Post on 14-Jan-2016
Protease and Polymerase Inhibitors Protease and Polymerase Inhibitors
for the Treatment of Hepatitis Cfor the Treatment of Hepatitis C
Tarik AsselahTarik Asselah
MD, PhDMD, PhDService d’Hépatologie & INSERM U773, CRB3 Service d’Hépatologie & INSERM U773, CRB3
Hôpital Beaujon, ClichyHôpital Beaujon, Clichytarik.asselah@bjn.aphp.frtarik.asselah@bjn.aphp.fr
• Unmet NeedsUnmet Needs
• Mechanisms of Non ResponseMechanisms of Non Response
• Protease InhibitorsProtease Inhibitors
• Polymerase InhibitorsPolymerase Inhibitors
• ConclusionConclusion
Protease and Polymerase Inhibitors Protease and Polymerase Inhibitors for the Treatment of Hepatitis Cfor the Treatment of Hepatitis C
PEG-IFNPEG-IFN IFN+RibaIFN+Riba
6 16%6 16%18 23%18 23%
47% 63%47% 63%
35 43%35 43%
PEG-IFN+RibaPEG-IFN+Riba
19891989 2009 2009
IFNIFN
Progress in the Treatment of Hepatitis CProgress in the Treatment of Hepatitis C
PEG-IFN-a + RibavirinPEG-IFN-a + RibavirinIncidence of Therapeutic FailureIncidence of Therapeutic Failure
PEG-IFN-a 2aPEG-IFN-a 2a+ ribavirin + ribavirin (Fried et al., 2002)(Fried et al., 2002)
PEG-IFN-a 2bPEG-IFN-a 2b+ ribavirin+ ribavirin(Manns et al., 2001)(Manns et al., 2001)
Manns et al. Lancet 2001; Manns et al. Lancet 2001; Fried et al. NEJM 2002; Fried et al. NEJM 2002; Hadziyannis et al. Ann Intern Med 2004.Hadziyannis et al. Ann Intern Med 2004.
54%54%
24%24%
Genotype 1Genotype 1 Genotypes 2/3Genotypes 2/3
58%58%
48%48%
18%18%16%16%
PEG-IFN-a 2aPEG-IFN-a 2a+ ribavirin + ribavirin (Hadziyannis et al., 2004)(Hadziyannis et al., 2004)
How These Drugs will be Evaluated ?How These Drugs will be Evaluated ? Patterns of Virological ResponsePatterns of Virological Response
Sustained responderSustained responder(cure)(cure)
NonresponderNonresponder
BaselineBaseline TreatmentTreatment
TimeTime
RelapserRelapser
PartialPartialresponderresponder
HCV RNAHCV RNAUndetectableUndetectable
HC
V R
NA
HC
V R
NA
BreakthroughBreakthrough
Detection limitDetection limit
6 months6 months
ResponseResponse DefinitionDefinition
RVR* RVR* HCV RNA negative at week 4HCV RNA negative at week 4
EVR**EVR**
CompleteCompleteEVR EVR
HCV RNA positive at week 4 but HCV RNA positive at week 4 but negative at week 12negative at week 12
PartialPartialEVREVR
HCV RNA positive at week 4 and 12 but HCV RNA positive at week 4 and 12 but 2 log 2 log1010 drop from baseline at week drop from baseline at week 1212
Non-EVRNon-EVR < 2 log< 2 log1010 drop from baseline at week 12 drop from baseline at week 12
Response-guided Therapy Requires Precise Response-guided Therapy Requires Precise Definitions of on-Treatment ResponseDefinitions of on-Treatment Response
* RVR = rapid virological response* RVR = rapid virological response** EVR = early virological response** EVR = early virological response
Marcellin et al. AASLD 2007 Marcellin et al. AASLD 2007
Asselah T et al. Liver International 2009Asselah T et al. Liver International 2009
Asselah T et al. GUT 2009Asselah T et al. GUT 2009
InterferonInterferonStimulatedStimulated
GenesGenes
PEG-IFN-a + RibavirinPEG-IFN-a + Ribavirin
TimeTime
NRNR
SVRSVR
IFI6IFI6IFI27IFI27ISG15ISG15IL8IL8OAS..OAS..
Asselah T et al. GUT 2008Asselah T et al. GUT 2008Feld et al. Hepatology 2007Feld et al. Hepatology 2007Chen et al. Gastroenterology 2005Chen et al. Gastroenterology 2005
Prediction of Non responsePrediction of Non response
• Unmet NeedsUnmet Needs
• Mechanisms of Non Response Mechanisms of Non Response
• Protease InhibitorsProtease Inhibitors
• Polymerase InhibitorsPolymerase Inhibitors
• ConclusionConclusion
Protease and Polymerase Inhibitors for the Treatment of HepatitisC
Asselah T et al. Liver International 2009Asselah T et al. Liver International 2009
Enzyme InhibitorsEnzyme Inhibitors
Protease InhibitorsProtease InhibitorsTelaprevir (Vertex-Tibotec)Telaprevir (Vertex-Tibotec)
Boceprevir (Schering Plough)Boceprevir (Schering Plough)
BI 201335 (Bohringer)BI 201335 (Bohringer)
ITMN-19ITMN-191 (Intermune)1 (Intermune)
Polymerase InhibitorsPolymerase InhibitorsR7128R7128 (Pharmasset-Roche) (Pharmasset-Roche)
-6-6
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414
Duration of treatment (days)Duration of treatment (days)
Red
uct
ion
of
vira
l lo
adR
edu
ctio
n o
f vi
ral
load
(Lo
g 1
0 IU
/mL
)(L
og
10
IU/m
L)
VX-950 + PEG-IFNVX-950 + PEG-IFN
VX-950VX-950
Peg-IFN + placeboPeg-IFN + placebo
Telaprevir (Vertex-Tibotec)
Reesink et al. Gastroenterology 2006
Telaprevir : Prove 2Telaprevir : Prove 2
Zeuzem et al. AASLD 2008 – A243Zeuzem et al. AASLD 2008 – A243
PR48PR48(n = 82)(n = 82)
T12/PR24T12/PR24(n = 81)(n = 81)
T12/PR12T12/PR12(n = 82)(n = 82)
T12/P12T12/P12(n = 78)(n = 78)
PEG-IFNPEG-IFNαα-2a-2aRBVRBV
TVRTVRPEG-IFNPEG-IFNαα-2a -2a
RBVRBV
TVRTVRPEG-IFNPEG-IFNαα-2a-2a
Placebo + PEG-IFNPlacebo + PEG-IFNαα-2a + RBV-2a + RBV
727248482424121200
TVRTVRPEG-IFNPEG-IFNαα-2a -2a
RBVRBV
SVR SVR
00
2020
4040
6060
8080
PR48PR48 T12/PR24T12/PR24 T12/PR12T12/PR12 T12/P12T12/P12(no RBV)(no RBV)
4646
%%
69696060
3636
38/8238/82 56/8156/81 49/8249/82 28/7828/78
NS*NS*
p = 0.004*p = 0.004* p = 0.12*p = 0.12*
* vs PR48* vs PR48
Relapse (%)Relapse (%)
00
1010
2020
3030
5050
PR48PR48 T12/PR24T12/PR24 T12/PR12T12/PR12 T12/P12T12/P12(no RBV)(no RBV)
2222
%%
1414
3030
4848
10/4510/45 8/578/57 19/6319/63 22/4622/46
4040
Telaprevir : Prove 2Telaprevir : Prove 2
Telaprevir : Side Effects
• Rash Rash (( 10 % discontinuation for severe rash) 10 % discontinuation for severe rash)
• Pruritus Pruritus
• AnaemiaAnaemia
• Nausea, Diarrhoea
• HeadachesHeadaches
• FatigueFatigue
Kwo et al. AASLD 2008 –A LB16
Lead-in
No Lead-in
Low dose RBV
SOC
n = 103
n = 107
n = 104
P + R
P + R
P + R + B
P + R + B
FU 44 w.
FU 24 w.
P + R + B
P + R + B
FU 44 w.
FU 24 w.
P + R (LD) + B FU 24 w.
P + R (SOC) FU 24 w.
n = 103
n = 103
Boceprevir : Sprint 1
7248284 weeks0
Boceprevir : Sprint 1
Virological Response 12 to 24 weeksafter end of treatment (ITT)
100
80
60
40
20
0
% p
atie
nts
wit
h H
CV
RN
A u
nd
etec
tab
le
38
55 5666
74
n = 104 n = 107 n = 103 n = 103 n = 103
P/R 48 w
(n = 104)
P/R/B 28 w
(n = 107)
P/R/ 4 w → P/R/B 24 w(n = 103)
P/R/B 48 w
(n = 103)
P/R 4 w → P/R/B 44 w(n = 103)
Kwo et al. AASLD 2008 –A LB16
• Fatigue,
• Nausea,
• Headache
• Dysgeusia
• Anaemia (45 % receiving erythropoietin)
Boceprevir : Side Effetcs
BI 201335 (Bohringer)
Manns et al. AASLD 2008 –A 1849
20 mg /j 48 mg /j120 mg /j240 mg /jPlacebo
BI 201335
Days
-5
-4
-3
-2
-1
0
1
10 2 3 4 6 10 14 21 28
HC
V R
NA
L
og
10 U
I/m
l
BI 201335 or placebo BI 201335 + PEG-IFNα-2a + RBV
Manns et al. AASLD 2008 –A 1849
BI 201335
1
102
104
105
106
107
103
108
10 2 3 4 6 10 14 21 28
25 Limit of detection
PEG-IFNα + RBV treatment-experienced
patients with Genotype 1
Forestier et al. AASLD 2008 –A1847
ITMN-191 (Intermune)
Placebo
100 mg/12h
100 mg/8h
200 mg/12h200 mg/8h
300 mg/12h (NR)
7
HC
V R
NA
log
10 (
UI/m
l)
5
4
3
20 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Jours
6
(NR) : non-responders to PEG-IFNα + RBV
Lalezari et al. EASL 2008. Pharmasset. Press Release Sept 2008 Lalezari et al. EASL 2008. Pharmasset. Press Release Sept 2008
HCV GT 1 Naifs , RVRHCV GT 1 Naifs , RVR
R7128 (Pharmasset-Roche)
10%10%
20%
30%
88%
10%
45%
75%
85%
0%
20%
40%
60%
80%
100%
1 2 3 4
Weeks of Treatment
HC
V R
NA
<1
5 U
I/m
L
PR PR+R 500mg/12h PR+R 1000mg/12h PR+R 1500mg/12h
R7128
Gane EJ et al. AASLD 2008 –A LB10
-6
-4
-5
-2
0
M
ean
HC
V R
NA
-3
-1
0 1 2 3 4Weeks
SOC
1 500 mg 2x/j + SOC
G 2 & 3 NR or Relapsers
HCV resistance
NS4BNS4B NS5ANS5A4A4ACC E2E2 p7p7 NS2NS2 NS3NS3 NS5BNS5B
RNA-dependent RNA polymerase
NS3 protease
Serine protease domain
NS2–NS3 proteinase
Core Envelope
T54
R155
A156
D168
V36
S96
N142
S282
C316
M414
M419
P495
T423
Valopicitabine
R1479(R1626)
Nonnucleosides
VX-950; BILN 2061
BILN 2061
Sarrazin et al. Gastroenterology. 2007.Tong et al. Antiviral Res. 2006. De Francesco and Migliaccio. Nature. 2005.Le Pogam et al. Virology. 2006.Villano et al. Hepatology. 2006.
VX-950; BILN 2061; SCH 503034
VX-950; SCH 503034
HCV-796
VX-950
E1E1
Combination of Enzyme Inhibitors Combination of Enzyme Inhibitors in the Replicon Systemin the Replicon System
Protease Inhibitors Polymerase Inhibitors Replicon System
SCH 503034 HCV -796
Increase Anti-viral
Decrease Resistance
SCH 503034 NM 107
Increase Anti-viral
Decrease Resistance
VX-950 R1479
Increase Anti-viral
Decrease Resistance
++
++
++
EASL 2007- Howe AY - Kenilworth, USA, Abstract 432EASL 2007- Howe AY - Kenilworth, USA, Abstract 432EASL 2007- Ralston R - Kenilworth, USA, Abstract 793EASL 2007- Ralston R - Kenilworth, USA, Abstract 793EASL 2007- McCown M – Palo Alto, USA, Abstract 790EASL 2007- McCown M – Palo Alto, USA, Abstract 790
Potential Antiviral Targets and Approaches
Antiviral Targets
Enzymes
Potential use in Combination
Polymerase
Inhibitors
Protease
Inhibitors
Immune System
PEG-IFN Ribavirine
• Increase SVR from 50 to Increase SVR from 50 to 70 % 70 %
• Shorten the Duration of Treatment Shorten the Duration of Treatment
• New Definitions of ResponseNew Definitions of Response
• Resistance occurs RapidlyResistance occurs Rapidly
• Toxicity ConcernToxicity Concern
ConclusionConclusionEnzyme Inhibitor + SOC Enzyme Inhibitor + SOC (PEG-IFN + RBV)(PEG-IFN + RBV)
in Genotype 1 Naïve Patientsin Genotype 1 Naïve Patients
• Increase SVRIncrease SVR
• Decrease Treatment DurationDecrease Treatment Duration
• Side EffectsSide Effects
• Minimize Resistance Minimize Resistance
• Avoid Ribavirin, avoid PEG-IFN, When ?Avoid Ribavirin, avoid PEG-IFN, When ?
• Studies in other Populations : NR, other Studies in other Populations : NR, other
Genotypes, HIV-HCV Coinfected patients, Genotypes, HIV-HCV Coinfected patients,
Liver Transplant patients…Liver Transplant patients…
PerspectivesCombination of Enzyme InhibitorsCombination of Enzyme Inhibitors