future directions in hcv therapy eric lawitz, md, agaf,cpi medical director, the texas liver...
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![Page 1: Future Directions in HCV Therapy Eric Lawitz, MD, AGAF,CPI Medical Director, The Texas Liver Institute Clinical Professor of Medicine University of Texas](https://reader035.vdocuments.us/reader035/viewer/2022062515/56649c7b5503460f9492f0ad/html5/thumbnails/1.jpg)
Future Directions in HCV Therapy
Eric Lawitz, MD, AGAF,CPI
Medical Director, The Texas Liver Institute
Clinical Professor of Medicine
University of Texas Health Science Center
San Antonio, Texas
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IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12 m Peg-IFN 12m Peg-IFN/RBV 12m Peg-IFN/RBV/DAA0
20
40
60
80
100
SV
R (
%)
20011998
2011
StandardInterferon
+ Ribavirin
Peginterferon
1991
+ DAAs
Milestones in Therapy of CHC:Average SVR Rates from Clinical Trials
Adapted from US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring MD.
6%
16%
34%42% 39%
55%
70+%
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Generic Name Trade Name Manufacturer
BoceprevirTelaprevir
Victrelis™Incivek™
Merck Pharmaceuticals, IncVertex Pharmaceuticals, Inc
DAAs with an Indication for the Treatment of G1 Chronic Hepatitis C
• Both compounds act by inhibiting HCV nonstructural NS3/4A protease and are referred to as direct acting antivirals (DAAs)
US Food and Drug Administration. Available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
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Limitations of Current Therapy
• Telaprevir and boceprevir only approved for Genotype 1
• Interferon backbone required
• TID dosing for telaprevir/boceprevir
• Response guided therapy (both) and lead-in (boceprevir) complicated
• 24-48 week treatment
• Limited efficacy in difficult to cure patients (e.g., patients with cirrhosis, prior null responders, African-Americans)
• Hematologic (both) and rash/dermatological (telaprevir) adverse events
• Drug-drug interactions
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Sofosbuvir (SOF) (GS-7977)
• NS5B nucleotide polymerase inhibitor
• Favorable administration profile
– Once daily, no food effect
– No drug-drug interactions
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Completed Phase 3 Trials
• NEUTRINO
– GT 1, 4, 5, 6; treatment naïve
– No comparator
• FISSION
– GT 2 and 3; treatment naïve
– Compared to 24 weeks of peginterferon + ribavirin
• POSITRON
– GT 2 and 3; patients ineligible for or intolerant of interferon therapy
– Compared to placebo
• FUSION
– GT 2 and 3; patients unresponsive to prior treatment
– Compared to 16 weeks of sofosbuvir + ribavirin
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E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
NEUTRINO
• Patients– GT 1, 4, 5, 6 treatment naive
– 17% compensated cirrhosis
– 17% black
– 29% IL28B genotype CC
• Regimen for all patients– Sofosbuvir 400 mg qd
– Ribavirin 1000/1200 mg qd
– Peginterferon alfa-2a 180 mcg weekly
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SVR12Sofosbuvir/PEG/RBV, n=327
Week 0 12 24
NEUTRINO: Study Design
• Open label– SOF+PEG+RBV for 12 weeks (no response-guided therapy)
• Expanded inclusion criteria– No upper limit to age or BMI
– Opiate replacement therapy permitted
– Platelets ≥90,000/mm3, neutrophils ≥1,500/mm3 or
1,000/mm3 (blacks)
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
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Series10
20
40
60
80
100 9199 99 90
Post-treatment On treatment
299/327 321/325 326/327
Week 2 Week 4 Week 12 Week 12
295/327
>90% Of Patients Have Undetectable Virus After 2 Weeks and Achieve SVR
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
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n = 292 n = 28 n = 7
NEUTRINO: SVR by Genotype
All Patients 1 4 5, 60
20
40
60
80
10090 89
96100
Genotype
SV
R12
(%
)
295/327 261/292 27/28 7/7
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
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n = 273 n = 54 n = 54n = 95
NEUTRINO: SVR by Subgroup
Series10
20
40
60
80
10092
98
8780
87
SV
R12
(%
)
n = 232n = 273 n = 54 n = 54
No cirrhosis Cirrhosis CC CT/TT
IL28B genotype
Black
n = 95 n = 232
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
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Conclusions
• 12 weeks of SOF+PEG+RBV achieved 90% SVR in treatment naïve patients with GT 1, 4, 5, or 6
• 99% of patients had HCV RNA < LLOQ by treatment week 4 and all virologic failures were due to relapse
• This regimen was well tolerated
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013, 368: 1878-1887.
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FUSION (TE)
POSITRON (Intolerant)
Week 0 12 24 36
SOF + RBV, n=256 SVR12
Peg-IFN + RBV (SOC), n=243 SVR12
SOF + RBV, n=207 SVR12
Placebo, n=71 SVR12
Week 0 12 24
SOF + RBV, n=103 Placebo SVR12
SOF + RBV, n=98 SVR12
Week 0 12 16 24 28
RBV does 1000-1200 mg/day for SOF + RBV and 800 mg/day for Peg-IFN + RBV.
SOF dose 400 mg once daily; RBV dose 1000-1200 mg/day.
SOF dose 400 mg once daily; RBV dose 1000-1200 mg/day.
Jacobson et al. N Engl J Med 2013, 368: 1867-1877, Lawitz et al., N Engl J Med 2013, 368: 1878-1887,
GT2 and GT 3: Study DesignsFISSION (TN)
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P
<0.001
Overall GT 2 GT 30
20406080
100
SOF + RBV 12 weeks
SOF + RBV 16 weeks
P
<0.001FUSION (TE)
POSITRON (Intolerant)
Overall GT 2 GT 30
20406080
100
SOF + RBV 12 Weeks
Peg-IFN + RBV 24 Weeks
Overall GT 2 GT 30
20406080
100
SV
R1
2 (
%)
SV
R1
2 (
%)
SV
R1
2 (
%)
67 67
9778
5663
170/253
162/243
68/70
52/67
102/183
110/176
50/100
69/95
31/36
30/32 19/64
39/63
5073
86 94
30
62
161/207 101/109 60/98
7893
61
SOF + RBV 12 weeks
Jacobson et al. N Engl J Med 2013, 368: 1867-1877, Lawitz et al., N Engl J Med 2013, 368: 1878-1887,
GT2 and GT 3: SVR by GenotypeFISSION (TN)
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FUSION (TE)
POSITRON (Intolerant)
No cirrhosis Cirrhosis No cirrhosis Cirrhosis0
20
40
60
80
100
SOF + RBV 12 Weeks
Peg-IFN + RBV 24 Weeks
No Cirrhosis Cirrhosis0
20
40
60
80
100
GT 2 GT 30
20
40
60
80
100
No cirrhosis
Cirrhosis
SV
R1
2 (
%)
SV
R1
2 (
%)
SV
R1
2 (
%)
98 82 91
6234 30
58/59
44/54
25/26
96 100
6078
85/92 67/84
92 9468
21
16/17
6171
10/11 8/1
3
89/145
99/139 13/38 11/37
GT 2 GT 3
23/23 6/10 7/9
GT 2
No Cirrhosis Cirrhosis0
20
40
60
80
100
SOF + RBV 12 weeks
SOF + RBV 16 weeks
14/38
3763
19
61
25/40 5/26
14/23
GT 3
3/14
SVR: Patients with Cirrhosisvs No Cirrhosis
Jacobson et al. N Engl J Med 2013, 368: 1867-1877, Lawitz et al., N Engl J Med 2013, 368: 1878-1887,
FISSION (TN)
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• 12 weeks of SOF+RBV results in SVR>90% in GT 2 treatment naive patients with and without cirrhosis
• SVR rates were lower in GT 2 treatment experienced patients with cirrhosis compared to non-cirrhosis
• SOF+RBV led to similar results as PEG+RBV for GT 3 treatment naïve patients – Lowest rates observed in patients with cirrhosis
• SOF+RBV for 12 weeks is suboptimal for GT 3 treatment experienced patients– 16 weeks total duration significantly increased SVR rates
• SOF+RBV well tolerated with fewer adverse events than PEG+RBV
• Genotype 3 ≠ genotype 2 HCV– Strategies to improve GT 3 results are needed
Conclusions
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Simeprevir (TMC 435) (PI)
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• NS3/4A protease inhibitor
• Antiviral activity against GT 1, 2, 4, 5 and 6
• One capsule, once per day
Simeprevir (TMC 435)
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Completed Phase 3 Studies
• QUEST-1 and QUEST-2
– Same study design but studies conducted independent of one another
– Treatment naïve GT 1 patients
• PROMISE
– Same study design as QUEST-1 and QUEST-2
– GT 1 prior relapsers
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SMV 150 mg/PEG/RBV
PEG/RBVPEG/RBV
Post-Therapy Follow-Up Post-Therapy Follow-Up
Response Guided Treatment
Placebo/PEG/RBV
PEG/RBV PEG/RBV Post-Therapy Follow-Up
0 12 24 48 72Weeks
• Response Guided Therapy: if HCV RNA <25 IU/mL at Week 4
and undetectable at Week 12, complete treatment at Week 24
– 85-93% of patients met the criteria and qualified for total treatment
duration of 24 weeks.
QUEST-1, QUEST-2 andPROMISE Study Designs
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QUEST-1 QUEST-2 PROMISE0
20
40
60
80
100 Simeprevir/PEG/RBV PEG/RBV
SV
R12
(%
)
210/264
65/130
209/257
67/134
206/260
49/133
80%
Simeprevir + PEG/RBV Achieved SVR in ~80% of Treatment Naïve and Prior Relapsers
50%
81%
50%
79%
37%
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QUEST-1: SVR by Subgroup
F0-F2 F3-F4 1a 1b/other CC CT TT0
20
40
60
80
100
120
83
70 71
90 94
7665
60
28
49 52
78
42
24
SIM + PR PR
Pat
ien
ts A
chie
vin
g S
VR
12 (
%)
Fibrosis
152/183
I. Jacobson et al, Abstract 1425. EASL, April 2013
Genotype IL28B genotype
54/90
54/77
11/40
105/147
36/74
105/117
29/56
72/77
29/37
114/150
32/76
24/37
4/17
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Series10
20
40
60
80
100
84.6
66.7 64.7
51 52.9
40
Simeprevir/PEG/RBV PEG/RBV
Pat
ien
ts A
chie
vin
g S
VR
12 (
%)
F0-F2 F3 F4 (Cirrhosis)
Similar results seen in QUEST-1 and PROMISE studies
SVR Higher When Simeprevir Added to PEG/RBV For Patients With All Stages
of Fibrosis/Cirrhosis (QUEST-2)
165/195
52/102
24/36
9/17
11/17
6/15
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Conclusions
• Simeprevir 150 mg + PEG/RBV was highly effective against GT 1 treatment naïve patients with SVR (80%)
• Most patients (85%) receiving simeprevir were able to shorten therapy to 24 weeks
• Simeprevir 150 mg + PEG/RBV was generally well tolerated
– Rates of anemia and rash were similar in the simeprevir and placebo groups
I. Jacobson et al, Abstract 1425. EASL, April 2013
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Simeprevir (TMC 435) (PI) + Sofosbuvir (GS-7977) (nuc)
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Arm 1
Arm 2
Arm 3
Arm 4
Weeks
0 12 24 36 48
SMV + SOF + RBV
SMV + SOF + RBV
SMV + SOF
SMV+SOF
Post-treatment follow-up
Post-treatment follow-up
Post-treatment follow-up
n = 24
n = 15
n = 27
n = 14
Interim analysis SVR4 Primary endpoint SVR12
Post-treatment follow-up
• Cohort 1: n=80 patients randomized 2:1:2:1
• Cohort 2: n=87 patients randomized 2:1:2:1
• SMV 150 mg QD + SOF 400 mg QD with/without RBV (Copegus®) 1000 or 1200 mg/day (BID)
• Interim analysis of Cohort 1 conducted when all patients in 12 week treatment arms (arms 3 and 4) reached SVR4 time point or discontinued early
COSMOS: Study Design
Lawitz et al., CROI, March 2013
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• Chronic HCV GT 1 infection
• 78% GT 1a
• Prior null response to PEG/RBV
‒ Failure to achieve >2 log10 decline in HCV RNA by Week 12
• Fibrosis
• F0-F1: 41%
• F2: 59%
• IL28B
• CT: 70%
• TT: 24%
• 29% African-American
COSMOS: Key Eligibility Criteria –Cohort 1
Lawitz et al., CROI, March 2013
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COSMOS: Virologic Response (12 Week Arms)
0
20
40
60
80
100
85.2
10096.3 96.3
57.1
10092.9 92.9
SMV+SOF+RBV SMV+SOF
RVR, n/N (%) Undetectable end of treatment, n/N (%)
SVR4, n/N (%) SVR8, n/N (%)
23/27
8/14
27/27
14/14
26/27
13/14
26/27
13/14
Lawitz et al., CROI, March 2013
SV
R8
(%)
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Patients
24 weeks 12 weeks
SMV + SOF+ RBV
SMV + SOF SMV + SOF + RBV
SMV + SOF Total
(n=24) (n=15) (n=27) (n=14) (n=80)
AEs during treatment, % 87.5 93.3 88.9 78.6 87.5Grade 3/4 AEs1, % 4.2 13.3 18.5 0 10.0Serious AEs, % 0 0 0 0 0
Most common AEs (≥10% of total patients)
Fatigue, % 25.0 26.7 18.5 21.4 22.5
Headache, % 16.7 26.7 14.8 28.6 20.0
Insomnia, % 16.7 13.3 18.5 21.4 17.5
Nausea, % 4.2 6.7 18.5 28.6 13.8
Anemia, % 25.0 0 11.1 0 11.3
Cough, % 20.8 6.7 3.7 7.1 10.0
Rash, % 12.5 13.3 11.1 0 10.0
Treatment discontinuationDue to AEs, n 1 1 0 0 2Non-safety reason, n 2 1 0 0 3
RBV dose reduction, % 16.7 NA 3.7 NA 9.8
COSMOS: Safety & Tolerability
1WHO Toxicity Grading Scale, 2003
Lawitz et al., CROI, March 2013
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COSMOS: Cohort 2
• SMV+SOF+RBV for 12 weeks• GT 1 treatment naive and prior null
responders with advanced disease (F3/F4)• SVR4 results
– SMV+SOF+RBV: 96% (26/27)– SMV+SOF: 100% (14/14)
Medivir/Janssen Press Release, August 29, 2013
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COSMOS: Summary
• 12 weeks of SMV+SOF led to an SVR8 rate
of 96% with RBV and 93% without RBV in
prior null responders with F0-F2 disease
• 12 weeks of SMV+SOF led to an SVR4 rate
of 96% with RBV and 100% without RBV in
treatment naïve and prior null responders
with F3-F4 disease
• SMV+SOF+RBV was generally well
tolerated
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Daclatasvir (NS5A inhibitor) +
Sofosbuvir (GS-7977) (nuc)
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Background • Patients who experience virologic failure on telaprevir or
boceprevir-based regimens currently have no treatment options
• DCV plus SOF with or without RBV achieved SVR4 in 98% of 126 HCV GT 1-infected treatment-naive patients (Sulkowski et al. AASLD 2012)
• Study Aim
– To evaluate the efficacy and safety of DCV+SOF with or without RBV for 24 weeks in GT 1-infected patients who failed prior treatment with TVR or BOC + PEG/RBV
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
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Study Design
• Patients– GT 1, non-cirrhotic– Prior nonresponse, relapse, or breakthrough
during treatment with PEG/RBV+TVR or BOC– Patients who discontinued TVR or BOC due
to an AE were excluded
Week 24
Prior TVR/BOC Failures, GT 1a/1b(N = 41)
n = 21
Follow-upn = 20
DCV 60 mg QD + SOF 400 mg QD
DCV 60 mg QD + SOF 400 mg QD + RBV
Follow-up
SVR4
SVR12
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
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Virologic Response
• 1 patient missing at post-treatment (PT) Week 12: HCV RNA was
undetectable at PT Week 4 and at PT Week 24
• 21/41 patients have reached PT Week 24; all have achieved SVR24
0
20
40
60
80
100
EOT
HC
V R
NA
< L
LO
Q
(% p
atie
nts
)
Week 2 SVR4
N =
Week 4
21 20
SVR12
21 20
21 20
21 20
21 20
DCV + SOF
DCV + SOF + RBV
Missing
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
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Conclusions
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
• The all-oral, once-daily combination of DCV+SOF with or without RBV achieved SVR in all GT 1 infected patients (n=41) who failed prior treatment with TVR or BOC+PEG/RBV
• DCV+SOF with or without RBV waswell tolerated
• No Grade 3 or 4 hepatic or hematologic abnormalities
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Daclatasvir (BMS-790062) (NS5A inhibitor) +
Asunaprevir (BMS-650032) (PI)
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Study AI447-011 Expansion Cohort:Prior Null Responders to PEG/RBV
A. Lok, et al; APASL 2013.
A1 (DUAL): DCV 60 mg QD +ASV 200 mg BID (GT 1b only)
A2 (DUAL): DCV 60 mg QD +ASV 200 mg QD (GT 1b only)
B1 (QUAD): DCV 60 mg QD + ASV 200 mg BID + PEG/RBV (GT 1a/1b)
B2 (QUAD): DCV 60 mg QD + ASV 200 mg QD + PEG/RBV (GT 1a/1b)
B3 (TRIPLE): DCV 60 mg QD + ASV 200 mg BID + RBV (GT 1a/1b)
Follow-up
Follow-up
Follow-up
Follow-up
Follow-up
N = 21
N = 22
N = 20
N = 20
N = 18
Week 12 SVR4 SVR24
Week 24 SVR12 primary endpoint SVR48
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0 4 8 12 16 20 24 PT4012345678
GT 1a patients, n=18
Weeks
HC
V R
NA
, lo
g1
0 IU
/mL
TRIPLE Therapy (Arm B3): GT 1a vs GT 1bIndividual HCV RNA Levels
• 1/18 GT 1a patient completed triple therapy and achieved SVR4
0 4 8 12 16 20 24 PT4012345678
GT 1b patients, n=4
WeeksH
CV
RN
A, l
og
10
IU/m
L
DCV + ASV 200 mg BID + RBVGraphs truncated at viral breakthrough
LLOQLOD
LLOQLOD
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Conclusions
• In non-cirrhotic prior null responders,24 weeks of daclatasvir + asunaprevir appears to be an efficacious combination for GT 1b but not GT 1a
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Daclatasvir (BMS-790062) (NS5A inhibitor) +
Asunaprevir (BMS-650032) (PI) +
BMS-791325 (non-nuc)
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AI443-014: Study Design
• Treatment naïve non-cirrhotic patients• GT 1a: 74% and CT/TT: 70%
G. Everson et al, Abstract 1423. EASL, April 2013
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Summary
The all oral, IFN-free, RBV-free, ritonavir-free combination of DCV, ASV, and BMS-791325• Achieved >90% (61/66) SVR4 and SVR12
(30/32)
• Had infrequent virologic failure (4.5%, 3/66)
• Most common AEs (≥10% total) were headache, asthenia, and gastrointestinal
G. Everson et al, Abstract 1423. EASL, April 2013
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Faldaprevir (BI 201335) (PI)
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Faldaprevir: Phase 3 Studies (IFN-Containing)
• STARTVerso 1– Treatment naïve GT 1 patients
– All patients from Europe and Japan
– Only Phase 3 study with results reported as of October 2013
• STARTVerso 2– Treatment naïve GT 1 patients
– Studying shorter durations (12 vs 24 weeks)
• STARTVerso 3– Treatment experienced GT 1 patients
• STARTVerso 4– Treatment naïve/prior relapsers who are coinfected with HCV
and HIV
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STARTVerso1
• Phase III, randomized, double-blind, placebo-controlled trial • Patients
– Treatment naïve GT 1 infection– 78% Caucasian, 20% Asian– 39% IL28B CC– 66% GT 1b
• Regimen– PEG+RBV for 24 weeks plus faldaprevir/placebo
• Patients with early treatment success stopped all treatment atWeek 24
• Patients without Early Treatment Success and those in control arm received PEG/RBV for 48 weeks
P. Ferenci et al, Abstract 1416. EASL, April 2013
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PEG/RBVPBO/PEG/RBV Observation Period
Day 1 Week 12 Week 24 Week 48 Week 72
FDV 240 mg/PEG/RBV
Observation Period
PBO/ PEG/RBV
PEG/RBV Observation Period
ETS
No ETS
Observation Period
FDV 120 mg/ PEG/RBV
PEG/RBV Observation Period
ETS
No ETS FDV 120 mg/PEG/RBV
PBO/ PEG/RBV
STARTVerso1: Study Design
• Criteria for response guided therapy
– Early Treatment Success (ETS): HCV RNA <25 IU/mL at Week 4 and
undetectable at Week 12, complete treatment at Week 24
– 88% met the criteria and qualified for total treatment duration of 24 weeks.
P. Ferenci et al, Abstract 1416. EASL, April 2013
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STARTVerso1 SVR12 rates
PEG/RBV FDV 120 + PR FDV 240 + PR0
20
40
60
80
100
52
79 80
SV
R12
(%
)
69132
204259
210261
P. Ferenci et al, Abstract 1416. EASL, April 2013
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Series10
20
40
60
80
100
80%
56%
83%
40%SV
R (
%)
195/243 204/246 9/16 6/15
No Cirrhosis Cirrhosis
FDV 120 mg/PEG/RBV
FDV 120 mg/PEG/RBV
FDV 240 mg/PEG/RBV
FDV 240 mg/PEG/RBV
SVR in Patients With Cirrhosis
P. Ferenci et al, Abstract 1416. EASL, April 2013
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0
20
40
60
80
100
SV
R12
(%
) 60%
69%76%
36%
84% 83%
60/87 143/17168/90 142/17116/45 52/86
FDV 240 mg/PEG/RBV
FDV 120 mg/PEG/RBV
PEG/RBVFDV 240 mg/PEG/RBV
FDV 120 mg/PEG/RBV
PEG/RBV
SVR By GT 1 Subtype
P. Ferenci et al, Abstract 1416. EASL, April 2013
GT1a GT1b
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STARTVerso1 Conclusions
• FDV+PEG/RBV significantly increased SVR12 rates in
GT 1 patients compared with PEG/RBV
• In total, 88% of patients treated with FDV were eligible to
stop all treatment at Week 24
• Patients without cirrhosis had higher SVR than patients
with cirrhosis
• GT 1b infected patients had higher SVR than GT 1a
infected patients
• FDV+PEG/RBV was well tolerated
P. Ferenci et al, Abstract 1416. EASL, April 2013
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Faldaprevir (BI 201335) (PI) + Deleobuvir (non nuc)
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SOUND-C2: IFN-Free
– Faldaprevir + deleobuvir + RBV– SVR rates between 59-69% in GT 1 treatment
naïve patients with 16, 28 or 40 weeks of treatment
• Higher SVR in GT 1b (56-85%) vs GT 1a (38-47%)• High rate of relapse (41%) in GT 1a treated for 16
weeks
– Arm with no RBV had low SVR (39%)
Zeuzem et al., N Engl J Med 2013, 369; 630-639.
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Faldaprevir: IFN-Free(Results Are Anticipated in 2014)
• HCVerso 1 (NCT01732796) and HCVerso 2
(NCT01728324)– Faldaprevir + deleobuvir + RBV
– GT 1b only
– Includes IFN-ineligible patients as well as patients with cirrhosis
– Duration of therapy: 16 vs 24 weeks
– Anticipated primary results: 1H 2014
• Study with PPI-668 (NS5A inhibitor)(NCT01859962)– Faldaprevir + deleobuvir + PPI-668 + RBV – GT 1a– Treatment naïve– Anticipated primary results: 1H 2014
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ABT-450/r (PI with ritonavir), ABT-267 (NS5A inhibitor) and ABT-333
(non nuc)
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AVIATOR
• Phase 2b, randomized, open-label, multicenter study
• Patients– GT 1 (66% GT 1a)– Treatment-naive and prior null response– Non-cirrhotic
• Duration– 8, 12 and 24 weeks
K.V. Kowdley et al, Abstract 3. EASL, April 2013
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SVR12 (%)
SVR24(%)
VBT/Relapse
89 88 0/10
85 83 1/4
91 89 1/8
90 87 1/5
99 96 0/1
93 90 0/2
SVR12 (%)
SVR24(%)
VBT/Relapse
89 89 0/5
93 93 3/0
98 95 1/0
N Regimen/duration SVR12 (%)
SVR24**(%)
VBT/Relapse
80 ABT450 ABT267 ABT333 RBV 89 88 0/10
41 ABT450 ABT333 RBV 85 83 1/4
79 ABT450 ABT267 RBV 91 89 1/8
79 ABT450 ABT267 ABT333 90 87 1/5
79 ABT450 ABT267 ABT333 RBV 99 96 0/1
80 ABT450 ABT267 ABT333 RBV 93 90 0/2
N Regimen/duration SVR12 (%)
SVR24(%)
VBT/Relapse
45 ABT450 ABT267 RBV 89 89 0/5
45 ABT450 ABT267 ABT333 RBV 93 93 3/0
43 ABT450 ABT267 ABT333 RBV 98 95 1/0
Week 8 12 24
Trea
tmen
t n
aive
Nu
ll r
esp
on
se
** 8 patients who achieved SVR12 did not return >24 weeks and were counted as virological failures for SVR243 patients relapsed between SVR12 and SVR24
AVIATOR: Study Design
K.V. Kowdley et al, Abstract 3. EASL, April 2013
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Series10
20
40
60
80
10092 91 89
94 959498
94 91 89
% w
ith
SV
R2
4
SVR24 by Baseline Subgroups – Treatment-Naïve Patients*
*Includes patients randomized to the quad therapy arms (12 or 24 weeks duration).
Mal
e
Fem
ale 1a 1b
≥7 lo
g
<7
log
F0-
F1
F2-
F3
Non
-CC
CC
N= 78 81 108 50 35 124 113 42 115 44
K.V. Kowdley et al, Abstract 3. EASL, April 2013
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Series10
20
40
60
80
100 93 93 9195 9497 97 96 95
100
% w
ith
SV
R2
4
SVR24 by Baseline Subgroups – Null Responders*
*Includes patients randomized to the quad therapy arms (12 or 24 weeks duration).
Mal
e
Fem
ale 1a 1b
≥7 lo
g
<7
log
F0-
F1
F2-
F3
Non
-CC
CC
N= 55 33 55 33 22 66 41 45 85 3
K.V. Kowdley et al, Abstract 3. EASL, April 2013
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Event, %Total
(N=247)Treatment-Naïve
(N=159)Null Responders
(N=88)
Headache 31.2 31.4 30.7
Fatigue 29.6 32.7 23.9
Nausea 22.7 24.5 19.3
Insomnia 19.8 22.6 14.8
Diarrhea 15.0 13.2 18.2
*Includes patients randomized to the quad therapy arms (12 or 24 weeks duration)
K.V. Kowdley et al, Abstract 3. EASL, April 2013
Most Common Adverse Events*
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Safety
• 6 patients (2.4%) discontinued due to study drug-related AEs; 4 of 6 considered related to treatment.
• 4 patients (1.6%) experienced SAEs
– 1 (arthralgia) was possibly study drug-related
• Moderate-to-severe study drug-related AEs with >10% incidence in any arm were asthenia and fatigue.
• 6 patients (2.8%) and 1 patient (0.6%) experienced Grade 3-4 laboratory abnormalities in total bilirubin and ALT, respectively; all resolved with continued dosing.
K.V. Kowdley et al, Abstract 3. EASL, April 2013
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AVIATOR Conclusions
• Comparable SVR12 and 24 seen with 12 and 24 weeks of treatment
• SVR rates >90% were achieved in naiveand prior null responders with a3-DAA+RBV regimen
– No clinically meaningful differences were observedby gender, HCV subtype, IL28B genotype, baselineHCV-RNA or severity of fibrosis.
K.V. Kowdley et al, Abstract 3. EASL, April 2013
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Overall Summary
• All oral therapy expected to be available for GT2 and GT3 by early 2014.
• All oral therapy for GT 1 will be available no sooner than 2H2014.
• Even with PEG/RBV backbone, soon to be available DAAs for GT 1 offer advantages over currently approved DAAs.