Simply Speaking Hepatitis February 7 2014

New and Emerging Strategies
to Simplify the Cure of
Chronic Hepatitis C Infection
Sponsored for CME credit by
Rush University Medical Center
Supported by an independent educational
grant from Gilead Sciences Medical Affairs

2
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EducatorEducator
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● Disclosures
- Grants/Research Support: list here
- Consultant: list here
- Speakers’ Bureau: list here
- Stock Shareholder: list here
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Educator Title, Degree
Affiliation
City, State
EDUCATOR TO
COMPLETE

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Accreditation and DesignationAccreditation and Designation
Supported by an independent educational grant from
Gilead Sciences Medical Affairs.
Rush University (OH-390, 8/25/2014) is an approved provider of continuing
education by the Ohio Nurses Association (OBN-001-91), an accredited
approver by the American Nurses Credentialing Center’s Commission on
Accreditation. Rush University designates this live activity for one (1)
Continuing Nursing Education credit.
Rush University Medical Center is accredited by the Accreditation Council
for Continuing Medical Education to provide continuing medical education
for physicians. Rush University Medical Center designates this live activity
for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should
claim only credit commensurate with the extent of their participation in the
activity.
The University of Florida College of Pharmacy is accredited by the
Accreditation Council for Pharmacy Education as a provider of continuing
pharmacy education (UAN #0012-9999-13-013-L01-P). This activity is
accredited for 1 hour of continuing pharmacy education (CPE) credit. The
University of Florida College of Pharmacy will report all credit to CPE
Monitor within 30 working days after receiving evidence of successful
completion of the course. Successful completion means that you must
attend the entire program and complete an evaluation form.

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FacultyFaculty
CME Course DirectorCME Course Director
Harold A. Kessler, MD
rofessor of Medicine and Immunology/Microbiology
Associate Director,
Section of Infectious Diseases
Chicago, Illinois
Content Development and TrainingContent Development and Training
Mark S. Sulkowski, MD
Professor of Medicine
Medical Director, Viral Hepatitis Center
Johns Hopkins Medical Institution
Baltimore, Maryland
Program ChairProgram Chair
S. Martin Cohen, MD
Medical Director, Hepatology
Professor of Medicine
University Hospitals/Case Medical Center
Cleveland, Ohio
CME ReviewerCME Reviewer
David M. Simon, MD, PhD
Associate Professor of Medicine
Section of Infectious Diseases
Chicago, Illinois

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Faculty DisclosuresFaculty Disclosures
CME Course Director:
Harold A. Kessler, MD
Program Chair:
S. Martin Cohen, MD
Content Development
and Training:
Mark S. Sulkowski, MD
Grants/research
support
None None Anadys, BIPI, Genentech, Gilead
Sciences, Merck, Tibotec,
Vertex
Consultant None Bristol-Myers
Squibb, Gilead
Sciences, Vertex
AbbVie, Anadys, BIPI,
Genentech, Gilead Sciences,
Merck, Tibotec, Vertex
Speakers’
bureau
None Bristol-Myers
Squibb, Genentech,
Gilead Sciences,
Vertex
None
Stock
shareholder
AbbVie,
GlaxoSmithKline, Merck
None None
Other financial
or material
support
None None None

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Faculty DisclosuresFaculty Disclosures
CME Reviewer:
David M. Simon, MD, PhD
Medical Editor:
Peter Pinkowish
Grants/research
support
None None
Consultant None None
Speakers’ bureau None None
Stock shareholder None None
Other financial or
material support
None None

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Opinions and Off-Label DiscussionsOpinions and Off-Label Discussions
The opinions or views expressed in this educational program are
those of the participants and do not necessarily reflect the opinions
or recommendations of Gilead Sciences Medical Affairs,
Rush University Medical Center, Rush University College of Nursing,
or the University of Florida College of Pharmacy
The faculty may have included discussion on unlabeled uses
of a commercial product or an investigational use of a
product not yet approved for this purpose
Please consult the full prescribing information before usingPlease consult the full prescribing information before using
any medication mentioned in this programany medication mentioned in this program

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Learning ObjectivesLearning Objectives
(CME/CNE and CPE)(CME/CNE and CPE)
We Are Eliminating Hard Copy Evaluations!
● Upon completion of this activity, the
participant intends to incorporate the
following objectives into their practice
of medicine:
- Assess my hepatitis C (HCV)-infected
patients on their chances of achieving a
successful outcome after failing to
respond to either PI-based therapy of a
peginterferon-based initial regimen
- Appropriately select specifically
targeted antiviral HCV therapies agents
for my HCV-infected patients who are
not responding to current standard of
care, as they become available
- Appropriately select targeted antiviral
HCV therapies agents for my HCV-
infected patients who are not
candidates for initial therapy with PI-
based therapy of peginterferon +
ribavirin, as they become available
CME/CNECME/CNE
● Upon completion of this activity, the
pharmacist should be able to:
- Assess my hepatitis C (HCV)-infected
patients on their chances of achieving a
successful outcome after failing to
respond to either PI-based therapy of a
peginterferon-based initial regimen
- Review and discuss specifically
targeted antiviral HCV therapies agents
for my HCV-infected patients who are
not responding to current standard of
care, as they become available
- Review and discuss targeted antiviral
HCV therapies agents for my HCV-
infected patients who are not
candidates for initial therapy with PI-
based therapy of peginterferon +
ribavirin, as they become available
CPECPE

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Chronic HCV Therapy (Genotype 1):
Advances in Raising Cure Rates
SVR(%)
16%
44%
~70%
35%1991
1998
2001
2011
IFN
IFN/RBV
PegIFN/RBV
Telaprevir or
Boceprevir +
PegIFN/RBV
>90%
>2013
2nd
Generation DAAs
PegIFN-Free Regimens
Schaefer EA, et al. Gastroenterology. 2012;142:1340-1350.
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
Ghany MG, et al. Hepatology. 2011;54:1433-1444.

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SVR Rates in Treatment-Naïve,
Genotype 1 HCV: Telaprevir and Boceprevir
Patients(%)
T12/PR
(n=363)
75%*
69%*
44%
T8/PR
(n=364)
PR48
(n=361)
Patients(%)
68%* 67%*
40%
LI/B24/PR
(n=350)
LI/B44/PR
(n=354)
PR48
(n=344)
ADVANCE
(Telaprevir + PR)
SPRINT-2
(LI-PR, Boceprevir + PR)
*P<0.001 versus PR48.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
*P<0.0001 versus PR48.
T:telaprevir 750 mg tid; B:boceprevir 800 mg tid; PR: pegIFN + RBV.

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Toxicities Impacting Completion of
Telaprevir and Boceprevir Based Therapy
Patients(%)
Discontinuations
10%
7%
36%
Hemoglobin (g/dL)
ADVANCE
(Telaprevir + PR)
SPRINT-2
(LI-PR, Boceprevir + PR)
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
Telaprevir 12/PR (n=363)
PR48 (n=361)
LI:lead-in; PR: pegIFN + RBV.
AEs Rash <10 <8.5
Patients(%)
Discontinuations Hemoglobin (g/dL)
AEs Rash <10 <8.5
Pooled boceprevir (n=804)
PR48 (n=344)
7%
1%
14%
9%
2%
12%
N/A
16%
29%
6%
3%
49%

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Variation in SVR Rates: Previously Treated,
HCV Genotype 1 Patients (REALIZE Study)
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
Patients(%)
Prior
Relapsers
32%
86% 85%
F2-3
(n=62/15)
F0-1
(n=167/38)
F4
(n=57/15)
T:telaprevir 750 mg q8h; PR: pegIFN + RBV.
METAVIR: F0-1 (no, minimal, or portal fibrosis); F2-3 (bridging fibrosis); F4 (cirrhosis).
Patients(%)
Prior Partial
Responders
Null
Responders
13% 13%
84%
Pooled T12/PR
PR48
Pooled T12/PR
PR48
Pooled T12/PR
PR48
72%
56%
34%
18%
0%
20%
F2-3
(n=18/5)
F0-1
(n=47/17)
F4
(n=32/5)
F2-3
(n=38/9)
F0-1
(n=59/18)
F4
(n=50/10)
41%
39%
14%
6%
0%
10%
Patients(%)

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Treatment of Chronic HCV:
Recent Successes
● Telaprevir or boceprevir + PR
- Offer patients an improved chance of cure and the opportunity
for a shorter duration of therapy
- SVR rates
• Treatment-naïve patients: 68%-75%
• Prior relapsers, partial responders: 59%-88%
• Null responders: 40%-41%
● Potential for yet another quantum leap in the field
- Recent proof of concept studies demonstrating the capacity to
eradicate HCV without interferon
- PegIFN-free regimens for genotypes 1-6
Fox AN, et al. Clin Infect Dis. 2012;55(suppl 1):S16-S24.
Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411.
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
Updated
Slide

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Telaprevir or Boceprevir + PR:
Shortcomings of the Current Standard of Care
● Only effective in HCV genotype 1 patients
● Require PR therapy
● Thrice-daily dosing
● Cirrhotics not eligible for response-guided therapy
● Side effects
- Both agents: hemoglobin decline (1.0-1.5 g/dL >PR)
- Telaprevir: rash, anorectal discomfort
- Boceprevir: dysgeusia, neutropenia
● Low barrier to resistance, emergence of resistant variants
- >50% who fail to achieve an SVR have detectable variants (wane in frequency
over time off-therapy)
- Stopping rules designed to minimize resistance
● Potential for drug-drug interactions
- CYP3A4 inhibition
Fox AN, et al. Clin Infect Dis. 2012;55(suppl 1):S16-S24.
Updated
Slide

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Chronic HCV Infection:
Targets for Direct-Acting Antiviral Agents
● Prevent viral entry
- Polyclonal and monoclonal
antibodies
● Prevent translation of viral RNA
- NS3/4 protease inhibitors
● Inhibit HCV-RNA polymerase
- Nucleoside analogue NS5B
polymerase inhibitors
- Non-nucleoside analogue NS5B
polymerase inhibitors
- Replication complex inhibitor
- Cyclophilin B inhibitors
● Viral assembly/release
- Glucosidase inhibitor
Pereira AA, et al. Nat Rev Gastroenterol Hepatol. 2009;6:403-411.

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Selected Characteristics of Direct-Acting
Antiviral Agents for Chronic HCV Infection
Protease
Inhibitors
Nucleos(t)ide
Polymerase
Inhibitors
Non-Nucleoside
Polymerase
Inhibitors
NS5A
Inhibitors
Potency High
(varies by HCV genotype)
Moderate-to-high
(consistent across HCV
genotypes, subtype)
Variable
(HCV genotypes)
High
(multiple HCV
genotypes)
Barrier to
resistance
Low
(1a<1b)
High
(1a=1b)
Very low
(1a<1b)
Low
(1a<1b)
Potential for
drug
interactions
High Low Variable Low-to-
moderate
Toxicity Rash, anemia,
↑ Bilirubin
Mitochondrial, NRTI
interactions (ART, RBV)
Variable Variable
Dosing qd to tid qd to bid qd to tid qd
Comments 2nd
generation PIs
(higher barrier to
resistance, pan-genotype)
Single target
Active site
Allosteric
Many targets
Multiple
antiviral MOA
Schaefer EA, et al. Gastroenterology. 2012;142:1340-1350.

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Combination Therapy: Potential for Preventing
the Emergence of Resistant Variants
Variant NS3
Linear
NS3
Macrocytic
NS5A
Inhibitor
NS5B
Nuc
NS5B
Palm
NS5B
Thumb
NS5B
Finger IFN RBV
NS3 PI V36M R S S S S S S S S
T54A R S S S S S S S S
R155K R R S S S S S S S
A156T R R S S S S S S S
D168V S R S S S S S S S
NS5A L28V S S R S S S S S S
Y93H S S R S S S S S S
NS5B S282T S S S R S S S S S
C316Y S S S S R S S S S
M414T S S S S R S S S S
R422K S S S S S R S S S
M423T S S S S S R S S S
P495S S S S S S S R S S
HCV DrAG ResisSS. 2012;1.2. Available at http://www.hivforum.org.
S: susceptible and R: resistant based on arbitrary <4 and >4 fold shift in HCV replicon EC50, respectively.

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Program Overview
● DAA + pegIFN + ribavirin
● Multiple DAAs + pegIFN + ribavirin
● Interferon-free regimens

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DAA + PegIFN + Ribavirin in
Late Stage Clinical Development
NS3/4A
Protease
Inhibitors
Nucleotide
NS5B
Polymerase
Inhibitors
Non-
Nucleoside
NS5B
Polymerase
Inhibitors
NS5A
Replication
Complex
Inhibitors PegIFN RBV
Sofosbuvir
(genotypes 1-6)
PegIFN RBV
Daclatasvir
(genotypes 1-3)
PegIFN RBV
Danoprevir* PegIFN RBV
Simeprevir* PegIFN RBV
Faldaprevir* PegIFN RBV
*Genotype 1.
Updated
Slide

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ATOMIC Trial:
Sofosbuvir + PR
HCV RNA >50,000 IU/mL, no cirrhosis.
BMI: >18 kg/m2
.
Non-CC IL28B: 72.4%; genotype 1a: 71.4%.
Week 0 12 24 48
PR: pegIFN + RBV (weight-based dosing: 1000 or 1200 mg).
Follow-Up
Sofosbuvir (400 mg) +
PR
Stratified by IL28B (CC versus non-CC) and by HCV RNA (<800K and >800K IU/mL).
Kowdley KV, et al. Lancet. 2013;Mar 14. [Epub ahead of print].
G1
(n=52)
G1,4,6
(n=125)
GT 1
(n=155)
Sofosbuvir (400 mg) +
PegIFN + RBV
Sofosbuvir (400 mg) + PR
Sofosbuvir (n=75)
Sofosbuvir + RBV (n=75)
Follow-Up
Follow-Up
Phase 2b
Treatment-naïve
Updated
Slide

24
ATOMIC Trial:
Treatment Outcomes
● SVR12 and SVR24
- Similar among sofosbuvir regimens
(12 and 24 weeks)
- Genotype 4 (n=11)
• SVR12/SVR24: 82%/82%
- Genotype 6 (n=5)
• SVR12/SVR24: 100%/100%
● Sequence data from 4 patients who
relapsed showed no S282T
mutation (population sequencing)
- Deep sequencing for all patients
with relapse is ongoing
SVR12 and SVR24 (ITT)
Patients(%)
90%89%
93%
12
Sofosbuvir + PR (weeks)
SVR12 SVR24
91%
24 12 + 12
89% 87%
PR: pegIFN + RBV (weight-based dosing: 1000 or 1200 mg).
Updated
Slide

25
ATOMIC Trial:
Relapse and Safety and Tolerability
● Relapse: 3%
- No S282T mutation detected (phenotypic data generated in 10/11
relapse patients)
- No change in susceptibility to sofosbuvir
● Safety and tolerability
- Well tolerated up to 24 weeks, with no serious adverse events
• Discontinuation due to adverse events: <5%
● Most common adverse events
- Consistent with those associated with PR
• Constitutional symptoms, influenza-like symptoms, rash, anemia
Updated
Slide

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NEUTRINO Study: Sofosbuvir + PR in
Treatment-Naïve, HCV Genotype 1, 4, 5, and 6
Phase 3
Open-label
Treatment-Naïve
Genotype 1, 4, 5, and 6
Week 0 12 24 36
Sofosbuvir (nucleotide NS5B polymerase Inhibitor).
No upper limit to age or BMI.
Opioid substitution permitted.
Platelets >90,000/mm3
, neutrophils >1500/mm3
or 1000/mm3
(blacks).
Cirrhosis permitted (17% enrolled).
Primary efficacy endpoint: SVR12.
Prespecified comparison to historical SVR control rate of 60%.
Follow-UpSofosbuvir 400 mg qd +
PR (n=327)
New
Slide

27
NEUTRINO Study: SVR12 Rates
by Prespecified Subgroups
Patients(%)
82%
90%*
96%
92%
Overall
(n=327)
100%
96%
89%
92%
80%
98%
1a
(n=255)
1b
(n=66)
<6
(n=71)
>6
(n=256)
No
(n=273)
Yes
(n=54)
Genotype Baseline
HCV RNA (log)
Cirrhosis
CC
(n=98)
Non-CC
(n=232)
IL28B
87%
4
(n=28)
5/6
(n=7)
*P<0.001 versus historical SVR rate of 60%.
Sofosbuvir 400 mg qd + PR (12 weeks)
New
Slide

28
NEUTRINO Study:
Resistance and Safety
● No resistance detected in sofosbuvir + PR virologic failures and 1
relapse patient who discontinued therapy (HCV RNA >1000 IU/mL)
● Safety of sofosbuvir + PR
- Well tolerated and no additive effects of the addition of sofosbuvir to PR
• Discontinuations due to adverse events: 2%
- Most common adverse events
• Fatigue (59%), headache (36%), nausea (34%), insomnia (25%), anemia (21%),
rash (18%)
- Safety profile consistent with ribavirin
• Hemoglobin <10 g/dL: 23%
• Hemoglobin <8.5 g/dL: 2%
New
Slide

29
COMMAND-1 Study:
Daclatasvir + PR
PR: pegIFN + RBV.
All daclatasvir patients not achieving a protocol-defined response at week 12
(HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks.
HCV RNA: 6.5 log10 IU/mL.
Compensated cirrhosis: 7.3%.
BMI: >18 kg/m2
.
Non-CC IL28B: 69%; genotype 1a: 70%; genotype 4: 8%.
Week 0 12 24 48
Follow-UpDaclatasvir (20 mg) +
PR (n=159)
PR (n=78)
Daclatasvir 60 mg +
PR (n=158)
Daclatasvir + PR
Follow-Up
Phase 2b
Treatment-naïve
Genotype 1 or 4
Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755.
PR
Daclatasvir + PR
PR
PR (n=78)

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COMMAND-1 Study (ITT):
SVR12 Rates (All PDR)
Patients(%)
Genotype
67%65%
36%
100%
Genotype 1
(n=147/146/72)
64%
50%
DCV 20 mg + PR
DCV 60 mg + PR
PR
Genotype 4
(n=12/12/6)
Patients(%)
Genotype 1 Subgroup
78%
59%
38%
87%
Genotype 1a
(n=106/113/56)
58%
31%
DCV 20 mg + PR
DCV 60 mg + PR
PR
Genotype 1b
(n=41/31/16)
PDR: week-12 protocol-defined response (HCV RNA <LLOQ at week 4 and undetectable
[<10 IU/mL] at week 10) received PR for 24 weeks). PR: pegIFN + RBV.

31
COMMAND-1 Study:
SVR12 Rates by IL28B (All PDR)
Patients(%)
Genotype 1a
51%
85%
45%
31%
CC
(n=41/36/18)
61%
36%
CT
(n=51/61/26)
Patients(%)
Genotype 1b
DCV 20 mg + PR PR
DCV 60 mg + PR
PDR: week-12 protocol-defined response (HCV RNA <LLOQ at week 4 and undetectable
[<10 IU/mL] at week 10) received PR for 24 weeks). PR: pegIFN + RBV.
TT
(n=11/14/9)
78%
22%
CC
(n=11/7/4)
CT
(n=24/20/10)
TT
(n=6/4/2)
71%
40%
85%
67%
0%
75%
100%
25%
DCV 20 mg + PR PR
DCV 60 mg + PR

32
COMMAND-1 Study: Treatment Failure
and Safety and Tolerability
● Treatment failure
- Overall (daclatasvir versus PR): 35% versus 64%
• Treatment failure rates were lower in daclatasvir-treated patients
who achieved PDR (11%-24%)
- Similar adverse event profile between the daclatasvir + PR and
PR treatment arms
• Discontinuation due to adverse events: <5%
- Changes in laboratory parameters were consistent across all
treatment arms
● Future clinical trials will be with genotype 1b patients only
PR: pegIFN + RBV.
PDR: week-12 protocol-defined response.

33
COMMAND-2 Study:
Daclatasvir + PR
PR: pegIFN + RBV.
All daclatasvir patients not achieving a protocol-defined response at week 12
(HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks.
HCV RNA: 6.5 log10 IU/mL.
Compensated cirrhosis: 7.3%.
BMI: >18 kg/m2
.
Non-CC IL28B: 69%; genotype 1a: 70%; genotype 4: 8%.
Week 0 12 16 24 48
Follow-Up
Daclatasvir 60 mg qd
+ PR (n=50)
+ PR (n=50) Follow-Up
Follow-Up
Phase 2b
Treatment-naïve
Genotype 2, 3
Dore GJ, et al. J Hepatol. 2013;58(suppl 1):S570-S571. Abstract 1418.
PR
Daclatasvir
+ PR
PR
PR (n=51)
Follow-Up
Follow-Up (36 weeks)
New
Slide

34
COMMAND-2 Study (ITT):
SVR24 Rates (ITT)
Patients(%)
Genotype
69%
83%
63%
67%
Genotype 2
(n=24/23/24)
83%
59%
DCV + PR (12 weeks)
DCV + PR (16 weeks)
PR
Genotype 3
(n=26/27/27)
Patients(%)
IL28B Genotypes
50%
80%
85%
75%
CC
83%
64%
100%
Non-CC
Genotype 2
CC Non-CC
Genotype 3
75%
56%
81%
64%
56%
DCV + PR (12 weeks)
DCV + PR (16 weeks)
PR
New
Slide

35
COMMAND-2 Study: Treatment Failure
and Safety in Genotype 2/3
● Treatment failure (daclatasvir versus PR)
- Genotype 2: 5% versus 5%
- Genotype 3: 25% verus 14%
• With versus without baseline NS5A Y93 and/or A30 polymorphisms (50% versus 19%)
• Cirrhotics versus non-cirrhotics (36% versus 21%)
• No apparent effect of IL28B genotype or baseline HCV RNA on relapse
- Similar adverse event profile across all arms
• Discontinuation due to adverse events (daclatasvir versus PR): 7% versus 4%)
- Changes in laboratory parameters were consistent across all treatment arms
● Further evaluation of daclatasvir + PR in HCV genotype 2/3 patients is
planned
PR: pegIFN + RBV.
New
Slide

36
DAUPHINE Study:
Danoprevir/r + PR
*RGT (response-guided therapy): week 12 all drugs stopped if eRVR [HCV RNA <15 IU/L achieved during
weeks 2-10, if not then continue to week 24.
PR: pegIFN + RBV.
HCV RNA: >50,000 IU/Ml; fibrosis score: F0-F2; non-CC IL28B: 70%; genotype 1a: 60%; genotype 4: 8%.
Week 0 12 24 48
Follow-UpDanoprevir/r 200/100 mg + PR
(n=94)
PR (n=46)
Follow-Up
Phase 2b
Treatment-naïve
Genotype 1 or 4
Danoprevir/r 100/100 mg
+ PR (n=94)* Follow-Up
Danoprevir + PR
Danoprevir/r 100/100 mg + PR
(n=93)
Danoprevir/r 50/100 mg + PR
(n=94)
Follow-Up
eRVR: Follow-Up
Everson GT, et al. Hepatology. 2012;56(suppl 4):552A. Abstract 754.

37
DAUPHINE Study:
SVR24 Rates
● Dose-dependent increases in
SVR24
- Highest SRV24 rates achieved in
the danoprevir/r 200/100 mg
treatment arm
● Dose-response relationship seen
in a harder-to-treat subgroup
(genotype 1a, IL28B non-CC)
- 200/100 mg: 88%
- 100/100 mg: 70%
- 50/100 mg: 58%
● Genotype 1b/IL28B CC and
genotype 4 patients
- All achieved SVR24 in <12 weeks
SVR24 (ITT)
Patients(%)
1a
(n=56/56/58/49)
4
(n=8/8/7/7)
1b
(n=29/29/26/37)
84%
60%
70%
97%
93%
100%
88%
73%
100%
200/100 mg 50/100 mg
100/100 mg 100/100 mg RGT
Genotype
RGT: response-guided therapy.
Danoprevir/r was administered with PR (pegIFN + RBV).
59%
78%

38
DAUPHINE Study: Treatment Failure
and Safety and Tolerability
● Treatment failure: 17.5%
- Relapse: 11%
• Predominately genotype 1a and non-CC IL28G genotype
- Resistance uniquely associated with the NS3 R155K substitution
- Similar adverse event profile between the danoprevir/r + PR and
PR treatment arms
• Discontinuation of danoprevir/r due to adverse events: 5%
- Laboratory abnormalities were not dose related
- Anemia (hemoglobin <8.9 g/dL or any decrease >4.5 g/dL): 7%
Le Pogam, et al. Hepatology. 2012;56(suppl 4):571A-572A. Abstract 782.

39
QUEST-1 and -2 Trials: Simeprevir + PR
in Treatment-Naïve, HCV Genotype 1
Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425.
Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
Week 0 12 24 48 72
Simeprevir (NS3/4A protease inhibitor).
HCV RNA >10,000 IU/mL.
PR: pegIFN (alpha 2a or 2b) + RBV (weight-based dosing: 1000-1200 mg).
Patients stratified by HCV subtype and IL28B genotype.
Response-guided therapy criteria: HCV RNA <25 IU/mL at week 4 and undetectable at week 12.
METAVIR score: F0-F1 (~50%); >F2 (~50%).
Simeprevir
150 mg qd + PR
Follow-Up
Follow-Up
Phase 3
Treatment-naïve
Genotype 1
PR
PR
PR (n=134)
Follow-Up
New
Slide

40
QUEST-1 and -2 Trials: Overall SVR12
Rates by Genotype 1 Subgroup
Patients(%)
49%
80%*
71%*
90%*
50%
Overall
(n=264/130)
52%
Simeprevir + PR
PR
1a
(n=147/74)
1b
(n=117/56)
Genotype
*P<0.01 versus PR.
New
Slide
QUEST 1
Patients(%)
46%
81%* 80%* 82%*
50%
Overall
(n=257/134)
53%
Simeprevir + PR
PR
1a
(n=107/57)
1b
(n=150/77)
Genotype
QUEST 2
*P<0.01 versus PR.

41
QUEST-1 and -2 Trials: SVR12 Rates
Patients(%)
42%
94%*
76%*
65%*
78%
24%
Simeprevir + PR
PR
83%*
60%
CC
(n=77/37)
CT
(n=150/76)
TT
(n=37/17)
F0-F2
(n=183/90)
IL28B Genotype METAVIR Score
F3
(n=46/23)
F4
(n=37/17)
58%*
29%
78%*
26%
*P<0.01 versus PR.
New
Slide
Patients(%)
41%
96%*
80%*
58%*
81%
19%
Simeprevir + PR
PR
85%*
51%
CC
(n=75/42)
CT
(n=142/71)
TT
(n=40/21)
F0-F2
(n=195/102)
IL28B Genotype METAVIR Score
F3
(n=37/17)
F4
(n=17/15)
65%*
40%
67%*
53%
*P<0.01 versus PR.
QUEST 1 QUEST 2

42
QUEST-1 and -2 Trials:
● NS3 PI mutations were detected in the time of failure for the
majority (>90%) of simeprevir-treated patients not achieving an SVR
- Genotype 1: mainly R155 alone
- Genotype 1b: mainly D168V or Q80R + D168E
● Simeprevir + PR was well tolerated
- Simeprevir treatment discontinuations due to adverse events
• QUEST-1: 3%
• QUEST-2: 1.6%
● Adverse event profile of simeprevir + PR was similar to the PR arm
- Headache, pyrexia, fatigue, influenza-like illness, rash, anemia, pruritus
New
Slide

43
ASPIRE Study:
Simeprevir + PR
Week 0 12 24 48 72
SMV 100 mg
12/PR (n=66)
PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg).
Follow-Up
Phase 2b
Previously failed
Genotype 1
PR
SMV (150 mg qd)
+ PR
Follow-Up
PRSMV 150 mg
12/PR (n=66)
SMV 100 mg
24/PR (n=65)
SMV (100 mg qd) + PR
Follow-Up
PR
Follow-Up
PRSMV 150 mg
24/PR (n=66)
Follow-Up
SMV (100 mg qd)
+ PR
PR
Follow-Up
Follow-Up
Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract
2.
PR48
(n=66)
SMV 100 mg
48/PR (n=66)
SMV 150 mg
48/PR (n=65)

44
ASPIRE Trial:
SVR24 Rates With Simeprevir + PR
Patients(%)
Prior Relapsers
85% 85%
100 mg
(n=79)
150 mg
(n=79)
PR48
(n=27)
*Duration pooled. PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg).
Patients(%)
Prior Partial
Responders Null Responders
37%
75%
57%
9%
51%
46%
19%
Patients(%)
Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract
2.
Simeprevir + PR48
100 mg
(n=68)
150 mg
(n=69)
PR48
(n=23)
Simeprevir + PR48
100 mg
(n=68)
150 mg
(n=69)
PR48
(n=23)
Simeprevir + PR48

45
ASPIRE Trial: Resistance and
Safety and Tolerability
● Viral breakthrough/relapse was usually associated with
emerging mutations to simeprevir
- Q80K at baseline did not alter SVR24 rates in the simeprevir 150 mg
treatment arms
- Well tolerated, treatment discontinuations due to adverse
events: 7%)
- Hematologic abnormalities were similar across all treatment
arms
- Mild and reversible increases in bilirubin were seen in the
simeprevir arms
• No other liver changes
Lenz O, et al. J Hepatol. 2012;54(suppl 2):S5. Abstract 9.
Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract 2.

46
STARTVerso1 Trial: Faldaprevir + PR
in Treatment-Naïve, Genotype 1
Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416.
Week 0 12 24 48 72
ETS, Follow-Up
Follow-Up
Faldaprevir
120 mg qd + PR
(n=261)
PR
Faldaprevir
240 mg qd + PR
(n=262)
PR
ETS, Follow-Up
PR
Follow-Up
Faldaprevir (NS3/4A protease inhibitor).
Platelets >90,000 cells/mm3
.
No HBV or HIV coinfection. Fibrosis stage >F3: 17%
ETS: early treatment success (HCV RNA <25 IU/mL at week 4 and undetectable at week 8.
Primary efficacy endpoint: SVR12
Phase 3
Treatment-Naïve
Genotype 1
PR
Follow-Up
PRFaldaprevir + PR
No ETS
No ETS
New
Slide

47
STARTVerso1 Trial: SVR12 Rates
Patients(%)
36%
69%
84%83%
76%
Overall
(n=259/261/132)
60%
70%
90%
63%
69%
95%
51%
Faldaprevir 120 mg qd + PR
Faldaprevir 240 mg qd + PR
PR
76%
1a
(n=87/90/45)
1b
(171/171/86)
CC
(n=75/42)
CT
(n=142/71)
TT
(n=40/21)
Genotype IL28B Genotype
ETS
Patients
(n=225/232)
86%
89%
79%
28%
*P<0.0001 versus PR.
79%*80%*
52%
New
Slide

48
STARTVerso1 Trial:
● No significant effect of Q80K on SVR12 in genotype 1a patients
● Faldaprevir + PR was well tolerated
- Discontinuations due to adverse events: 4%
● Adverse event profile of faldaprevir + PR was similar to the PR arm
- Most common adverse events of at least moderate severity
• Rash (8%), anemia (12%)
● Total bilirubin elevations >2.6 x ULN with faldaprevir + PR were
benign and transient
- 120 mg qd: 12%
- 240 mg qd: 53%
The Q80K mutation is associated with a decreased susceptibility to some NS3/4A protease inhibitors.
New
Slide

49
SILEN-C2 Study:
Faldaprevir + PR (Non-Responders)
Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S30. Abstract 66.
Week 0 24 48 72
LI/240 mg qd/PR
(n=142)
240 mg qd/PR
(n=76)
eRVR, Follow-Up
Follow-Up
LI/120 mg qd/PR
(n=70)
Faldaprevir 240 mg qd
+ PR
LI*
PR
+ PR
PR
Follow-Up
+ PR
LI* PR
Follow-Up
*LI: 3-day lead-in with PR.
Relapsers excluded.
HCV RNA >100,000 IU/mL, no cirrhosis.
PR: pegIFN + RBV (weight-based ribavirin: 1000-1200 mg).
Phase 2b
Non-responders
Genotype 1

50
SILEN-C2 Study: SVR and
Overall Relapse With Faldaprevir
Patients(%)
LI/240 mg
qd/PR
(n=142)
Sustained Virologic Response
27%
41%
31%
Relapse: rebound from undetectable at end of all treatment.
240 mg
qd/PR
(n=76)
LI/240 mg
bid/PR
(n=70)
Patients(%)
Overall Relapse
25%
9%
19%
LI/240 mg
qd/PR
(n=142)
240 mg
qd/PR
(n=76)
LI/240 mg
bid/PR
(n=70)

51
SILEN-C2 Study: Virologic Failure,
Discontinuations, and Adverse Events
LI/240 mg qd/PR
(n=142)
240 mg qd/PR
(n=76)
LI/240 mg bid/PR
(n=70)
Virologic failure (%)
During faldaprevir
During PR phase
25
5
28
7
17
6
Discontinuation (%)
Adverse events 6 4 23
Adverse events (%)
Rash
Jaundice
Nausea
Diarrhea
Vomiting
34
19
48
32
17
28
21
53
32
22
42
41
64
39
32

52
Program Overview

53
Multiple DAA + PegIFN + Ribavirin in
NS3/4A
Protease
Inhibitors
Nucleotide
NS5B
Polymerase
Inhibitors
Non-
Nucleoside
NS5B
Polymerase
Inhibitors
NS5A
Replication
Complex
Danoprevir Mericitabine PegIFN RBV
Asunaprevir Daclatasvir PegIFN RBV

54
Phase 2a
Genotype 1
Prior Partial
Responders
Prior Null
Responders
MATTERHORN Study:
Danoprevir/r + Mericitabine + PR
Week 0 24 48 72
Danoprevir/r + Mericitabine
+ PR (n=50)
Danoprevir/r + PR
(n=49)
QUAD
+ RBV (n=52)
IFN Free
Feld JJ, et al. Hepatology. 2012;56(suppl 4):231A-232A. Abstract 81.
Triple
+ PR (n=77)
Danoprevir/r + PR
(n=77)
+ RBV (n=74)
QUADPR
Absence of cirrhosis.
Mericitabine dosed bid. PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg).
QUAD
IFN Free

55
MATTERHORN Study:
Treatment Outcomes
● QUAD regimen produced the highest
overall SVR12 rates
- Genotype 1b patients (91% to 100%)
- Genotype 1a
• Adding mericitabine increased SVR12
from 30% to 75%
● Virologic breakthrough was
associated with resistance to
danoprevir (R155K, D168E/T)
● QUAD, triple, and IFN-free regimens
were safe and well tolerated
- Addition of mericitabine did not change
the safety profile of danoprevir/r +
pegIFN + RBV
Patients(%)
SVR12
84%86%
39%
N/A
Prior Partial
Responders
(n=50/48/23)
56% 55%
QUAD IFN free
Triple
Prior Null
Responders
(n=74/31)
Feld JJ, et al. Hepatology. 2012;56(suppl 4):231A-232A. Abstract 81.

56
Study 011 (Expansion Cohort):
Daclatasvir + Asunaprevir + PR
Week 0 24 36 48
Dual-1
(n=18)
Daclatasvir 60 mg qd +
Asunaprevir 200 mg bid
(Genotype 1b only)
Follow-Up
Lok AS, et al. Hepatology. 2012;56(suppl 4):230A. Abstract 79.
SVR12
Primary Endpoint
Dual-2
(n=20)
QUAD-1
(n=20)
QUAD-2
(n=21)
Triple
(n=22)
Phase 2a
Genotype 1
Prior null responders
Asunaprevir 200 mg qd
(Genotype 1b only)
Asunaprevir 200 mg bid + PR
(Genotype 1a/1b)
Asunaprevir 200 mg qd + PR
(Genotype 1a/1b)
Asunaprevir 200 mg bid + RBV
(Genotype 1a/1b)
Follow-Up
Follow-Up
Follow-Up
Follow-Up
Non-cirrhotic
PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg).

57
Study 011:
Treatment Outcomes
● SVR12 rates higher in the
QUAD arm compared with the
dual arm
● Virologic breakthrough
- IFN-free arm: 56%
● QUAD, triple, and IFN-free
regimens were well tolerated
- Discontinuations due to
adverse events: 0%
- Headache, diarrhea, fatigue,
and insomnia
SVR12 Rate
Patients(%)
Dual-1
(n=78)
Dual-2
(n=65)
78%
97%
90%
65%
QUAD-1
(n=20)
QUAD-2
(n=21)
Lok AS, et al. Hepatology. 2012;56(suppl 4):230A. Abstract 79.

58
Program Overview

59
Interferon-Free Regimens in
NS3/4A
Protease
Inhibitors
Nucleotide
NS5B
Polymerase
Inhibitors
Non-Nucleoside
NS5B Polymerase
Inhibitors
NS5A
Replication
Complex
Sofosbuvir
Sofosbuvir RBV
Sofosbuvir Daclatasvir
Sofosbuvir Daclatasvir RBV
Faldaprevir BI 207127
Faldaprevir BI 207127 RBV
Faldaprevir PegIFN RBV
ABT-450/r ABT-333 ABT-267 RBV
ABT-450/r ABT-333 RBV
ABT-450/r ABT-267 RBV
ABT-450/r ABT-333 ABT-267

60
FISSION Trial: Sofosbuvir + RBV in
Treatment-Naïve, HCV Genotype 2 or 3
Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.
Phase 3
Open-label
Treatment-Naïve
Genotype 2 or 3
Week 0 12 24 36
Sofosbuvir (nucleotide NS5B polymerase inhibitor).
Platelet >75,000/mm3
(cirrhotic: 20% maximum).
Stratified by genotype, HCV RNA, and cirrhosis.
Primary efficacy endpoint: SVR12 (non-inferiority margin: 15%).
RBV 1000-1200 mg/day
(n=256)
PegIFN + RBV (800 mg/day)
(n=243)
Follow-Up
New
Slide

61
FISSION Trial: SVR12 Rates
Patients(%)
78%
67%
97%
56%
67%
Overall*
(n=253/243)
63%
66%
75%
62%
72%
67%
74%
Sofosbuvir + RBV
PR
47%
38%
2
(n=70/67)
3
(n=183/176)
<6
(n=107/106)
>6
(n=146/137)
No
(n=204/193)
Yes
(n=49/50)
Genotype Baseline
HCV RNA (log)
Cirrhosis
Male
(n=168/156)
Female
(n=85/87)
Gender
79%76%
61% 62%
*Non-inferiority criteria met.
New
Slide

62
FISSION Trial: SVR12 Rates
by Genotype and Cirrhosis
Patients(%)
Genotype 2
98%
91%
82%
62%
No Cirrhosis
(n=59/54)
Cirrhosis
(n=11/13)
Patients(%)
Genotype 3
61%
71%
34%
30%
No Cirrhosis
(n=145/139)
Cirrhosis
(n=38/37)
Sofosbuvir + RBV
PR
Sofosbuvir + RBV
PR
New
Slide

63
FISSION Trial:
● No resistance detected in sofosbuvir + RBV
virologic failures
- Relapse accounted for all but 1 virologic failure
(nonadherence)
● Safety of sofosbuvir + RBV
- Well tolerated and few adverse events
• Fatigue (36%), headache (25%), nausea (18%), insomnia
(12%)
New
Slide

64
FUSION Trial:
Sofosbuvir + RBV for 12 Versus 16 Weeks in
HCV Genotype 2/3, Previously Failed PR Therapy
Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.
Phase 3
Double-blind
Failed Prior PegIFN-Based Therapy
Genotype 2 or 3
Platelet >50,000/mm3
, no neutrophil minimum.
Cirrhosis at baseline (34%). Prior relapsers (76%).
Stratified by genotype and cirrhosis.
(n=103)
Week 0 12 16 24
Placebo
Sofosbuvir 400 mg qd +
RBV 1000-1200 mg/day (n=98)
Follow-Up
New
Slide

65
FUSION Trial: SVR12 Rates
Patients(%)
94%
50%
86%
30%
73%*
Overall
(n=100/95)
62%*
77%
50% 50%
61%62%
76%
Sofosbuvir + RBV
12 weeks
16 weeks
31%
66%
2
(n=36/32)
3
(n=64/63)
<6
(n=26/29)
>6
(n=74/66)
No
(n=64/63)
Yes
(n=36/32)
Genotype Baseline
HCV RNA (log)
Cirrhosis
Male
(n=71/64)
Female
(n=29/31)
Gender
69%
87%
42%
66%
*P<0.001 versus 12 weeks of active therapy.
New
Slide

66
FUSION Trial: SVR12 Rates
by Genotype and Cirrhosis
Patients(%)
Genotype 2
96%
60%
100%
78%
No Cirrhosis
(n=26/23)
Cirrhosis
(n=10/9)
Patients(%)
Genotype 3
37%
63%
19%
61%
No Cirrhosis
(n=38/40)
Cirrhosis
(n=26/23)
Sofosbuvir + RBV
12 weeks
16 weeks
Sofosbuvir + RBV
12 weeks
16 weeks
New
Slide

67
FUSION Trial:
● No resistance detected in sofosbuvir + RBV virologic
failures
• No discontinuations due to adverse events
• Fatigue (46%), headache (27%), nausea (21%), insomnia (24%)
• Hemoglobin <10 g/dL: 7.5%
New
Slide

68
POSITRON Trial: Sofosbuvir + RBV in HCV
Genotype 2 or 3 With Limited Options
Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61.
Phase 3
Double-blind, placebo-controlled
Interferon-Ineligible, Intolerant, or unwilling
Genotype 2 or 3
No lower limit to platelet or neutrophil count.
Cirrhosis at baseline (16%). Prior relapsers (76%).
Stratified by presence or absence of cirrhosis.
(n=207)
Week 0 12 24
Placebo (n=71)
Follow-Up
New
Slide

69
POSITRON Trial: SVR12 Rates With
Sofosbuvir + RBV by Prespecified Subgroups
Patients(%)
93%
78%
Overall
(n=207)
61%
79%76%
81%
61%
2
(n=109)
3
(n=98)
<6
(n=67)
>6
(n=140)
No
(n=176)
Yes
(n=31)
Genotype Baseline
HCV RNA (log)
Cirrhosis
Male
(n=117)
Female
(n=90)
Gender
84%
73%
SVR12 rate was 0% in the placebo arm.
New
Slide

70
POSITRON Trial: SVR12 Rates With
Sofosbuvir + RBV by Genotype and Cirrhosis
Patients(%)
Genotype 2
92% 94%
No Cirrhosis
(n=92)
Cirrhosis
(n=17)
Patients(%)
Genotype 3
68%
21%
No Cirrhosis
(n=84)
Cirrhosis
(n=14)
SVR12 rate was 0% in the placebo arm.
New
Slide

71
POSITRON Trial:
● No resistance detected in sofosbuvir + RBV virologic
failures
• Treatment discontinuations due to adverse events: 2%
• Fatigue (44%), headache (21%), nausea (22%), insomnia (19%)
• Hemoglobin <10 g/dL: 7%
New
Slide

72
ELECTRON Study:
Sofosbuvir + Ribavirin
Week 0 4 8 12 24
Follow-Up
Treatment-Naïve
Genotype 2, 3
(n=10)
Sofosbuvir (nucleotide NS5B polymerase Inhibitor). PR: pegIFN + RBV.
HCV RNA >50,000 IU/mL. No cirrhosis.
Weight-based ribavirin dosing (800-1200 mg).
Sofosbuvir 400 mg qd
+ PR
Follow-Up
Sofosbuvir 400 mg qd + RBV
Null Responders
Genotype 1
(n=10)
Follow-Up
Treatment-Naïve
Genotype 1
(n=25)
Follow-Up
Treatment-Experienced
Genotype 2, 3
(n=25)
Gane EJ, et al. N Engl J Med. 2013;368:34-44.
Phase 2b

73
ELECTRON Study:
SVR Rates in HCV Genotype 2/3 and 1
Patients(%)
Genotype 2/3
SVR12
SVR24
100%
68%
100%
NR
PR: pegIFN + RBV; NR: not reported.
Treatment-Naïve
Sofosbuvir + PR
8 weeks (n=10)
Treatment-Experienced
Sofosbuvir + RBV
12 weeks (n=25)
Patients(%)
Genotype 1
SVR12
SVR24
84%
10%
NR NR
Null Responders
Sofosbuvir + RBV
12 weeks (n=10)
Treatment-Naïve
Sofosbuvir + RBV
12 weeks (n=25)
Gane EJ, et al. N Engl J Med. 2013;368:34-44.

74
ELECTRON Study: Sofosbuvir + RBV + Either Ledipasvir
(NS5A Inhibitor) or GS-9669 (NS5B Non-Nucleoside Inhibitor)
Week 0 4 8 12 24
Follow-Up
Treatment-Naïve
(n=25)
Sofosbuvir (nucleotide NS5B polymerase Inhibitor).
No cirrhosis. Weight-based ribavirin dosing (1000-1200 mg).
Null Responders
(n=10)
Sofosbuvir 400 mg qd + Ledipasvir
+ RBV
Follow-Up
Treatment-Naïve
(n=25)
Sofosbuvir 400 mg qd + Ledipasvir
+ RBV
Follow-Up
Null Responders
(n=9)
Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14.
Phase 2b
Genotype 1 Follow-Up
Sofosbuvir 400 mg qd + GS-9669
+ RBV
Follow-Up
Treatment-Naïve
(n=25)
Sofosbuvir 400 mg qd + GS-9669
+ RBV
Follow-Up
Null Responders
(n=9)
New
Slide

75
ELECTRON Study (Genotype 1 Cohort):
Interim Analysis of SVR12 Rates
Patients(%)
Treatment-Naive
84%
92%
Sofosbuvir
+ RBV
(n=25)
Null Responders
100%
Sofosbuvir
+ Ledipasvir
+ RBV
(n=25)
Sofosbuvir
+ GS-9669
+ RBV
(n=25)
Patients(%)
10%
100%
Sofosbuvir
+ RBV
(n=10)
100%
Sofosbuvir
+ Ledipasvir
+ RBV
(n=9)
Sofosbuvir
+ GS-9669
+ RBV
(n=3)
New
Slide

76
ELECTRON Study
(Genotype 1 Cohort): Safety
● Adding ledipasvir to sofosbuvir + RBV
- No additional safety or tolerability issues
● Adding GS-9669 to sofosbuvir + RBV
- No additional safety or tolerability issues
● Fix-dose combination of sofosbuvir/ledipasvir
- Undergoing phase 3 trial in patients with and without
cirrhosis
- Additional studies exploring shorter duration of
therapy
New
Slide

77
Phase 2a
Treatment-naïve
Genotype 2/3
Genotype 1
Study 040:
Sofosbuvir + Daclatasvir + Ribavirin
Week 0 12 24 48
Daclatasvir 60 mg qd (n=16)
Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
Follow-Up
Daclatasvir 60 mg qd + RBV (n=14)
*LI: 7-day lead-in with sofosbuvir 400 mg qd. HCV RNA >50K IU/mL, no cirrhosis. Primary outcome: SVR12.
LI*
Follow-Up
Follow-Up
LI*
Follow-Up
Follow-Up
+ RBV (n=15)
Follow-Up

78
Study 040 (24-Week Treatment):
SVR12 and SVR24 Rates
Patients(%)
Genotype 2/3
SVR12
SVR24
88% 86%
93% 93%
LI/SOF/
DCV
(n=16)
100%
SOF/DCV
(n=14)
SOF/DCV
+ RBV
(n=14)
LI: 7-day lead-in with sofosbuvir 400 mg qd.
Patients(%)
Genotype 1
SVR12
SVR24
100%
93%
100%
LI/SOF/
DCV
(n=15)
100%
SOF/DCV
(n=14)
SOF/DCV
+ RBV
(n=15)

79
● Sofosbuvir + daclatasvir + RBV was well tolerated
- Discontinuations due to adverse events: 3%
- Fatigue (36%)
- Headache (27%)
- Nausea (26%)
● No grade 3/4 elevations in ALT, AST, or total bilirubin
● Anemia (hemoglobin <9 g/dL): 7%
• All in the RBV-containing arms

80
SVR4 Rate and Safety
Patients(%)
Genotype 1: SVR4
98% 95%
SOF/DCV
(n=41)
SOF/DCV
+ RBV
(n=41)
● No virologic failure
reported
● SVR12 evaluable for 68 of
82 patients: 100%
● Safety
- No discontinuations due to
adverse events
- Hemoglobin <9 g/dL
• Without ribavirin: 0%
• With ribavirin: 12%

81
Phase 2a
Prior Nonresponse, Relapse, or Breakthrough with Telaprevir or Boceprevir With PR
Genotype 1
Study 040: Sofosbuvir + Daclatasvir + RBV in
Previous Telaprevir or Boceprevir Failures
Week 0 12 24 48
Follow-Up
Follow-Up
Daclatasvir (NS5A replication complex inhibitor).
HCV RNA >105
IU/mL.
METAVIR score: F0-F1 (12%), >F2 (88%).
NS3 polymorphisms conferring resistance to boceprevir or telaprevir as baseline: 46%
NS5A polymorphisms conferring resistance to daclatasvir: 7%
Excluded: patients who discontinued telaprevir or boceprevir due to an adverse event.
New
Slide

82
SVR4 and SVR12 Rates
● No virologic failures
● Neither baseline NS3 PI resistance nor
use of RBV influenced response
● Sofosbuvir + daclatasvir + RBV was
well tolerated
- No discontinuations due to adverse
events
● Most common adverse events (without
RBV)
- Fatigue (29%), headache (33%),
arthralgia (14%)
● No grade 3/4 elevations in ALT, AST, or
total bilirubin
● Anemia (hemoglobin <9 g/dL): 0%
Patients(%)
Genotype 1
SVR4 SVR12
100% 100%
95%*
Sofosbuvir +
Daclatasvir
(n=21)
100%
Sofosbuvir +
Daclatasvir +
RBV (n=20)
*1 patient missing at post-treatment 12 weeks,
HCV RNA undetectable at post-treatment week 24 (preliminary).
New
Slide

83
Study 014: Asunaprevir +
Daclatasvir + BMS-791325
● Phase 2a, open-label study in
treatment-naïve, HCV genotype 1
patients (n=32)
- Non-cirrhotic
- HCV RNA 6.3 log10 IU/mL
- Genotype 1b (75%)
- IL28B CC genotype: 28%
● Asunaprevir + daclatasvir + BMS-
791325 75 mg
- 24 or 12 weeks of therapy
● Primary outcome: SVR12
- Interim analysis
• SVR4: 24 and 12-week arms
• SVR12: 12-week arm only)
24-Week
Treatment
(n=16)
12-Week
Treatment
(n=16)
SVR4 (%)
Overall
Genotype 1a
94
92
94
100
SVR12 (%) N/A 94
Safety (%)
Discontinuations due
to adverse events
Grade 3/4 laboratory
abnormalities
Headache
Diarrhea
Asthenia
0
0
25
13
13
0
6
38
38
19
Interim Outcomes
Everson GT, et al. Hepatology. 2012;56:1517A-1518A. Abstract LB-3.

84
SOUND-C2 Study:
Faldaprevir + BI 207127 + Ribavirin
Week 0 16 28 40
TID16W
(n=81)
Follow-Up
TID28W
No RBV
(n=46)
TID28W
(n=80)
Follow-Up
Faldaprevir + BI 207127 TID
+ RBV
Follow-UpTID40W
(n=77)
BID28W
(n=78)
Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232.
+ RBV
Faldaprevir + BI 207127 BID
+ RBV
Follow-Up
Follow-Up
HCV RNA >100K IU/mL, cirrhotic patients permitted.
Faldaprevir (NS3/4A inhibitor), BI 207127 (non-nucleoside NS5B inhibitor).
Phase 2b
Treatment-naïve
Genotype 1 Faldaprevir +
BI 207127
TID + RBV

85
SOUND-C2 Study:
Final SVR12 Results
Patients(%)
Overall
69%
59%
52%
39%
59%
Patients(%)
Genotype 1 Subtypes
Genotype 1a
Genotype 1b
TID16W
(n=81)
TID28W
No RBV
(n=46)
TID28W
(n=80)
TID40W
(n=77)
BID28W
(n=78)
TID16W
(n=34/47)
TID28W
No RBV
(n=18/28)
TID28W
(n=32/48)
TID40W
(n=34/43)
BID28W
(n=30/48)
38%
75%
44%
68%
47%
56%
43%
85%
11%
57%

86
SOUND-C2 Study: SVR12 by
Genotype Subtype and METAVIR Score
Patients(%)
Genotype 1a
METAVIR Score
F0-F2
F3-F4
TID16W
(n=27/7)
TID28W
No RBV
(n=16/2)
TID28W
(n=26/6)
TID40W
(n=29/5)
BID28W
(n=25/5)
Zeuzem S, et al. J Hepatol. 2013;58(suppl 1):S498. Abstract 1227.
44%
14%
40%
67%
45%
60%
44%
40%
13%
0%
Patients(%)
Genotype 1b
METAVIR Score
F0-F2
F3-F4
TID16W
(n=36/10)
TID28W
No RBV
(n=19/9)
TID28W
(n=33/15)
TID40W
(n=33/10)
BID28W
(n=32/16)
78%
70%
64%
80%
52%
70%
91%
75%
63%
44%
New
Slide

87
SOUND-C2 Study: Virologic Failure
and Baseline Predictors of SVR12
● Virologic failure (twice daily, 28-week treatment arm)
- Genotype 1a versus 1b: 47% versus 8%
- Genotype-1a patients had a higher rate of resistance compared
with genotype-1b patients
● Baseline predictors of SVR12 (multivariate odds ratio)
- Gender (female:male): 3.99 (P<0001)
- HCV subtype (1b:1a): 7.11 (P<0.0001)
- IL28B genotype (CC:non-CC): 4.94 (P<0.0001)
- GGT (normal:>ULN): 2.08 (P=016)

88
SOUND-C2 Study:
● Twice daily, 28-week treatment arm
- Most favorable safety and tolerability profile
• Grade 3/4 bilirubin increase: 39%
• Grade 3/4 hemoglobin decrease: 2%
• No adverse hematologic effects
● The inclusion of ribavirin remains necessary
component of treatment
● Future phase 3 studies (genotype 1b only)
- Faldaprevir 120 mg bid + BI 207600 600 mg bid + RBV

89
Phase 2
Treatment-naïve
Genotype 1
AVIATOR Study: ABT-450/r-Based
Therapy (Treatment-Naïve Cohort)
Week 0 8 12 24
ABT-450/r 150/100 mg qd +
ABT-267 + ABT-333 + RBV (n=80)
Follow-Up
ABT-450/r 150/100 mg qd +
ABT-333 + RBV (n=41)
Follow-Up
ABT-450/r 100/100 or 200/100 mg qd +
ABT-267 + RBV (n=79)
ABT-450 (NS3/4A protease inhibitor); ABT-267 (NS5A replication complex inhibitor);
ABT-333 (non-nucleoside NS5B polymerase inhibitor).
HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV.
ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid.
Primary outcome: SVR24.
Follow-Up
ABT-450/r 150/100 mg qd +
ABT-267 + ABT-333 (n=79)
Follow-Up
ABT-450/r 100/100 or 150/100 mg qd +
ABT-267 + ABT-333 + RBV (n=79)
Follow-Up
ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=80)
Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
New
Slide

90
AVIATOR Study (ITT): Overall
SVR Rates (Treatment-Naïve Cohort)
Patients(%)
83%
89%
85%
91%88%
ABT-450/r
ABT-267
ABT-333
RBV
(n=80)
8 Weeks 12 Weeks
ABT-450/r
--
ABT-333
RBV
(n=41)
ABT-450/r
ABT-267
--
RBV
(n=79)
ABT-450/r
ABT-267
ABT-333
--
(n=79)
ABT-450/r
ABT-267
ABT-333
RBV
(n=79)
89%
96%
90%
99%
93%
87%
90%
ABT-450/r
ABT-267
ABT-333
RBV
(n=80)
24 Weeks
SVR12
SVR24
New
Slide

91
AVIATOR Study: SVR24 by Baseline
Subgroups (Treatment-Naïve Cohort)
Patients(%)
98%
92% 91%
94%
Male
(n=78)
89% 91%
94% 94% 95%
89%
ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined)
Female
(n=81)
1a
(n=108)
1b
(n=50)
>7
(n=35)
<7
(n=124)
F0-F1
(n=113)
F2-F3
(n=42)
Non-CC
(n=115)
CC
(n=44)
Genotype HCV RNA
(log)
Fibrosis
Stage
IL28B
Genotype
New
Slide

92
Phase 2
Null Responders
Genotype 1
AVIATOR Study: ABT-450/r-Based
Therapy (Null Responders Cohort)
Week 0 8 12 24
Received at least 12 weeks of pegIFN + RBV and failed to achieve >2 log10 IU/mL HCV RNA decrease.
HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV.
IL28B CC genotype (~3%).
ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid.
Primary outcome: SVR24.
Follow-Up
Follow-Up
ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=43)
ABT-450/r 100/100 or 200/100 mg qd +
ABT-267 + RBV (n=45)
ABT-450/r 100/100 or 150/100 mg qd +
ABT-267 + ABT-333 + RBV (n=45)
New
Slide

93
AVIATOR Study (ITT): Overall
SVR Rates (Null Responders Cohort)
Patients(%)
89% 89%
12 Weeks
ABT-450/r
ABT-267
--
RBV
(n=45)
ABT-450/r
ABT-267
ABT-333
RBV
(n=45)
ABT-450/r
ABT-267
ABT-333
RBV
(n=43)
24 Weeks
SVR12
SVR24
93% 93%
98% 95%
New
Slide

94
AVIATOR Study: SVR24 by Baseline
Subgroups (Null Responders Cohort)
Patients(%)
97%
93% 93%
97%
Male
(n=55)
91% 93%
96% 95% 94%
100%
ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined)
Female
(n=53)
1a
(n=55)
1b
(n=33)
>7
(n=22)
<7
(n=66)
F0-F1
(n=41)
F2-F3
(n=45)
Non-CC
(n=85)
CC
(n=3)
Genotype HCV RNA
(log)
Fibrosis
Stage
IL28B
Genotype
New
Slide

95
AVIATOR Study:
Virologic Relapse and Safety
● Virologic relapse in prior null responders
- 8-, 12-, and 24-week arms: 12.5%, 6.3%, 2.5%
● Discontinuations due to adverse events in the 12- and
24-week arms: 2.4%
- Considered related to treatment (n=4/6): hepatitis cholestatic, feeling
jittery, homicidal ideation, decreased creatinine clearance
- Headache (31%), fatigue (30%), nausea (23%), insomnia (20%),
diarrhea (15%)
- Bilirubin increase: 2.4%
- Anemia (hemoglobin 6.5 to <8 g/dL): 2.4%
New
Slide

96
New and Emerging Strategies:
Clinical Considerations
● Recent recommendations from the CDC
emphasize the importance to screen and early
diagnosis of HCV infection
● Newly diagnosed patients with chronic HCV
infection still require comprehensive counseling
● For patients who are candidates for therapy
- Initiate treatment with currently available therapy
- Defer treatment until availability of new antiviral
agents with the potential for increased efficacy,
decreased adverse events, and shorter duration of
therapy over existing regimens

97
New and Emerging Strategies:
Conclusions
● Results from phase 2 trials for all oral agents are excellent, with
well tolerated regimens and high SVR rates
● High SVR rates with interferon-free regimens are possible in a
variety of patient populations, including difficult-to-treat patient
populations (prior null responders and cirrhotics)
- Ribavirin and IL28B status remain important for some regimens
● Non-CC and genotype 1a status remain important for DAA +
peginterferon + ribavirin regimens
● Further study is needed for DAAs in special patient populations
- Cirrhosis
- HIV coinfection
- Liver transplant recipients

98
New Electronic Evaluation ProcessNew Electronic Evaluation Process
We Are Eliminating Hard Copy Evaluations!• You will receive an electronic evaluation to the email
address provided within 1 business day
• Reminder email communications will be sent up to
5 days post lecture until the evaluation is completed
• Completion Is Required for CME/CNE/CPE credit and
future attendance
• Incomplete evaluations will preclude attendees from
receiving their CME/CNE/CPE certificate & future
communications about lectures in your area

99
Outcomes Measurement ReminderOutcomes Measurement Reminder
• We are required to assess “changes in learners’
competence, performance or patient outcomes achieved
as a result of their participation in a CME/CNE/CPE
sponsored educational activity”
• As a result of this requirement you will receive a short
survey via email 8 to 12 weeks after completing this
course
• We consider the survey to be an additional component of your
overall participation in this educational activity and would urge
you to reflect on what you learned in the activity and then
complete this survey

Simply Speaking Hepatitis February 7 2014

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