Ju C, Tacke F. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Disclaimer, National Library of Medicine doi:10.1038/nrgastro.2017.38, 17. Devisscher L, Verhelst X, Colle I, Van Vlierberghe H, Geerts A. Cenicriviroc is an oral inhibitor of the chemokine ligand 2/C-C chemokine receptor 2 pathway, which plays . 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). Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. 2021 was a record-breaking year, with more businesses breaking into the billion-dollar club. The pharmaceutical industry's most comprehensive news and information delivered every month. The information provided in this website is intended for healthcare professionals only. 2019;69(3):10751086. AURORA: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adult Subjects With Nonalcoholic Steatohepatitis This information was retrieved directly from the website clinicaltrials.gov without any changes. 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. Cenicriviroc, a selective dual inhibitor/antagonist of CCR2/CCR5 chemokine receptors, represents a prototype immune modulator and distinctive anti-NASH candidate that defy the norm by exerting. Standardized Tools for Cellular Immune Assays, Customised Clinical Supply and Biological Sample Services. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. Terminated. This phase 3 clinical trial aims to evaluate and confirm the efficacy and safety of CVC for the treatment of adults with NASH. Cenicriviroc is a dual antagonist for CC-chemokine receptor 2 (CCR2) and CCR5 (ref. The portal can access those files and use them to remember the user's data, such as their chosen settings (screen view, interface language, etc. The phase 3 AURORA trial will provide further confirmation of the safety and efficacy profile to clarify the potential role for CVC in the treatment of NASH fibrosis. Cenicriviroc treatment has no notable effect on body or liver . 2020-07-04 08:00. (NASH) in Adult Participants With Liver Fibrosis. Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of CVC in Participants With Mild or Moderate Hepatic Impairment. Would you like email updates of new search results? Part 2 includes 800 participants with histological evidence of NASH and stage F3 fibrosis with primary endpoint of clinical endpoints including time to adjudicated event (death, histopathologic progression to cirrhosis, liver transplantation, Model of End-Stage Liver Disease [MELD] score 15, ascites, hospitalization due to liver decompensation). Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Its effect on decreasing the migration of monocytes was proven in a thioglycolate-induced peritonitis mouse model in which CVC reduced monocyte infiltration into the peritoneal cavity.20 Likewise, in a carbon tetrachloride (CCl4) mouse model, CVC significantly decreased MoMF in acutely injured liver tissue21 but did not change hepatic lymphoid populations in vivo.21 Additionally, the antifibrotic properties of CVC were demonstrated in a streptozocin/high fat mouse model, with significant reduction of collagen deposition in the liver, percentage of fibrosis area and NAFLD activity score (NAS).20 In the choline-deficient/high fat mouse model of NASH, CVC resulted in significant decreases in histologic and molecular markers (hepatic hydroxyproline levels, COL1A1 mRNA expression) of hepatic fibrosis, although without significant changes in hepatic steatosis or inflammation.22 These findings were corroborated by findings from a thioacetamide (TAA) rat model in which CVC resulted in a significant reduction of liver collagen deposition,20 and a decrease in insulin resistance, steatohepatitis and liver fibrosis in human liver tissue from patients with NASH.23 Furthermore, pharmacologic inhibition of CCR2/5 signaling with CVC was associated with prevention and reversal of alcohol-induced liver injury, steatosis, and inflammation in a mouse model.24, A favorable safety and tolerability profile for CVC has been supported by several clinical studies including the Phase 1, open-label, nonrandomized, single-center study.25 In this study, 29 participants with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic insufficiency (HI) were matched by age, body weight and gender with healthy participants and were administered CVC 150mg daily for 14 days. Herein, we report the final data from Year 2 exploratory analyses. I certify that I am a healthcare professional. 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. Liver biopsy assessments are performed at screening, 1 year and 5 years, and patient reported outcome (PRO) measures are collected longitudinally over 5 years, including the Chronic Liver Disease Questionnaire-Nonalcoholic Fatty Liver Disease, Work Productivity and Activity Impairment in NASH and 36-Item Short Form Health Survey Version 2.32 The anticipated primary completion date for AURORA is October 2021. Raeman R, Anania FA. Tobira is developing novel therapeutics to treat liver disease, fibrosis, and inflammatory diseases. 2022 Jun 24;18(6):e1010547. Unfortunately, the trial failed to meet both the primary and secondary endpoints. Liver Int. The study is organized and carried out in two parts over 5 years. The purpose of this study is to determine whether Cenicriviroc is effective and safe in the treatment of nonalcoholic steatohepatitis (NASH) in adult subjects with liver fibrosis. UK VAT Group: GB 365 4626 36. Younossi ZM, Stepanova M, Rafiq N, et al. Primary efficacy endpoints will include the proportion of subjects with 1-stage improvement in liver fibrosis and no worsening of steatohepatitis at Month 12 relative to screening (Part 1), and time to first occurrence of any adjudicated event: death; histopathologic progression to cirrhosis; liver transplant; Model of End-Stage Liver Disease score 15; ascites; hospitalization due to liver decompensation (Part 2). The Phase II CENTAUR results demonstrated an underwhelming inflammation impact, and the observed placebo effect madeavailable data harder to interpret, interviewed experts noted. Tsuchida T, Friedman SL. Hepatology. Copyright 2017 Informa PLC. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Based on the results of the phase 2b CENTAUR trial, the response rate of improvement in fibrosis of 1 stage with CVC monotherapy at week 48 in patients with F2 and F3 fibrosis is modeled at approximately 35%.27 TXR monotherapy is currently under investigation in an independent phase 2b monotherapy study (FLIGHT-FXR); preliminary data have revealed robust, dose-dependent reductions in hepatic fat and liver transaminases versus placebo at 12 weeks.33 The TANDEM study is estimated to reach completion in September 2020. Detailed Description: The AURORA study will be conducted in 2 parts. doi:10.1111/liv.14354, 40. Ann Transl Med. Part 2 includes 800 participants with histological evidence of NASH and stage F3 fibrosis with primary endpoint of clinical endpoints including time to adjudicated event (death, histopathologic progression to cirrhosis, liver transplantation, Model of End-Stage Liver Disease [MELD] score 15, ascites, hospitalization due to liver decompensation). Abbreviations: CCL-2, chemokine (C-C motif) ligand 2; CCR2, C-C chemokine receptor 2; TFGB, transforming growth factor ; PDGF, platelet-derived growth factor. CAS#: 497223-28-6 (mesylate) Description: Cenicriviroc, also known as TAK-652 and TBR-652, is an experimental drug candidate for the treatment of HIV infection. about navigating our updated article layout. Top, Copyright 2022 Dove Press Ltd Open access peer-reviewed scientific and medical journals. JKL reports research contracts (to Yale University) from Allergan, Conatus, Genfit, Gilead, and Intercept. CVC showed promising results in various preclinical models. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. CCR-2/5 have been linked to the inflammatory and fibrogenic pathways in non-alcoholic steatohepatitis (NASH), and by inhibiting CCR-2/5 it is anticipated that cenicriviroc will reduce inflammation and fibrosis. Pedrosa M, Seyedkazemi S, Francque S, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. TXR is a non-bile acid farnesoid X receptor (FXR) agonist which has demonstrated important effects on bile acid, glucose, and lipid metabolism.34,35 TXR alone has shown efficacy in preclinical models of NASH in which it has reduced bile acid and triglyceride synthesis, and has decreased hepatic steatosis, hepatic inflammation, and hepatocyte ballooning.36 Preclinical and phase 1 studies evaluating the combination of TXR plus CVC have revealed a significant reduction in hepatic inflammation and ballooning with acceptable safety and tolerability. Year 1 primary analysis of the 2-year CENTAUR study showed that CVC had an antifibrotic effect without impacting steatohepatitis. doi:10.1002/hep.29367, 2. 1Department of Medicine, Yale School of Medicine, New Haven, CT, USA, 2Yale Liver Center and Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA. Efficacy and Safety Study of Cenicriviroc for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Adult Participants With Liver Fibrosis Conditions: Nonalcoholic Steatohepatitis NCT02342067 Completed Pharmacokinetic and Safety Study of Cenicriviroc and Pioglitazone, When Dosed Alone or in Combination Conditions: Healthy NCT03028740 Terminated Although current trial design and endpoints are limited by heterogeneous clinical phenotypes, long latency period between diagnosis and clinical outcomes (eg, cirrhosis, liver cancer), intrinsic flaws and variability in the biopsy gold standard, and slow acceptance of validated NASH biomarkers, the continued expansion of novel investigational agents targeting a diverse spectrum of metabolic and fibrosis pathways have created optimism for major advances in the treatment of patients with NASH fibrosis. Non-alcoholic steatohepatitis (NASH) is associated with significant morbidity and mortality due to liver cirrhosis, liver failure, and hepatocellular carcinoma, and represents a leading indication for liver transplantation in the United States (U.S.). drug (8) Funder Type. The most common adverse effects of grade 2 severity or greater among patients randomized to CVC included headache (1.4%), fatigue (2.8%), and diarrhea (2.1%).25,31 Similar safety and tolerability were observed upon completion of year two of the protocol. Patients will be randomized in a 1:1:1:1 ratio to receive TXR 140ug qd, CVC 150mg qd, TXR 140ug + CVC 150mg qd or TXR 90ug + CVC 150mg qd. CVC was well tolerated with few safety concerns identified in healthy participants and those with mild or moderate HI. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. -Primary completion date for is estimated to be in Oct 2021. open access to scientific and medical research. Dove Medical Press is part of Taylor & Francis Group, the Academic Publishing Division of Informa PLC government site. Taken together, these data paved the way for the ongoing multicenter phase IIb trial, CENTAUR (652-2-203; NCT02217475), which will evaluate the efficacy and safety of cenicriviroc 150 mg once daily for the treatment of NASH and liver fibrosis over 2 years, with a primary end point at Year 1, in 289 participants with NASH and liver fibrosis at . Ratziu V, Harrison SA, Francque S, et al. Allergan is now part of AbbVie, which announced the closing of the acquisitionvalued at approximately$63bnon 8 May 2020. No deaths were observed in this phase 2b trial. 35. doi:10.1080/13543784.2020.1718106, 12. JKL reports research contracts (to Yale University) from Allergan, Conatus, Genfit, Gilead, and Intercept. Read our report and gather insights on the following topics: Hard data and deep insights on clinical trials strategy & operations, Receive our newsletter - data, insights and analysis delivered to you. cenicriviroc (8) placebo (2) dolutegravir (1) famotidine (1) midazolam (1) omeprazole (1) pioglitazone (1) Study Documents. 2019;49(11):12561262. Terms & Conditions Hepatol Res. 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. Bookshelf Although early clinical data support direct antifibrotic effects of CVC, effects on metabolic components of NAFLD and NASH have been limited. Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design. The aim of this concise review is to explore the therapeutic potential of cenicriviroc by summarizing key results of major preclinical and clinical studies and discussing the future direction for cenicriviroc as a potential treatment for NASH. doi:10.1007/s12072-019-10001-4, 39. Hepatology. We offer real benefits to our authors, including fast-track processing of papers. PLoS Pathog. 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. 2018 Mar;27(3):301-311. doi: 10.1080/13543784.2018.1442436. The .gov means its official. Axon 2665. Secondary: determine efficacy of the combination regimen on histological improvement (at least a 1-point improvement in fibrosis score or resolution of steatohepatitis) vs monotherapies. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Federal government websites often end in .gov or .mil. PLoS One. Purity: 99% Soluble in DMSO ; Description. A member of the Allergan Clinical Operations Team will contact you via email soon. 2018;67(4):12701283. Ekstedt M, Hagstrom H, Nasr P, et al. You can learn about our use of cookies by reading our Privacy Policy. Younossi ZM, Stepanova M, Rafiq N, et al. Abbreviations: CCL-2, chemokine (C-C motif) ligand 2; CCR2, C-C chemokine receptor 2; TFGB, transforming growth factor ; PDGF, platelet-derived growth factor. 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. Files DC, Tacke F, O'Sullivan A, Dorr P, Ferguson WG, Powderly WG. NASH is a complex entity in which numerous signaling pathways are involved in disease pathophysiology. Nat Rev Mol Cell Biol. If all goes. official website and that any information you provide is encrypted The authors report no other conflicts of interest in this work. Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, Francque S, Farrell G, Kowdley KV, Craxi A, Simon K, Fischer L, Melchor-Khan L, Vest J, Wiens BL, Vig P, Seyedkazemi S, Goodman Z, Wong VW, Loomba R, Tacke F, Sanyal A, Lefebvre E. Hepatology. An official website of the United States government. Cell Mol Immunol. Other Therapies in Phase 3 Clinical Trials for NASH (Clinicaltrials.gov). BOSTON Cenicriviroc (Tobira Therapeutics), an investigational once-daily oral therapy, can improve fibrosis in patients with nonalcoholic steatohepatitis (NASH), according to preliminary . Industry (7) . Our services are intended for corporate subscribers and you warrant that the email address submitted is your corporate email address. Nonalcoholic Steatohepatitis; Placebo; Cenicriviroc; Birmingham, Alabama +345 more; Feb 11, 2022. Secondary: Resolution of SH and no worsening of fibrosis; improvement of fibrosis 1 stage and no worsening of SH. Additional studies evaluating its role in combination with alternative mechanisms of action focused on metabolic endpoints targeted at liver steatosis and steatohepatitis may help determine a future role as part of oral combination regimens. Careers, Correspondence: Joseph K Lim Professor of Medicine, Yale Liver Center and Section of Digestive Diseases, Yale School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT, 06520-8019, USA, Phone: Tel +1 (203) 737-6063, Fax: Fax +1 (203) 785-7273, Email joseph.lim@yale.edu. NCI CPTC Antibody Characterization Program. 8600 Rockville Pike Abbreviations: FXR, farnesoid X receptor; NASH, non-alcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; SCD, stearoyl-CoA desaturase 1. The most common adverse effects of grade 2 severity or greater among patients randomized to CVC included headache (1.4%), fatigue (2.8%), and diarrhea (2.1%).25,31 Similar safety and tolerability were observed upon completion of year two of the protocol. Two specific pathways, macrophage-mediated inflammation and hepatic stellate cell activation, have been identified as key pathways in disease progression (Figure 1).11 Accumulation of fat in the liver may be associated with inflammation and hepatic injury (ballooning), which in turn may activate hepatocytes, liver macrophages (Kupffer cells) and hepatic stellate cells (HSC) to release chemokines which interact with the CCR2 receptor on circulating monocytes to promote infiltration into the liver where they differentiate into pro-inflammatory macrophages.12,13 This population of cells is referred to as monocyte-derived macrophages (MoMF) which are distinct from the tissue-resident macrophages, Kupffer cells (KC).12,13 Both MoMF and KC release proinflammatory cytokines such as transforming growth factor (TGF-) and platelet-delivered growth factor (PDGF) which activates HSC.14,15 Activated HSC differentiate into myofibroblast-like cells which produce collagen resulting in liver fibrosis.16 The CCR5 chemokine receptor is also expressed in a subpopulation of lymphocytes and HCS and contributes to profibrogenic activation and proliferation.17,18 Cenicriviroc (CVC), an oral dual CCR2/CCR5 antagonist is under investigation as a potential treatment for NASH due to its broad spectrum of anti-inflammatory and anti-fibrotic effects.19. 34. Differential impact of the dual CCR2/CCR5 inhibitor cenicriviroc on migration of monocyte and lymphocyte subsets in acute liver injury. doi:10.1016/j.jhep.2017.02.026, 20. Tobira is advancing cenicriviroc to treat non-alchoholic steatohepatitis (NASH) as one of the first immunomodulatory approaches . doi:10.1002/hep.24268, 7. Front Pharmacol. Chalasani N, Younossi Z, Lavine JE, et al. 2016;64(1):7384. Pharmacokinetics, safety, and CCR2/CCR5 antagonist activity of cenicriviroc in participants with mild or moderate hepatic impairment. Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis. 2018;67(1):123133. 1)Compare the PK of CVC in participants with mild or moderate HI (Child-Pugh A and B) with healthy participants. By clicking the Download Free Whitepaper button, you accept the terms and conditions and acknowledge that your data will be used as described in the GlobalData privacy policy Please enter a work/business email address. AbbVie Inc. and Allergan plc are a new combined company. 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. 26 one-year follow-up results were available for 252 participants which confirmed that cvs failed to demonstrate a statistically significant Cenicriviroc (CVC), is a novel, orally administered, potent, small molecule agonist that acts to block chemokine 2 and 5 receptors (CCR2/CCR5), both with well-known roles in liver inflammation and fibrosis (Figure 2).18 CVC has been developed by Allergan Inc (an AbbVie Inc company) and has received a Fast Track designation by the FDA for the treatment of NASH. In this context, the phase 2b TANDEM trial33 is a randomized, placebo-controlled, multicenter trial evaluating the combination of CVC and tropifexor (TXR). Alkhouri N, Scott A. Phase 3. doi:10.1002/hep.29477, 27. eCollection 2022 Jun. Ambade A, Lowe P, Kodys K, et al. Tobira gains rights to second asset for NASH in North America, Europe & Australia First combination study with cenicriviroc to begin late 2016 Conference Call Scheduled for today at 8:30 a.m.
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