Assessing the Evolving Evidence g gof HCV Treatment Options
Paul Y. Kwo, MDAssociate Professor of Medicine
Medical Director, Liver TransplantationGastroenterology/Hepatology DivisionIndiana University School of MedicineIndiana University School of Medicine
Indianapolis, IN
Faculty Disclosure
• The faculty reported the following financial relationships or y grelationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: – Paul Y. Kwo, MD
• Consulting Fees: Abbott; Anadys; BMS; Gilead; Merck; Novartis; RocheNovartis; Roche
• Fees for Non-CME Services Received Directly from a Commercial Interest or their Agents: BMS; Gilead; Merck; Roche
• Contracted Research: Abbott; Anadys; BMS; Conatus; Gilead; Merck; Roche; Vertex
Objective
• Review the evolving evidence on current and gemerging treatment options for HCV including efficacy, safety, and therapeutic options
Current Status of Response-guided Therapy: 2011Therapy: 2011
Genotype 2 or 3 infection RVR
Genotype 1 with RVR Low viral loadLow viral load
Genotype 1 withGenotype 1 with Late virologic response (week 12 to 24)
72 2412-16
Treatment Duration (Weeks)
Baseline
Mangia A, et al. N Engl J Med. 2005;253:2609-2617.Zeuzem S, et al. J Hepatol. 2006;44:97-103.Berg T, et al. Gastroenterology. 2006;130:1086-1097.
RVR=rapid virological response.
Current Standard of Care for Patients With HCV Genotype 1With HCV Genotype 1
Rates of SVR are not significantly different between the two available G f G f 2
P=.20
P=.57
PEG IFN–RBV regimens or between doses of PEG IFN alfa-2b
McHutchison JG, et al. N Engl J Med. 2009;361:580-593.
SVR=sustained virologic response.HCV RNA=hepatitis C virus-ribonucleic acid.
PEG-IFN=pegylated interferon.RBV=ribavirin.
Multiple Host Factors Are Predictive of Response to TreatmentResponse to Treatment
ImmuneAge Ethnicity Genomics ImmuneStatusAge
Gender
AdherenceInsulin ResistanceHepatic
SteatosisSeverity of
Liver Disease ResistanceSteatosisLiver Disease
Pharmacogenomics Hold Promise for Predicting Responders to HCV TreatmentPredicting Responders to HCV Treatment
“-Omics” Technologies
Responder Adverse Event Non-responder
Allows for rationale selection of patients for different treatment strategies
Recent Evidence Suggest a Polymorphism on Chromosome 19 Predicts SVRon Chromosome 19 Predicts SVR
13 3p13.3
p13.2
p13.1
60 M
b
IL28B gene; IFN Lambda-3 genep12
p12
3 kb19q13.13
p12
p13.1
p13.2
Polymorphism rs12979860p13.3
p13.4
Chromosome 19Ge D, et al. Nature. 2009;461:399-401.
Chromosome 19 graphic courtesy of Oak Ridge National Laboratory. http://www.ornl.gov/sci/techresources/meetings/ecr2/olsen.gif. Accessed on: October 21, 2009.
SVR=sustained virologic response.
C Allele Is Associated With Sustained Virologic ResponseVirologic Response
100(%)
807060
90
Res
pons
e (
P=1.06x10-25 P=1.37x10-28P=4.39x10-3P=2.06x10-3
60504030
d Vi
rolo
gica
l
20100Su
stai
ned
T/T T/C C/C T/T T/C C/C T/T T/C C/C T/T T/C C/C
N=102 N=336 N=70
N=30
N=14
N=35
N=26 N=186
N=559
N=392
N=433
N=91
Caucasians AfricanAmericans Hispanics Combined
12979860
Ge D, et al. Nature. 2009;461:399-401.
Sustained Virological Response (SVR, %)Non-SVR (%)
rs12979860
Treatment-associated Decline in HCV Is Influenced by the IL28B SNP Genotype Present
Caucasian Patients Infected With HCV-2 or -3
Influenced by the IL28B SNP Genotype Present
0) 0
-1
(Log
UI/m
l)
-2
3A D
eclin
e (
rs12979860 genotype:
-3
-4
n H
CV
RN
A
CC (N=37)
-50 7 14 21 28
Mea
n
CT (N=21)TT (N=4)
Days on Peg-IFN and RBV Therapy
Neumann AU, et al for the DITTO-HCV group. Presented at the 45th Annual Meeting of the European Association for the Study of the Liver. Vienna, Austria. April 14-18, 2010.
SNP=single nucleotide polymorphism. HCV gen 2-3=hepatitis C virus genotype 1 or 2. Peg-IFN=pegylated interferon.
Days on Peg IFN and RBV Therapy
Factors That Predict SVR in Patients With HCV Genotype 1With HCV Genotype 1
Odds Ratio IC 95 % P
G t CC IL28B CC 5 2 4 1 6 7 0001Genotype CC IL28B vs non-CC 5.2 4.1 6.7
CC IL28 Genotype Predicts SVR in Non-RVR CC Genotype HCV PatientsNon-RVR CC Genotype HCV Patients
RVR=14% Non-RVR=86%
CC vs non CCP>.25 CC vs non-CCP
Pretreatment Serum Levels of IP-10 Improves Predictive Value for SVR of IL28B PolymorphismPredictive Value for SVR of IL28B Polymorphism
• Data from the VIRA-HEP C cohortD t i ti f IP 10 l l ( 272) d IL28B ( 210)• Determination of IP-10 level (n=272) and IL28B (n=210)
RSV
R
Combination of IP-10 and IL28B genotypes improve predictive value for SVR particularly in patients with CT/TT genotypes
Darling JM, et al. Hepatology. 2011;53:14-22.
SVR=sustained virologic response.IP-10=inducible protein 10.
The HCV Treatment Landscape Continues to EvolveContinues to Evolve
PreclinicalNucleoside
DAA combinations
Phase I
Phase II
Polymerase inhibitors
OthersNitazoxanide
Vertex
BMS/Pharmasset
Roche
Gilead
Japan Tobacco
BI
R0622 (Roche)
Medivir (Tibotec)
GL59393 (GSK)
Phase III
Filed
Nitazoxanide(Romark)
INF lambada (Zymogen / NovoNordisk
DEB025 cyclophilins
Taribavirin(Valeant)
IDX-184 (Idenix)
R7128 (Roche/Pharmasset)
PSI-7977 (Pharmasset)
( )
PSI938(Pharmasset)
Biocryst
INX189 (Inhibitex)
MSD
Idenix
AZD07259 NSSA (AZN)
BMS790052 NSSA (BMS)
PresidioGSK
Boceprevir (MSD)
TMC435
Telaprevir (J&J/Vertex)
GS9190 (Gilead)
ANA598 (Anadys) IDX375
(Idenix/NVS)
ABT33. ABT7072 (ABT)
BMS-791325 (nuc/non-nuc BMS))
ABT450
Non Nucleoside-Polymerase
inhibitors
NS5A inhibitor
BMS824393 NSSA (BMS)
Enanta
Vertex
(J&J/Tobizer)
GS9256 (Gilead)
MK5172 (MSD)
MK7009 (MSD)
BMS650032 (BMS)
BI201335 (BI)
ACH1625
ITMN-191/R7227 (Roche/Intermune)
VX222 (Vertex)
BI201127 (BI)
(Idenix/NVS)
ABT450 (ABT)
Proteaseinhibitors
(Achillion)
ADVANCE: a Phase III Study of Telaprevir in Combination With Peg-interferon and RibavirinCombination With Peg interferon and Ribavirin
• Efficacy and safety of telaprevir + PEG IFN alfa-2a and RBV vs standard care• Primary endpoint: Proportion of patients with SVR 24 weeks after last dose
T12PR TVR + PR
eRVR +Follow-up
SVR
PR
72 weeks
Follow-up
Primary endpoint: Proportion of patients with SVR 24 weeks after last dose
n=1088
T12PR TVR + PR
Follow-upSVR
eRVR- PR .
PR
SVReRVR +
Follow-upSVR
TVR +
PRT8PR
eRVR- PR .
Pbo +
PR
Follow-upPR
Follow-up
240 48 72Weeks 128 36
Follow-upPR48 (control)
SVRPbo + PR PR
(T) TVR=telaprevir 750 mg q8h.(P) Peg-IFN=pegylated interferon alfa-2a (40 kD) 180 µg/wk.(R) RBV=ribavirin 1,000 or 1,200 mg/day.
Pbo=Placebo. eRVR=extedned RVR defined as HCV RNA
undetectable at Week 4 and Week 12.
Jacobson IM, et al. Presented at the 61st AASLD. Boston, MA. October 29-November 2, 2010. Abstract 211.
Telaprevir Elicited Significantly Higher SVR Rates Vs Current Standard of CareSVR Rates Vs Current Standard of Care
T12PR T8PR PR (control)
75%
P
Telaprevir-treated Patients Had Undetectable HCV RNA at Week 4 (RVR) and Weeks 4 and 12 (eRVR)RNA at Week 4 (RVR) and Weeks 4 and 12 (eRVR)
100 T12PR T8PR PR
68% 66%58% 57%n
ts W
ith
tect
able
70
8090 Patients eligible to
receive 24 weeks of total treatment
58% 57%
ent o
f Pat
ien
V R
NA
Und
et
40
50
60
9% 8%
Perc
eH
CV
10
20
30
246/363 242/364 34/361 29/361207/364212/363Week 4 (RVR) Weeks 4 and 12 (eRVR)
n/N =0
RVR=rapid virologic response.eRVR=HCV RNA undetectable at Week 4 and Week 12eRVR=HCV RNA undetectable at Week 4 and Week 12.T12PR=telaprevir + pegylated-interferon + ribavirin for 12 wks followed by pegylated-interferon and ribavirin.T8PR=telaprevir + pegylated-interferon + ribavirin for 8 wks followed by pegylated-interferon and ribavirin.PR=pegylated-interferon and ribavirin alone for 48 weeks.
Jacobson IM, et al. Presented at the 61st AASLD. Boston, MA. October 29-November 2, 2010. Abstract 211.
Higher SVR Rates Were Observed in Telaprevir-treated Patients Regardless of Race or Ethnicity*
R 90100
T12PR T8PR PR
treated Patients Regardless of Race or Ethnicity
75%70%
62% 58%
74%
66%
s W
ith S
VR
60
70
80
90
46%
39%
of P
atie
nts
30
40
50
60
25%
Perc
ent
0
10
20
30
*Race and ethnicity were self-reported.SVR=sustained virologic response
244/325220/315147/318 15/3829/4426/35Black/African
AmericanCaucasian
n/N =Hispanic/Latino
7/2823/4016/260
SVR sustained virologic response.T12PR=telaprevir + pegylated-interferon + ribavirin for 12 wks followed by pegylated-interferon and ribavirin.T8PR=telaprevir + pegylated-interferon + ribavirin for 8 wks followed by pegylated-interferon and ribavirin.PR=pegylated-interferon and ribavirin alone for 48 weeks.
Jacobson IM, et al. Presented at the 61st AASLD. Boston, MA. October 29-November 2, 2010. Abstract 211.
Telaprevir Was Generally Well-tolerated in the ADVANCE Trialtolerated in the ADVANCE Trial
• Adverse events occurring in ≥25% of patients:g p– Fatigue, pruritus,* headache, nausea,* rash,* anemia,*
insomnia, diarrhea,* flulike symptoms, pyrexiaR h t i il t d l d• Rash events primarily eczematous and resolved with discontinuation of therapy
• Sequential discontinuation of drugs if rashSequential discontinuation of drugs if rash moderate or severe
• Telaprevir followed 7 days later by RBV then by PEG IFN if h dPEG IFN if rash progressed
*Adverse event rates ≥10% higher in telaprevir arms vs PEG FN/RBV.
Jacobson IM, et al. Presented at the 61st AASLD. Boston, MA. October 29-November 2, 2010. Abstract 211.
ILLUMINATE: a Phase III Non-inferiority Trial Comparing a Short Vs Long Course of Telaprevir
• To evaluate differences in SVR between a 24-week and 48-week TVR in patients who achieved eRVR and Safety of TVR in combination with PEG IFN and RBV
Comparing a Short Vs Long Course of Telaprevir
who achieved eRVR and Safety of TVR in combination with PEG IFN and RBV
Follow-upSVR
T12PR PR
PR
Randomized TreatmentseRVR+*Non-inferiority (Margin:-10.5%)
Follow-upSVR
SVR
PR
Assigned TreatmenteRVR-
n=540
Patients discontinued for any reason before Wk 20 were categorized as “Other”
Follow-up
24 48 726036
SVR
20
PR
0 12 20
eRVR
Patients discontinued for any reason before Wk 20 were categorized as OtherStopping Rules:• Week 4 HCV RNA >1000 IU/mL patients were to discontinue TVR and continue PR• Week 12 HCV RNA 10 IU/mL patients were to discontinue all study drugs
*eRVR=extended RVR
(T) TVR=telaprevir 750 mg q8h.(P) Peg-IFN=pegylated interferon alfa-2a (40 kD) 180 µg/wk.(R) RBV=ribavirin 1,000 or 1,200 mg/day.
T12PR=telaprevir + pegylated-interferon + ribavirin for 12 wks followed by pegylated-interferon and ribavirin.
PR=pegylated-interferon and ribavirin alone for 48 weeks.
Sherman KE, et al. Presented at the 61st AASLD. Boston, MA. October 29-November 2, 2010. Abstract LB-2.
eRVR=extended RVR.
Non-inferior Virologic Responses to Telaprevir Treatment in the Intent-to-treat PopulationTreatment in the Intent to treat Population
SVR Rates: Non-inferiority of 24-week RegimenUndetectable HCV RNA Over Time
e
4.5% (2-sided 95% CI=-2.1% to +11.1%)
)
ndet
ecta
ble
evel
s (%
)
With
SVR
(%)
ient
s W
ith U
HC
V R
NA
Le
Patie
nts
W
389/540 352/540n/N=
Pati H
469/540 388/540 149/162 140/160n/N=
SVR=sustained virologic response.RVR=rapid virologic response.eRVR=extended RVR.
EOT=end of treatment.SVR was comparable regardless of race
or ethnicity and liver fibrosis stage.
Sherman KE, et al. Presented at the 61st AASLD. Boston, MA. October 29-November 2, 2010. Abstract LB-2.
ILLUMINATE Trial: Summary
• 24-week telaprevir-based regimen is non-inferior to a 48-week regimen in patients with eRVR (92% vs 88% SVR)regimen in patients with eRVR (92% vs 88% SVR)
• 65% of patients were eligible for a shorter duration of treatment
72% ll SVR b d i th i t t t t t l ti• 72% overall SVR observed in the intent-to-treat population– 63% SVR in patients with bridging fibrosis and cirrhosis – 60% SVR in African American patients – 67% SVR in Hispanic/Latino patients67% SVR in Hispanic/Latino patients
• Most common adverse events included: rash (primarily eczematous), fatigue, pruritus, nausea, and anemia
• An 18% overall rate of discontinuation was noted for all study drugs due to adverse events– 1% and 2% overall treatment discontinuation rates due to rash and
anemia respectivelyanemia, respectively
Sherman KE, et al. Presented at the 61st AASLD. Boston, MA. October 29-November 2, 2010. Abstract LB-2.
REALIZE: Phase III Trial of Telaprevir in Genotype 1 HCV Patientsin Genotype 1 HCV Patients
n=662 Genotype 1 patients who failed to achieve*
*
n 662 Genotype 1 patients who failed to achieve SVR with prior pegylated interferon-based therapy
*
††
*P
SPRINT 2: Phase III Trial of Boceprevir in HCV Patients New to Treatment
• Study to compare safety/efficacy of two treatment strategies with boceprevir added to peginterferon/ribavirin (PR) versus PR alone in treatment-naïve HCV genotype 1 patients
in HCV Patients New to Treatment
Week 4 Week 48
PR + Placebo Follow-upPRlead in
Week 28 Week 72Control48 P/R
p g ( ) g yp p
plead-in
TW 8-24 HCV-RNA Undetectable
Follow-up
(n=363)
n=1097
PR + BoceprevirTW 8-24 HCV-RNA Detectable
PR + Placebo Follow-up
BOCRGT
(n=368)
PRlead-in
PR + Boceprevir Follow-upBOC/PR48
(n=366)
PRlead-in
Peginterferon (P) administered subcutaneously at 1.5 μg/kg once weekly, plus ribavirin (R) using weight-based dosing of 600-1400 mg/day in a divided daily dose.
Boceprevir dose of 800 mg 3x/daily.Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
Two-thirds of Boceprevir-treated Patients Achieved SVR* in the SPRINT 2 TrialAchieved SVR in the SPRINT 2 Trial
P 0001
Sustained virologic response Relapse Rate
80
100
67 6880100 P
Boceprevir Elicited SVR Following 4 Weeks of P/R Lead-in Therapy4 Weeks of P/R Lead-in Therapy
≥1 log 10 HCV RNA decline from baseline
SVR in Patients With Undetectable HCV RNA
SVR in Patients With Detectable HCV RNA at Least
Between Weeks 8-24
97 96 95100
Once Between Weeks 8-24
100 Non black patients96
87
95
859095 143
147137142
1819 88
859095
Non-black patients
Black patients
758085 13
15
VR (%
)
74 74758085 7
8
47% of patients in
606570S
V
58606570 5270
4865
47% of patients in Cohort 1 RGT arm were treated with
short duration22% of patients in Cohort 1 RGT arm
505560 58
505560
712
short duration Cohort 1 RGT arm were treated with >28
weeks of therapy
BOC RGT BOC/PR48 BOC RGT BOC/PR48BOC RGT=boceprevir response-guided therapy.P/R=peglyated interferon + ribavirin.BOC/PR=boceprevir + peglyated interferon + ribavirin. Poordad F, et al. N Engl J Med. 2011;364:1195-206.
Boceprevir Generally Well-tolerated by Patients in the SPRINT 2 Trialby Patients in the SPRINT 2 Trial
• Anemia and dysgeusia occurred more often in the y gboceprevir groups than the control groups (20% and 19-25% higher, respectively) EPO d i 19% b i i i t• EPO was used in 19% more boceprevir recipients compared to controls; discontinuation due to anemia occurred in
RESPOND 2: Phase III Study of Boceprevirin Patients Who Failed Prior Therapyin Patients Who Failed Prior TherapyWeeks 24 48 728 124
Arm 1
CO
NTR
OL
Follow-upPlacebo + PEG + RBV PEG +RBV
Genotype 1 HCV Patients Who Experienced a Relapse or Non-response to Prior Therapy (n=403*)
ENIN
G
Arm 2
p24 wk44 wk
Follow-up
RBV4 wk
TW 8 & 12 HCV RNA Undetectable
Response-guided Therapy
SCR
E
ENTA
L A
RM
S PEG +RBV4 wk
Follow up24 wk
Follow-up24 wk
Boceprevir + PEG + RBV32 wk TW 8 HCV-RNA Detectable and TW 12 Undetectable
Placebo + PEG + RBV
Response guided Therapy
EXPE
RIM
E
Arm 3
PEG +RBV4 wk
Boceprevir + PEG + RBV 44 wk
Follow-up24 wk
24 wk12 wk
4 wk
*Patient distribution was 67% male, 12% black, and 12% cirrhotic.Bacon B, et al. N Engl J Med. 2011;364:1207-17.
Boceprevir-treated Patients Had Significant Increases in SVR RatesSignificant Increases in SVR Rates
90% End of therapy response
70%77%
59%67%
60%70%80% Relapse rates
SVR ††
95
124161
107161
114162
31% 32%
21%30%40%50%
25
95162
815% 12%
21%
0%10%20%
P/R 48 Wk BOC RGT* P/R 4 Wk P/R 4 Wk
80
17111 14121
1780
25
*RGT based on HCV negativity at week 8: a) Patients with undetectable HCV RNA received 28 more weeks of P/R/BOC; b) Patients with detectable HCV RNA received 28 more weeks of P/R/BOC followed by 12 weeks of P/R
P/R 48 Wk BOC RGT*: P/R 4 Wk + P/R/BOC 32 Wk +/- P/R
12 Wk
P/R 4 Wk + P/R/BOC 44 Wk
P/R/BOC; b) Patients with detectable HCV RNA received 28 more weeks of P/R/BOC followed by 12 weeks of P/R. †P
RESPOND-2 Trial: Summary
• The combination of boceprevir, peglyated interferon, p , p g y ,and ribavirin leads to high SVR rates in G1 previous non-responders/relapsers to P/R therapy, with significant but lower response rates in poor responderssignificant but lower response rates in poor responders
• This therapy was generally well tolerated, and offers substantial benefit to patients who failed prior P/Rsubstantial benefit to patients who failed prior P/R therapy
Bacon B, et al. N Engl J Med. 2011;364:1207-17.
Additional HCV Therapies in Development
Direct Antiviral Agents for HCV: Overview
Moderate-to-high potency High-potency
Overview
g p y+/- Multi-genotypic coverage
Intermediate barrier to resistance
g p yMulti-genotypic coverageLow barrier to resistance
NS5B Nucleoside Inhibitors (NI)Intermediate to high potency
Pan genotypic coverage
NS5B Non-nucleoside Polymerase Inhibitors (NNPI)
Low potencyPan genotypic coverage
High barrier to resistanceLimited-genotypic coverage
Low barrier to resistance
Combination Therapies With 2 or More Direct Antiviral Agents: Lessons LearnedDirect Antiviral Agents: Lessons Learned
D C bi i Cl M f Phase ofDrug Combinations Class Manufacturer Phase of Development
BMS-650032+ PI+NS5a BMS2a
BMS-790052 PI+NS5a BMS
Danoprevir (RG7227)+ PI+NPI Genentech 2bp ( )RG7128 Genentech 2b
GS-9190+ PI+NNPI Gil d 2GS-92568 PI+NNPI Gilead 2a
BI-201335+BI 207127 PI+NNPI
BoehringerI lh i 2aBI-207127 PI NNPI Ingelheim 2a
NNPI=non-nucleoside polymerase inhibitors.NPI=nucleoside polymerase inhibitor.
NS5a=non-structural 5A protein of HCV.PI=protease inhibitor.
Multiple Anti-HCV Potential CombinationsCombinations
Linear class Active siteRG7128Telaprevir
BoceprevirNarlaprevir
RG7128IDX184
PSI-7977
NS3Protease NS5A
NS5BPolymerase
Macrocyclic classRG7227/ITMN-191
TMC 435350MK 7009
BMS-790052 ABT-267
ThumbVCH-759VCH-916VX-222
PalmABT-333ABT-072GS 9190MK 7009
BI 201335BMS-650032
VX 222 BI 207127Filibuvir
GS 9190ANA598
Cyclophilin
AlisporivirSCY635
Therapies Anticipated After 2015
Triple Therapy With P/RCost restrained P/R+
DAA or
Host Targeting Agent
markets: IL28CC + RVR:
Peg IFN + RBV
GT1
Quadruple Combination of P/R and+
DAAsGT1 DAAsand/or
Host Targeting Agent
Triple or Quadruple all oral therapy,
including ribavirin
Positive baseline predictors of
response c ud g ba
GT1=genotype 1.RVR=rapid virologic response.
RBV=ribavirin.Peg IFN=Peginterferon alfa-2b.
P/R=Peginterferon alfa-2b/Ribavirin.DAA=direct antiviral agent.
Evolution of Therapy in HCV Genotype 1
1990 2001 2011 20151999
100
1990 2001 2011 20151999
60
80
(%) *
20
40
4060
75SVR
90
0
20
2 10 1525
40
IFN6m
IFN/RBV6m
PEG/RBV12m
IFN12m
IFN/RBV12m
PEG/R/PI6-12m
*Difficult to treat populations
Future Individualized Standard of Care
• Patient demographicsg p– Age, ethnicity, histology, compliance, genomics, treatment
historyR i l ti• Regimen selection– Based on above criteria and ease of regimen, expected
duration, adverse events, payer preferences, emerging p y p g gnewer therapies
• Better SVR rates with greater toxicityWith 1 t ti t i hibit t it• With 1st generation protease inhibitors, must monitor for resistance