Pawlotsky Hcv RéSistance
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HHéépatite patite C: RC: Réésistancesistanceaux aux TraitementsTraitements
Prof. JeanProf. Jean --Michel PawlotskyMichel Pawlotsky
CNR des CNR des HHéépatites patites B, C et deltaB, C et deltaLaboratoire Laboratoire de de Virologie Virologie & INSERM U635& INSERM U635
HHôpital ôpital Henri Henri MondorMondorUniversitUniversit éé Paris XIIParis XII
CrCrééteilteil
HCV Resistance
• HCV resistance to IFN -αααα therapy
• HCV resistance to ribavirin ?
• HCV resistance to specific antiviral molecules
I
HCV resistance to IFN-α α α α Therapy
Incidence of Peg -IFNαααα-RibavirinTreatment Failures
2%2%
00
1515
3030
4545
6060 54%54%48%48%
58%58%
24%24%
16%16% 18%18%
Genotype Genotype 1 1 Genotypes Genotypes 2/32/3
PEGPEG--IFNIFN--αα2a+2a+ribavirin ribavirin ((Fried Fried et al)et al)
PEGPEG--IFNIFN--αα2a+2a+ribavirin ribavirin ((Hadziyannis Hadziyannis et al)et al)
PEGPEG--IFNIFN--αα2b+2b+ribavirin ribavirin ((Manns Manns et al)et al)
((Manns Manns et al, et al, Lancet Lancet 2001 ; 2001 ; Fried Fried et al, N et al, N Engl Engl J J Med Med 2002 ; 2002 ; Hadziyannis Hadziyannis et al, et al, Ann Intern Med Ann Intern Med 2004) 2004)
TreatmentTreatmentFailureFailure
TreatmentTreatmentScheduleSchedule
TreatmentTreatmentFailureFailure
HostHostFactorsFactors
TreatmentTreatmentScheduleSchedule
TreatmentTreatmentFailureFailure
DiseaseDiseaseCharacteristicsCharacteristics
HostHostFactorsFactors
TreatmentTreatmentScheduleSchedule
TreatmentTreatmentFailureFailure
Viral FactorsViral FactorsDiseaseDiseaseCharacteristicsCharacteristics
HostHostFactorsFactors
TreatmentTreatmentScheduleSchedule
TreatmentTreatmentFailureFailure
Viral FactorsViral FactorsDiseaseDiseaseCharacteristicsCharacteristics
HostHostFactorsFactors
TreatmentTreatmentScheduleSchedule
TreatmentTreatmentFailureFailure
SNP and SVR in the IDEAL Trial1 3 5 7 9 11 13 15 17 19 21 X M
2 4 6 8 10 12 14 16 18 20 22 Y
-log 1
0(P
)
0.0
15.0
30.0
-log 1
0(P
)
0.0
15.0
30.0
-log 1
0(P
)
0.0
15.0
30.0
Chromosome 19 ideogram
0 M 10 M 20 M 30 M 40 M 50 M 60 M
39,623 K 39,666 K 39,708 K 39,750 K 39,793 K 39,835K
PAK4 SYCN IL28B IL29 LRFN1NCCRP1 AC011445.6IL28A GMFG
IL28B IL28AAC011445.6
39,711 K 39,721 K 39,732 K 39,743 K 39,753 K 39,764K
rs12979860P=1.37×10-28
1 3 5 7 9 11 13 15 17 19 21 X M2 4 6 8 10 12 14 16 18 20 22 Y
-log 1
0(P
)
0.0
15.0
30.0
-log 1
0(P
)
0.0
15.0
30.0
-log 1
0(P
)
0.0
15.0
30.0
Chromosome 19 ideogram
0 M 10 M 20 M 30 M 40 M 50 M 60 M
39,623 K 39,666 K 39,708 K 39,750 K 39,793 K 39,835K
PAK4 SYCN IL28B IL29 LRFN1NCCRP1 AC011445.6IL28A GMFG
IL28B IL28AAC011445.6
39,711 K 39,721 K 39,732 K 39,743 K 39,753 K 39,764K
rs12979860P=1.37×10-28
IL28B
((Ge Ge et al, Nature, 2009;461:399et al, Nature, 2009;461:399 --401)401)
rs12979860 Allele and SVR
((Ge Ge et al, Nature, 2009;461:399et al, Nature, 2009;461:399 --401)401)
rs12979860 Allele Frequency
12%12%
39%39%
49%49%
37%37%
16%16%
47%47%
C/CC/C C/TC/T T/TT/T
CaucasianCaucasianancestryancestry
n=871n=871
African AmericanAfrican Americanancestryancestry
n=191n=191
((Ge Ge et al, Nature, 2009;461:399et al, Nature, 2009;461:399 --401)401)
Geographic Distribution
(Thomas et al, Nature, 2009;461:798(Thomas et al, Nature, 2009;461:798 --801)801)
Effect on HCV Kinetics (Caucasians )
∆∆H
CV
RN
A (
Log
HC
V R
NA
(Lo
g1010
IU/m
L)IU
/mL)
CT
TT-3.0
-2.0
-1.0
0
Weeks
-4.0
-5.0
2 4 120
-6.0 CC
(Thompson et al, AASLD 2009) (Thompson et al, AASLD 2009)
∆∆H
CV
RN
A (
Log
HC
V R
NA
(Lo
g1010
IU/m
L)IU
/mL)
CTTT
-3.0
-2.0
-1.0
0
Weeks
-4.0
-5.0
2 4 120
-6.0
CC
Effect on HCV Kinetics(African Americans )
(Thompson et al, AASLD 2009) (Thompson et al, AASLD 2009)
SVR Predictors
<0.0001<0.00012.22.21.31.31.71.7Fasting blood sugar < 5.6 mmol/LFasting blood sugar < 5.6 mmol/L
<0.0001<0.00014.14.12.32.33.13.1HCV RNA HCV RNA ≤≤ 600,000 IU/mL600,000 IU/mL
<0.0001<0.00014.04.02.02.02.82.8Caucasian Caucasian vs vs African AmericanAfrican American
0.0040.0043.63.61.31.32.12.1Hispanic Hispanic vs vs African AmericanAfrican American
<0.0001<0.00016.76.74.14.15.25.2rs12979860 CC rs12979860 CC vs vs nonnon --CCCC
<0.0001<0.00014.04.01.81.82.72.7METAVIR score METAVIR score ≤≤F2 F2
pp--valuevalue95% CI95% CIOdds RatioOdds Ratio
(Thompson et al, AASLD 2009) (Thompson et al, AASLD 2009)
Summary
• In patients infected with HCV genotype 1, the rs12979860 genotype :
• Is strongly associated with the SVR
• Explains 60% of the ethnic influence on SVR
• Influences HCV kinetics on therapy
• Is probably a marker of patient cell “resistance“to the effect of IFN -αααα through mechanisms that remain to be elucidated
Viral Resistance
• Intrinsic properties of viral strains that counteract the antiviral action of antiviral drugs
Incidence of Peg -IFNαααα-RibavirinTreatment Failures
2%2%
00
1515
3030
4545
6060 54%54%48%48%
58%58%
24%24%
16%16% 18%18%
Genotype Genotype 1 1 Genotypes Genotypes 2/32/3
PEGPEG--IFNIFN--αα2a+2a+ribavirin ribavirin ((Fried Fried et al)et al)
PEGPEG--IFNIFN--αα2a+2a+ribavirin ribavirin ((Hadziyannis Hadziyannis et al)et al)
PEGPEG--IFNIFN--αα2b+2b+ribavirin ribavirin ((Manns Manns et al)et al)
((Manns Manns et al, et al, Lancet Lancet 2001 ; 2001 ; Fried Fried et al, N et al, N Engl Engl J J Med Med 2002 ; 2002 ; Hadziyannis Hadziyannis et al, et al, Ann Intern Med Ann Intern Med 2004) 2004)
HCV Kinetics by GenotypeEC-sponsored DITTO -Trial
(Pawlotsky et al., manuscript in preparation)
00
11
22
33
44
55
66
77 HCV RNA (log IU/ml)HCV RNA (log IU/ml)
00 44 77 88 1515 2222 292911--77--2828
Genotype Genotype 44
GenotypeGenotype 11
GenotypeGenotype 33
** == significant differencesignificant difference , 4, 4 andand 11 vsvs 33
**
**
****
** ****
QuantitativeQuantitative assay cutoffassay cutoff
QualitativeQualitative assay cutoffassay cutoff
HCV Kinetics by GenotypeEC-sponsored DITTO -Trial
00
11
22
33
44
55
66
77 HCV RNA (log IU/ml)HCV RNA (log IU/ml)
00 44 77 88 1515 2222 292911--77--2828
GenotypeGenotype 44
GenotypeGenotype 11
GenotypeGenotype 33
** == significant differencesignificant difference , 4, 4 andand 11 vsvs 33
**
**
****
** ****
QuantitativeQuantitative assay cutoffassay cutoff
QualitativeQualitative assay cutoffassay cutoff
(Pawlotsky et al., manuscript in preparation)
HCV Kinetics by GenotypeEC-sponsored DITTO -Trial
00
11
22
33
44
55
66
77 HCV RNA (log IU/ml)HCV RNA (log IU/ml)
00 44 77 88 1515 2222 292911--77--2828
GenotypeGenotype 44
GenotypeGenotype 11
GenotypeGenotype 33
** == significant differencesignificant difference , 4, 4 andand 11 vsvs 33
**
**
****
** ****
QuantitativeQuantitative assay cutoffassay cutoff
QualitativeQualitative assay cutoffassay cutoff
(Pawlotsky et al., manuscript in preparation)
HCV Kinetics by GenotypeEC-sponsored DITTO -Trial
00
11
22
33
44
55
66
77 HCV RNA (log IU/ml)HCV RNA (log IU/ml)
00 44 77 88 1515 2222 292911--77--2828
Genotype Genotype 44
GenotypeGenotype 11
GenotypeGenotype 33
** == significant differencesignificant difference , 4, 4 andand 11 vsvs 33
**
**
****
** ****
QuantitativeQuantitative assay cutoffassay cutoff
QualitativeQualitative assay cutoffassay cutoff
(Pawlotsky et al., manuscript in preparation)
Viral FactorsViral Factors
AntiviralAntiviralrresistanceesistance
DelayedDelayedclearanceclearance
LongerLongerhalfhalf --life oflife of
infected cellsinfected cells
Summary
• HCV resistance to IFN -αααα antiviral effect exists
• Its molecular mechanisms are unknown and probably complex
• It accounts for only a small part of IFN -αααα-based treatment failures
II
HCV Resistance to Ribavirin ?
• Direct inhibition of HCV RNA -dependent RNA polymerase ?
• Depletion of intracellular GTP pools via IMPDH inhibition ?
• RNA mutagenesis leading to "error catastrophe" ?
• Enhancement of IFN -induced responses in the liver ?
Ribavirin ’s Antiviral Mechanisms
Ribavirin ’s Antiviral Effect
(Pawlotsky et al., Gastroenterology 2004;126:703-14 )
--1.01.0
--0.50.5
0.00.0
0.50.5
00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626 2828
Mean HCV RNA decrease (log IU/ml)Mean HCV RNA decrease (log IU/ml)
Time (days)Time (days)
ControlsControls
RibavirinRibavirinmonotherapymonotherapy
--1.51.5
--1.01.0
--0.50.5
0.00.0
+0.5+0.5
00 22 44 66 88 1010 1212 1414
DaysDays
HCV RNA changes (log IU/ml)HCV RNA changes (log IU/ml)
--1.51.5
--1.01.0
--0.50.5
0.00.0
+0.5+0.5
00 22 44 66 88 1010 1212 1414
DaysDays
HCV RNA changes (log IU/ml)HCV RNA changes (log IU/ml)
--1.51.5
--1.01.0
--0.50.5
0.00.0
+0.5+0.5
00 22 44 66 88 1010 1212 1414
DaysDays
HCV RNA changes (log IU/ml)HCV RNA changes (log IU/ml)
--1.51.5
--1.01.0
--0.50.5
0.00.0
+0.5+0.5
00 22 44 66 88 1010 1212 1414
DaysDays
HCV RNA changes (log IU/ml)HCV RNA changes (log IU/ml)
(Pawlotsky et al., Gastroenterology 2004;126:703-14 )
Ribavirin ’s Antiviral Effect
Summary
• Ribavirin mechanisms of action in chronic hepatitis C remain unknown
• Ribavirin direct antiviral effect is modest and transient
• Long -term ribavirin administration does not select for specific resistance substitutions
III
HCV Resistance to Specific Inhibitors
HCV ResistanceHCV Resistance
• Definition� Selection of viral variants bearing amino acid
substitutions that alter the drug target and thereby confer reduced susceptibility to the drug
• Resistant variants are pre-existing at baseline as minor viral populations� All single mutants� ~10% of double mutants
(Pawlotsky JM, (Pawlotsky JM, Ther Ther Adv Adv Gastroenterol Gastroenterol 2009;2:2052009;2:205 --219; 219; Perelson Perelson AS, unpublished data) AS, unpublished data)
sensitivesensitive
resistantresistant
Mechanisms of Resistance
sensitivesensitive
resistantresistant
DrugDrug
Mechanisms of Resistance
sensitivesensitive
resistantresistant
DrugDrug
resistantresistant
Mechanisms of Resistance
sensitivesensitive
sensitivesensitive
resistantresistant
DrugDrug Stop drugStop drug
resistantresistant
Mechanisms of Resistance
sensitivesensitive
sensitivesensitive
resistantresistant
sensitivesensitive
resistantresistant
DrugDrug Stop drugStop drug
resistantresistant
Mechanisms of Resistance
sensitivesensitive
sensitivesensitive
resistantresistant
sensitivesensitive
resistant + fitresistant + fit
DrugDrug Stop drugStop drug
resistantresistant
Mechanisms of Resistance
sensitivesensitive
sensitivesensitive
resistantresistant
DrugDrug Stop drugStop drug
resistantresistant
Mechanisms of Resistance
sensitivesensitive
resistant + very fitresistant + very fit
sensitivesensitive
DAA Drugs Targets
Virion assembly
RNA replication
(+) RNA
Fusion and uncoating
Translation and polyprotein processing
Transport and
release
Receptor binding and endocytosis
Viral entry inhibitorsViral entry inhibitorsHepatitis C immunoglobulin Hepatitis C immunoglobulin HCIgHCIg))HCVHCV--Ab 68 and Ab 65 (monoclonal Ab)Ab 68 and Ab 65 (monoclonal Ab)
HCV RNA translation inhibitorsHCV RNA translation inhibitorsISIS 14803 (antisense) ISIS 14803 (antisense) AVI AVI –– 4065 (antisense) 4065 (antisense) Heptazyme (ribozyme)Heptazyme (ribozyme)VGXVGX--410C (small molecule IRES inhibitor)410C (small molecule IRES inhibitor)TT 033 (TT 033 (siRNAsiRNA ) )
Posttranslational processing inhibitorsPosttranslational processing inhibitorsNS3NS3--4A serine proteinase inhibitors4A serine proteinase inhibitors
BILN 2061BILN 2061ITMN 191ITMN 191VXVX--950 950 SCH 503034SCH 503034ACHACH--806/GS806/GS--91329132
HCV replication inhibitorsHCV replication inhibitorsNS5B polymerase inhibitorsNS5B polymerase inhibitors
MKMK--06080608HCVHCV--796796R1626R1626JTKJTK--003003NMNM--283283XTL 2125XTL 2125
Cyclophilin B inhibitorsCyclophilin B inhibitorsDEBIODEBIO--025025NIM 811NIM 811
NS5A inhibitorsNS5A inhibitorsAA--831, A831, A--689689
Helicase inhibitorsHelicase inhibitorsQU663 QU663 RRecombinant Ab fragmentsecombinant Ab fragments
Virus assembly and release inhibitorsVirus assembly and release inhibitorsUTUT--231B (231B (iminosugariminosugar --glucosidase glucosidase inhibitor)inhibitor)Celgosivir (glucosidase inhibitor) Celgosivir (glucosidase inhibitor)
Phase of DevelopmentPhase of Development
**
**
****
PreclinicalPreclinical II IIII IIIIII IVIV
**
**
**
HCV DAA Drug Development
(Pawlotsky JM, Chevaliez S, McHutchison JG, Gastroe nterology 2007;132:1979-98)
IRES
RNA-Dependent RNA Polymerase
NS3 Protease
Targets for New HCV Inhibitors
Resistance to NS3/4A Protease Inhibitors
Antiviral Efficacy of NS3/4A Protease Inhibitors
-3.33 days300 mg bidIBMS-650032
II
II
II
II
II
III
III
Phase
-4.27 days400 mg bidNarlaprevir
-4.78 days
-4.014 days240 mg qdBI201335
700 mg bidMK-7009
-3.814 days200 mg q8hITMN-191/R7227
-4.17 days200 mg qdTMC435
-1.67 days400 mg tidBoceprevir
-4.4 14 days750 mg q8hTelaprevir
Median/mean logHCV RNA reduction
DurationDoseDrug
MacrocyclicMacrocyclic LinearLinear
BILN 2061BILN 2061((CiluprevirCiluprevir ))
R7227 R7227 (ITMN(ITMN--191)191)
VXVX--950950(Telaprevir)(Telaprevir)
SCH503034SCH503034(Boceprevir)(Boceprevir)
A156V/TA156V/T, , D168A/VD168A/V, ,
R155QR155Q
A156S/V,A156S/V,D168AD168A, Q41R, , Q41R, F43S, S138T, F43S, S138T,
S489LS489L
A156S/T/VA156S/T/V A156S/TA156S/T, , T54A, V170AT54A, V170A
No dataNo data No dataNo dataA156S/T/VA156S/T/V, , R155K/TR155K/T, ,
T54A, V36A/MT54A, V36A/M
V36M/A, V36M/A, T54A/S, T54A/S, R155KR155K
In v
itro
In v
itro
In v
ivo
In v
ivo
((Kwong Kwong et al., et al., Curr Opin PharmacolCurr Opin Pharmacol , 2008;8:522, 2008;8:522 --531; 531; Susser Susser et al., J et al., J Hepatol Hepatol 2009;50(2009;50(SupplSuppl .1):S7) .1):S7)
Amino Acid Substitutions Associated with ResistanceAmino Acid Substitutions
Associated with Resistance
Asp168
Ala156
Arg155
Thr54
Val36
(Pawlotsky J(Pawlotsky J --M, M, Ther Ther Adv Adv Gastroenterol Gastroenterol 2009;2: 2052009;2: 205 --219) 219)
Amino Acid Substitutions Associated with ResistanceAmino Acid Substitutions
Associated with Resistance
Telaprevir (Vertex & Tibotec )
Paramètres Associésà la Résistance
• Niveau de résistance au m édicament conféré par la ou les substitutions amino acidiques
• In vivo “fitness “ des variants viraux sélectionn és
PROVE 2 Trial (Phase II)Naïve, Genotype 1, Europe
����Weeks on therapy480 2412
Placebo + Peg-IFN αααα2a + Ribavirin (RBV)
Telaprevir 750 mg q8h + Peg-IFNαααα2a
+ RBV
Telaprevir 750 mg q8h + Peg-IFNαααα2a
Telaprevir 750 mg q8h + Peg-IFNαααα2a
+ RBV
Peg-IFNαααα2a + RBV FollowFollow --upup
FollowFollow --upup
FollowFollow --upup
PR48
T12/PR24
T12/PR12
T12/P12
FollowFollow --upup
72
((HHéézode zode et al., N et al., N Engl Engl J Med 2009;360:1839J Med 2009;360:1839 --50)50)
00
2020
4040
6060
8080
100100
1212 --
wee
k S
VR
rat
es (
%)
wee
k S
VR
rat
es (
%)
T12/P12 (no RBV)T12/P12 (no RBV)
3%3%
24%24%
T12/PR12T12/PR12+ T12/PR24+ T12/PR24
PROVE 2 Trial (Phase II)Breakthoughs through week 12
((HHéézode zode et al., N et al., N Engl Engl J Med 2009;360:1839J Med 2009;360:1839 --50)50)
00
2020
4040
6060
8080
100100
SV
R r
ates
(%
)S
VR
rat
es (
%)
T12/P12 (no RBV)T12/P12 (no RBV)((n=78n=78))
48%48%
T12/PR12T12/PR12((n=82n=82))
30%30%
T12/PR24T12/PR24((n=81n=81))
14%14%22%22%
PR48PR48((n=82n=82))
PROVE 2 Trial (Phase II)Relapses after treatment
((HHéézode zode et al., N et al., N Engl Engl J Med 2009;360:1839J Med 2009;360:1839 --50)50)
Boceprevir Boceprevir ((SP/MerckSP/Merck ))
Patterns of Responseto Boceprevir
Patterns of ResponsePatterns of Responseto to BoceprevirBoceprevir
((Susser Susser et al., et al., Hepatology Hepatology 2009;50:17092009;50:1709 --18) 18)
N=22 non-responders to previous standard treatment who were dosed for 14 days with BOC (Phase 1b)
In vitro Resistance toBoceprevir (replicon )IIn vitron vitro Resistance toResistance toBoceprevir Boceprevir ((repliconreplicon ))
((Susser Susser et al., et al., Hepatology Hepatology 2009;50:17092009;50:1709 --18) 18)
Relative in vivo Fitness of Boceprevir -Resistant Variants
Relative Relative in vivoin vivo Fitness of Fitness of BoceprevirBoceprevir --Resistant Resistant VariantsVariants
((Susser Susser et al., et al., Hepatology Hepatology 2009;50:17092009;50:1709 --18) 18)
Dynamics of NS3Protease VariantsDynamics of NS3Dynamics of NS3Protease VariantsProtease Variants
((Susser Susser et al., et al., Hepatology Hepatology 2009;50:17092009;50:1709 --18) 18)
SummarySummarySummary
•• During During telaprevir telaprevir or or boceprevir monotherapyboceprevir monotherapy , pre, pre --existing resistant HCV variants are rapidly selecte d in existing resistant HCV variants are rapidly selecte d in virtually all treated patientsvirtually all treated patients
•• Both single mutants (36, 54, 155 and 156) and doubl e Both single mutants (36, 54, 155 and 156) and doubl e mutants (36/155, 26/156) can be selectedmutants (36/155, 26/156) can be selected
•• The corresponding viral variants generally have The corresponding viral variants generally have reduced fitness compared to wildreduced fitness compared to wild --type HCVtype HCV
•• Most of these amino acid substitutions confer crossMost of these amino acid substitutions confer cross --resistance to all of the NS3/4A protease inhibitors in resistance to all of the NS3/4A protease inhibitors in developmentdevelopment
Summary (cont’d)Summary (cont’d)
•• Failure of the triple combination of Failure of the triple combination of pegylated pegylated IFNIFN--αααααααα, , ribavirin ribavirin and and telaprevir telaprevir to clear HCV is associated with to clear HCV is associated with the selection of the selection of telaprevirtelaprevir --resistant resistant variantsvariants
•• These variants may persist after therapy or be These variants may persist after therapy or be progressively replaced by wildprogressively replaced by wild --type virustype virus
•• Telaprevir Telaprevir resistant variants remain sensitive to resistant variants remain sensitive to pegylated pegylated interferon and interferon and ribavirin ribavirin
Resistance to Inhibitors of HCV Replication
Inhibitors of HCV Replication
• RNA-dependent RNA polymerase (RdRp ) inhibitors
• Nucleoside analogues• Non-nucleoside inhibitors (NNIs)
• NS5A inhibitors
• Cyclophilin inhibitors
• miR122 antagonists
In vitro Resistance
Copyright © 2006 Merck & Co., Inc., Whitehouse Stati on, New Jersey, USA All rights reserved
22’’--methyl nucleosidesmethyl nucleosidesSer Ser 282282
44’’ azidoazido--cytidinecytidineSer Ser 9696
2’C-Me-ATP in the catalytic site
(Migliaccio et al., J Biol Chem 2003;278:49164-70)
HCV Resistance to 2 ’-C-Methyl Nucleoside Inhibitors
7-Deaza-2’-C-Methyl-Adenosine (MK-0608) in Chimpanzees
7-Deaza-2’-C-Methyl-Adenosine (MK-0608) in Chimpanzees
0
1
2
3
4
5
6
7
-15 -10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70
Days
HC
V R
NA
(Lo
g IU
/mL)
TMA + + + + - - - - - - - - + +
LOQ (20 IU/mL)
MK-0608 at 1mg.kg -1 orally
- 4,6 - 4,1
wt S282R/T/I wt S282
(Carroll et al., (Carroll et al., Antimicrob Antimicrob Agents Agents Chemother Chemother 2009;53:9262009;53:926 --934) 934)
((Afdhal Afdhal et al, EASL 2006)et al, EASL 2006)
Valopicitabine (NM283)Phase IIb , IFN Nonresponders
Weeks
Week 24 n=7
-0.27
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 4 8 12 16 20 24 28 32 36 40 44 48
NM283 800 mg monotherapy
HC
V R
NA
red
uctio
n
Antiviral Efficacy of NNIs
-1.52 days600 mg bidIIABT-333
-3.73 days750 mg bidIbVX-222
-1.710 days400 mg tidIIVCH-759
Ib
II
II
II
II
Phase
-1.3 (1a), -3.8 (1b)7 days800 mg bidMK-3281
-3.13 days800 mg q8hBI207127
-2.93 days800 mg bidANA598
-2.18 days300 mg bidFilibuvir
-1.4 8 days40 mg bidGS-9190
Median/mean logHCV RNA reduction
DurationDoseDrug
In vitro Resistance
Copyright © 2006 Merck & Co., Inc., Whitehouse Stati on, New Jersey, USA All rights reserved
AA
NNI site ANNI site AIndolesIndoles, , BenzimidazolesBenzimidazoles
Pro 495, Pro 496, Val 499Pro 495, Pro 496, Val 499
NNI site BNNI site BThiopheneThiophene--COOHCOOH
Met 423Met 423
BB
NNI site CNNI site CBenzothiadiazineBenzothiadiazine
Asn Asn 411, Met 414, 411, Met 414, Tyr Tyr 448448
Allosteric Allosteric GTPGTP
CC
NNI site DNNI site DBenzofuransBenzofurans
Cys Cys 316, Val 201316, Val 201
AA
BBCC
DD
EE
NNI siteNNI site E (hypothetical)E (hypothetical)Cys Cys 445, 445, Tyr Tyr 448, 448, Tyr Tyr 452452
HCV 796 (ViroPharma & Wyeth )Antiviral efficacy
(Chandra et al, DDW 2006)(Chandra et al, DDW 2006)
--11 22 55 88 1111 1144 1177 2200 2233 2266 2299--33
--22
--11
00
11
PPllaacceebboo5500 mmgg110000 mmgg225500 mmgg550000 mmgg11000000 mmgg11550000 mmgg
SSttuuddyy DDaayy
Log
HC
V R
NA
cha
nge
Log
HC
V R
NA
cha
nge
TreatmentTreatment FollowFollow --upup
Prevention of Resistance
Prevention of Resistance to HCV Inhibitors
• Exclude use as a monotherapy
• Combine with one or several other antivirals with :
• At least additive antiviral effect• No cross-resistance
R7128/R7227 CombinationINFORM Trial
Day0 2 4 6 8 10 12 14
-7
-6
-5
-3
-2
-1
0
1
Mea
n lo
g10
HC
V R
NA
cha
nge
from
-4
Placebo
R7128 500b D1-7/R7227 100t D4-7-Na
R7227 100t D1-7/R7128 500b D4-7-Na
500b/200t 1000b/200t
500b/100t
1000b/100t
(Gane et al., EASL 2009)
R7128/R7227 CombinationINFORM Trial
Day0 2 4 6 8 10 12 14
-7
-6
-5
-3
-2
-1
0
1
Mea
n lo
g10
HC
V R
NA
cha
nge
from
-4
Placebo
1000b/900b-TE
1000b/600b-TE
(Gane et al., AASLD 2009)
1000b/900b-Na
Cure with IFN -Free Regimens ?
Combination of MK -7009 andMK-608 (Merck ) in vitro
Synergy in the genotype 1bSynergy in the genotype 1breplicon replicon at low MKat low MK --0608,0608,
high MKhigh MK --7009 doses7009 doses
--55
00
55
1010
0.020.020.150.15
1.201.201212
0.30.3
MKMK--608 608 pol pol inhibitor (inhibitor ( mMmM))
MKMK--7009 NS3 7009 NS3 inhibitor (inhibitor ( nMnM))
55--1010
00--55
--55--00
(Olsen et al., APASL 2008)(Olsen et al., APASL 2008)
MK 7009monotherapy
0
1
2
3
4
5
6
0 50 90 130 170 210 250
Day
log
IU/m
L
LOQLOQ
Combination of MK -7009 andMK-608 (Merck ) in vivo
MK 7009+ MK-608 Chimp AChimp A
Chimp BChimp B
Chimp CChimp C
SVR
(Olsen et al., APASL 2008)(Olsen et al., APASL 2008)