IN VITRO CHARACTERIZATION OF EYP001 A NOVEL, POTENT
AND SELECTIVE FXR AGONIST ENTERING PHASE 2 CLINICAL
TRIALS IN CHRONIC HEPATITIS B
Raphaël Darteil1, Stéphane Joly1, Pauline Radreau1, Marine
Porcherot1, Jacky Vonderscher1, Pietro Scalfaro1, Eric
Meldrum1 and Patrice Andre2, (1)Enyo Pharma SA, (2)
Inserm U1111 - Cnrs UMR5308 - Université Lyon 1 and Ecole
Normale Supérieure De Lyon, Ciri
Background: More than 240 million individuals worldwide
are chronically infected with hepatitis B virus (HBV), one
of the main causes of liver-related morbidity and mortality
Nucleos(t)ide-analogue (NUCs) therapy achieves potent
viral suppression and reduces the incidence of liver-related
complications However, cure rates are low and most patients
require life-long medication There is therefore a need for new
therapeutic approaches for chronic hepatitis B (CHB) One
novel approach for CHB targets the farnesoid X bile acid
receptor (FXR). It is known that HBV infection modifies bile
acid metabolism to impact the FXR pathway FXR agonists
have been reported to inhibit HBV cccDNA transcription
in primary human hepatocytes (PHH) EYP001 is a novel
and selective non-bile acid second generation FXR agonist
currently being evaluated in clinical Phase 2 against CHB
and NASH Methods: EYP001, other FXR agonists in clinical
development, and NUCs were tested in in vitro models
supporting the complete HBV replication cycle: differentiated
HepaRG cells and/or PHH. A broad range of HBV markers
were measured, including viral antigens and nucleic acids
Results: EYP001 repressed significantly all HBV markers
in a dose-dependent manner in HepaRG cells: secreted
HBsAg (60% inhibition), HBeAg (60% inhibition) and rcDNA
(79% inhibition), and intracellular pg/pcRNA (75% inhibition)
and cccDNA (71% inhibition) A comparison of EYP001 with
other FXR agonists currently in clinical development was
carried out All FXR agonists tested do not share the same
antiviral potency and maximal efficacy. Extensive combination
experiments with EYP001 and NUCs were also carried out in
infected HepaRG cells Unlike EYP001, NUCs alone showed
negligible effects on HBsAg, HBeAg and cccDNA levels
and combining with the EYP001 FXR agonist resulted in a
profile superior to NUCs alone. All compound concentrations
presented in this work were shown not to be cytotoxic
Conclusion: The non-bile acid specific FXR agonist EYP001
was shown to repress the replication of HBV in 2 in vitro
hepatic models of full viral cycle Other FXR agonists in clinical
development have similar effects but do not share the same
antiviral potency and maximal efficacy. The mode of action
of FXR agonists against HBV is currently under investigation
with evidence showing a reliance on FXR for the recruitment of
HBx and other cellular factors to the trans-activating complex
on the cccDNA (Lacombe et al EASL ILC 2019, SAT-175)
The effects of EYP001 on both cccDNA transcription and
HBsAg secretion, along with additive effects observed in
combination treatments with NUCs make of EYP001 a good
clinical candidate to achieve CHB functional cure in humans作者: StephenW 时间: 2019-10-23 15:27