1. Current and Future Treatment of Chronic Hepatitis C
John Scott, MD, MSc
University of Washington

2. Case
43 yo Asian woman w/ chronic Hep C, GT 1, HCV RNA level of 2 million IU/ml
ALT 53, INR 1.0, Albumin 4.1
Liver biopsy: grade 2 inflammation, stage 2 fibrosis
HTN
What to do next?
Treat now or wait?

3. Outline Epidemiology Natural History Current Therapy -Efficacy
-Side effects
-Mechanism of action
-Kinetics
Future Therapy

4. Epidemiology 3.9-4.1 million Americans are HCV Ab+
May be as high as 7 million
million are chronically infected
Highest prevalence in yo
Highest prevalence in African Americans and Hispanics
CDC. MMWR (RR-19):1-38
Alter M. NEJM :546-52
Armstrong GL. Ann Intern Med :705-14

5. Risk Factors for HCV Injection drug use (60%)
Blood transfusion before 1992
Multiple sex partners
Iatrogenic (hemodialysis, re-use of vials, etc)
Intranasal cocaine
Piercing, tattooing, scarification
Unknown (10%)

7. Evolution of therapy for HCV
~1990’s mid-90’s ~

8. What is Pegylation?
Covalent attachment of polyethelene glycol to peptide
Increases hydrodynamic size
Prolonged circulation, delayed renal clearance
PegIntron (12kd, Schering), Pegasys (40kd, Roche)
Enzon pharmaceutical
Adenosine deaminase
Others: Neulasta (GCSF), doxorubicin

9. Side Effects of PegIFN/Ribavirin
Depression ranging from mild to suicidality
Irritability, aggressive behavior
Worsening of mania
Fatigue
Insomnia
Myalgias, fever, flu-like symptoms
Hair loss
Cytopenias
“Interferon Man”
Slide courtesy Chia Wang

11. The importance of viral kinetics
Scott J and Gretch DR. JAMA 2007.

12. Kinetics and SVR GT 1 (Pegasys + RVN)
Time
HCV RNA status
Wk 4
Neg
<2 log
Any
Wk 12
>2 log
Wk 24
Pos
SVR
91%
60%
43% 2%
Ferenci P. J Hepatol 2005; 43:425-33

13. Mechanism of Action: Interferon
HCV
HCV virions
Interferon alfa
Assembly
IFN receptors
JAK
OAS: activates antiviral RNAses
PKR: inactivates viral ptn translation
ADA: edits viral RNA
HCV replicative
complex
Viral RNA
PKR
ADA
IRF9
STAT
OAS
STAT1
ISG mRNA
ISGF3
ISRE
Adapted from
Hoofnagle J. NEJM 2006

14. Effect of IFN-/Ribavirin
Average HCV RNA level reduction (log IU/ml)
+0.5
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
Group A: untreated
-4.0
Group C: IFN-3 MU tiw
Group D: IFN-3 MU tiw + ribavirin g qd
-4.5
-5.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Days
(Pawlotsky et al., Gastroenterology 2004;126:703-14) slide courtesy of JM Pawlotsky

15. Ribavirin Prevention of Relapse
Treatment
Follow-up 5 *
Continue ribavirin > wk 24 * 4
Stop ribavirin at wk 24 *
% relapse (HCV RNA +) 3
* p<0.05 2
The difference between the two groups progressively increased after treatment withdrawal, with a significantly higher incidence of virological relapse in the group receiving peginterfeorn only as compared to the peginterferon-ribavirin combination group. * * 1 24 30 36 48 52 60 72
Weeks of treatment
(Bronowicki et al., Gastroenterology 2006;131:1040-8) slide courtesy of JM Pawlotsky

16. Ribavirin’s Antiviral Mechanisms
Direct inhibition of HCV RNA-dependent RNA polymerase ?
Depletion of intracellular GTP pools via IMPDH inhibition ?
RNA mutagenesis leading to "error catastrophe" ?

17. Ribavirin Antiviral Mechanisms
2’5’OAS
PKR Mx
ADAR1
ISG20
ISG54
ISG56 … O N H 2 ? ? ?
Slide courtesy JM Pawlotsky

18. Future Therapies Coming soon! (2011?) Potent
Rapid antiviral resistance if used by itself
More side effects

19. HCV Life Cycle: Key Features
Multiple proteins mediate HCV entry:
CD81, Scavenger Receptor B1, Claudin 1, Occludin, Very Low Density Lipoprotein Receptor
Input HCV RNA is translated, a polyprotein is formed, and individual viral proteins are released from polyprotein by cellular and viral proteases
HCV proteins associate with endoplasmic reticulum membranes, the site of HCV replication
Virion assembly occurs at lipid droplets
HCV leaves the cell by hitching a ride on the apolipoprotein B secretion pathway
HCV life cycle is intimately tied with lipid metabolism
Slide courtesy S Polyak

20. HCV Variability RNA virus, RDRP lacks proof-reading function
Mutations arise during replication are not corrected
Genotypes
genetically divergent HCV isolates that can be grouped phylogenetically
Quasispecies
Highly related yet genetically distinct viruses
Slide courtesy S Polyak

21. Drug Development is NOT Easy
one for every 1,000 drugs makes it into humans
One in 5 receive FDA approval
Slide courtesy S Polyak

22. HCV Drug Development * * * * * * * Phase of Development
Preclinical I II III IV
Viral entry inhibitors Hepatitis C immunoglobulin HCIg) HCV-Ab 68 and Ab 65 (monoclonal Ab)
HCV RNA translation inhibitors ISIS (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
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 2007;132: )

23. HCV Lifecycle

24. HCV Lifecycle

25. NS3 Protease Targets Serine proteinase catalytic site
(Pawlotsky JM, Chevaliez S, McHutchison JG, Gastroenterology 2007;132: )

26. NS3 Protease Inhibitors Having Reached Clinical Development
Peptidomimetic inhibitors
BILN 2061 (Boehringer-Ingelheim)
Telaprevir (VX950, Vertex & Tibotec)
Boceprevir (SCH503034, Schering-Plough)
TMC (Tibotec)
ITMN-191 (InterMune)
MK-7009 (Merck)
BI (Boehringer-Ingelheim

27. VX-950 Alone or in Combination with Pegasys: Mean Viral Response1 -2 -3 -4 -1 -5 -6
Baseline
Pegasys + placebo
HCV RNA Change from
Baseline (Log10 IU/mL)
VX-950
Reference:
1. Reesink H et al. Initial Results of a 14-Day Study of the Hepatitis C Virus Protease Inhibitor VX-950, In Combination with PEGASYS. Presented at EASL. April 26-30, Vienna, Austria. Abstract 737.
VX Peg-IFN B 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Study Time (In Days)
Reesink H et al. EASL. April 26-30, 2006.
Vienna, Austria. Abstract 737.
Slide courtesy Roche Medical Affairs
Data have not been reviewed or approved by FDA.

28. Phenotypic Characterization of Telaprevir-Resistant Variants
Highly sensitive clonal method
Detect 5% frequency of variants
Performed at days 4, 8, 12, 14
80 sequences/patient/time point
Wild type
T54A
V36A/M
R155K/T
36/155
A156V/T
Low resistance
High resistance
Adapted from Kieffer T, et al AASLD, Boston, #92

29. Log(10) HCV RNA IU/ml
Days 8 6 4 2 14
Telaprevir
Peginterferon + Ribavirin
LOD = 10 IU/ml
100

30. Telaprevir +
Peg/RVN
Peginterferon + Ribavirin 8 6 4 2
Log(10) HCV RNA IU/ml 14
100
Days
Adapted from Kieffer T, et al AASLD, Boston, #92

31. Telaprevir Plus Pegasys ± Copegus in Naïve G1–PROVE2 (Europe): Study Design
References
Dusheiko GM, Hezode C, Pol S, et al. Treatment of chronic hepatitis C with telaprevir in combination with peginterferon alfa-2a with or without ribavirin: Further interim analysis results of the PROVE 2 study. Presented at EASL April 23-27, 2008; Milan, Italy. Abstract #58 and oral presentation.
Zeuzem S, Hezode C, Ferenci P, et al. Telaprevir in combination with peginterferon-alfa-2a with or without ribavirin in the treatment of chronic hepatitis C: final results of the PROVE2 study. Presented at AASLD Nov 1-4, 2008; San Francisco, CA. Oral presentation #243. 31

32. Telaprevir Plus Pegasys ± Copegus in Naïve G1–PROVE2 (Europe): SVR Rates
Reference
Zeuzem S, Hezode C, Ferenci P, et al. Telaprevir in combination with peginterferon-alfa-2a with or without ribavirin in the treatment of chronic hepatitis C: final results of the PROVE2 study. Presented at AASLD Nov 1-4, 2008; San Francisco, CA. Oral presentation #243. 32

33. PROVE3: Study Design
Reference
McHutchison JG, Shiffman ML, Terrault N, et al. A phase 2b study of telaprevir with peginterferon alfa-2a and ribavirin in hepatitis C genotype 1 non-responders and relapsers following a prior course of peginterferon alfa-2a/b and ribavirin therapy: PROVE3 interim results. Presented at AASLD Nov 1-4, 2008; San Francisco, CA. Oral presentation #269. 33

34. PROVE3: Undetectable HCV RNA at Weeks 4, 12, and 24 (ITT)
Reference
McHutchison JG, Shiffman ML, Terrault N, et al. A phase 2b study of telaprevir with peginterferon alfa-2a and ribavirin in hepatitis C genotype 1 non-responders and relapsers following a prior course of peginterferon alfa-2a/b and ribavirin therapy: PROVE3 interim results. Presented at AASLD Nov 1-4, 2008; San Francisco, CA. Oral presentation #269. 34

35. PROVE3: Undetectable HCV RNA at 12 Weeks Post-treatment (ITT)
Reference
McHutchison JG, Shiffman ML, Terrault N, et al. A phase 2b study of telaprevir with peginterferon alfa-2a and ribavirin in hepatitis C genotype 1 non-responders and relapsers following a prior course of peginterferon alfa-2a/b and ribavirin therapy: PROVE3 interim results. Presented at AASLD Nov 1-4, 2008; San Francisco, CA. Oral presentation #269. 35

36. IFN sparing regimens? Roche: protease + polymerase inhibitor (phase I)
Merck/Schering: protease + polymerase inhibitors

37. Remaining questions Why doesn’t IFN work in some patients?
Is IFN necessary if you have two potent antivirals?
How many antiviral targets are needed and how long is therapy needed?
Target lipid metabolism?

38. Back to the case…
43 yo Asian woman w/ chronic Hep C, GT 1, HCV RNA level of 2 million IU/ml
ALT 53, INR 1.0, Albumin 4.1
Liver biopsy: grade 2 inflammation, stage 2 fibrosis
HTN
What to do next?
Treat now or wait?

39. Thanks! Larry Corey, MD Chia Wang, MD Dave Gretch, MD, PhD
Erica Coppel
Erica Seddig
Wan Chong Qiu
Steve Polyak, PhD
Jean Michel Pawlotsky, MD
Patients
NIH/NCRR