Assessinggg the Evolving Evidence of HCV Treatment Options 1 Chapter 2.pdfJacobson IM, et al....

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.


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.


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.


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.


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


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

Assessinggg the Evolving Evidence of HCV Treatment Options 1 Chapter 2.pdfJacobson IM, et al....

Documents

Transcript of Assessinggg the Evolving Evidence of HCV Treatment Options 1 Chapter 2.pdfJacobson IM, et al....