Table 1.

Pre-Clinical Studies and Clinical Trials Evaluating Cenicriviroc for NASH Treatment

	Study Type	Objectives	Description	Results
Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis	Pre-clinical	Evaluate CVCs anti-inflammatory and antifibrotic effects in a range of pre-clinical models	1)Monocyte/macrophages recruitment evaluated in mouse model of thioglycolate induced peritonitis 2) CVCs antifibrotic effects were evaluated in thioacetamide induced rat model of liver fibrosis and mouse models of diet induced NASH	-CVC significantly reduced monocyte/macrophage recruitment in vivo. -Also showed significant reduction in collagen deposition. -In NASH model, CVC significantly reduced NAFLD activity score -CVC did not affect body or liver weight
Differential impact of the dual CCR2/CCR5 inhibitor cenicriviroc on migration of monocyte and lymphocyte subsets in acute liver injury	Pre-clinical	Evaluate the impact of CVC in the composition of myeloid and lymphoid immune cell populations in acute liver injury	Acute liver injury was induced in mice by single injection of CCL4 intraperitoneally, CVC was given by oral gavage	-Simultaneous administration of CCL4 and CVC in mice significantly decreased the number of MoMF in acutely injured livers -CVC had no impact on the composition of hepatic lymphoid cell population in vivo
Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet-induced mouse model of nonalcoholic steatohepatitis.	Pre-clinical	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). CVC was initiated simultaneously with the CDAHFD	-High dose CVC in CDAHFD mice for 4 and 14 weeks inhibited intrahepatic accumulation of bone marrow derived macrophages -Despite ongoing steatohepatitis, there was significantly less fibrosis in CDAHFD mice receiving high dose CVC for 14 weeks
Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of CVC in Participants With Mild or Moderate Hepatic Impairment.	Phase 1	1)Compare the PK of CVC in participants with mild or moderate HI (Child-Pugh A and B) with healthy participants. 2) Evaluate the safety and tolerability of CVC and its effects on CCR2/CCR5 ligands, proinflammatory cytokines, and biomarkers of bacterial translocation.	Open label, nonrandomized, single center study. participants with mild (Child-Pugh class A) and moderate (Child-Pugh class B) HI were matched by age, body weight and gender with healthy participants and were given CVC 150mg daily for 14 days.	-CVC was well tolerated and no safety concerns were identified in healthy participants as well as those with mild and moderate HI. -Moderate HI but not mild HI increase CVC exposure -Proinflammatory cytokines and bacterial translocation biomarkers were no different between HI and healthy participants.
CENTAUR part I	Phase 2b	Primary: ≥ 2-point improvement in NAS and no worsening of fibrosis at year 1. Secondary: Resolution of SH and no worsening of fibrosis; improvement of fibrosis ≥ 1 stage and no worsening of SH	Randomized, double blinded, placebo controlled, multinational study of 289 adults with NASH, a NAS ≥ 4 at least 1 in each component, and liver fibrosis stages 1–3. Participants were randomized 2:1:1 to arm A (CVC 150mg daily for 2 years), arm B (placebo for 1 year then CVC 150mg daily for 1 year), or arm C (placebo for 2 years).	-No significant difference between CVC and placebo achieving primary outcome -Significant difference in the CVC group of improvement in fibrosis by ≥ 1 stage and no worsening of SH compared to those on placebo - Subgroup analysis showed greater CVC treatment benefits in subjects with higher disease activity and fibrosis stage - CVC did not improve the histologic component of HS (NAS score) nor did it affect body weight, liver function tests or insulin resistance
CENTAUR part II	Phase 2b	Same as above	Of 289 participants 242 entered the second year	-Over 2 years a similar proportion on CVC or placebo achieved > 1 stage fibrosis and no worsening of NASH - Double the proportion on CVC who achieved fibrosis response at end of year 1 maintained benefit at year 2 (60% vs 30%). -The durability of antifibrotic response of CVC treatment was higher in those with stage 3 fibrosis
AURORA	Phase 3	Part I: to demonstrate histologic improvement at the end of 1 year with CVC vs placebo, specifically improvement in liver fibrosis > 1 stage and no worsening of SH part II: to demonstrate superiority of CVC vs placebo on the composite endpoint of histopathologic progression to cirrhosis, liver related clinical outcomes and all-cause mortality.	Part 1 will include 1200 participants with histological evidence of NASH and stage F2 or F3 fibrosis randomized 2:1 to CVC 150mg daily or placebo. Part II will include 800 newly randomized participants with histological evidence of NASH and stage F3 fibrosis plus the 1200 participants from part I	-Primary completion date for is estimated to be in Oct 2021.
TANDEM	Phase 2b	Primary: Evaluate the safety and tolerability of TXR and CVC combination therapy compared with monotherapies in 200 patients with NASH and liver fibrosis stage F2/F3 over 48 weeks. 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.	randomized, placebo controlled, multicenter clinical trial. Randomization 1:1:1:1 ratio to receive either TXR 140ug qd, CVC 150mg qd, TXR 140ug + CVC 150mg qd or TXR 90ug + CVC 150mg qd	Estimated completion date is September 2020.

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.