Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design

Anstee, Quentin M.; Neuschwander‐Tetri, Brent A.; Wong, Vincent Wai‐Sun; Abdelmalek, Manal F.; Younossi, Zobair M.; Yuan, Jiacheng; Pecoraro, Maria Lucia; Seyedkazemi, Star; Fischer, Laurent; Bédossa, Pierre; Goodman, Zachary; Alkhouri, Naim; Tacke, Frank; Sanyal, Arun J.

doi:10.1016/j.cct.2019.105922

Cited by 111 publications

(89 citation statements)

References 53 publications

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“…For example, increase in serum levels of CCL2 is associated with progression from hepatic steatosis to NASH [ 63 ], and CCL2 expression is correlated with disease severity in Hepatitis C-dependent liver fibrosis [ 64 ]. On the other hand, pharmacological inhibition of CCL2 accelerated fibrosis resolution in mouse models of liver fibrosis [ 65 ], thereby supporting the development of drugs targeting CCL2 receptors for NASH therapy [ 66 ]. As expected, with the increase in CCL2 levels, fibrosis was present in the Cdk1 Liv-/- liver, apparent by the up-regulation of fibrosis-associated genes ( Fig 4C ) and prevalent Sirius Red staining ( Fig 4D ).…”

Section: Discussionmentioning

confidence: 99%

Loss of hepatocyte cell division leads to liver inflammation and fibrosis

Dewhurst

Zafer

et al. 2020

PLoS Genet

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The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. Here, we investigate whether blocking hepatocyte division using two different mouse models affects physiology as well as clinical liver manifestations like fibrosis and inflammation. We find that in P14 Cdk1 Liv-/- mice, where the division of hepatocytes is abolished, polyploidy, DNA damage, and increased p53 signaling are prevalent. Cdk1 Liv-/- mice display classical markers of liver damage two weeks after birth, including elevated ALT, ALP, and bilirubin levels, despite the lack of exogenous liver injury. Inflammation was further studied using cytokine arrays, unveiling elevated levels of CCL2, TIMP1, CXCL10, and IL1-Rn in Cdk1 Liv-/- liver, which resulted in increased numbers of monocytes. Ablation of CDK2-dependent DNA re-replication and polyploidy in Cdk1 Liv-/- mice reversed most of these phenotypes. Overall, our data indicate that blocking hepatocyte division induces biological processes driving the onset of the disease phenotype. It suggests that the decrease in hepatocyte division observed in liver disease may not only be a consequence of fibrosis and inflammation, but also a pathological cue.

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Section: Discussionmentioning

confidence: 99%

Loss of hepatocyte cell division leads to liver inflammation and fibrosis

Dewhurst

Zafer

et al. 2020

PLoS Genet

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“…The AURORA study Q7 (NCT03028740) investigated cenicriviroc, an oral, small molecule-based dual CCR2/CCR5 antagonist with nanomolar potency against both receptors, for the treatment of liver fibrosis in adults with NASH. 12 In rodent studies, cenicriviroc significantly ameliorated steatohepatitis and fibrosis, 13 presumably by reducing the infiltration of Ly-6C þ monocytes. 4 In order to better understand differential effects of CCR2 and CCR5 on liver disease progression, we studied CCR2 and CCR5 deficiency separately on the background of the NEMO LPC-KO model that age-dependently reflects human disease phases (steatosis, inflammation, fibrosis, cancer).…”

Section: Ccr2 and Ccr5 Deficiency Differentially Affects Spontaneous mentioning

confidence: 99%

Roles of CCR2 and CCR5 for Hepatic Macrophage Polarization in Mice With Liver Parenchymal Cell-Specific NEMO Deletion

Bartneck

Koppe

Fech

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Macrophages critically regulate liver inflammation. Using a genetically determined hepatitis mouse model we found that CCR2 controls monocyte and macrophage recruitment to injured livers, while CCR5-dependent functions of liver macrophages limit hepatic injury, thereby reducing steatosis and hepatocarcinogenesis. BACKGROUND & AIMS: Macrophages are key regulators of inflammation and cancer promotion in the liver, and their recruitment and activation is linked to chemokine receptor signaling. However, the exact roles of the chemokine receptors CCR2 and CCR5 for macrophage functions in the liver is obscure. METHODS: To study CCR2 and CCR5 in inflammatory liver injury, we used mice with a hepatocyte-specific knockout of the nuclear factor kB (NF-kB) essential modulator (NEMO), termed NEMO LPC-KO mice, and generated NEMO LPC-KO Ccr2-/and NEMO LPC-KO Ccr5-/mice. NEMO LPC-KO mice develop hepatitis and fibrosis after two and liver tumors after six months. RESULTS: We found that both CCR2 and CCR5 deficiency led to reduced fibrosis, while CCR5 deficiency increased steatosis and tumor burden in NEMO LPC-KO mice. CCR2 was required for recruitment of hepatic macrophages, whereas CCR5 promoted stellate cell activation. The reduction of monocytes and macrophages by either anti-Gr1 antibody or clodronate-loaded liposomes (CLL), but not of CD8 þ T cells or NK cells, significantly aggravated liver injury in NEMO LPC-KO mice and was further increased in NEMO LPC-KO Ccr5-/mice. CLLinduced liver injury was dampened by the adoptive transfer of ex vivo generated macrophages, whereas the adoptive transfer of control CD115 þ immature monocytes or B cells did not reduce liver injury. CONCLUSIONS: Although CCR2 and CCR5 principally promote liver fibrosis, they exert differential functions on hepatic macrophages during liver disease progression in NEMO LPC-KO mice. While CCR2 controls the recruitment of monocytes to injured livers, CCR5-dependent functions of liver macrophages limit hepatic injury, thereby reducing steatosis and hepatocarcinogenesis.

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“…Cenicriviroc is an oral inhibitor of the C-C motif chemokine receptor-2/5, which plays an important role in the hepatic recruitment of macrophages [92]. AURORA, a phase 3 study [93], will evaluate the effects of cenicriviroc on hepatic fibrosis in 2000 patients with NASH and is ongoing. A phase 2a, multi-center RDBPCT of cenicriviroc is being conducted with approximately 50 adult obese subjects (BMI ≥ 30 kg/m 2 ) with prediabetes or T2D and suspected NAFLD (ORION study, NCT02330549).…”

Section: Combination Therapiesmentioning

confidence: 99%

Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis

Sumida

Yoneda

Tokushige

et al. 2020

IJMS

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Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are Int.expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D.

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Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design

Cited by 111 publications

References 53 publications

Loss of hepatocyte cell division leads to liver inflammation and fibrosis

Loss of hepatocyte cell division leads to liver inflammation and fibrosis

Roles of CCR2 and CCR5 for Hepatic Macrophage Polarization in Mice With Liver Parenchymal Cell-Specific NEMO Deletion

Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis

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