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