Transcript Document

Programme Information


Target Audience
– This CME activity is designed for
gastroenterologists, hepatologists, and other
clinicians who treat patients with HCV infection.
Activity Goal
– The goal of this activity is to provide state-of-theart, clinically relevant information that will provide
clinicians with new insights into HCV, molecular
approaches to anti-HCV therapy, pipeline protease
and polymerase inhibitors, and enable them to
identify the potential role that these agents may
play in the future.
Learning Objectives

Integrate knowledge of molecular interactions with
HCV at the cellular level and mechanism of action
of protease and polymerase inhibitors to
determine the potential role of these therapies in
HCV patients.

Relate viral kinetics to patient outcomes in
evaluating HCV patient response to therapy.
Learning Objectives (cont’d)


Differentiate potential efficacy and safety
considerations of protease and polymerase
inhibitors, based on preliminary data, as
therapeutic options in the future treatment of
patients with HCV infection.
Assess potential therapeutic strategies involving
protease and polymerase inhibitors to improve
patient response based on preliminary data.
CME Information
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Accreditation Council for Continuing Medical
Education to provide continuing medical
education for physicians.
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
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activity for a maximum of 1.5 AMA PRA Category
1 CreditsTM. Physicians should only claim credit
commensurate with the extent of their participation
in the activity.
– This activity is planned and implemented as an
independent CME activity in accordance with the
ACCME Essential Areas and Policies.
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
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requires that presenters comply with the Updated
Standards for Commercial Support. All faculty are
required to disclose any personal interest or
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supporters of this activity or any commercial interest
that is discussed in their presentation. Any discussions
of unlabeled/unapproved uses of drugs or devices will
also be disclosed in the course materials.

For complete prescribing information on the products
discussed during this CME activity, please see your
current Physicians’ Desk Reference (PDR).
Disclosure Information (cont’d)

Alfredo Alberti, MD, has received grant/research support
from Roche Pharmaceuticals and Schering-Plough
Corporation; is a consultant for Gilead Sciences, Inc, Idenix
Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation,
Roche Pharmaceuticals, Schering-Plough Corporation, and
Vertex Pharmaceuticals Incorporated; and is on the speakers
bureau of Roche Pharmaceuticals and Schering-Plough
Corporation. Dr. Alberti has disclosed that he will reference
unlabeled/unapproved uses of BILN 2061, SCH 503034, and
VX-950.
Disclosure Information (cont’d)

Yves Benhamou, MD, has received grant/research support from
Abbott Laboratories, Gilead Sciences, Inc, Roche Pharmaceuticals,
and Schering-Plough Corporation; is a consultant for Abbott
Laboratories, Boehringer Ingelheim Pharmaceuticals, Inc, Human
Genome Sciences, Idenix Pharmaceuticals Inc, Novartis
Pharmaceuticals Corporation, Roche Pharmaceuticals, ScheringPlough Corporation, Valeant Pharmaceuticals International, and
Vertex Pharmaceuticals Incorporated; and is on the speakers
bureau of Abbott Laboratories, Boehringer Ingelheim
Pharmaceuticals, Inc, GlaxoSmithKline, Human Genome Sciences,
Idenix Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation,
Roche Pharmaceuticals, Schering-Plough Corporation, and Valeant
Pharmaceuticals International. Dr. Benhamou has disclosed that he
will reference unlabeled/unapproved uses of NM-283, R1626,
SCH 503034, and VX-950.
Disclosure Information (cont’d)

John G. McHutchison, MD, FRACP, has received grant/research
support from Coley Pharmaceutical Group, First Circle Medical, Inc,
GlaxoSmithKline, Human Genome Sciences, Idenix Pharmaceuticals Inc,
InterMune Inc, Roche Pharmaceuticals, Schering-Plough Corporation,
SciClone Pharmaceuticals, Valeant Pharmaceuticals International, and
Vertex Pharmaceuticals Incorporated; and is a consultant for or on the
speakers bureau of Anadys Pharmaceuticals, Inc, Aus Bio PTL, Coley
Pharmaceutical Group, First Circle Medical, Inc, GlaxoSmithKline, Human
Genome Sciences, Idenix Pharmaceuticals Inc, National Genetics
Institute, Novartis Pharmaceuticals Corporation, Nucleonics, Inc, Otsuka
America Pharmaceutical, Inc, Peregrine Pharmaceuticals, Inc, Roche
Pharmaceuticals, Schering-Plough Corporation, SciClone
Pharmaceuticals, United Therapeutics, Valeant Pharmaceuticals
International, Vertex Pharmaceuticals Incorporated, and XTL. Dr.
McHutchison has disclosed that he will reference unlabeled/unapproved
uses of NM-283, SCH 503034, and VX-950.
Disclosure Information (cont’d)

Stefan Zeuzem, MD, has received grant/research
support from, is a consultant for, and is on the
speakers bureau of Gilead Sciences, Inc, Idenix
Pharmaceuticals Inc, InterMune Inc, Roche
Pharmaceuticals, Schering-Plough Corporation,
Novartis Pharmaceuticals Corporation, Valeant
Pharmaceuticals International, and Vertex
Pharmaceuticals Incorporated. Dr. Zeuzem has
disclosed that he will reference unlabeled/unapproved
uses of NM-283, SCH 503034, and VX-950.
Disclosure Information (cont’d)



Peer Reviewer has disclosed no significant
relationships.
Projects In Knowledge’s staff members have no
significant relationships to disclose.
Conflicts of interest are thoroughly vetted by the
Executive Committee of Projects In Knowledge.
All conflicts are resolved prior to the beginning
of the activity by the Trust In Knowledge peer
review process.
Disclosure Information (cont’d)


The opinions expressed in this activity are those
of the faculty and do not necessarily reflect
those of Projects In Knowledge.
This CME activity is provided by Projects In
Knowledge solely as an educational service.
Specific patient care decisions are the
responsibility of the clinician caring for the
patient.
This independent CME activity is supported by
an educational grant from
Vertex Pharmaceuticals Incorporated.
Contract for Mutual
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
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Introduction
Alfredo Alberti, MD
Associate Professor
Department of Clinical and Experimental Medicine
University of Padova
Padova, Italy
Current Level of
Therapeutic Success
Acute HCV
Chronic HCV
Genotype 1
Genotype 2/3
Genotype 4
Genotype 5/6
Curable1
~50% SVR2,3
~65–80% SVR2,3,4
>60% SVR5
???
1. Jaeckel E, et al. N Engl J Med. 2001;345:1452. 2. Manns MP, et al. Lancet. 2001;358:958.
3. McHutchison JP, et al. Gastroenterology. 2002;123:1066. 4. Shiffman M, et al. 41st EASL. April 26-30, 2006.
Abstract 734. 5. Kamal SM, et al. Gut. 2005;54:858.
Anti-HCV Treatment Paradigm
is Changing





New interferons
Oral interferon inducers
Ribavirin alternatives
Immune therapies
VIRAL ENZYME INHIBITORS
Viral Enzyme Inhibitors
Emerging Therapies
Viral Enzyme Targets
Polymerase
Protease
Helicase
STAT-C
Specifically Targeted
Anti-Viral Therapy for
HCV
Protease and Polymerase Inhibitors
in Development
Drug
Inhibitor Type
Status
BILN 2061
Protease
Failed
HCV-796
Polymerase
Phase 1
ITMN-191
Protease
Preclinical*
NM-283
Polymerase
Phase 2
R1626
Polymerase
Phase 1
SCH 503034
Protease
Phase 2
VX-950
Protease
Phase 2
*Many others also in preclinical development
STAT-C Agents



Mathematical modeling will allow us to compare the ability
of STAT-C agents to disrupt steady-state HCV replication
kinetics
– Define treatment duration
– Identify and predict emergence of resistance
– Individualize strategies
STAT-C agents are progressing in clinical development
– NM-283, SCH 503034, VX-950 in phase 2 testing
– R1626 in phase I testing
Future role of STAT-C agents may be to meet currently
unmet clinical needs and improve overall standard of care
Modeling, Kinetics, and Resistance
Profiles of New Protease and
Polymerase Inhibitors
Stefan Zeuzem, MD
Professor of Internal Medicine
Department of Internal Medicine, Gastroenterology,
Hepatology, and Endocrinology
University Hospital
Homburg/Saar, Germany
HCV Dynamics
Y
Y
Y
p
Y
Y
b
Y
Y
Y
Virus Infectious Cycle
dT/dt = s–dT–(1–h)bVT
dI/dt = (1–h)bVT–dI
dV/dt = (1–e)pI–cV
b: de novo infection rate
d
c
Degradation
- Antigen-specific
- Unspecific
Cell Death
c: Clearance rate (virions/day)
d: Decay rate of infected cells
d: Decay rate of infectable cells
I: Infected cells
p: Production rate (virions/cell/day)
s: Production rate of infectable cells
T: Infectable cells
V: Viral load
(1 – h): Reduction of de novo infection
(1– e): Reduction of virus production
Herrmann E, et al. Eur J Gastroenterol Hepatol. 2006;18:339. Graphic courtesy of Dr. S. Zeuzem.
Kinetic Analyses in Chronic HCV, HBV,
and HIV Infection
HCV
HBV
HIV
2–5 h
19–38 h
4–8 h
97%–99%
35%–58%
87%–98%
4 x 1010–1 x 1013
5 x 1010–1 x 1013
4 x 108–3 x 1010
2–>70 d
10–30 d
1–3 d
<1%–33%
2%–7%
23%–50%
Virus
Half-life
Daily turnover
Daily production
Infected cells
Half-life
Daily turnover
Hermann E, et al. Antivir Ther. 2000;5:85. Reprinted with permission from International Medical Press.
Modeling
(Peg)Interferon alfa
Phase 1 HCV RNA Decline
10
8
—
—
6
10
4
10
2
HCV RNA (IU/mL)
10
—
0
7
14
Initial 24–48 hours1,2
Extent of decline represents efficacy of
therapy (ε)1,2
Exponential rate corresponds with viral
decay (c)1,2
21
28
35
42
Time (Days)
1. Herrmann E, et al. Antivir Ther. 2000;5:85. 2. Perelson AS, et al. Hepatology. 2005;42:749. Graph courtesy of Dr. S. Zeuzem.
Phase 2 HCV RNA Decline
10
8
—
HCV RNA (IU/mL)
—
10
6
10
4
10
2
—
0
7
14
After 24–48 hours1,2
Exponential rate corresponds to the
loss rate of infected cells (d)1,2
Highly correlated with SVR in
interferon-based therapies
21
28
35
42
Time (Days)
1. Herrmann E, et al. Antivir Ther. 2000;5:85. 2. Perelson AS, et al. Hepatology. 2005;42:749. Graph courtesy of Dr. S. Zeuzem.
Genomic Response to Interferon alfa
Implications of Rapid Downregulation for
Hepatitis C Kinetics

Transcriptional response to interferon alfa in uninfected chimpanzees

1778 genes were altered in expression ≥2 fold
Response partially tissue-specific, 538 and 950 being unique to liver
or PBMC, respectively
Most induced genes achieved maximal response within 4 h, began
to decline by 8 h, and were at baseline levels by 24 h, a time when
high levels of PEG IFN were still present
Rapid downregulation may be involved in the transition between
phase 1 and 2 viral kinetics



PBMC = peripheral blood mononuclear cell
Lanford RE, et al. Hepatology. 2006;43:961.
Modeling
(Peg)Interferon alfa + Ribavirin
Effect of Ribavirin on HCV Kinetics in Patients
Treated with Peginterferon alfa-2a
Peginterferon alfa
Monotherapy
Copies/mL
107
105
103
Peginterferon alfa
+ Ribavirin
Copies/mL
107
105
103
Zeuzem, S. Unpublished data.
0
7
14 21 28 35 42 49 56
Days
0
7
14 21 28 35 42 49 56
Days
Viral Kinetic Parameters in Patients
Treated with Peginterferon alfa ± RBV
PEG IFN/RBV
PEG IFN
IFN/RBV
8/10
9/17
4/7
Efficiency factor (ε)
0.67 ± 0.3
0.63 ± 0.3
0.36 ± 0.3
Degradation rate (c)
4.7 ± 2.6
3.7 ± 2.3
4.9 ± 3.6
Death rate (d)
0.05 ± 0.1
0.02 ± 0.04
0.08 ± 0.1
New death rate (Md)
0.51 ± 0.6
0.22 ± 0.3
0.24 ± 0.3
Start of 3rd phase
16 ± 10
18 ± 9
15 ± 8
V1 at 3rd phase
4.9 ± 0.6
5.2 ± 0.8
5.2 ± 0.5
Triphasic decay
Herrmann E, et al. Hepatology. 2003;37:1351. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.
Modeling
Protease Inhibitors
HCV Protease Inhibitor BILN 2061
Virologic Efficacy in HCV-1 Phase 1 Study
BILN 2061
HCV RNA (IU/mL)
10,000,000
Placebo
1,000,000
100,000
BILN 2061
Placebo
Treatment-naive
Nonresponders
10,000
1000
0
2
4
6
8
Days
Reprinted from Hinrichsen H, et al. Gastroenterology. 2004;127:1347-1355, with permission from Elsevier.
Viral Kinetics in Patients Treated with
PEG IFN or Protease Inhibitor
Kinetics in Patients Treated with PEG IFN + RBV1
C=7.0, d=0.84, Є=0.925 106
104
104
102
102
0
1
2
Days
3
4
5
C=2.7, d=0.51, Є=0.702
0
1
2
Days
3
4
5
Kinetics in Patients Treated with BILN 20612
C=5,4, d=0.01, Є=0.999 106
C=8.0, d=0.37, Є=0.997
HCV RNA (IU/mL)
HCV RNA (IU/mL)
106
106
104
104
102
102
0
1
2
Days
3
4
5
0
1
2
Days
3
4
1. Zeuzem S, et al. Unpublished data. 2. Herrmann E, et al. Antivir Ther. 2006;11:371. Reprinted with permission from International
Medical Press.
5
Phase 1 and 2 Summary


Phase 1 HCV RNA decline represents direct inhibition of
viral replication by interferon alfa
– Mathematical modeling
– In vitro studies (replicon)
– Direct antiviral substances
Phase 2 HCV RNA decline represents elimination of
infected cells
– Mathematical modeling
– Direct antiviral substances
New HCV Inhibitors
Drug Targets and Resistance
Specific Inhibitors of HCV

NS3 protease

NS3 helicase

NS3 bifunctional
protease/helicase

NS5B RNA-dependent
RNA polymerase
NM-283 +/- PEG IFN Phase 2a Study
Week 12 Viral Response
Mean Serum HCV RNA: Change
from Baseline (log10 IU/mL)
Patients with Data Past Week 1 (n = 28)
Week 12
= day 85

0
-0.5
-1
NM-283 (n = 12)
-1.5
- 0.87 log10 IU/mL
-2
-2.5
-3
NM-283 + PEG IFN -2b 1.0 g/kg
(n = 16)
-3.5
- 3.01 log10 IU/mL
-4
-4.5
-5
0
10
20
30
40
50
60
70
Study Day
NM-283 + PEG IFN at week 12:12 patients > 1.7 log10 reduction; 4 PCR negative
Reprinted from Afdhal N, et al. J Hepatol. 2005;42:A93, with permission from Elsevier.
80
90
VX-950 750 mg q8h
Individual Change from Baseline HCV RNA
1
Median, placebo group
0.0
0
*
HCV RNA Change from
Baseline (Log10 IU/mL)
-1
-2
-1.0
-2.0
-3
-3.0
-4
-4.0
-5
-5.0
-6
-6.0
*
-7
0
1
2
Lowest VX-950 exposure in dose group
3
4
5
6
7
8
-7.0
9
10
11
12
13
Study Time (Days)
Reesink HW, Zeuzem S, et al. DDW May 14–19, 2005. Abstract 527. Reprinted with permission from Dr. S. Zeuzem
14
Protease Inhibitor Resistance
VX-950
PI Resistance: Alanin 156
• Reversible, covalent warhead motif
• Ki, at steady state: 3 nM
BILN 2061
PI Resistance: Asparagin 168
• Reversible binding
• Competitive
• Noncovalent
• Ki: 7.5 nM
VX-950
BILN 2061
Lin C, et al. J Biol Chem. 2004;279:17508. Reprinted with permission.
Sensitivity of Variant Proteases to VX-950
A156T/V
Upper Limit of
Assay
V36M/
A156T
Enzyme IC50 (nM)
10,000
Upper Limit of
Assay
10
A156S
T54A
1000
1b
T54S
100
R155K/M/S/T
V36M/L/A
V36A/M+
R155K/T
1
Wild-Type
Sensitivity
1a
10
100
Wildtype
0.1
Single Amino Acid Change
Double Change
Kieffer T, et al. 41st EASL. April 26-30, 2006. Abstract 12. Reprinted with permission from Dr. T. Kieffer and Dr. S. Zeuzem.
Replicon Cell IC50 (µM)
100,000
Combination Therapy
Peginterferon alfa
+ Protease Inhibitor
+/- Ribavirin
SCH 503034 + PEG IFN
Mean HCV RNA Change (Log10)
Median HCV RNA Change in HCV-1 Nonresponders
PEG IFN alfa-2b
alone (n = 22)
0
Mean, -1.1
-0.5
PEG IFN alfa-2b
+ SCH 503034
200 mg TID
(n = 12)
-1
-1.5
PEG IFN alfa-2b
+ SCH 503034
400 mg TID
(n = 12)
Mean, -2.4
-2
-2.5
-3
0
Mean, -2.9
5
10
Treatment Day
15
SCH 503034 alone (not pictured)
200 mg TID monotherapy: range 0.4–1.77
400 mg TID monotherapy: range 0.5–2.5
Zeuzem S, et al. Hepatology. 2005;42:276A. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.
VX-950 750 mg q8h + PEG IFN, Phase 1b
Individual HCV RNA Curves
HCV RNA (Log10 IU/mL)
8
7
6
5
4
3
2
Limit of Quantitation
1
Limit of Detection
0
B
1
2
3
4
5
6
7
8
9
10
Study Time (Days)
11 12
13 14
Reesink HW, et al. 41st EASL. April 26-30, 2006. Abstract 737. Reprinted with permission from Dr. Reesink.
15
VX-950 + PEG IFN alfa-2a/RBV
HCV RNA in HCV-1 Treatment-Naïve Patients, Phase 2b
N = 12
8
7
HCV RNA (Log10 IU/mL)
median
6
5
4
3
2
Limit of Quantitation
1
Limit of Detection
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Study Time (in Days)
Lawitz EJ, et al. DDW 2006. May 20–25, 2006. Abstract 686.
HCV RNA (IU/mL)
Prediction of Treatment Duration
to Achieve SVR
10
6
Limit of HCV RNA Detection
10
0
10
-x
0
Fictitious Threshold
to Achieve SVR
4
8
12
Time (Weeks)
Zeuzem, S. Unpublished data.
16
20
24
Open Questions






Duration of combination therapy to achieve SVR?
Emergence of resistant strains during combination therapy
(protease inhibitor, PEG IFN, ribavirin)?
Viral fitness of mutant strains in vivo and sensitivity to
PEG IFN ± RBV?
Slope of phase 2/3 constant below the level of HCV RNA
quantification?
Extrahepatic replication sites (different accessibility of
different antiviral drugs)?
Restoration of (innate) immunity and response to IFN during
anti-HCV protease inhibitors?
Conclusions



Current mathematical models are at best an
approximation of the biological situation and require
further refinement
Mathematical modeling cannot substitute for appropriate
clinical studies, but can help to ask the right questions
Viral kinetics allow for direct assessment and
comparison of the efficacy of antivirals
– May help to define duration of therapy
– May help to individualize antiviral strategies
Update on Current
Clinical Trial Results
Yves Benhamou, MD
Praticien Hospitalier
Service d’Hepato-Gastro-Enterologie
Groupe Hospitalier Pitié-Salpêtrière
Paris, France
Anti-HCV Therapeutic Approaches
STAT-C
Improving existing drugs
Tailoring therapy
with existing drugs
Viramidine
Albumin-interferon alfa
TLR
2006
Courtesy of Dr. Y. Benhamou.
2007?
2009
-R1626
-NM-283
-SCH 503034
-VX-950
Fibrogenesis
inhibitors
2010
2011
R1626
R1626 Phase 1b Study in HCV-1
Treatment-Naïve Patients
Change in HCV RNA from Baseline
Mean viral load decrease at day 14, 1500 mg: 1.2 log10 (0.5 to 2.5)
Treatment
Mean HCV RNA (log10)
Decrease from Baseline
1.0
Follow-up
Placebo (n = 5)
500 mg (n = 9)
0.5
1500 mg (n = 9)
0.0
-0.5
-1.0
-1.5
-2.0
0
5
10
15
20
Study Day
25
30
Roberts S, et al. 41st EASL. April 26-30, 2006. Abstract 731. Reprinted with permission from Dr. Roberts.
R1626 Phase 1b Study in HCV-1
Treatment-Naïve Patients
Change in Haemoglobin from Baseline
Mild decrease in Haemoglobin at day 14, 1500 mg: 0.8g/dL*
1.0
Mean haemoglobin Change
from Baseline (g/dL)
Follow-up
Treatment
Placebo (n = 5)
500 mg (n = 9)
0.5
1500 mg (n = 9)
0.0
-0.5
}
-1.0
-08 g/dL
-1.5
-2.0
0
5
10
15
20
Study Day
25
30
*relative to placebo
Roberts S, et al. 41st EASL. April 26-30, 2006. Abstract 731. Reprinted with permission from Dr. Roberts.
Valopicitabine (NM-283)
NM-283 Phase 2b Study in
HCV-1 Treatment-Naïve Patients
Initial Study Design
Baseline
A
Week 1
No treatment
Week 4
PEG IFN-α only
Week 48
PEG IFN-α + 800 mg NM-283
Week 72
Follow-up
B
200 mg
NM-283 QD
PEG IFN-α + 200 mg NM-283
Follow-up
C
400→800 mg
NM-283 QD
PEG IFN-α + 800 mg NM-283
Follow-up
D
800 mg
NM-283 QD
PEG IFN-α + 800 mg NM-283
Follow-up
PEG IFN-α + 800 mg NM-283
Follow-up
E
Dieterich DT, et al. 41st EASL. April 26-30, 2006. Abstract 736. Reprinted with permission from Dr. Dieterich.
NM-283 in HCV-1 Treatment-Naïve Patients
Convergence of HCV RNA Reductions by Week 12
PEG IFN-α
initiated in
arms A–D
Mean log10 Reduction in HCV RNA
from Baseline (IU/mL)
1
0
-1
NM 283 started for Group A
No PEG IFN-α alone
arm after week 4
-2
EVR* (%)
-3
-4
-5
0
A
B
C
D
E
2
4
-3.93 log10
-3.99 log10
-4.27 log10
-4.32 log10
-4.46 log10
B: 87%
E: 81%
A: 87%
C: 94%
D: 90%
6
8
10
12
Weeks
Week 12 (partial data)
PEG IFN 180 µg QW @ d8 + NM-283 400→800 mg QD @ d29
(n = 30)
NM-283 200 mg QD @ d1 + PEG IFN 180 µg QW @ d8
(n = 31)
NM-283 400→800 mg QD ramp @ D1 + PEG IFN 180 µg QW @ d8
(n = 31)
NM-283 800 mg QD @ d1 + PEG IFN 180 µg QW @ d8
(n = 30)
NM-283 800 mg QD @ d1 + PEG IFN 180 µg QW @ d1
(n = 31)
*EVR = Early virologic response
Dieterich DT, et al. 41st EASL. April 26-30, 2006. Abstract 736. Reprinted with permission from Dr. Dieterich.
NM-283 in HCV-1 Treatment-Naïve Patients
HCV RNA at Weeks 12 and 16
HCV RNA PCR Negative,
Patients (%)
90
83
80
70
70
71
77
77
73
80
76
67
65
Solid Bars
<600 IU/mL
(Amplicor detection limit)
60
50
40
30
67
60
20
45
48
B
C
52
61
62
72
60
50
Shaded Bars
<20 IU/mL
(Taqman detection limit)
10
0
A
Week 12
D
E
A
B
C
D
E
Week 16
A PEG IFN 180 µg QW @ d8 + NM-283 400→800 mg QD @ d29
B NM-283 200 mg QD @ d1 + PEG IFN 180 µg QW @ d8
C NM-283 400→800 mg QD ramp @ D1 + PEG IFN 180 µg QW @ d8
D NM-283 800 mg QD @ d1 + PEG IFN 180 µg QW @ d8
E NM-283 800 mg QD @ d1 + PEG IFN 180 µg QW @ d1
Dieterich DT, et al. 41st EASL. April 26-30, 2006. Abstract 736. Reprinted with permission from Dr. Dieterich.
NM-283 Phase 2b Study in
HCV-1 Nonresponders
Initial Study Design
Baseline
Week 1
A
Week 48
Week 72
800 mg NM-283 monotherapy
Follow-up
B
400 mg
NM-283 QD
PEG IFN-α + 400 mg NM-283
Follow-up
C
400→800 mg
NM-283 QD
PEG IFN-α + 800 mg NM-283
Follow-up
D
800 mg
NM-283 QD
PEG IFN-α + 800 mg NM-283
Follow-up
No
treatment
PEG IFN-α + 1000–1200 mg ribavirin
Follow-up
E
Afdhal N, et al. 41st EASL. April 26-30, 2006. Abstract 39. Reprinted with permission from Dr. Afdhal.
NM-283 in HCV-1 Nonresponders
Mean Reduction HCV RNA to Week 24
Serum HCV RNA
(Mean Log10 Change from Baseline)
0
Wk 12–24 (n = 7)
A 0.46 log
-0.5
-1
-1.5
-2
E 2.27 log
B 2.45 log
-2.5
-3
C 2.99 log
D 3.29 log
-3.5
0
6
12
18
24
30
Study Week
A
B
C
D
E
NM-283 800 mg QD
NM-283 400 mg QD + PEG IFN 180 µg QW
NM-283 400→800 mg QD ramp (1st week)→ 800 mg QD + PEG IFN 180 µg QW (n = 41)
NM-283 800 mg QD + PEG IFN 180 µg QW
Ribavirin + PEG IFN 180 µg QW @ d8
Afdhal N, et al. 41st EASL. April 26-30, 2006. Abstract 39. Reprinted with permission from Dr. Afdhal.
(n = 21)
(n = 41)
(n = 41)
(n = 34)
n = ITT Population
NM-283 Development
Next Steps




200–400 mg NM-283 doses chosen for further study in
treatment-naïve patients
Ribavirin/NM-283 interaction study expected to start
in 2006
Potential investigation of double and triple regimens in
phase 3 clinical trials
– NM-283 + PEG IFN + ribavirin
GI adverse effects common with initial dosing
– Studies of high dosing in animal model under way to
evaluate mechanism and prevention of GI toxicity
SCH 503034
SCH 503034 Monotherapy Phase 1b Study
Dose-Related Antiviral Response in
HCV-1 Nonresponders
Max HCV RNA Log10 Reductions
(n)
Treatment
n
≤1
>1–2
>2–3
Placebo
16
10
6
0
100 mg BID
12
8
3
1
200 mg BID
12
6
4
2
400 mg BID
11
2
7
2
400 mg TID
10
0
4
6
Zeuzem S, et al. Hepatology. 2005;42:233A. Reprinted with permission from Dr. Zeuzem.
SCH 503034 + PEG IFN alfa-2b
in HCV-1 Nonresponders
Phase 1b Study Design




3-way crossover design
Random sequence
Open label
3-wk washout between
treatments
Genotype 1,
refractory to
PEG IFN ± RBV
Zeuzem S, et al. Hepatology. 2005;42:276A.
A. SCH 503034
200 or 400 mg TID
as monotherapy
for 7 days
B. PEG IFN alfa-2b
1.5 g/kg/QW
as monotherapy
for 14 days
A+B
Combination therapy
for 14 days
SCH 503034 +/- PEG IFN
Antiviral Activity in HCV-1 PEG IFN
Nonresponders
HCV RNA Change
PEG IFN alfa-2b (n = 22)
Mean
PEG IFN alfa-2b + SCH 503034 200 mg TID (n = 12)
Range
PEG IFN alfa-2b + SCH 503034 400 mg TID (n = 12)
-1.1
SCH 503034 alone (not pictured)
200 mg TID
-0.4 to
-1.77
400 mg TID
-0.5 to
-2.5
SCH 503034 + PEG IFN
200 mg TID
-2.4
-1 to
-4.5
400 mg TID
-2.9
-2.3 to
-4.1
Mean HCV RNA Change (Log10)
PEG IFN alone
0
Mean, -1.1
-0.5
-1
-1.5
Mean, -2.4
-2
-2.5
-3
Mean, -2.9
0
5
10
15
Treatment Day
Zeuzem S, et al. Hepatology. 2005;42:276A. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.
SCH 503034 + PEG IFN
Undetectable HCV RNA in HCV-1 Nonresponders


Endpoint HCV RNA undetectable (<29 IU/mL) at day 14
– SCH 503034 (400 mg TID) + PEG IFN alfa-2b
 4/10 patients in the 400 mg
– PEG IFN alfa-2b
 0/22 patients
AE profile for combination treatment was
similar to PEG IFN
Zeuzem S, et al. Hepatology. 2005;42:276A.
SCH 503034 + PEG IFN ± RBV
Phase 2 Study Design




Dose-finding study in PEG IFN/RBV nonresponders
Study design: randomized, double-blind,
placebo-controlled, parallel assignment, safety/efficacy
study
– 300 patients
– 24 or 48 weeks
– SCH 503034 + PEG IFN alfa-2b +/- RBV
Eligibility
– Age: 18–65 years
– Genders: both
Enrollment completed
http://www.clinicaltrials.gov/ct/show/NCT00160251?order=1.
VX-950
VX-950 Monotherapy
Undetectable HCV RNA at Day 14
HCV RNA*
<30 IU/mL
HCV RNA*
<10 IU/mL
450 mg q8h
(n = 10)
1
0
750 mg q8h
(n = 8)
4
2
1250 mg q12h
(n = 10)
0
0
*COBAS Taqman HCV RNA assay, Roche Molecular Diagnostics
Reesink HW, et al. Hepatology. 2005;42:234A. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.
VX-950 750 mg q8h + PEG IFN, Phase 1b
Median Change from Baseline HCV RNA
1
HCV RNA Change from
Baseline (Log10 IU/mL)
0
Baseline
-1
PEG IFN alfa-2a +
placebo
-2
-3
-4
VX-950
-5
VX-950 +
PEG-IFN alfa-2a
-6
B
1
2
3
4
5
6
7
8
9
10
11
12 13 14
Study Time (Days)
Reesink HW, et al. 41st EASL. April 26-30, 2006. Abstract 737. Reprinted with permission from Dr. Reesink.
VX-950 750 mg q8h + PEG IFN, Phase 1b
Individual HCV RNA Curves
HCV RNA (Log10 IU/mL)
8
7
6
5
4
3
2
Limit of Quantitation
1
Limit of Detection
0
B
1
2
3
4
5
6
7
8
9
10
Study Time (Days)
11 12
13 14
Reesink HW, et al. 41st EASL. April 26-30, 2006. Abstract 737. Reprinted with permission from Dr. Reesink.
15
VX-950 + PEG IFN alfa-2a/RBV
HCV RNA in HCV-1 Treatment-Naïve Patients,
Phase 2b
N = 12
HCV RNA *
<30 IU/mL
HCV RNA*
<10 IU/mL
Week 1
6/12
2/12
Week 2
11/12
3/12
Week 3
12/12
9/12
Week 4
12/12
12/12
*COBAS Taqman HCV RNA assay, Roche Molecular Diagnostics
Lawitz EJ, et al. DDW 2006. May 20–25, 2006. Abstract 686.
VX-950 + PEG IFN ± RBV
Phase 2b Studies
HCV-1 Treatment-Naïve (N = 580)
Patients in the 12 & 24 W arms and

HCV RNA < 10 UI/mL @ W4 – W10 & W20
– Stop @ W12 or W24

HCV RNA > 10 UI/mL @ W4 – W10 & W20
– PEG/RBV until W48
Vertex Pharmaceuticals Incorporated. Press release; May 23, 2006. Available at: http://www.vpharm.com/Pressreleases2006/pr052306.html.
VX-950 + PEG IFN ± RBV
Phase 2b Studies
HCV-1 Treatment-Naïve (N = 580)
Phase II Studies for VX-950
Patients in
PROVE 2
Total
20
80
100
12-week regimens of VX-950 in combination with only peg-IFN)
0
80
80
12-week regimens of VX-950 in combination with peg-IFN and
RBV, followed by 12 weeks of therapy with peg-IFN and RBV
80
80
160
12-week regimens of VX-950 in combination with peg-IFN
and RBV, followed by 36 weeks of therapy with peg-IFN and RBV
80
0
80
Standard of Care HCV Treatment
80
80
160
260
320
580
Treatment Regimen
12-week regimens of VX-950 in combination with
peglyated interferon (peg-IFN) and ribavirin (RBV)
Total
Patients in
PROVE 1
Vertex Pharmaceuticals Incorporated. Press release; May 23, 2006. Available at: http://www.vpharm.com/Pressreleases2006/pr052306.html.
VX-950
Summary




VX-950 750 mg q8h, 14 days
Monotherapy
– >4-log reduction in median HCV RNA1
– Rebound or plateau in 4/8 patients2
Combination with PEG IFN alfa-2a3
– 5.5-log reduction in median HCV RNA
– No rebound observed
Combination with PEG IFN alfa-2a and RBV4
– All patients <10 IU/mL by day 14
1. Reesink HW, et al. Hepatology. 2005;42:234A. 2. Reesink HW, et al. 41st EASL. April 26-30, 2006. Abstract 737.
3. Reesink HW, et al. 41st EASL. April 26-30, 2006. Abstract 737. 4. Lawitz EJ, et al. DDW 2006. May 20–25, 2006. Abstract 686.
Conclusion




STAT-C
– Promising in the treatment of chronic HCV
genotype 1
– Next step: phases 2b/3
 Dose selection and duration of therapy
 Registration 2009–2010?
Interferon will remain the backbone of anti-HCV therapy
for many years
Role of RBV in future strategies?
Treatment of nongenotype 1: PEG IFN + RBV
Clinical Implications of
Treatment Paradigm Shifts
in HCV
John G. McHutchison, MD, FRACP
Professor of Medicine
Duke Clinical Research Institute and
Division of GI/Hepatology
Duke University Medical Center
Durham, North Carolina
Viral Enzyme Inhibitors
Emerging Therapies
Viral Enzyme Inhibitors
Polymerase
Protease
Helicase
STAT-C
Specifically Targeted
Anti-Viral Therapy for
HCV
New STAT-C Drugs
Goals of Future Therapy: 2006–2010

Multiple drugs and mechanism of action

Effective across a range of genotypes

Enhanced response

Decreased duration

Improved tolerability

Diminished resistance

Applicable to difficult-to-treat populations

How will they eventually be used?
Can STAT-C Drugs Be Designed That
Are Equally Effective
Across Genotypes?
10,00,000
HCV RNA (IU/mL)
Phase 11
BILN 2061
Placebo
1,000,000
100,000
BILN 2061 Rx
Placebo
Tx-Naïve
Non responders
10,000
1,000
0
2
4
6
8
Days
1. Reprinted from Hinrichsen H, et al. Gastroenterology. 2004;127:1347, with permission from Elsevier.
2. Reiser M, et al. Hepatology. 2005;41:832.
Rates of Early Viral Clearance Predict
SVR with PEG IFN/RBV
Patients with SVR (%)
100
91
80
PEG IFN -2a 180 µg QW
+ RBV 1000–1200 mg/d
72
60
60
48
43
40
20
0
HCV RNA Status
Week 4
Negative
Week 12
Negative
Week 24
Negative
≥2 log 
Negative
Negative
<2 log 
Negative
Negative
≥2 log 
≥2 log 
Negative
Reprinted from Ferenci P, et al. J Hepatol. 2005;43:4251, with permission from Elsevier.
<2 log 
≥2 log 
Negative
STAT-C Triple Therapy
PEG IFN alfa-2a + RBV + VX-950
RVR rates exceed those with PEG IFN/RBV
PCR +
PCR -*
12
No. Patients
10
8
Week 4 RVR = 100%
6
Week 4 RVR
PEG IFN/RBV  10%
4
2
0
1
2
3
Week
4
*PCR neg is <10 IU/mL
RVR = Rapid virologic response
Lawitz EJ, et al. DDW 2006. May 20–25, 2006. Abstract 686. Graphic courtesy of Dr. J. McHutchison.
Applying HCV Kinetics to Future Therapies
Can We Shorten Therapy?
Viral Load (log IU/mL)
7 Lag
6
Blocking Virion Production
1st phase
5 1011–1012
High Viral Burden
4
2nd phase
Net Loss Infected Cells
3
Half-Life Measured in Hours
2
1
0
Cutoff
1
2
3
14
7
Days
Neumann AU, et al. Science. 1998;282:103. Graphic courtesy of Dr. J. McHutchison.
T(n)
The “Accordion” Effect in anti-HCV Therapy
The Earlier HCV RNA Clears, the Shorter the Treatment Required
Start
HCV RNA neg
End of Treatment
How much will this effect pertain to STAT-C therapies?
Courtesy of Dr. I. Jacobson.
HCV Evades the Immune Response—
Can We Replace/Dispense Interferon?
X
X
X
X
X
X
X
X
X
X X
X
X
Adapted from Rehermann, B, et al. Nat Rev Immunol. 2005;5:215. Reprinted with permission.
X
Mechanisms of Action of
Interferon on HCV

Antiviral but not via replication complex

Induction of IFN-stimulated genes (ISGs)
– Produces a non–virus-specific antiviral state

Inhibits translation of viral proteins

May decrease RNA stability
Feld JJ, et al. Nature. 2005;436:967.
Mechanisms of Action of
HCV on Interferon

HCV protease blocks IFN-regulatory factor 3 (IRF-3)

HCV protease blocks retinoic-acid-inducible gene 1 (RIG-1)

Certain proteins interfere with IFN signaling
Feld JJ, et al. Nature. 2005;436:967.
Future of Ribavirin
Can it Be Discarded or Replaced?



Ribavirin effects
– Increases end-of-treatment response
– Decreases relapse
– Small effect on early viral kinetics
Next steps
– Prove its redundancy
– Prove relapse is not dependent on ribavirin
– Consider nucleoside analog issues
– Perform studies
Then, and only then, dispense with ribavirin
Prevention of Viral Resistance





Maximally reduce virus replication
– Use of highly potent antiviral
Raise the “pharmacologic barrier” to viral escape
– High trough levels
– Tissue distribution that permits no sanctuaries
– Optimal patient adherence
Raise the “genetic barrier” to viral escape
– Combination therapies
Forseeable, unavoidable, preventable
Must be tested for thoroughly and systematically
Detecting Resistance is a Function
of How Carefully you Look
Probability of Detecting a Minority Clone
No. of clones analysed
75%
85%
90%
95%
10
13%
17%
21%
26%
12
11%
15%
17%
22%
20
7%
9%
11%
14%
30
5%
6%
7%
10%
40
3%
5%
6%
7%
50
3%
4%
5%
6%
60
2%
3%
4%
5%
70
2%
3%
3%
4%
80
2%
2%
3%
4%
90
2%
2%
3%
3%
100
1%
2%
2%
3%
Courtesy of Dr. J. McHutchison.
STAT-C Agents in Combination
with PEG IFN +/- RBV

Greater antiviral effect compared with monotherapy

Reduced development of resistance

Reduced duration of therapy
NS3/4A Interference with the
Innate Immune Response to HCV
A Viral On/Off Switch for Interferon – Is the Protease a Better Target for this Reason?
X
Adapted with permission from Williams BRG, et al. Science. 2003;300:1100. Copyright 2003, AAAS.
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HCV Protease Inhibitors Have
Significant Viral Load Reductions
1
HCV RNA Change from
Baseline (Log10 IU/mL)
0
Baseline
-1
PEG IFN alfa-2a +
placebo
-2
-3
-4
VX-950
-5
VX-950 +
PEG-IFN alfa-2a
-6
B
1
2
3
4
5
6
7
8
9
10
11
12 13 14
Study Time (Days)
Reesink HW, et al. 41st EASL. April 26–30, 2006. Abstract 737. Reprinted with permission from Dr. Reesink .
HCV RNA-dependent RNA Polymerase
Thumb
Fingers
Flap
Palm
Butcher SJ, et al. Nature. 2001;410:235. Reprinted with permission.
•
•
•
•
•
Unique shape
3 closely related domains
Large binding cleft
Highly conserved across genotypes
No mammalian RdRp
HCV Polymerase Inhibitors To Date All
Have Similar Viral Load Reductions
14 days, monotherapy
NM-2831
Polymerase Inhibitors
R16262
HCV-7963
-1 log
>2.5–5.5 logs
Protease inhibitors
1. Godofsky E, et al. DDW 2004. May 15–20, 2004. Abstract 407. 2. Roberts S, et al. 41st EASL. April 26–30, 2006. Abstract 731.
3. Chandra P, et al. DDW 2006. May 20–25, 2006. Abstract 1.
Development of HCV Direct
Enzyme Inhibitors
Dual Time Frames


Short-term development for unmet medical needs
– Decompensated cirrhosis
– Nonresponders to previous treatments
– Prevention of recurrent HCV after liver transplant
– Acute hepatitis C
– End-stage renal disease
– Hard-to-treat patients: HIV/HCV, recurrent HCV
– Hemoglobinopathies, cytopenia, thalassemia
Long-term development for improving standard of care
– Combined with PEG IFN +/- RBV
New STAT-C Antiviral Agents
as Monotherapy?





Patients with advanced liver cirrhosis
Patients with contraindications to or intolerant
of IFN or RBV
Patients with difficulty adhering to PEG IFN/RBV
therapy
High likelihood of drug resistance
Transplant patients
– Possible prevention of reinfection
of the donor liver?
Predictors of Adherence to
HCV Therapy1,2
How will this apply to STAT-C?
Increase
Decrease
No Effect
Patient belief
in treatment
Active IVDU
or EtOH
Race
Provider
experience
Active
psychiatric
disease
Social supports
Adherence to visits
Gender
Inactive IVDU
Disease stage
Side effects
1. Gebo KA, et al. 8th CROI; February 5–8, 2001. Abstract 477. 2. Ostrow D, et al. 8th CROI: February 5–8, 2001. Abstract 484.
STAT-C
Likely Picture—Near Future
Viral Enzyme
Inhibitors
±
RBV or
Related Drugs
±
Immune
Modulation
Interferon as a Platform for Future Combinations
STAT-C
Likely Picture—Future
Potent Viral
Enzyme Inhibitors







±
Other Viral Enzyme
Inhibitors
- Same Class?
- Different Class?
±
Immune
Modulator
Will an immunologic component always be needed to eradicate infection?
Will there be synergy between drugs of various potencies & different classes?
Can we develop new rules for very rapid viral response that predict SVR?
How much can therapy be truncated?
Will q8h or q6h dosing of STAT-C drugs be feasible?
Will monotherapy ever be sufficiently effective for clinical use?
What are the most effective strategies to prevent resistance?
Conclusion

Exciting advances in anti-HCV treatment

Much work to be done

Clinical algorithms will need to be established

Goals for future therapies
– Greater efficacy and applicability
– Improved tolerability
– Translate into community settings and practice
guidelines
Questions & Answers
Conclusion
Alfredo Alberti, MD
Modeling, Kinetics, and Resistance
Profiles of New Protease and
Polymerase Inhibitors



Steady-state HCV kinetics involves equilibrium between
infected cells, uninfected cells, and circulating virions
Mathematical modeling of HCV therapies helps in identifying
relevant questions but cannot give definitive answers
STAT-C agents exhibit different HCV RNA kinetics compared
with each other and compared with interferon alfa
– Emergence of resistance cannot be modeled
Update on Current Clinical
Trial Results



Interferon will remain the backbone of anti-HCV treatment
for many years but STAT-C drugs show significant
potential for future treatment of HCV
Three direct viral enzyme inhibitors—NM-283,
SCH 503034, and VX-950—are now in phase 2 testing
– Have demonstrated potent antiviral effects in
genotype 1 infection, particularly when administered in
combination with peginterferon
Other targeted drugs, such as R1626, are still in phase 1
testing but show promising preliminary antiviral effects
Clinical Implications of Treatment
Paradigm Shifts in HCV




Many clinical needs remain unmet by current therapy
– Enhanced response in genotype 1 and other hard-to-treat
infection, decreased duration of therapy, and improved tolerability
As alternatives to or in combination with peginterferon with or without
ribavirin, STAT-C agents may have dual role
– Meet these unmet clinical needs
– Improve overall standard of care
Resistance to STAT-C agents is foreseeable and unavoidable, but also
preventable
Questions answered and future role of STAT-C agents defined through
ongoing clinical development