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
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
(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
• 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
Response-Guided Therapy Peg-IFN + Ribavirin + Telaprevir
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
Response-Guided Therapy Peg-IFN + Ribavirin + Telaprevir
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%)
(Hézode et al., HepDart 2011)
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%)
(Hézode et al., HepDart 2011)
• 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
Boceprevir + PegIFN/RBV
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
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)
Boceprevir + PegIFN/RBV
Boceprevir + PegIFN/RBV
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
Boceprevir
W4 W0 W12 W24 W36 W48
Boceprevir + PegIFN/RBV PegIFN RBV
PegIFN/RBV
W0 W4 W12 W24 W48
Boceprevir + PegIFN/RBV PegIFN RBV
Boceprevir
Treatment-
experienced
patients
(excluding null-
responders and
F4)
F4 patients and
null-responders
Treatment naive
patients
(excluding F4)
Boceprevir + PegIFN/RBV
Boceprevir + PegIFN/RBV
Response-Guided Therapy Peg-IFN + Ribavirin + Boceprevir
• 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
(Hézode et al., HepDart 2011)
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%)
(Hézode et al., HepDart 2011)
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%)
(Hézode et al., HepDart 2011)
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
Drug Phase Dose Duration
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
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
Antiviral Efficacy of
Cyclophylin Inhibitors
Drug Phase Dose Duration
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)