creative Commons Attribution - Non Commercial (unported, v3.0) License. J Leukoc Biol. Ann Transl Med. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Lancet. . In this context, the phase 2b TANDEM trial33 is a randomized, placebo-controlled, multicenter trial evaluating the combination of CVC and tropifexor (TXR). However, the start-up ecosystem is now facing turbulent times for fundraising as investors seek long-term business strategies, valuations, and a route to profitability amid uncertain market circumstances. 2021 Jan;14(1):11-19. doi: 10.1111/cts.12839. Terminated. 2019;69(2):564572. Discovery of TRopifexor (LJN452), a highly potent non-bile acid FXR agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). Hepatol Res. 2011;53(6):18741882. Marra F, Tacke F. Roles for chemokines in liver disease. Hepatology. software development by maffey.com Two important secondary outcomes included: 1) complete resolution of steatohepatitis (SH) without worsening of liver fibrosis; 2) improvement in liver fibrosis by 1 stage (NASH CRN) without worsening of SH.26 One-year follow-up results were available for 252 participants which confirmed that CVS failed to demonstrate a statistically significant improvement in the primary endpoint of NASH resolution, which was achieved in 1619% of patients treated with CVC and placebo, respectively (p=0.52). Although early clinical data support direct antifibrotic effects of CVC, effects on metabolic components of NAFLD and NASH have been limited. Devisscher L, Verhelst X, Colle I, Van Vlierberghe H, Geerts A. 2016;150(5):114759 e5. Oral CCR5-antagonist for treatment of HIV infection (IC50 value 0.043 nM for the wild-type virus (KKWT) was in PBMCs) that also has activity against the . No significant differences were observed in treatment-emergent adverse events, adverse events leading to treatment discontinuation, or serious adverse events. Hepatology. PLoS One. In order to provide our website visitors and registered users with a service tailored to their individual preferences we use cookies to analyse visitor traffic and personalise content. eCollection 2022 Jun. Year 1 primary analysis of the 2-year CENTAUR study showed that CVC had an antifibrotic effect without impacting steatohepatitis. The pharmaceutical industry's most comprehensive news and information delivered every month. Latest Information Update: 01 Apr 2022. Enter your details here to receive your free Whitepaper. The site is secure. Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Federal government websites often end in .gov or .mil. If all goes. Indications Status Purpose Phase; DBCOND0069294 (Non Alcoholic Steatohepatitis (NASH)) Terminated: Treatment: 3: clinicaltrials.gov Identifier Title Drugs; NCT03028740: Roles of hepatic stellate cells in NAFLD: From the perspective of inflammation and fibrosis. doi:10.1189/jlb.5RU0116-016R, 14. Other Therapies in Phase 3 Clinical Trials for NASH (Clinicaltrials.gov). Cenicriviroc (TAK-652) | CCR Antagonist | Cas# 497223-25-3 - GlpBio JavaScript seems to be disabled in your browser. Abstract Background and aims: Cenicriviroc (CVC) is a C-C chemokine receptors type 2 and 5 dual antagonist under evaluation for treating liver fibrosis in adults with nonalcoholic steatohepatitis (NASH). As of 13 January, the likelihood of approval (LoA) for Allergans cenicriviroc (CVC) for NASH in the US fell 17 points, according to GlobalDatas LoA data. Cenicriviroc Treatment for Adults with Nonalcoholic Steatohepatitis and Fibrosis: final Analysis of the Phase 2b CENTAUR Study. Clin Liver Dis. doi:10.1021/acs.jmedchem.7b00907, 37. 2017;14(7):397411. Dove Medical Press is part of Taylor & Francis Group, the Academic Publishing Division of Informa PLC In animal models of liver diseases, CVC potently inhibits macrophage accumulation in the liver and ameliorates fibrosis. In fact, the foggy Phase IIb data may have contributed to AURORA patient accrual delays, this news service subsequently reported 13 April 2019. Importantly, subgroup analysis demonstrated greater effect of CVC on liver fibrosis among subjects with higher disease activity (NAS 5, prominent hepatocellular ballooning) and liver fibrosis (stages 2 and 3), as well as more profound effects of CVC on reduction of systemic inflammatory markers including high sensitive C reactive protein (hsCRP), interleukin 1 (IL-1), interleukin 6 (IL-6), and fibrinogen, although without effect on body weight or insulin resistance.26 These results strengthened the observation that CVC may have important direct antifibrotic effects in patients with NASH without affecting underlying steatohepatitis. 2016;9(3):139148. As one of the leading contenders for the huge addressable market for NASH therapeutics, its. doi:10.1097/QAD.0000000000000988, 32. doi:10.1002/hep.28431, 8. -CVC significantly reduced monocyte/macrophage recruitment in vivo. Pre-Clinical Studies and Clinical Trials Evaluating Cenicriviroc for NASH Treatment. 2016;13(3):316327. Younossi ZM, Tampi R, Priyadarshini M, Nader F, Younossi IM, Racila A. Get access to cutting edge treatment via Cenicriviroc. Number 3099067. doi:10.1016/S0016-5085(99)70506-8, 4. The safety and efficacy of cenicriviroc and/or uses under investigation have not been established. Cenicriviroc (CVC) is a CCR2 and CCR5 dual antagonist under evaluation for treating liver fibrosis in adults with NASH . Expert Opin Investig Drugs. Bookshelf It did, however, show some benefit for improving fibrosis. Am J Physiol Gastrointest Liver Physiol. Based on 95 publications in PubMed 10 10 95. Two-year follow-up results in patients randomized to CVC versus placebo were subsequently reported and confirmed durability of liver fibrosis regression at the later timepoint, although without further reduction in liver fibrosis stage.27 Among patients who achieved at minimum a one stage fibrosis regression at one year, this endpoint was durable in 6030% of patients treated with CVC versus placebo, respectively, and subgroup analyses further revealed greater effects among patients with advanced liver fibrosis (stage 3). 2003;285(5):G94958. Herein we review results from the phase 2b CENTAUR trial and study designs for the phase 2b TANDEM and phase 3 AURORA trials and discuss the potential role of cenicriviroc in future pharmacotherapy for NASH fibrosis.Keywords: cenicriviroc, fatty liver, non-alcoholic steatohepatitis, liver fibrosis, antifibrotic therapy, clinical trials. Angulo P, Kleiner DE, Dam-Larsen S, et al. 3740 The regulatory framework for the approval of novel NASH-specific therapies requires demonstration of either histologic NASH resolution (without worsening liver fibrosis) or histologic liver fibrosis regression of at least one stage (without worsening NASH) within an adaptive phase 3/4 trial design with demonstration of clinical outcome improvement upon long-term follow-up. doi:10.1002/hep.30249, 24. Epub 2022 Jul 21. Rationale of using the dual chemokine receptor CCR2/CCR5 inhibitor cenicriviroc for the treatment of COVID-19. The study will be terminated when prespecified adjudicated events, including death, histopathologic progression to cirrhosis, liver transplant, MELD score 15, ascites requiring intervention, or hospitalization (as defined by a stay of 24 hours) for onset of variceal bleed, hepatic encephalopathy, or spontaneous bacterial peritonitis, have been accrued in approximately 367 unique subjects, Historical biopsy may be substituted as specified in the protocol, Male and female subjects aged between 18-75 years, Histological evidence of NASH based on central reading of the Screening biopsy*, Histological evidence of Stage 2 or 3 liver fibrosis per the NASH CRN System based on central reading of the Screening biopsy*.
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