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Hepatitis C:
Emerging
Therapies
Educational Objectives
• Identify new compounds currently under investigation for
the treatment of chronic hepatitis C
• Recognize the potential efficacy and safety benefits of
new therapies for chronic hepatitis C currently under
investigation
• Describe how new compounds might fit into the future
treatment armamentarium for chronic hepatitis C
• The International Liver Congress™ 2012 took place
in Barcelona (Spain) April 18 - 22, 2012 at the
Centre Convencions Internacional (CCIB)
• 47th annual meeting of the European Association
for the Study of the Liver
• A record event with 9415 participants
Hepatitis C: Emerging Therapies
Goals for Hepatitis C Emerging Therapies
• Compared to PegIFN/RBV, new products should
offer:
– Improved efficacy
– Efficacy in all patient types including previously
treated patients, cirrhotic and black patients
– Orally effective regimen, IFN free
– Shorter treatment duration
– Improved side-effect profile
EASL 2012: The Main Themes
• Several classes of direct-acting antiviral drugs (DAAs) add
efficacy when added to Peg-IFN/RBV
• We have gone from proof of concept that IFN-free
regimens can cure HCV infection to evidence that this can
be accomplished in a very high proportion of patients
• To an unexpected degree, interferon responsiveness
plays a role in mediating response to IFN-free DAA
regimens
• Genotype 1a is more difficult to cure than genotype 1b
with some DAA regimens
Emerging Therapies for the Treatment of
Chronic Hepatitis C, 2012
Compound Manufacturer Activity
ABT-072 Abbott Non-nucleoside NS5B
polymerase inhibitor
ABT-333 Abbott Non-nucleoside NS5B
polymerase inhibitor
ABT-450 Abbott/Enanta
NS3 protease inhibitor
ACH-1625 Achillion NS3 protease inhibitor
Asunaprevir
(BMS-650032)
Bristol-Myers Squibb NS3 protease inhibitor
BI201335 Boehringer-Ingelheim NS3 protease inhibitor
Emerging Therapies for the Treatment of
Chronic Hepatitis C, 2012 (cont)
Compound Manufacturer Activity
BI207127 Boerhinger-Ingelheim Non-nucleoside RNA
polymerase inhibitor
Daclatasvir
(BMS-790052)
Bristol-Myers Squibb NS5A replication
complex inhibitor
Danoprevir Roche Macrocyclic NS3/4A
protease inhibitor
GS-7977 (PSI-7977) Gilead (Pharmasset) Uridine nucleotide
analog NS5B
polymerase inhibitor
GS-9256 Gilead
NS3 serine protease
inhibitor
Emerging Therapies for the Treatment of
Chronic Hepatitis C, 2012 (cont)
Compound Manufacturer Activity
Peginterferon
Lambda-1a
Bristol-Myers Squibb Interferon
Tegobuvir Gilead Non-nucleoside NS5B
polymerase inhibitor
TMC435 Tibotec/Medvir NS3/4A protease
inhibitor
Not all-inclusive, but indicates drugs covered in this presentation
A 12-Week Interferon-Free Regimen of ABT-450/r, ABT-072,
and Ribavirin was Well Tolerated and Achieved Sustained
Virologic Response in 91% Treatment-Naïve HCV IL28B-CC
Genotype-1-Infected Subject
Lawitz E, Poordad F, Kowdley KV, Jensen D, Cohen DE, Siggelkow
S, Wikstrom K, Larsen L, Menon RM,
Podsadecki T, Bernstein B Abstract 13, Oral Presentation
47th Annual Meeting of the European Association for the Study of
the Liver
Barcelona, Spain
April 19, 2012
12-Week IFN-Free Regimen of ABT-450/r,
ABT-072, and RBV: Objective
• ABT-450 is a potent NS3HCV protease inhibitor
and ABT-072 is a non-nucleoside NS5B
polymerase inhibitor – ABT-450/r indicates dosing with low-dose
ritonavir
• Objective: To assess the safety, tolerability,
pharmaco-kinetics, and antiviral activity of ABT-
450/r, ABT-072, and RBV in treatment-naïve,
non-cirrhotic HCV genotype-1 infected subjects
with IL28B rs12979860 genotype CC
Lawitz E et al. J Hepatol 2012;56(Suppl 2):S7.
12-Week IFN-Free Regimen of ABT-450/r,
ABT-072, and RBV: Methods
• 11 treatment-naïve, non-cirrhotic HCV genotype-
1 infected subjects with IL28B rs12979860
genotype CC enrolled in an open-label study
• 8 genotype 1a, 3 genotype 1b
• Received ABT-450/r 150/100 mg QD + ABT-072
400 mg QD + weight-based RBV 1000-1200
mg/day dosed twice daily for 12 weeks
Lawitz E et al. J Hepatol 2012;56(Suppl 2):S7.
12-Week IFN-Free Regimen of ABT-450/r,
ABT-072, and RBV: Results
• All 11 subjects completed 12 weeks of treatment and were followed
for 24 weeks post-treatment
– A rapid decrease in HCV RNA level was observed; all subjects
had HCV RNA levels <25 IU/mL by week 3
– All subjects maintained HCV RNA <25 IU/mL from weeks 4
through 12; all had undetectable HCV RNA from weeks 5
through 12
– 10 subjects (91%) achieved SVR24; 1 subject relapsed at post-
treatment week 8. A second subject relapsed 36 weeks post-
treatment; had non-nuc resistant variants
• There were no deaths, serious or severe AEs, or premature
discontinuations
• Most common AEs were mild in severity and included headache,
fatigue, nausea, and dry skin; 2 patients had reversible elevations of
indirect bilirubin
Lawitz E et al. J Hepatol 2012;56(Suppl 2):S7.
12-Week IFN-Free Regimen of ABT-450/r,
ABT-072, and RBV: Results (cont)
Lawitz E et al. J Hepatol 2012;56(Suppl 2):S7.
Individual Changes in Plasma HCV RNA (log10 IU/mL)
Through 12 Weeks of Treatment
12-Week IFN-Free Regimen of ABT-450/r,
ABT-072, and RBV: Conclusions
Lawitz E et al. J Hepatol 2012;56(Suppl 2):S7.
• SVR was achieved in 82% of treatment-naïve,
non-cirrhotic HCV genotype 1-infected subjects
with IL28B CC genotype after 12 weeks of
treatment with ABT-450/r + ABT-072 + RBV
• ABT-450/r + ABT-072 + RBV was well tolerated
• Late relapser emphasizes importance of long
term followup in DAA studies
12-Week Interferon-Free Regimen of ABT-450/r+ABT-
333+Ribavirin Achieved SVR12 in More Than 90% of
Treatment-Naïve HCV Genotype-1-Infected Subjects
and 47% of Previous Non-Responders
Poordad F, Lawitz E, Kowdley KV, Everson GT, Freilich B,
Cohen D, Siggelkow S, Heckaman M, Menon R, Pilot-Matias T,
Podsadecki T, Bernstein B
Abstract 1399, Oral Presentation
47th Annual Meeting of the European Association for the Study of
the Liver
Barcelona, Spain
April 21, 2012
IFN-Free Regimen of ABT-450/r + ABT-333 + RBV in Treatment-Naïve Genotype-1
HCV Patients: Objective
• ABT-450 is an NS3 HCV protease inhibitor, ABT-
450/r is ABT-450 boosted with low-dose ritonavir,
and ABT-333 is a non-nucleoside NS5B
polymerase inhibitor
• Objective: To evaluate the efficacy and safety of
ABT-450/r plus ABT-333 in combination with
RBV in both treatment naïve and treatment-
experienced patients with HCV infection
Poordad F et al. J Hepatol 2012;56(Suppl 2):S549-S550.
IFN-Free Regimen of ABT-450/r + ABT-333 + RBV in Treatment-Naïve Genotype-1
HCV Patients: Methods
• Open-label study of HCV genotype-1, non-
cirrhotic subjects
• Subjects were administered ABT-450/r QD +
ABT-333 BID + weight based RBV (1000 - 1200
mg total daily dose administered twice daily) ‒ Two different doses of ABT-450/r were evaluated
in treatment-naïve subjects; one dose was
evaluated in treatment experienced subjects
• Treatment duration was 12 weeks
Poordad F et al. J Hepatol 2012;56(Suppl 2):S549-S550.
IFN-Free Regimen of ABT-450/r + ABT-333 + RBV in Treatment-Naïve Genotype-1
HCV Patients: Results
*6 were null responders and 11 were partial responders
Poordad F et al. J Hepatol 2012;56(Suppl 2):S549-S550.
Treatment Naive Previous Non-
Responders*
ABT-450/r 250/100
mg + ABT-333 400
mg + RBV
(n=19)
ABT-450/r 150/100
mg + ABT-333 400
mg + RBV
(n=14)
ABT-450/r 150/100
mg + ABT-333 400
mg + RBV
(n=17)
Male. n (%) 10 (52.6) 14 (100) 11 (64.7)
White, n (%) 15 (78.9) 12 (85.7) 13 (76.5)
Age, Years, Mean SD 53.6 9.78 50.9 10.45 52.3 9.03
BMI, kg/m2, Mean SD 27.3 3.84 24.6 3.08 28.3 5.11
HCV Genotype 1a, n (%) 17 (89.5) 11 (78.6) 16 (94.1)
IL28B CC Genotype, n (%) 10 (52.6) 5 (35.7) 0
Baseline HCV RNA, log10
IU/mL, Mean SD
6.25 0.80 6.44 (1.15) 6.93 0.47
Baseline Demographics
IFN-Free Regimen of ABT-450/r + ABT-333 + RBV in Treatment-Naïve Genotype-1
HCV Patients: Results (cont)
a1 subject discontinued due to ALT and AST; b1 subject discontinued due to failed compliance; c6 subjects had viral breakthrough; d3 subjects relapsed; e3/6 null responders and 5/11 partial
responders achieved SVR12
Poordad F et al. J Hepatol 2012;56(Suppl 2):S549-S550.
Treatment Naive Previous Non-
Responders
ABT-450/r 250/100
mg + ABT-333 400
mg + RBV
(n=19)
ABT-450/r 150/100
mg + ABT-333 400
mg + RBV
(n=14)
ABT-450/r 150/100
mg + ABT-333 400
mg + RBV
(n=17)
RVR: HCV RNA
<25 IU/mL at wk 4, n (%) 19 (100)a 13 (92.9)b 15 (88.2)
SVR4: HCV RNA
<25 IU/mL 4 wks after
end of treatment, n (%)
18 (94.7) 13 (92.9) 8 (47.1)c,d
SVR12: HCV RNA
<25 IU/mL 12 wks after
end of treatment, n (%)
18 (94.7) 13 (92.9) 8 (47.1)e
Virologic Results
IFN-Free Regimen of ABT-450/r + ABT-333 + RBV in Treatment-Naïve Genotype-1
HCV Patients: Results (cont)
Poordad F et al. J Hepatol 2012;56(Suppl 2):S549-S550.
• Virologic responses appear to be independent of
ABT-450/r dose and IL28B genotype in
treatment-naïve subjects
• There were no deaths or serious AEs
– The most common AEs were fatigue (42%),
nausea (22%), and headache (20%)
– Most AEs were mild or moderate; 4 subjects
experienced severe AEs (fatigue, pain,
hyperbilirubinemia, and vomiting); none resulted
in study drug interruption or discontinuation
IFN-Free Regimen of ABT-450/r + ABT-333 + RBV in Treatment-Naïve Genotype-1
HCV Patients: Conclusions
Poordad F et al. J Hepatol 2012;56(Suppl 2):S549-S550.
• An IFN-free 12-week regimen of ABT-450/r +
ABT-333 + RBV was well tolerated and achieved
SVR12 in 93 - 95% of treatment-naïve and 47% of
previous non-responder subjects infected with HCV
genotype-1.
• ABT-450/r 250/100 mg and 150/100 mg doses show
comparable efficacy in treatment-naïve subjects.
• The difference in SVR rates observed in naïve and
previous non-responders suggest that extrapolation
of results across these populations must be done
with caution
ELECTRON: Once Daily PSI-7977 plus RBV in HCV
GT1/2/3
Gane EJ, Stedman CA, Hyland RH, Sorensen RD, Symonds WT,
Hindes RG, Berrey MM Abstract 1113, Poster Presentation
47th Annual Meeting of the European Association for the Study of
the Liver
Barcelona, Spain
April 21, 2012
Once Daily PSI-7977/RBV PegIFN in Genotype-1/2/3 HCV Patients: Objective
• PSI-7977 (now GS-7977) is a uridine nucleotide
analog NS5B polymerase inhibitor
• Objective: Additional cohorts have been enrolled
in the ELECTRON study to evaluate the efficacy
of PSI-7977/RBV PegIFN in genotype 1, 2, or
3 HCV populations historically considered
difficult-to-treat with IFN and to explore shorter
durations of therapy
Gane EJ et al. J Hepatol 2012;56(Suppl 2):S438-S439.
Once Daily PSI-7977/RBV PegIFN in Genotype-
1/2/3 HCV Patients: Methods
Gane EJ et al. J Hepatol 2012;56(Suppl 2):S438-S439.
Study
Arm
Patient-type/
Genotype
n Treatment Regimen
6 Non-cirrhotic
treatment-naïve; G2/3
10 GS-7977 + PegIFN/RBV x 8 wks
7 Prior null responders;
G1
10 GS-7977 + RBV x 12 wks
8 Prior non-responders;
G2/3
25 GS-7977 + RBV x 12 wks
9 Non-cirrhotic
treatment-naïve; G1
25 GS-7977 + RBV x 12 wks
Once Daily PSI-7977/RBV PegIFN in Genotype-
1/2/3 HCV Patients: Results
Gane EJ et al. J Hepatol 2012;56(Suppl 2):S438-S439.
80%88%
11%
0
20
40
60
80
100
G2/3 naive G1 null G1 naive G2/3
experienced
Is SVR4
the
correct
End
Point
100%
8 wks 12 wks
GS-7977/Peg/RBV GS-7977/RBV
10/10 1/9 22/25 12/15
SVR4
(%)
Once Daily PSI-7977/RBV PegIFN in Genotype-
1/2/3 HCV Patients: Results (cont)
Gane EJ et al. J Hepatol 2012;56(Suppl 2):S438-S439.
• Overall, GS-7977 was well tolerated and
exhibited a favorable safety profile
– No patients discontinued therapy due to an AE
– The most common adverse events were fatigue,
dizziness and headache
– Two grade 3/4 laboratory abnormalities were
reported
• No patients experienced viral rebound during
treatment
Once Daily PSI-7977/RBV PegIFN in Genotype-
1/2/3 HCV Patients: Conclusions
Gane EJ et al. J Hepatol 2012;56(Suppl 2):S438-S439.
• Preliminary results suggest that 12 wks of
therapy with oral GS-7977/RBV may be enough
to cure hepatitis C in many treatment-naive
genotype 1 patients, including those who are
currently not candidates to receive interferon
• 8 wks of a GS-7977/PegIFN/RBV treatment
regimen appears to be effective in 100% of
genotype 2/3 patients
New
SVR4 and SVR12 with an Interferon-Free Regimen of
BI201335 and BI207127, +/- Ribavirin, in Treatment-
Naïve Patients with Chronic Genotype-1 HCV Infection:
Interim Results of Sound-C2
Zeuzem S, Soriano V, Asselah T, Bronowicki J-P, Lohse A,
Müllhaupt B, Schuchmann M, Bourliere M, Buti M, Roberts S, E.
Gane E, Stern JO, Kukolj G, Dai L, Böcher WO, Mensa FJ Abstract 101, Oral Presentation
47th Annual Meeting of the European Association for the Study of
the Liver
Barcelona, Spain
April 21, 2012
SVR4 and SVR12 with BI201335 and BI207127 in Treatment-Naïve Genotype 1 HCV Patients:
Objective
• BI201335 is an HCV protease inhibitor and
BI207127 is a non-nucleoside RNA polymerase
inhibitor
• Objective: SOUND-C2 is an open-label, randomized
phase IIb study with 5 treatment arms to evaluate
the safety and efficacy of IFN-free combination
regimens of BI201335 and BI207127 RBV for up
to 40 weeks in HCV genotype 1 treatment naive
patients
• This is an interim analysis of SVR4 and SVR12
rates Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S45.
SVR4 and SVR12 with BI201335 and BI207127 in Treatment-Naïve Genotype 1 HCV Patients:
Methods
• 362 treatment naïve patients (including 10% compensated cirrhotics) were randomized and treated in 5 arms:
‒ A) 120 mg QD BI2011335 (1335QD) combined with 600 mg TID BI207127 (7127TID) and RBV for 16 weeks
‒ B) 1335QD + 7127TID + RBV for 28 weeks
‒ C) 1335QD + 7127TID + RBV for 40 weeks
‒ D) 1335QD + 600 mg BID BI207127 (7127BID) + RBV for 28 weeks
‒ E) 1335 + 7127TID for 28 weeks
• Randomization was stratified by HCV subtype (1a vs. 1b) and IL28B genotype
• Pre-specified interim analysis was performed after all patients (except arm C) had reached SVR12
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S45.
SVR4 and SVR12 with BI201335 and BI207127 in Treatment-Naïve Genotype 1 HCV Patients:
Results (cont)
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S45.
39%
68%
56%61%59%
0
20
40
60
80
SVR12
(%)
16 Wk 28 Wk
40 Wk
1335QD/
7127TID
28 Wk
SVR12
1335QD/7127TID/RBV 1335QD/
7127BID/
RBV
28 Wk
SVR4 and SVR12 with BI201335 and BI207127 in Treatment-Naïve Genotype 1 HCV Patients:
Results (cont)
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S45.
11%
43%47%
44%38%
57%
83%
63%
73%75%
0
20
40
60
80
100
SVR12
(%)
16 Wk 28 Wk
40 Wk
1335QD/
7127TID
28 Wk
SVR12 by HCV subtype
1335QD/7127TID/RBV 1335QD/
7127BID/
RBV
28 Wk
Genotype 1a
Genotype 1b
SVR4 and SVR12 with BI201335 and BI207127 in Treatment-Naïve Genotype 1 HCV Patients:
Results (cont)
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S45.
33%
64%
52%57%57% 58%
79%
68%71%
67%
0
20
40
60
80
100
SVR12
(%)
16 Wk 28 Wk
40 Wk
1335QD/
7127TID
28 Wk
SVR12 by IL28B gene
1335QD/7127TID/RBV 1335QD/
7127BID/
RBV
28 Wk
non-CC
CC
SVR4 and SVR12 with BI201335 and BI207127 in Treatment-Naïve Genotype 1 HCV Patients:
Results (cont)
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S45.
• Tested regimens were generally well tolerated
overall
– Mild skin and gastrointestinal disorders were the
most commonly reported AEs, with 1335QD +
7127BID + RBV
• Discontinuation rates due to AEs in treatment
arms A through E were 5, 13, 25, 8 and 11%,
respectively
SVR4 and SVR12 with BI201335 and BI207127 in Treatment-Naïve Genotype 1 HCV Patients:
Conclusions
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S45.
• INF-free combination therapy with BI201335,
BI207127 and RBV achieved 59% SVR12 in HCV
genotype 1 treatment-naïve patients after 16 weeks
of treatment and 68% SVR12 with a lower BI207127
dose (600 mg BID) for 28 weeks of treatment
• Response rates in all treatment arms were greater in
patients with genotype 1b HCV than in those with
genotype 1a
• Response rates in all treatment arms were greater in
patients with IL28B CC than in those with IL28B
non-CC
Important Points From SOUND C2
• Largest study yet showing curability of HCV
infection without interferon
• SVR rates lower than in other recent studies
– Related to “suboptimal” regimen?
• Demonstrates importance of genotype 1 subtype
and role of host response pathways in mediating
response to IFN free regiments
– Host-virus interactions illustrated by relationship
of IL28B genotype and HCV G1 subtype
The Efficacy and Safety of the Interferon-Free
Combination of BI201335 and BI207127 in Genotype 1
HCV Patients with Cirrhosis - Interim Analysis from
SOUND-C2
Soriano V, Gane E, Angus P, Stickel F, Bronowicki J-P, Roberts S,
Manns M, Zeuzem S, Dai L, Boecher W, Stern J, Mensa F Abstract 1420, Poster Presentation
47th Annual Meeting of the European Association for the Study of
the Liver
Barcelona, Spain
April 19, 2012
Efficacy and Safety of Combination BI201335 and BI207127 in Genotype1 HCV Patients with
Cirrhosis: Objective
• Interim sub-analysis of patients with compensated
liver cirrhosis enrolled in SOUND-C2
Soriano V et al. J Hepatol 2012;56(Suppl 2):S559.
Efficacy and Safety of Combination BI201335 and BI207127 in Genotype1 HCV Patients with
Cirrhosis: Methods
• 37 patients with biopsy or Fibroscan confirmed cirrhosis were treated in 5 arms:
‒ A) 120 mg QD BI2011335 (1335) combined with 600 mg TID BI207127 (7127TID) and RBV for 16 weeks
‒ B) 1335 + 7127TID + RBV for 28 weeks
‒ C) 1335 + 7127TID + RBV for 40 weeks
‒ D) 1335 + 600 mg BID BI207127 (7127BID) + RBV for 28 weeks
‒ E) 1335 + 7127TID for 28 weeks
• All 37 patients had compensated liver disease, 25 were genotype 1b and 30 had IL-28b genotype CT/TT
• Patients who received the same dose for 16, 28, or 40 weeks (arms A, B and C) were pooled
Soriano V et al. J Hepatol 2012;56(Suppl 2):S559.
Efficacy and Safety of Combination BI201335 and BI207127 in Genotype1 HCV Patients with
Cirrhosis: Results
Soriano V et al. J Hepatol 2012;56(Suppl 2):S559.
1335QD/7127TID/RBV
(n=21)
Pooled arm A, B, & C
1335QD/7127BID/RBV
(n=13)
Arm D
1335QD/7127TID
(n=3)
Arm E
GT1a
(n=5)
GT1b
(n=16)
GT1a
(n=7)
GT1b
(n=6)
GT1a
(n=0)
GT1b
(n=3)
SVR12, n (%) 3 (60) 9 (56) 2 (29) 5 (83) 0 (0) 1 (33)
Early
Discontinuation
(DC) due to
AEs, n (%)
6 (29)
-- 1 (8)
-- 0 (0)
--
Early DC due
to rash, n (%)
5 (24)
-- 0 (0)
-- 0 (0)
--
Early DC due
to
photosensitivity
n (%)
2 (10)
-- 0 (0)
-- 0 (0)
--
Efficacy and Safety of Combination BI201335 and BI207127 in Genotype1 HCV Patients with
Cirrhosis: Results
Soriano V et al. J Hepatol 2012;56(Suppl 2):S559.
• Mild skin and gastrointestinal disorders were the
most commonly reported AEs
• The safety and tolerability was more favorable in
the BI207127 BID arm than in the BI207127TID
arms
Efficacy and Safety of Combination BI201335 and BI207127 in Genotype1 HCV Patients with
Cirrhosis: Conclusions
Soriano V et al. J Hepatol 2012;56(Suppl 2):S559.
• These SVR12 rates suggest that IFN-free
combination regimens of BI201335 and BI207127
RBV may obtain similar SVR rates to those
achieved with approved DAAs + PegIFN/RBV
regimens, but with a shorter treatment duration
Potent Viral Suppression with All-Oral Combination of
Daclatasvir (NS5A Inhibitor) and GS-7977 (NS5B
Inhibitor), +/-Ribavirin, In Treatment-Naïve Patients with
Chronic HCV GT1, 2, or 3
Sulkowski M, Gardiner D, Lawitz E, Hinestrosa F, Nelson D,
Thuluvath P, Rodriguez-Torres M, Lok A, Schwartz H,
Reddy KR, Eley T, Wind-Rotolo M, S.-P. Huang S-P, Gao M,
McPhee F, Hindes R, Symonds B, Pasquinelli C, Grasela D,
AI444040 Study Group Abstract 1422, Poster Presentation
47th Annual Meeting of the European Association for the Study of
the Liver
Barcelona, Spain
April 19, 2012
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Objective
• Daclatasvir (DCV; BMS-790052) is an NS5A
replication complex inhibitor and GS-7977 (PSI-
7977) is a nucleotide analog NS5B inhibitor
• Objective: Study AI444040 is designed to evaluate
the safety and efficacy of IFN-free combination
regimens of DCV and GS-7977 RBV for 24 weeks
in HCV genotype 1a/1b, 2, and 3 treatment naive
patients
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Methods
• A randomized phase 2a, parallel, open-label study
• 44 noncirrhotic patients with HCV genotype 1 and 44
noncirrhotics with HCV genotype 2/3 were randomized
(1:1:1) to:
‒ GS-7977 for 7 days, then DCV + GS-7977 for 23 weeks, or
‒ DCV + GS-7977 for 24 weeks, or
‒ DCV + GS-7977 + RBV for 24 weeks
• Primary endpoint is undetectable HCV RNA at 12
weeks post-treatment; interim 4-week post-treatment
efficacy and 12-week on-treatment safety results were
presented
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Results
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
GS-7977 x 7d,
then DCV +
GS-7977
DCV +
GS-7977
DCV +
GS-7977 +
RBV
GT1
n=15
GT2/3
n=16
GT1
n=14
GT2/3
n=14
GT1
n=15
GT2/3
n=14
HCV Genotype, n (%)
1a
1b
2
3
11 (73)
4 (27)
0
0
0
0
9 (56)
7 (44)
10 (71)
4 (29)
0
0
0
0
8 (57)
6 (43)
11 (73)
4 (27)
0
0
0
0
9 (64)
5 (36)
IL28B genotype CC
(rs 12979860), n (%)
CC
CT/TT
Missing
4 (27)
11 (73)
0
8 (50)
7 (44)
1 (6)
8 (57)
6 (43)
0
5 (36)
9 (64)
0
4 (27)
10 (67)
1 (7)
7 (50)
7 (50)
0
Patients Demographics: HCV Genotype and IL28B Genotype
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Results (cont)
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
GS-7977 x 7d,
then DCV +
GS-7977 (n=31)
DCV +
GS-7977
(n=28)
DCV +
GS-7977 +
RBV (n=29)
Grade 3-4 AEs 0 4 (14) 1 (4)
Discontinuations
due to AEs
0 1 (4) 1 (4)
SAEs 2 (6) 5 (18) 3 (10)
Grade 3-4 AEs, Discontinuations due to AEs, and SAEs
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Results (cont)
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
GS-7977 x 7d,
then DCV +
GS-7977 (n=31)
DCV +
GS-7977
(n=28)
DCV +
GS-7977 +
RBV (n=29)
Fatigue 8 (26) 14 (50) 9 (31)
Headache 5 (16) 8 (29) 9 (31)
Nausea 5 (16) 9 (32) 8 (28)
Anxiety 3 (10) 2 (7) 4 (14)
Back pain 1 (3) 5 (18) 3 (10)
Diarrhea 3 (10) 3 (11) 3 (10)
Insomnia 2 (7) 2 (7) 5 (17)
AEs occurring in 10% of patients
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Results (cont)
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
GS-7977 x 7d,
then DCV +
GS-7977 (n=31)
DCV +
GS-7977
(n=28)
DCV +
GS-7977 +
RBV (n=29)
Total cholesterol
elevated
1 (3) 0 0
Fasting glucose
elevated
0 0 1 (3)
Glucose elevated 0 0 1 (4)
Anemia 0 0 6 (21)
Lymphopenia
(absolute)
0 0 1 (3)
Low phosphorus 0 1 (4) 1 (3)
Grade 3-4 Laboratory Abnormalities
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Results (cont)
*LOD=<10 IU/mL
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
47
87
100
87
14
93 93
86
100
20
73
100
93
100100
0
20
40
60
80
100
Wk2 Wk4 Wk12 Wk 24(EOT)
PT Wk 4(SVR4)
HCV RNA
<LOD*
(% of
Patients)
GS-7977 x 7d, then DCV + GS-7977 (n=15)
DCV + GS-7977 (n=14)
DCV + GS-7977 + RBV (n=15)
Virologic Response (<LOD)
Before and After Treatment
of HCV Genotype 1a/1b
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Results (cont)
*LLOQ=25 IU/mL
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
67
100 100
87
79
100
93
86
100
67
100 100
93
100100
0
20
40
60
80
100
Wk2 Wk4 Wk12 Wk 24(EOT)
PT Wk 4(SVR4)
HCV RNA
<LLOQ*
(% of
Patients)
GS-7977 x 7d, then DCV + GS-7977 (n=15)
DCV + GS-7977 (n=14)
DCV + GS-7977 + RBV (n=15)
Virologic Response (<LLOQ)
Before and After Treatment
of HCV Genotype 1a/1b
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Results (cont)
*LOD=<10 IU/mL
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
31
88 8893
29
79
93 93
100
29
64
93
86
79
88
0
20
40
60
80
100
Wk2 Wk4 Wk12 Wk 24(EOT)
PT Wk 4(SVR4)
HCV RNA
<LOD*
(% of
Patients)
GS-7977 x 7d, then DCV + GS-7977 (n=16)
DCV + GS-7977 (n=14)
DCV + GS-7977 + RBV (n=14)
Virologic Response (<LOD)
Before and After Treatment
of HCV Genotype 2/3
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Results (cont)
*LLOQ=25 IU/mL
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
81
100
8894
86
100
93
100 100
86
100 100
86 8688
0
20
40
60
80
100
Wk2 Wk4 Wk12 Wk 24(EOT)
PT Wk 4(SVR4)
HCV RNA
<LLOQ*
(% of
Patients)
GS-7977 x 7d, then DCV + GS-7977 (n=16)
DCV + GS-7977 (n=14)
DCV + GS-7977 + RBV (n=14)
Virologic Response (<LLOQ)
Before and After Treatment
of HCV Genotype 2/3
All-Oral Combination of Daclatasvir and GS-7977
in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Results (cont)
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
0
20
40
60
80
100
Genotype 1a Genotype 1b
SVR4
(% of
Patients)
SVR4 by Genotype 1 Subtype and IL288 Genotype
CC
CT/TT
100% 100% 100% 100%
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Conclusions
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
• The all oral IFN-free regimen of DCV + GS-7977
with or without RBV for 24 wks attained SVR4 in
>95% of genotype 1, 2, or 3 infected treatment naive
patients including 100% of genotype 1 patients
treated
• The all oral, once daily, IFN-free, RBV-free of DCV +
GS-7977 attained SVR4 100% of genotype 1 and
>90% of genotype 2 and 3 treatment naive patients
• DCV + GS-7977 achieved SVR independent of
IL288 genotype or HCV subtype
All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV
GT1, 2, or 3: Conclusions (cont)
Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.
• RBV contributed AEs but had no effect on virologic
response
• DCV + GS-7977 was generally well tolerated based on
the interim 12 week on-treatment data
• DCV + GS-7977 may represent a significant advance in
the treatment of HCV
– More generally, 2 potent drugs with at least one
component also featuring a high barrier to resistance
may represent an important new paradigm; need studies
in nonresponders, cirrhotics
• Further follow-up and additional studies in progress
Dual Oral Therapy with the NS5A Inhibitor Daclatasvir
(BMS-790052) and NS3 Protease Inhibitor Asunaprevir
(BMS-650032) in HCV Genotype 1B-Infected Null
Responders or Ineligible/Intolerant to
Peginterferon/Ribavirin
Suzuki F, Ikeda K, Toyota J, Karino Y, Ohmura T, Chayama K,
Takahashi S, Kawakami Y, Ishikawa H, Watanabe H, Hu W,
McPhee F, Hughes E, Kumada H Abstract 14, Oral Presentation
47th Annual Meeting of the European Association for the Study of
the Liver
Barcelona, Spain
April 19, 2012
Daclatasvir and Asunaprevir Dual Therapy in HCV Genotype 1B Null Responders or
Ineligible/Intolerant: Objective
• Daclatasvir (DCV; BMS-790052) is a highly selective
NS5A replication complex inhibitor and asunaprevir
(BMS-650032) is a selective inhibitor of HCV NS3
protease
• Objective: To evaluate the safety and efficacy of
dual therapy with daclatasvir and asunaprevir, two
direct-acting antivirals, in HCV genotype 1B patients with
intolerance or prior null response to PegIFN/RBV
Suzuki F et al. J Hepatol 2012;56(Suppl 2):S7-S8.
Daclatasvir and Asunaprevir Dual Therapy in HCV Genotype 1B Null Responders or
Ineligible/Intolerant: Methods
• Open-label study of 21 null responders (<2 log10 HCV
RNA after 12 weeks of Peg-IFN/RBV, group A) and
22 patients ineligible for IFN-containing regimens for
medical reasons or who discontinued Peg-IFN/RBV
after <12 weeks due to intolerance (group B)
• Patients received daclatasvir 60 mg QD and
asunaprevir 200 mg BID (initially 600 mg BID in 10/21
subjects in group A) for 24 weeks
• Addition of Peg-IFN was permitted for Group A
patients with virologic failure
Suzuki F et al. J Hepatol 2012;56(Suppl 2):S7-S8.
Daclatasvir and Asunaprevir Dual Therapy in HCV Genotype 1B Null Responders or
Ineligible/Intolerant: Results
Suzuki F et al. J Hepatol 2012;56(Suppl 2):S7-S8.
Null Responders
(Group A, N=21)
Ineligible/
Intolerant
(Group B, N=22)
IL28B genotype CC,
n/N (%)
3/21 (14.3) 16/22 (72.7)
HCV undetectable wk 4 (RVR),
n/N (%)
11/21 (52.4) 19/22 (86.4)
HCV undetectable wk 12 (cEVR),
n/N (%)
19/21 (90.5) 20/22 (90.9)
HCV undetectable wk 24 (EOT),
n/N (%)
18/32 (85.7) 16/22 (72.7)
HCV below LLOQ post-treatment
week 12 (SVR12), n/N (%)
19/21 (90.5) 14/22 (63.6)
Daclatasvir and Asunaprevir Dual Therapy in HCV Genotype 1B Null Responders or Ineligible/Intolerant: Results (cont)
Suzuki F et al. J Hepatol 2012;56(Suppl 2):S7-S8.
• All 43 enrolled patients were Japanese with HCV genotype 1b
• Baseline characteristics were similar other than a higher
proportion of IL28B genotype CC in group B vs. A (73% vs.
14%)
• 3 patients discontinued prematurely for AEs, 1 for lack of
efficacy (group A) and 2 per patient request
• 3 patients had viral breakthrough, 1 before wk 12; HCV
variants associated with asunaprevir and daclatasvir
resistance were identified
• Serious AEs included 1 patient with hyperbilirubinemia and
gastroenteritis, 3 with pyrexia, and 1 hypochondriasis
Daclatasvir and Asunaprevir Dual Therapy in HCV Genotype 1B Null Responders or Ineligible/Intolerant: Conclusions
Suzuki F et al. J Hepatol 2012;56(Suppl 2):S7-S8.
• The dual oral DAA combination of daclatasvir
and asunaprevir, without PegIFN/RBV, may offer
a needed therapeutic alternative to
PegIFN/RBV-containing regimens for many
patients, including some difficult-to-treat groups
• Difference between genotype 1a and 1b shown
in earlier study of this regimen emphasizes
importance of G1 subtype, at least with
regimens lacking a component with high
resistance barrier (or, perhaps, lacking RBV)
Confirmation that Quadruple Therapy with Daclatasvir
(NS5A Inhibitor), Asunaprevir (NS3 Inhibitor) and
Peginterferon/Ribavirin Results in High Rate of SVR4 in
HCV Genotype 1 Null Responders
Lok A, Gardiner D, Hézode C, Lawitz E, Bourlière M, Everson G,
Marcellin P, Rodriguez-Torres M, Pol S, Serfaty L, Eley T, Huang
S-P, Wind-Rotolo M, McPhee F, Grasela D,
Pasquinelli C Abstract 1415, Poster Presentation
47th Annual Meeting of the European Association for the Study of
the Liver
Barcelona, Spain
April 19, 2012
Daclatasvir, Asunaprevir and Peg-IFN/RBV in HCV
Genotype 1 Null Responders: Objective
• Daclatasvir is an NS5A inhibitor; asunaprevir is an
NS3 inhibitor
• Objective: Using a lower asunaprevir dose in a
larger null-responder population, to confirm results
of a preliminary study that found combination
therapy with declatasvir (DCV), asunaprevir (ASV),
Peg-IFN, and RBV resulted in a 90% SVR rate in
HCV patients with a prior null-response to Peg-
IFN/RBV
Lok A et al. J Hepatol 2012;56(Suppl 2):S557.
Daclatasvir, Asunaprevir and Peg-IFN/RBV in HCV
Genotype 1 Null Responders: Methods
• Randomized, open label, phase 2a study in non-
cirrhotic HCV null-responders to Peg-IFN/RBV
• Patients received ASV 200 mg QD (n=21) or BID
(n=20), each combined with DCV 60 mg QD and
Peg-IFN/RBV x 24 weeks
Lok A et al. J Hepatol 2012;56(Suppl 2):S557.
Daclatasvir, Asunaprevir and Peg-IFN/RBV in HCV
Genotype 1 Null Responders: Results
• Patients had multiple negative predictors of SVR to
Peg-IFN/RBV therapy:
‒ 88% were HCV GT1a
‒ 61% had baseline HCV RNA 106 IU/mL
‒ 100% were IL28B genotype CT/TT
• AEs and laboratory abnormalities were typical of
Peg-IFN/RBV; none led to treatment discontinuation
‒ Most common AEs were headache, asthenia, diarrhea,
irritability, and fatigue
‒ Most common grade 3/4 laboratory abnormalities were
neutropenia (11 patients), decreased white blood cells (6),
lymphopenia (6), and low phosphorus (2)
Lok A et al. J Hepatol 2012;56(Suppl 2):S557.
Daclatasvir, Asunaprevir and Peg-IFN/RBV in HCV
Genotype 1 Null Responders: Results
Lok A et al. J Hepatol 2012;56(Suppl 2):S557.
85%90%
95%
75%
95%100%
95%
71%
0
20
40
60
80
100
120
Week 4 Week 12 Week 24
(EOT)
SVR4
Patients
<LOD
(%)
DCV + ASV 200 mg BID + Peg-IFN/RBV (n=20)
DCV + ASV 200 mg QD + Peg-IFN/RBV (n=21)
Daclatasvir, Asunaprevir and Peg-IFN/RBV in HCV
Genotype 1 Null Responders: Results
Lok A et al. J Hepatol 2012;56(Suppl 2):S557.
0
20
40
60
80
100
Week 4 Week 12 Week 24
(EOT)
SVR4
Patients
<LLOQ
(%)
DCV + ASV 200 mg BID + Peg-IFN/RBV (n=20)
DCV + ASV 200 mg QD + Peg-IFN/RBV (n=21)
95% 95% 100% 100% 100% 100% 95% 100%
Daclatasvir, Asunaprevir and Peg-IFN/RBV in HCV
Genotype 1 Null Responders: Conclusions
Lok A et al. J Hepatol 2012;56(Suppl 2):S557.
• The expansion cohort confirmed that the
quadruple combination of DCV, ASV, and Peg-
IFN/RBV provided rapid viral suppression with
SVR4 rates over 90% in this difficult-to-treat
patient population
Peginterferon Lambda-1a (Lambda) Compared to
Peginterferon Alfa-2A (ALFA) in Treatment-Naïve
Patients with HCV Genotypes (G) 2 or 3: First SVR 24
Results from EMERGE Phase IIB
Zeuzem S, Arora S, Bacon B, Box T, Charlton M, Diago M, Dieterich D, Mur RE,
Everson G, Fallon M, Ferenci P, Flisiak R, George J, Ghalib R, Gitlin N, Gladysz
A, Gordon S, Greenbloom S, Hassanein T, Jacobson I, Jeffers L, Kowdley K,
Lawitz E, Lee SS, Leggett B, Lueth S, Nelson D, Pockros P,
Rodriguez-Torres M, Rustgi V, Serfaty L, Sherman M, Shiffman M, Sola R,
Sulkowski M, Vargas H, Vierling J, Yoffe B, Ishak L, Fontana D, Xu D, Gray T,
Horga A, Hillson J, Lopez-Talavera JC, Muir A, EMERGE Study Group
Abstract 10, Oral Presentation
47th Annual Meeting of the European Association for the Study of
the Liver
Barcelona, Spain
April 19, 2012
PegIFN lambda-1A Compared to PegIFN alfa-2a in Treatment Naïve HCV Genotype 2 or 3 Patients:
Objective
• PegIFN lambda exerts antiviral effects through a
unique receptor with limited distribution outside the
liver and is expected to have an improved tolerability
profile vs. PegIFN alfa
• Objective: To assess safety and efficacy of PegIFN
lambda-1a/RBV in treatment-naïve HCV genotype 2
and genotype 3 patients compared to PegIFN alfa-
2a/RBV
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S5-S6.
TMC435 in HCV Genotype 1 Patients who Have Failed
Previous Pegylated Interferon/Ribavirin Treatment: Final
SVR 24 Results of the ASPIRE Trial
Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW,
Hezode C, Hirschfield G, Jacobson I, Nikitin I, Pockros P,
Poordad F, Lenz O, Peeters M, V. Sekar V, De Smedt G,
Beumont-Mauviel M
Abstract 2, Oral Presentation
47th Annual Meeting of the European Association for the Study of
the Liver
Barcelona, Spain
April 19, 2012
TMC435 in HCV Genotype 1 Patients who Have Failed Previous PegIFN/RBV Treatment: Objective
• TMC435 is an oral, once-daily, HCV NS3/4A
protease inhibitor
• Objective: ASPIRE is an international Phase IIb,
randomized, double-blind, placebo-controlled trial
investigating the efficacy, tolerability, safety, and
pharmacokinetics of TMC435 administered with
PegIFN/RBV
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S1-S2.
TMC435 in HCV Genotype 1 Patients who Have Failed Previous PegIFN/RBV Treatment: Methods
• Patients were chronically-infected with HCV genotype
1, with documented evidence of null-response (<2
log10 reduction wk 12), partial response ( 2 log10
reduction wk 12; detectable end-of-treatment) or
relapse (undetectable end-of-treatment; detectable
within 24 wks post-treatment) following 1 course of
PegIFN/RBV therapy
• Patients were randomized to 1 of 7 treatment arms:
• TMC435 (100 or 150 mg once-daily) for 12, 24, or 48 wks
in combination with 48 wks of PegIFN/RBV, or
• Placebo with PegINF/RBV for 48 wks
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S1-S2.
TMC435 in HCV Genotype 1 Patients who Have Failed Previous PegIFN/RBV Treatment: Results
(cont)
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S1-S2.
38
56
44
53
41
59
19
70
48
55
65
75
86
9
89 89
77 77
89 89
37
0
20
40
60
80
100
TMC12/
PR48
100 mg
TMC24/
PR48
100 mg
TMC48/
PR48
100 mg
TMC12/
PR48
150 mg
TMC24/
PR48
150 mg
TMC48/
PR48
150 mg
PBO48/
PR48
SVR24
Patients
(%)
Prior Null Responder Prior Partial Responder Prior Relapser
TMC435 in HCV Genotype 1 Patients who Have Failed Previous PegIFN/RBV Treatment: Results
(cont)
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S1-S2.
• Of 462 patients enrolled:
– 19% had Metavir score F3 and 18% F4
– 41% were infected with genotype 1a and 58% 1b
• Discontinuation due to viral breakthrough or lack of on-
treatment response was 9 - 17% in TMC435-treated
groups compared to 53% for the control group
• Viral relapse occurred in 6 - 18% of TMC435-treated
patients compared to 44% in the control group
• Incidence of AEs leading to treatment discontinuation
and serious AEs was similar across all groups
– Mild, transient, asymptomatic bilirubin increases were observed
with TMC435, with no significant differences between 100 mg
and 150 mg doses
TMC435 in HCV Genotype 1 Patients who Have Failed Previous PegIFN/RBV Treatment:
Conclusions
Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S1-S2.
• Patients who failed previous PegIFN/RBV
treatment exhibited significantly higher SVR24
rates following treatment with TMC435 plus
PegIFN/RBV compared with placebo, including
difficult-to-treat prior null-responders with
cirrhosis
• TMC435 was well tolerated in this population
Hepatitis C: Emerging Therapies
Conclusions (cont)
• Promising studies of IFN-free regimens with high
levels of efficacy and short durations (12-24 weeks)
• Host-virus interactions are important with some
regimens:
– Genotype 1a, IL28B CT/TT, null response to earlier
PR therapy adversely impact response with
regimens that lack “optimal” potency and/or high
resistance barrier
– Will “optimized” regimens overcome these factors?
Hepatitis C: Emerging Therapies
Conclusions
• No data were presented which specifically
addressed response rates in black patients; need
much more data on cirrhotics
• Most studies are too preliminary for definitive
conclusions regarding safety; encouraging signal of
no unusual safety issues to date
• The future is unfolding rapidly – optimal decision-
making requires knowledge of current developments