1. Direct Acting Antivirals: What are they
Direct Acting Antivirals: What are they? What is their place in HCV management?
Mark Sulkowski, MD
Associate Professor of Medicine Johns Hopkins University School of Medicine

2. Limitations of PegIFN + Ribavirin (with or without protease inhibitors)
Antiviral activity is host + virus genotype dependent
IL28B CC genotype > TC and TT
Safety and tolerability risk outweighs treatment benefit for some individuals
“IFN unwilling and/or unable”
Finite number of expert healthcare providers
Cost

3. Therapeutic Targets for DAAs
Prevent viral entry
Polyclonal and monoclonal antibodies
SRB1 receptor blockers
Prevent translation of viral RNA
NS3/4 protease inhibitors
Inhibit HCV-RNA polymerase
Nucleoside analogue NS5B polymerase inhibitors
Non-nucleoside analogue NS5B polymerase inhibitors
NS5A inhibitor
Cyclophilin B inhibitors
Viral assembly/release
Slide: HCV Life Cycle and Targets for STAT-C/DAAs
This slide shows a schematic diagram of the HCV life cycle and potential drug targets for STAT-C drugs.1
Prevent viral entry: polyclonal and monoclonal antibodies
Prevent translation of viral RNA: NS3/4 protease inhibitors and NS3-NS4A inhibitors.
Inhibit HCV-RNA polymerase: nucleoside analogue NS5B polymerase inhibitors, non-nucleoside analogue NS5B polymerase inhibitors, NS5A inhibitor, and cyclophilin B inhibitors.
Viral assembly/release: glucosidase inhibitor.
Reference
Pereira AA, Jacobson IM. New and experimental therapies for HCV. Nat Rev Gastroenterol Hepatol. 2009;6:
Pereira AA, et al. Nat Rev Gastroenterol Hepatol. 2009;6:

4. Direct Acting Antivirals for Hepatitis C
Nature Reviews Drug Discovery 10, (February 2011) | doi: /nrd3361

5. New Targets Peginterferon lambda (PegIL-29) Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations

6. Percentage of patients ± 95% CI
Peginterferon lambda + RBV Virologic response by IL28B Genotype in patients with HCV Genotypes 1, 4
Hatched bars: CT/TT
Solid bars: CC
RVR
cEVR
100 90 80 70 60
Percentage of patients ± 95% CI 50 40 30 20 10
120 μg 180 μg 240 μg
PegIFN-λ
180 μg
PegIFN-α-2a
120 μg 180 μg 240 μg
PegIFN-λ
180 μg
PegIFN-α-2a
n =
Zeuzem et al. EASL 2011

7. Changes in Hematologic Parameters Over Time and Hematology-associated PegIFN and RBV Dose Reductions
PegIFN-λ 120 µg PegIFN-λ 180 µg
PegIFN-λ 240 µg PegIFN-α-2a
PegIFN-λ
PegIFN α-2a
Lab Toxicity, %
120 µg (N=128)
180 µg (N=131)
240 µg (N=134)
180 µg (N=133)
Hemoglobin low
20.5
15.4
12.9
43.9
RBV dose reduction, % (due to Hb abnormality)
2.3
1.5
0.7
12.8
Neutrophils Low
0.8
15.2
Platelets Low
14.4
PegIFN dose reduction, % (due to hematologic abnormality)
17.3
LLN
Study Week
150
140
130
120 6 8 10 12 2 4
300
250
200 5 1 3
Hemoglobin (g/L)
Total Neutrophils (GI/L)
Update plot with new axes
Platelets (GI/L)
Zeuzem et al EASL 2011

8. New Targets Peginterferon lambda (PegIL-29) Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations

9. PILLAR Study: TMC435 + PegIFN/RBV
PILLAR Week 24 Analysis: Proportion of Patients Achieving Virologic Response at Weeks 4 and 12
Week Week 12
*** *** *** *** *** *** *** ***
Fried et al. AASLD 2010
Fried MW, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-5.

10. PILLAR Study: Role of IL28B Genotype
PILLAR Week 24 Analysis: Mean Change in HCV RNA from Baseline According to IL28B Genotype*
Placebo 4 8 16 24 -2 -4 -6
Week 12 20 CC CT TT
Mean(+/- SE) Change in Plasma HCV RNA (log10 IU/mL) from Baseline
All TMC 435 (75 mg)
Week -2 -4 -6 4 8 16 24 12 20
All TMC 435 (150 mg)
Week -2 -4 -6 4 8 16 24 12 20
Fried et al. AASLD 2010
Fried MW, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-5.

11. SILEN-C1: BI-1335 + PegIFN/RBV with or without 3-day lead-in
Sulkowski et al. EASL 2011

12. New Targets Peginterferon lambda (PegIL-29) Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations

13. Mericitabine + PegIFN/RBV for HCV genotype 1 patients
*Roche COBAS® HCV Test; LLOD = 15 IU/mL
ITT population, n=408
Jensen DM, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. 81.

14. Non-RVR PEG-IFN -2a + RBV Non-RVR PEG-IFN -2a + RBV
PSI-7977 Phase 2b Study
GT-1 treatment-naïve
Weeks 12 24 48 72
PSI mg QD
+ PEG-IFN -2a + RBV
PEG-IFN -2a + RBV
STOP
N=50
Non-RVR PEG-IFN -2a + RBV
RG mg QD
+ PEG-IFN -2a + RBV
PEG-IFN -2a + RBV
SVR
Follow-Up
STOP
N=50
Non-RVR PEG-IFN -2a + RBV
PEG-IFN -2a + RBV
N=25
GT-2/3 treatment-naïve open-label
PSI mg QD
+ PEG-IFN -2a + RBV
SVR
Follow-Up
N=25
“12+0”
150 patients GT-1, 2 & 3, treatment-naïve
Response-guided
IL28B stratified (GT-1, 125 patients)
Primary efficacy endpoint : Safety and tolerability
Lalezari et al. EASL 2011

15. PSI-7977 + PegIFN + RBV 121 patients with HCV genotype 1
41% IL28B CC
No viral breakthrough observed
No safety signal detected

16. New Targets Peginterferon lambda (PegIL-29) Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations

17. BMS-790052 Replication Complex Inhibitor:
Change in HCV RNA after administration of single dose
M Gao et al. Nature 000, 1-5 (2010) doi: /nature08960

18. NS5A replication complex inhibitor + PegIFN/RBV
Pol et al. EASL 2011

19. New Targets Peginterferon lambda (PegIL-29) Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations

20. Alisporivir (DEB025): Oral cyclophilin B inhibitor
Synthesized from cyclosporin A
No immunosuppressive activity; Potent Cyp inhibition
Active all HCV genotypes
In vitro resistance in the NS5A region
Also active against HIV
Flisiak et al. Hepatology May;49(5):

21. Alisporivir + PegIFN/RBV in HCV genotype 1, treatment naïve patients
Flisiak R et al. EASL 2011

22. New Targets Peginterferon lambda (PegIL-29) Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations

23. INFORM-1: RG RG7227
1st clinical trial to investigate the combination of DAA in the absence of interferon and ribavirin
Assessed safety and antiviral activity of RG RG7227 x13d
Rx-naïve, null and relapser GT-1 HCV patients (N ~90)
No evidence of resistance breakthrough in any cohort
Gane et al. The Lancet 15 Oct 2010

24. Telaprevir + VX-222 with or with PegIFN/RBV

25. SOUND C-1: PI (1335) + non-nucleoside polymerase (7127) + RBV
Day 8
Day 15
Day 22
Day 29
Group 1:
7127 (400 mg TID) RBV
(N=15)
27%
40%
67%
73%
Group 2:
7127 (600 mg TID) RBV
(N=17)
18%
82%
100%
HCV RNA < 25 IU/mL, undetectable
Two genotype 1a patients in the low dose group had viral rebound during treatment
Zeuzem S., et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-7.

26. PI + NS5A inhibitor ± PegIFN/RBV in prior null responder
↓ Indicates Initiation of PegIFN/RBV ↓
LOQ IU/mL
LOD < 10 IU/mL
LOQ
LOD
Lok AS, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-8.

27. PI + NS5A inhibitor ± PegIFN/RBV in prior null responder
No PegIFN/RBV
4/11 patients had SVR-12 with no PegIFN/RBV
1a, 2/3 SVR with 1 relapse; 1b; 2/2
6/11 patients had breakthrough with PegIFN/RBV added  4 achieve undetectable HCV RNA (treatment ongoing)
QUAD therapy (PegIFN/RBV)
10/10 patients had SVR-12
Lok AS, et al. EASL; Berlin, Germany 2011

28. Future HCV therapies Multiple agents in phase 2 or later development
Effective across viral genotypes and subtypes
Different resistant variants
Improved safety and tolerability
Oral (with the exception of IFN λ)
Less frequent dosing
Increase HCV treatment rates with IFN alfa free regimens