TREATMENT WITH THE CCR2/CCR5 ANTAGONIST CENICRIVIROC DOESNOT AFFECT MASH AND FIBROSIS DEVELOPMENT IN LDLR-/-.LEIDEN
MICE, TRANSLATIONAL TO CLINICAL PHASE 3 TRIAL RESULTS
Introduction

CVC shows target engagement as observed in clinical trials

Cenicriviroc (CVC) is a dual CCR2/CCR5 antagonist that was indevelopment for the treatment of metabolic dysfunctionassociated steatohepatitis (MASH) and associated fibrosis.
While CVC showed antifibrotic potential in the phase 2B
CENTAUR trial, the phase 3 AURORA trial was terminated after1y due to lack of efficacy on improvement of fibrosis.

•CCR2 ligand: CCL2 (MCP-1)•

CCR5 ligands: CCL3 (MIP-1α),CCL4 (MIP-1β) and CCL5 (RANTES)

Effect of CVC on obesity and metabolic risk factors

Ldlr-/-.Leiden
MASH model

HFD

HFD+CVC

Effects of CVC treatment on metabolic risk factors in week 28

chow
Blood glucose (mM)
Plasma insulin (ng/ml)
Plasma cholesterol (mM)
Plasma triglycerides (mM)

HFD

HFD
+CVC

6.9 ± 0.8a 7.9 ± 0.7b 7.2 ± 0.6a
2.3 ± 2.0a 9.6 ± 5.7b 13.7 ± 6.4b
8.1 ± 2.1a 35.5 ± 6.2b 38.6 ± 8.9b
1.0 ± 0.6a 6.7 ± 1.9b 8.9 ± 3.0c

Treatment with CVC did not affect food intake and body weight. CVC lowered
fasting blood glucose relative to HFD controls in week 28 of the study, but did
not affect plasma insulin, plasma cholesterol or plasma triglycerides.

As observed in the phase 3 AURORA trial, treatment with CVC did not affecthepatic fibrosis, as demonstrated by biochemical analysis of collagen and by
image analysis of Sirius-red-stained liver sections.

CVC does not affect ALT and AST or plasma markers of fibrosis

Conclusion
While many preclinical models have shown efficacy of CVC that contrasts
clinical observations, CVC treatment (at a translational dose that did show
efficacy in other preclinical models) in the HFD-fed Ldlr-/-.Leiden mouse did not
reduce hepatic fibrosis – in line with the outcome of the phase 3 AURORA trial.
This lack of effect was observed despite adequate target engagement, similar
to clinical observations.

HFD
HFD+CVCHFD+CVC

Fibrosis(Sirius-red)
chowchow

HFD

HFD

Treatment with CVC did not affect liver weight. Analysis of HE-stained sections
by a pathologist showed that CVC also had no effect on total steatosis or
hepatic inflammation.
Fibrosis(collagen content)

t=34 weeks

t=20

t=0

Inflammation

Clinical trials: increased plasma
levels of CCR2 and CCR5 ligands.

Aim

Male Ldlr-/-.Leiden mice were fed a MASH and fibrosis-inducing
high-fat diet (HFD) for 20 weeks, after which the 14-weektreatment with CVC (20 mg/kg BW, provided as dietary admix)
was started in one group of mice (HFD+CVC) and another groupof mice was kept on HFD as an untreated control. A chow-fed
group was included as an aging reference. All mice wereterminated at t=34 weeks for histological and biochemical
analysis of MASH and fibrosis development as well as analysisof MASH- and fibrosis-related biomarkers.

CVC does not affect liver steatosis, inflammation or fibrosischow

In line with observations in clinical studies, we observed a significant increasein plasma MCP-1 and non-significant increases in MIP-1a and RANTES,indicative of adequate target engagement.

Methods

Department of Metabolic Health Research, the Netherlands
Organisation for Applied Scientific Research (TNO), Leiden,
the Netherlands.

Steatosis

In contrast with these results in humans, many preclinical studies
have shown anti-inflammatory and anti-fibrotic efficacy of CVC –which brings into question the translational value of these models
for human MASH.

Study
theeffectsofCVC
treatment
intheLdlr-/-.Leiden mouse model for obesity-associated MASH andliver fibrosis, to investigate if this model can more accurately
predict treatment effects in MASH patients

Morrison MC, Gart E, van Duyvenvoorde W,
Snabel J, Menke A, van den Hoek AM,Kleemann R

CVC did not affect plasma levels of the liver damage markers ALT and AST orthe fibrosis markers TIMP-1, CK-18 M30 or PIIINP (measured in terminalplasma).

These findings underline the importance for validation of preclinical MASH
models not only with treatments that have been found to have clinical efficacy,
but also with treatments that have failed clinically.

martine.morrison@tno.nl