Transcript FLISIAK et al, Hepatology 2009

Future treatment of HCV
with Host Targeting Antivirals
Francesco Negro
University Hospitals, Geneva, Switzerland
Host-Targeting Antivirals (HTA)
vs. Direct Acting Antivirals (DAA)
PRO’s
 Less or no risk of selecting drug resistance
 Pan-genotypic activity
CON’s
 Risk of toxicity due to interference with
cellular functions
Host factors as target for anti-HCV therapy
Compound
Host factor
targeted
HCV life cycle
phase targeted
Current clinical
phase
CD81 antibodies
CD81
Entry
Preclinical
ITX 5061 (iTherX)
SCARB1
Entry
1b
Ezetimibe
NPC1L1
Entry
Preclinical
Erlotinib
EGF-R
Entry
Preclinical
Dasatinib
Ephrin RA2
Entry
Preclinical
Alisporivir (Novartis)
CypA
RNA replication
3
(siRNA)
PI4KIII-a
RNA replication
Preclinical
Miravirsen
miR122
RNA replication
2
Statins
HMGCoAR
RNA replication
NA
(siRNA)
DGAT1
Assembly
Preclinical
Celgosivir
a-glucosidase I Assembly/release
Terminated
Adapted from VON HAHN et al, 2011; HERKER et al, 2010; SAINZ et al, 2012
TROTARD et al, 2009; LUPBERGER et al, 2011
Alisporivir (DEBIO-025), a cyclophilin inhibitor
without immunosuppressive effects
DEBIO-025
CsA
Cyclophilin
binding
domain
Calcineurin
binding
domain
Alisporivir binds to cyclophilin but not to calcineurin
CyP
CyP
Cyclosporin Acyclophilin complex
binds calcineurin
Alisporivir-Cyp complex does
NOT bind to CN leaving
immune response intact
alisporivir
CsA
CN
NF-ATc
dephosphorylation
is blocked
CN
P
P
NF-ATc
Activation
of immune
response
CN
NF-ATc
NF-ATc
CYCLOPHILINS ARE CHAPERONES
 Cyclophilins have diverse cellular functions
 Ubiquitous proteins
– Expressed in various tissues
(liver, muscle, CNS)
– >7 subtypes reported in humans
– Detected in cytosol, nucleus, ER,
mitochondria (depending on subtype)
 Peptidyl prolyl isomerase (PPIase) activity
– Catalyzes isomerization of peptidic bonds
from trans to cis to facilitate the de novo
protein unfolding
– HCV exploits the PPIase activity of
CypA for its own replication
PENG et al, 2005; RYFFEL et al, 1991; COLGAN, et al. 2004
Cyclophilin A (CyPA) is the main
cyclophilin involved in HCV replication
Yang F, et al. J Virol 2008;82:5269–5278; Chatterji U, et al. J Biol Chem 2009;284:16998–17005
Kaul A, et al. PLoS Pathog 2009;5:e1000546
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Additional effects of cyclophilin
inhibition in HCV infection
 Restoration of mitochondrial function
QUARATO et al, Hepatology 2011
 Reduction of autophagy, thus limiting the
inhibitory effect of autophagy on innate
immune response
CARREIRA et al, Autophagy 2010
Alisporivir
Pan-genotype antiviral activity
• As a monotherapy or added to SOC, G1-4
High resistance barrier
• Mutations associated with resistance to Cyp inhibitors can be selected in
vitro within NS5A (a substrate of PPIase activity of CypA) but appear very
slowly (28 passages, 4-6 months)
• The D320E (domain III of NS5A) mutation is associated with resistance to
alisporivir (cross-resistance to CsA and alisporivir) but is not sufficient to
lead to breakthrough in patients
• Resistance is low-level (<5-fold) and involves reduced binding to CyPA
FLISIAK et al, Hepatology 2009; FERNANDEZ et al. Hepatology 2007; GOTTO et al, Cancer Sci 2009
CRABBE et al Expert Opin Investig Drugs 2009; WIEDERMANN et al, Antimicrob Agents Chemother 2010
FLISIAK et al, EASL 2011; CHATTERJI et al, J Hepatol 2010; COLMONT et al, PLoS One 2010
Alisporivir monotherapy
or in combination with SOC
[4 weeks, treatment-naive, HCV genotypes 1 and 4]
FLISIAK et al, Hepatology 2009;49:1460–1468
Alisporivir monotherapy
or in combination with SOC
[4 weeks, treatment-naive, HCV genotypes 2 and 3]
FLISIAK et al, Hepatology 2009;49:1460–1468
Dreaming about an IFN-a-free world...
The ESSENTIAL Study (205 Study)
Multicenter (EU), 48 weeks, treatment-naive, HCV-1, phase IIb RCT
ITT population (n=288)
PEG-IFN-a/RBV (n=73)
FU
Placebo + PEG-IFN-a /RBV 48 weeks
600
mg
BID
first
week
then
600
mg
QD
Alisporivir48 (n=72)
FU
Alisporivir + PEG-IFN-a /RBV 48 weeks
RVR
Alisporivir-RGT (n=71)
Alisporivir + PEG-IFN-a /RBV 24-48 weeks
FU
non-RVR
Alisporivir24 (n=72)
FU
Alisporivir + PEG-IFN-a /RBV 24 weeks
0
24
48
72
FLISIAK et al, EASL 2011
The ESSENTIAL Study – SVR
ITT population (n=288)
P=0.008
80
70
60
50
40
30
20
10
39/73
54/72
49/71
34/72
PEG-IFN/RBV
Alisporivir48
Alisporivir-RGT
Alisporivir24
0
FLISIAK et al, EASL 2011
The ESSENTIAL Study (205 Study)
ITT population (n=288)
 Alisporivir + PEG-IFN-a/RBV is superior to PEG-IFN-a/RBV:
– RVR was ~3-fold higher in all alisporivir-containing arms
– SVR increased from 55% to 76% in the 48-week triple regimen
– Improvement of SVR was independent of IL28B genotype
– Triple regimen was well tolerated (transient, reversible
hyperbilirubinemia in ~1/3 of patients, without cholestasis or
hepatotoxicity)
FLISIAK et al, EASL 2011
Alisporivir disposal and risk of DDIs
 DEB025 is mainly metabolised through
cytochrome P450 3A4
 DEB025 is an inhibitor of P-gp, BSEP, MRP2
(leading to hyperbilirubinemia), NTCP,
OATP1B1 and OATP1B3
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Alisporivir – Ongoing phase III program
Patients’ population
Comparator
HCV GT 1 naive
PegIFN + RBV
HCV GT 1 naïve, African American
BOC+PegIFN+RBV
miRNA-122 is essential to HCV replication
Miravirsen (Santaris) is a small LNA modified phosphorothioate
anti-sense oligonucleotide targeting (and blocking) miR-122
JOPLIN et al, Science 2005; JANSSEN et al, AASLD 2011
Preclinical and phase 1 data on Miravirsen
 Miravirsen inhibits HCV in vitro (EC50 0.67 mm)
 No resistance-conferring mutations in the miR-122
seed regions (conserved among HCV genotypes)
 In healthy volunteers, safe and well tolerated, with
no dose limiting toxicity
LANFORD et al, Science 2010; ELMEN et al, Nature 2008
Proof-of-concept study of Miravirsen (oligonucleotide
targeting miR-122) in treatment-naïve HCV-1
JANSSEN et al, AASLD 2011
Mean HCV RNA Log changes during Miravirsen
Prolonged dose-dependent antiviral activity well beyond the
end of therapy, consistent with 30 day terminal half-life
No evidence of drug resistance
JANSSEN et al, AASLD 2011