les inhibiteurs de protéase du vhc - académie nationale … · · 2014-02-09les inhibiteurs de...

Les Inhibiteurs de

Protéase du VHC

Pr Jean-Michel Pawlotsky

National Reference Center for Viral

Hepatitis B, C and delta

Department of Virology & INSERM U955

Henri Mondor Hospital

University of Paris-Est

Créteil, France

Chronic Hepatitis C

• 120-130 million chronically infected patients

worldwide

• 1st cause of chronic liver disease and of

hepatocellular carcinoma

• 1st indication for liver transplantation in

industrialized areas

Worldwide HCV Prevalence

HCV Genotypes

(Simmonds P., et al., Hepatology 2006)

Standard-of-Care (EU label)

Genotype 1 Genotype 2,3 Genotype 4, 5, 6

PegIFN +

ribavirin

48 weeks

PegIFN +

ribavirin

24 weeks

PegIFN +

ribavirin

48 weeks

46% 52%

42%

76% 84% 82%

Genotype 1 Genotypes 2/3

PEG-IFN-α2a+ribavirin (Fried et al)

PEG-IFN-α2a+ribavirin (Hadziyannis et al)

PEG-IFN-α2b+ribavirin (Manns et al)

(Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)

SVR Rates in Pivotal Trials

HCV protease inhibitors

HCV Life Cycle

(Popescu & Dubuisson, Biol Cell 2009;102:63-74)

NS3/4A Protease Inhibitors

(Raney et al., J Biol Chem 2010:285:22725-31)

(Reesink HW, et al. Gastroenterology 2006;131:997-1002)

Telaprevir Resistance

-5

-4

-3

-2

-1

0

1

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Study Time (Days)

Med

ian

HC

V R

NA

Ch

an

ge

f

rom

Baseli

ne

(L

og

10 IU

/mL

)

Placebo VX-950 450 mg q8h VX-950 1250 mg q12h

Asp168

Ala156

Arg155

Thr54

Val36

(Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219)

Amino Acid Substitutions

Associated with PI Resistance

Boceprevir

Telaprevir

Ribavirin Pegylated

IFN-

+

New Standard-of-Care

for HCV Genotype 1

Telaprevir

• HCV Genotype 1

• Triple combination PegIFN-2a: 180 g/wk; or PegIFN-2b: 1.5 g/kg/wk

Ribavirin: 0.8-1.2 g/d

Telaprevir 375mg: 750 mg tid (every 7-9 hours with food/fat)

• Treatment schedule Telaprevir: starts at day 0

Response-guided therapy

Telaprevir Label

Response-Guided Therapy Peg-IFN + Ribavirin + Telaprevir

W4 W24 W48 W72 W36 W12 W0

Treatment-naive

or responder-

relapser

Partial responder

or null-responder


W4 W24 W48

Follow-up: 24 weeks

Follow-up: 24 weeks

TVR + PR

PR

eRVR: undetectable HCV RNA at weeks 4 and 12

HCV RNA detectable at weeks 4 and/or 12 but ≤1000 UI/mL

W72

PR

W36 W12 W0

Treatment-naive

or responder-

relapser

Partial responder

or null-responder


W4 W24 W48

Follow-up: 24 weeks

Follow-up: 24 weeks

TVR + PR

PR

eRVR: undetectable HCV RNA at weeks 4 and 12

HCV RNA detectable at weeks 4 and/or 12 but ≤1000 UI/mL

W72

PR

W36 W12

Follow-up: 24 weeks PR TVR + PR

W0

Treatment-naive

or responder-

relapser

Partial responder

or null-responder

• HCV RNA >1000 IU/mL at W4 or W12

• HCV RNA detectable (>10-25 IU/mL)

at W24

Futility Rules Peg-IFN + Ribavirin + Telaprevir

75% 69%

44%

P<0.0001

P<0.0001

T12/PR

N=363

T8/PR

N=364

PR

N=361

% p

ati

en

ts w

ith

SV

R

0

10

20

30

40

50

60

70

80

90

100

ADVANCE Rx-naive, Gen 1, Telaprevir

(Jacobson et al., N Engl J Med 2011;364:2405-16)

0

20

40

60

80

100

83%

Pati

en

ts W

ith

Un

dete

cta

ble

HC

V R

NA

(%

)

Prior

null-response

Prior partial

response

Prior

relapse

REALIZE Rx-experienced, Gen 1, Telaprevir

88%

24%

54%

15%

33%

5%

59%

29%

T12/PR48

Lead-in/T12/PR48

PR48 (control)

P<0.01 vs placebo

(Zeuzem et al., N Engl J Med 2011;364:2417-48)

Severe Cutaneous Adverse

(SCAR) Reactions with Telaprevir

11 cases suggestive of DRESS

SCAR Acute generalized

exanthematous pustulosis (AGEP) and Erythema

Multiforme Major (EMM)

Drug rash/reaction with eosinophilia and

systemic symptoms (DRESS)

Toxic epidermal necrolysis (TEN) and Stevens-

Johnson Syndrome (SJS)

((of which 1 case considered not related to

telaprevir, onset 11 weeks after telaprevir

discontinuation)

3 cases suggestive of SJS

(http://www.fda.gov/downloads/AdvisoryCommittees Committees/Meeting

Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf)

CUPIC-Telaprevir SAEs

Exposure and SAEs TVR (n=176)

Median exposure to telaprevir 85.0 days

Severe adverse events (SAE) 90 (51%)*

Discontinuations due to SAEs 21 (12%)

Deaths 3 (1.7%)

*228 SAEs in 90 patients

(Hézode et al., HepDart 2011)

CUPIC-Telaprevir Clinical SAEs

Clinical SAEs TVR (n=176)

Grade 3/4 rash

Grade 3

SCAR

12 (6.8%)

0 (0%)

Grade 3/4 infection 6 (3.4%)

Other grade 3/4 SAEs 92 (52%)


CUPIC-Telaprevir Biological

Adverse Events

Biological adverse events TVR (n=176)

Anemia

Grade 2 (8.0-<10,0 g/dl) 58 (33%)

Grade 3/4 (<8,0 g/dl) 23 (13%)

EPO use 96 (55%)

Transfusion 32 (18%)

Neutropenia

Grade 3 (500-<1000/mm3) 20 (11%)

Grade 4 (<500/mm3) 2 (1%)

G-CSF use 5 (3%)

Thrombocytopenia

Grade 3 (25,000-<50000) 26 (15%)

Grade 4 (<25000) 12 (7%)


Boceprevir

• HCV Genotype 1

• Triple combination PegIFN-2b: 1.5 g/kg/wk; or PegIFN-2a: 180 g/wk

Ribavirin: 0.8-1.4 g/d

Boceprevir 200 mg: 800 mg tid (every 7-9 hours with food)

• Treatment schedule Lead-in: 4 weeks

Boceprevir: starts at week 4

Response-guided therapy

Boceprevir Label

Treatment-

experienced

patients

(excluding null-

responders and

F4)

F4 patients and

null-responders

Treatment naive

patients

(excluding F4)

Response-Guided Therapy Peg-IFN + Ribavirin + Boceprevir

W0 W4 W8 W12 W24 W28 W36 W48

Boceprevir

Undetectable HCV RNA at week 8

PegIFN/ RBV

PegIFN/RBV

Detectable HCV RNA at week 8

Treatment-

experienced

patients

(excluding null-

responders and

F4)

F4 patients and

null-responders

Treatment naive

patients

(excluding F4)

Boceprevir + PegIFN/RBV



W0 W4 W8 W12 W24 W28 W36 W48

Boceprevir


PegIFN/ RBV

PegIFN/RBV


Boceprevir

W4 W0 W12 W24 W36 W48

Boceprevir + PegIFN/RBV PegIFN RBV

PegIFN/RBV

Treatment-

experienced

patients

(excluding null-

responders and

F4)

F4 patients and

null-responders

Treatment naive

patients

(excluding F4)




W0 W4 W8 W12 W24 W28 W36 W48

Boceprevir


PegIFN/ RBV

PegIFN/RBV


Boceprevir

W4 W0 W12 W24 W36 W48


PegIFN/RBV

W0 W4 W12 W24 W48


Boceprevir

Treatment-

experienced

patients

(excluding null-

responders and

F4)

F4 patients and

null-responders

Treatment naive

patients

(excluding F4)




• HCV RNA ≥100 IU/mL at W12

• HCV RNA detectable (>10-25 IU/mL)

at W24

Futility Rules Peg-IFN + Ribavirin + Boceprevir

SPRINT-2 SVR (non-black)

67% 68%

40%

P<0.0001

P<0.0001

BOC/RGT

N=368

BOC/PR48

N=366

48P/R

N=363

% p

ati

en

ts w

ith

SV

R

0

10

20

30

40

50

60

70

80

90

100

(Poordad et al., N Engl J Med 2011;364:1195-206)

0

20

40

60

80

100

69%

Pati

en

ts W

ith

Un

dete

cta

ble

HC

V R

NA

(%

)

Prior partial

response

Prior

relapse

75%

29%

52%

7%

40%

BOC/RGT

BOC/PR48

48P/R (control)

RESPOND-2 SVR

(Bacon et al., N Engl J Med 2011;364:1207-17)

Anemia with Boceprevir in

Phase II/III Clinical Trials

45%

5% 9%

% p

ati

en

ts

0

10

20

30

40

50

60

70

80

90

100

Hemoglobin

<10 to 8.5 g/dL

Hemoglobin

<8.5 g/dL

41%

BOC/RGT

BOC/PR48

(http://www.fda.gov/downloads/AdvisoryCommittees Committees/Meeting

Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf)

26%

4%

PR48

CUPIC-Boceprevir SAEs

Exposure and SAEs BOC (n=134)

Median exposure to boceprevir 84.0 days

Severe adverse events (SAE) 39 (29%)*

Discontinuations due to SAEs 8 (6%)

Deaths 1 (1%)

*85 SAEs in 39 patients


CUPIC-Boceprevir Clinical SAEs

Clinical SAEs BOC (n=134)

Grade 3/4 rash

Grade 3

SCAR

0 (0%)

0 (0%)

Grade 3/4 infection 0 (0%)

Other grade 3/4 SAEs 43 (32%)


CUPIC-Boceprevir Biological

Adverse Events

Biological adverse events BOC (n=134)

Anemia

Grade 2 (8.0-<10,0 g/dl) 41 (31%)

Grade 3/4 (<8,0 g/dl) 8 (6%)

EPO use 70 (52%)

Transfusion 8 (6%)

Neutropenia

Grade 3 (500-<1000/mm3) 10 (7%)

Grade 4 (<500/mm3) 5 (4%)

G-CSF use 7 (5%)

Thrombocytopenia

Grade 3 (25,000-<50,000) 8 (6%)

Grade 4 (<25,000) 3 (2%)


Future HCV therapies

HCV Life Cycle

(Popescu & Dubuisson, Biol Cell 2009;102:63-74)

NS3/4A Protease Inhibitors

(Raney et al., J Biol Chem 2010:285:22725-31)

Antiviral Efficacy of NS3/4A

Protease Inhibitors

Drug Phase Dose Duration

Median/mean

log HCV RNA

reduction

Telaprevir (Janssen) Approved 750 mg q8h 14 days -4.4

Boceprevir (Merck) Approved 400 mg tid 7 days -1.6

TMC435 (Janssen) III 200 mg qd 7 days -4.1

Danoprevir (RG7227, Roche) II 200 mg q8h 14 days -3.8

Vaniprevir (MK-7009, Merck) II 700 mg bid 8 days -4.7

BI201335 (BI) II 240 mg qd 14 days -4.0

Narlaprevir (Merck) II 400 mg bid 7 days -4.2

Asunaprevir (BMS) II 300 mg bid 3 days -3.3

ABT-450/r (Abbott) II 200 mg qd 3 days -4.1

GS-9451 (Gilead) I 400 mg qd 3 days -3.5

MK-5172 (Merck) I 400 mg qd 7 days -5.4

HCV RNA-Dependent RNA

Polymerase (RdRp)

Catalytic

Site


Median/mean log

HCV RNA level

reduction

Mericitabine (RG7128, Roche) II 1500 mg bid 14 days -2.7

GS-7977 (Gilead) II 400 mg qd 3 days -3.7

INX-189 (Inhibitex) Ib 100 mg qd 7 days -2.5

IDX184 (Idenix) II 100 mg qd 3 days -0.7

Nucleoside/Nucleotide Analogue

Inhibitors of HCV RdRp

Non-Nucleoside Inhibitors (NNI)

A

NNI site A (Thumb/fingertips) Indoles

Benzimidazoles

NNI site B (Thumb) Phe derivatives

Thiophene-COOH Dihydroxypirones

Pyranoindoles (HCV371)

B

NNI site C (Palm) Benzothiadiazine (A-848837)

Acyl-pyrrolidine Proline sulfonamide

Acrylic acid derivatives

C

NNI site D (R200 hinge) Benzofurans (HCV086, HCV796)

A

B C

D

Non-Nucleoside Inhibitors

of HCV RdRp (NNIs)

Drug Phase Dose Duration Median/mean log

HCV RNA reduction

Tegobuvir (Gilead) II 40 mg bid 8 days -1.4

Filibuvir (Pfizer) II 300 mg bid 8 days -2.1

Setrobuvir (Roche) II 800 mg bid 3 days -2.9

BI207127 (BI) II 800 mg q8h 3 days -3.1

ABT-333 (Abbott) II 600 mg bid 2 days -1.5

VX-222 (Vertex) Ib 750 mg bid 3 days -3.7

HCV Replication Complex

(Membranous Web)

(Moradpour et al., Nature Rev Microbiol 2007;5:453-63)

NS5A Protein

Antiviral Efficacy of

NS5A Inhibitors

Drug Phase Dose Duration Median/mean log

HCV RNA reduction

Daclatasvir (BMS) II 10 mg qd 1 day -3.2

PPI-461 (Presidio) Ib 100 mg qd 3 days -3.7

GS-5885 (Gilead) Ib 30 mg qd 3 days -3.3

Cyclophilins

Cyclophilin A

Antiviral Efficacy of

Cyclophylin Inhibitors


Median/mean

log HCV RNA

reduction

Alisporivir (DEBIO-025) II 1200 mg bid 14 days -3.6

SCY-465 Ib 900 mg qd 15 days -2.2

GS-7977 + Ribavirin 12 weeks

• Treatment-naive, gen 2/3 10/10 SVR12

• Null-responder, gen 1 6/8 relapses

(Gane et al., AASLD 2011; Gilead press release, February 17, 2012)

Daclatasvir (NS5A)

+ Asunaprevir (PI)

Daclatasvir + Asunaprevir

Daclatasvir + Asunaprevir

N=11

N=10

(Lok et al., N Engl J Med 2012;366:216-24; Chayama 2012;55:742-8)

SVR

2/9 genotype 1a

2/2 genotype 1b

SVR

9/10 genotype 1b

les inhibiteurs de protéase du vhc - académie nationale … · · 2014-02-09les inhibiteurs de...

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