Prsentation PowerPoint

1
Novel HCV Inhibitors Prof. Jean-Michel
Pawlotsky, MD, PhD French National Reference
Center for Hepatitis B, C and delta Department of
Virology INSERM U955 Henri Mondor
Hospital University of Paris 12 Créteil, France
2
Future HCV Therapy
pegIFN
Ribavirin
3
Future HCV Therapy
pegIFN
pegIFN
Ribavirin
Ribavirin
HCVinhibitor
4
Future HCV Therapy
pegIFN
HCVinhibitor
pegIFN
Ribavirin
HCVinhibitor
HCVinhibitor
Ribavirin
Ribavirin ?
HCVinhibitor
5
HCV Life Cycle
6

• Virtually any step of the HCV lifecycle can be a
  target for HCVinhibitors

7
HCV Drug Development
Phase of Development
Preclinical I II III IV
Viral entry inhibitorsHepatitis C immunoglobulin
HCIg)HCV-Ab 68 and Ab 65 (monoclonal Ab) HCV RNA
translation inhibitors ISIS 14803 (antisense)
AVI 4065 (antisense) Heptazyme
(ribozyme)VGX-410C (small molecule IRES
inhibitor)TT 033 (siRNA) Posttranslational
processing inhibitors NS3-4A serine proteinase
inhibitors BILN 2061 ITMN 191 VX-950 SCH
503034 ACH-806/GS-9132 HCV replication
inhibitors NS5B polymerase inhibitors MK-0608
HCV-796 R1626 JTK-003 NM-283 XTL 2125
Cyclophilin B inhibitors DEBIO-025 NIM 811
NS5A inhibitors A-831, A-689 Helicase
inhibitors QU663 Recombinant Ab
fragments Virus assembly and release
inhibitors UT-231B (iminosugar-glucosidase
inhibitor) Celgosivir (glucosidase inhibitor)







(Pawlotsky JM, Chevaliez S, McHutchison JG,
Gastroenterology 20071321979-98)
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NS3/4A Protease Inhibitors
9
NS3/4A Protease Active Site
10
NS3/4A Protease Inhibitors in Clinical Development

• Peptidomimetic inhibitors
• Telaprevir (VX-950, Vertex Tibotec)
• Boceprevir (SCH503034, Schering-Plough)
• TMC 435 (Tibotec)
• ITMN-191/R7227 (InterMune Roche)
• MK-7009 (Merck)
• BI 201335 (Boehringer-Ingelheim)
• SCH 900518 (Schering-Plough)

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Telaprevir (VX-950)Antiviral Efficacy
1
0
Placebo
-1
Median HCV RNA Change
from Baseline (Log10 IU/mL)
-2
-3
VX-950 750 mg q8h
-4
-5
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Study Time (Days)
(Reesink HW, et al. Gastroenterology
2006131997-1002)
12
TMC435 Trial (Phase Ib)
1
Dosing period TMC 435350, 200 mg QD
Median
0
-1
HCV viral load change from baseline Log10 (IU /
mL)
-2
-3
-4
-5
2
1
3
4
5
6
7
8
Baseline
Wk 1post-tt
Wk 4 post-tt
Study day
(Reesink et al., EASL 2008)
13
Antiviral Efficacy of NS3/4A Protease Inhibitors
14
NS3/4A Protease Inhibitor Resistance Mutations

• Compounds
• Ciluprevir (BILN 2061)
• Telaprevir (VX-950)
• Boceprevir (SCH 503034)
• ITMN-191
• TMC435350

In vitro A156V/T, D168V/A/Y, R155Q A156V/T A1
56S/T, V170A, T54A A156V/T, D168V/A, R155K/Q ?
In vivo No data A156S/V/T, R155K/T, T54A,
V36A/M T54A No data No data
15
Telaprevir Resistance
1
0
-1
Median HCV RNA Change
from Baseline (Log10 IU/mL)
-2
-3
-4
-5
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Study Time (Days)
Placebo
VX-950 450 mg q8h
VX-950 1250 mg q12h
(Reesink HW, et al. Gastroenterology
2006131997-1002)
16
BI201335 Resistance
(Manns et al., AASLD 2008)
17
PROVE 1 Trial (Phase II)Naïve, Genotype 1, US
Placebo Peg-IFN?2a Ribavirin (RBV)
Follow-up
PR48
VX-950 750 mg q8h Peg-IFN?2a RBV
Peg-IFN?2a RBV
Follow-up
T12/PR48
VX-950 750 mg q8h Peg-IFN?2a RBV
Follow-up
Peg-IFN?2a RBV
T12/PR24
VX-950 750 mg q8h Peg-IFN?2a RBV
Follow-up
T12/PR12
24
12
72
48
0
Weeks on therapy
(McHutchison et al., N Engl J Med
20093601827-38)
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PROVE 1 Trial (Phase II)Naïve, Genotype 1, US
p 0.001
100
p 0.020
80
67
61
60
SVR rate ()
41
35
40
20
0
PR48 (n75)
T12/PR12 (n17)
T12/PR24 (n79)
T12/PR48 (n79)
(McHutchison et al., N Engl J Med
20093601827-38)
19
PROVE 2 Trial (Phase II)Naïve, Genotype 1, Europe
Placebo Peg-IFN?2a Ribavirin (RBV)
Follow-up
PR48
VX-950 750 mg q8h Peg-IFN?2a RBV
Peg-IFN?2a RBV
Follow-up
T12/PR24
VX-950 750 mg q8h Peg-IFN?2a RBV
Follow-up
T12/PR12
VX-950 750 mg q8h Peg-IFN?2a
Follow-up
T12/P12
24
12
72
48
0
Weeks on therapy
(Hézode et al., N Engl J Med 20093601839-50)
20
PROVE 2 Trial (Phase II)Naïve, Genotype 1, Europe
p gt 0.001
100
p 0.12
p gt 0.20
80
69
60
60
SVR rates ()
46
36
40
20
0
Telaprevir PegIFN 12w (no RBV) (n78)
Telaprevir PegIFN ribavirin 12w (n82)
TelaprevirPegIFN ribavirin 12w gt PegIFN
ribavirin 12w (n81)
control (n82)
(Hézode et al., N Engl J Med 20093601839-50)
21
PROVE 2 Trial (Phase II)Breakthoughs through
week 12
100
80
60
12-week SVR rates ()
40
24
20
3
0
TelaprevirPegIFN ribavirin 12w PegIFN
ribavirin 12w (n81)
Telaprevir PegIFN 12w (no RBV) (n78)
(Hézode et al., N Engl J Med 20093601839-50)
22
PROVE 2 Trial (Phase II)Relapses after treatment
100
80
60
48
SVR rates ()
40
30
22
20
14
0
Telaprevir PegIFN 12w (no RBV) (n78)
Telaprevir PegIFN ribavirin 12w (n82)
TelaprevirPegIFN ribavirin 12w gt PegIFN
ribavirin 12w (n81)
control (n82)
(Hézode et al., N Engl J Med 20093601839-50)
23
Telaprevir Resistance (PROVE2)
7
D
B
C
F
A
E
6
TVR-Peg-IFN
5
4
HCV RNA (Log10 IU/mL)
A
B
C
WT
3
WT
2
V36L/M
R155K/N
D
E
A40T
V36L/M A40T
1
R155K/N A40T
V36L/M R155K/N
V36L/M R155K/N A40T
0
0
10
20
30
40
50
60
70
80
90
Weeks
(Chevaliez et al., EASL 2009)
24
Telaprevir Resistance (PROVE2)
7
SOC
C
6
TVR-Peg-IFN
WT
A
B
D
5
B
A
E
4
WT
HCV RNA (Log10 IU/mL)
D
E
C
3
2
WT
R155K/E T42S
1
0
0
8
16
24
32
40
48
56
64
72
Weeks
(Chevaliez et al., EASL 2009)
25
PROVE 3 Trial (Phase II)Nonresponders, Genotype 1
Placebo Peg-IFN?2a Ribavirin (RBV)
Follow-up
PR48
VX-950 750 mg q8h Peg-IFN?2a RBV
Peg-IFN?2a RBV
Follow-up
T12/PR24
VX-950 750 mg q8h Peg-IFN?2a
Follow-up
T24/P24
VX-950 750 mg q8h Peg-IFN?2a RBV
Peg-IFN?2a RBV
Follow-up
T12/P12
24
12
48
36
0
Weeks on therapy
(McHutchison et al., AASLD 2008)
26
PROVE 3 Trial (Phase II)Nonresponders, Genotype 1
100
80
60
52
51
SVR rates ()
40
23
20
14
0
Telaprevir PegIFN 24w (no RBV) (n111)

• Telaprevir PegIFN
• ribavirin 12w
• PegIFN
• ribavirin 12w
• (n115)

• TelaprevirPegIFN
• ribavirin 24w
• PegIFN
• ribavirin 24w
• (n113)

control (n114)
(Manns et al., EASL 2009)
27
PROVE 3 Trial (Phase II)Nonresponders, Genotype 1
100
90
76
80
69
70
60
Percent with SVR ()
50
39
38
40
30
20
20
10
9
10
0
control T24/P24 T12/PR24
T24/PR48 control T24/P24
T12/PR24 T24/PR48
Prior Relapsers
Prior Non-responders
(Manns et al., EASL 2009)
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Telaprevir Side-Effects

• More frequent than SOC
• Rash
• Severe (grade 3) rash lt10
• No grade 4 rash
• Pruritus
• Anemia

29
SPRINT-1 Trial (Naive, Gen 1)
PEG-IFN?2b, 1.5 mg/kg/wk
28w, L/I n 103
RBV, 0.8-1.4 g/d
Follow-up
Boceprevir, 800 mg tid
PEG-IFN?2b, 1.5 mg/kg/wk
28w, no L/I n 107
RBV, 0.8-1.4 g/d
Follow-up
Boceprevir, 800 mg tid
PEG-IFN?2b, 1.5 mg/kg/wk
48w, L/I n 103
RBV, 0.8-1.4 g/d
Follow-up
Boceprevir, 800 mg tid
PEG-IFN?2b, 1.5 mg/kg/wk
48w, no L/I n 103
RBV, 0.8-1.4 g/d
Follow-up
Boceprevir, 800 mg tid
Control n 104
PEG-IFN?2b, 1.5 mg/kg/wk
Follow-up
RBV, 0.8-1.4 g/d
0
48
24
12
36
60
72
(Kwo et al., EASL 2009)
30
SPRINT-1 Trial (Naive, Gen 1)
100
75
80
67
56
60
54
SVR rates ()
38
40
20
0
28w, L/I n 103
28w, no L/I n 107
48w, L/I n 103
48w, no L/I n 103
Control n 104
(Kwo et al., EASL 2009)
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SPRINT-1 Trial (Naive, Gen 1)
PEG-IFN?2b, 1.5 mg/kg/wk
48w n 16
RBV, 0.8-1.4 g/d
Follow-up
Boceprevir, 800 mg tid
PEG-IFN?2b, 1.5 mg/kg/wk
48w Low dose RBV n 59
RBV, 0.4-1.0 g/d
Follow-up
Boceprevir, 800 mg tid
0
48
24
12
36
60
72
(Kwo et al., EASL 2009)
32
SPRINT-1 Trial (Naive, Gen 1)
100
80
50
60
36
SVR rates ()
40
20
0
48w n 16
48wklow dose RBV n 59
(Kwo et al., EASL 2009)
33
Boceprevir Resistance in the SPRINT-1 Trial
(Kwo et al., EASL 2009)
34
Boceprevir Side-Effects

• More frequent than SOC
• Anemia
• 1g/dL incremental hemoglobin decrease
• Management with EPO is associated with increased
  completion rates
• Dysgueusia

35
Inhibitors of HCV Replication
36
Inhibitors of HCV Replication

• RNA-dependent RNA polymerase (RdRp) inhibitors
• Nucleoside analogues
• Non-nucleoside inhibitors (NNIs)
• NS5A inhibitors
• Cyclophilin inhibitors

37
Nucleoside Analogue Inhibitors
Active Site
2-methyl nucleosides 4 azido-cytidine
38
Nucleoside Analogues inClinical Development

• R7128 (Pharmasset/Roche)

39
R7128 (Phase Ib)
(Reddy et al., AASLD 2007)
40
R7128 (Phase II)
PegIFN riba placebo
0
PegIFN riba R7128 500 mg bid
PegIFN riba R7128 1500 mg bid
-
1
-
2
Log HCV RNA reduction
-
3
-
4
-
5
-
6
0
5
1
0
1
5
2
0
2
5
3
0
Days
(Lalezari et al., EASL 2008)
41
HCV Resistance to 2-C-Methyl Nucleoside
Inhibitors
2C-Me-ATP in the catalytic site
(Migliaccio et al., J Biol Chem
200327849164-70)
42
Non-Nucleoside Inhibitors (NNI)
NNI site C (Palm) Benzothiadiazine
(A-848837) Acyl-pyrrolidine Proline
sulfonamide Acrylic acid derivatives
NNI site A (Thumb/fingertips) Indoles
Benzimidazoles
A
A
E
B
B
C
C
D
NNI site B (Thumb) Phe derivatives Thiophene-COOH
Dihydroxypirones Pyranoindoles (HCV371)
NNI site E (hypothetical) Imidazopyridines
(GS-9190)
NNI site D (R200 hinge) Benzofurans (HCV086,
HCV796)
43
NNIs Having Reached Clinical Development

• GS-9190 (Gilead)
• Filibuvir (PF-00868554, Pfizer)
• ANA598 (Anadys)
• BI207127 (Boehringer-Ingelheim)
• VCH-916 (Vertex)

44
Antiviral Efficacy of NNIs
45
RdRp Resistance Mutations
(courtesy of Isabel Najera, Roche)
46
NS5A Inhibitors inClinical Development

• BMS-790052 (Bristol-Myers Squibb)

47
BMS-790052NS5A Inhibitor, in vivo efficacy
(Nettles et al., AASLD 2008)
48
Cyclophilins
Cyclophilin A
Cyclophilin B
49
Cyclophilin Inhibitors inClinical Development

• DEBIO-025 (DebioPharm)
• SCY-635 (Scynexis)
• NIM811 (Novartis)

50
DEBIO-025 (Phase Ib)
(Flisiak et al., Hepatology 200847817-26)
51
DEBIO-025 Peg-IFN-?2a Genotypes 1 and 4
0
-
1
10
-
2
Mean log HCV RNA reduction
-
3
-
4
-
5
d
a
y

1
d
a
y

8
d
a
y

1
5
d
a
y

2
2
d
a
y

2
9
(Flisiak et al., Hepatology 200847817-26)
52
DEBIO-025 Peg-IFN-?2a Genotypes 2 and 3
0
-
1
-
2
Mean log HCV RNA reduction
-
3
-
4
-
5
-
6
d
a
y

1
d
a
y

8
d
a
y

1
5
d
a
y

2
2
d
a
y

2
9
(Flisiak et al., Hepatology 200847817-26)
53
Other Cyclophilin Inhibitors

• SCY-635
• -2.2 log maximum HCV RNA decrease over 15 days of
  administration at 900 mg/day
• NIM811
• 600 mg bid had no antiviral effect alone
• 600 mg bid with pegIFN-?2a reduced HCV RNA levels
  by -2.7 log vs -0.6 log for pegIFN-?2a alone,
  over 14 days of administration

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Conclusions

• HCV offers a variety of targets for antiviral
  inhibition
• The mid-term future of HCV therapy is a triple
  combination of one of these inhibitors with
  pegylated IFN and ribavirin
• On the long-term, combinations of safe oral
  inhibitors are expected to yield high cure rates