Transcript Option A - IC-HEP

Michael P. Manns, MD
Hannover, Germany
Jointly sponsored by the Duke University School of Medicine and the Chronic Liver Disease Foundation
1
• Advisory Board Membership:
Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Janssen, Merck, Novartis,
Roche
2
3
SVR results of a once-daily regimen of simeprevir (TMC435) plus
sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic
HCV genotype 1 treatment-naïve and prior null responder patients:
The COSMOS study
Ira M. Jacobson1, Reem H. Ghalib2, Maribel Rodriguez-Torres3, Zobair M. Younossi4, Ana Corregidor5, Mark
S. Sulkowski6, Edwin DeJesus7, Brian Pearlman8, Mordechai Rabinovitz9, Norman Gitlin10, Joseph K. Lim11,
Paul J. Pockros12, Bart Fevery13, Tom Lambrecht14, Sivi Ouwerkerk-Mahadevan13, Katleen Callewaert13,
William T. Symonds15, Gaston Picchio16, Karen Lindsay16, Maria Beumont-Mauviel13, Eric Lawitz17
1. Weill Cornell Medical College, New York, NY, United States.
2. Medicine and Gastroenterology and Hepatology, The Liver Institute, Dallas, TX,
United States.
3. Fundación de Investigación, San Juan, Puerto Rico, United States.
4. Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, United States.
5. Borland-Groover Clinic, 4800 Belfort Rd, Jacksonville, FL, United States.
6. Johns Hopkins University School of Medicine, Baltimore, MD, United States.
7. Orlando Immunology Center, Orlando, FL, United States.
8. Atlanta Medical Center, Atlanta, GA, United States.
9. University of Pittsburgh Medical Center, Pittsburgh, PA, United States.
10. Atlanta Gastroenterology Association, Atlanta, GA, United States.
11. Yale School of Medicine, New Haven, CT, United States.
12. Scripps Clinic, La Jolla, CA, United States.
13. Janssen Research & Development, Beerse, Belgium.
14. Novellas Healthcare, Zellik, Belgium.
15. Gilead Sciences Inc, Foster City, CA, United States.
16. Janssen Research & Development LLC, Titusville, NJ, United States.
17. The Texas Liver Institute, University of Texas Health Science Center, San
Antonio, TX, United States.
4
• Simeprevir (TMC435) is an investigational, one pill, once-
daily, potent oral HCV NS3/4A protease inhibitor recently
approved in Japan and currently under regulatory review in
North America and Europe
• Sofosbuvir (GS-7977) is an HCV nucleotide NS5B
polymerase inhibitor also currently under regulatory review
• COSMOS is a Phase IIa, randomized, open-label study
investigating simeprevir + sofosbuvir +/- ribavirin
• Interim analysis
5
0
4
12
24
36
48
Week
N=14
Arm 1
SMV + SOF + RBV
Post-treatment follow-up
N=24
Arm 2
SMV + SOF
Post-treatment follow-up
N=14
Arm 3
SMV + SOF + RBV
Post-treatment follow-up
N=27
Arm 4
SMV + SOF
Post-treatment follow-up
Enrollment ratio 2:1:2:1
• Cohort 1: Prior null responders (METAVIR F0-F2)
– Final SVR12 for all arms
• Cohort 2: Treatment-naïve and prior null responders (METAVIR F3-F4)
– Interim SVR4 for Arms 3 and 4
6
Patients (%)
100
90
80
70
60
50
40
30
20
10
0
1/15
24 week treatment
4.2
1/24
6.7
4/24
16.7
93.3
14/15
SMV/SOF
24 wks
100
90
80
70
60
79
50
40
30
20
10
19/24
0
SMV/SOF/RBV
24 wks
12 week treatment
7.8
1/14
3.7
92
96
13/14
26/27
SMV/SOF
SMV/
SOF…
12 wks
1/27
SMV/SOF/RBV
SMV/
SOF/RBV…
12 wks
SVR12 (SMV/SOF)
Non-virologic failure
SVR12 (SMV/SOF/RBV)
Relapse
7
Patients (%)
12 week treatment
100
90
80
70
60
50
40
30
20
10
0
1/27
100
96.3
1/15
100
100
100
93.3
SVR4 (SMV/SOF)
SVR4 (SMV/SOF/RBV)
Relapse
14/14
26/27
Total
7/7
12/12
Naives
7/7
14/15
Nulls
8
24 weeks
12 weeks
SMV + SOF +
RBV (n=54)
SMV + SOF
(n=31)
SMV + SOF +
RBV (n=54)
SMV + SOF
(n=28)
Fatigue
20 (37.0)
10 (32.3)
13 (24.1)
7 (25.0)
Headache
11 (20.4)
7 (22.6)
9 (16.7)
6 (21.4)
Nausea
6 (11.1)
4 (12.9)
8 (14.8)
6 (21.4)
Insomnia
9 (16.7)
2 (6.5)
5 (9.3)
4 (14.3)
Rash
7 (13.0)
3 (9.7)
8 (14.8)
1 (3.6)
Pruritus
9 (16.7)
1 (3.2)
5 (9.3)
3 (10.7)
Photosensitivity/sunburna
2 (3.7)
1 (3.2)
3 (5.6)
2 (7.1)
11 (20.4)
1 (3.2)
6 (11.1)
0
Patients, n (%)
Anemia
aNo
sun-protective measures were in place for this trial
RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir
9
• Treatment with SMV + SOF ± RBV results in:
– High SVR12 rates in HCV GT 1 null responder patients
– High SVR4 rates in naïve and null-responder patients with METAVIR
F3-F4
• Addition of RBV to SMV + SOF may not be needed to
achieve high rates of SVR in this patient population
• 12 weeks of treatment may confer similar SVR rates
compared with 24 weeks of treatment
• SMV + SOF ± RBV was generally well tolerated
10
All-oral Combination of Daclatasvir Plus Asunaprevir in
Interferon Ineligible Naive/Intolerant and Nonresponder
Japanese Patients Chronically Infected with HCV Genotype
1b: Results from a Phase 3 Trial
Kazuaki Chayama1, Yoshiyuki Suzuki2, Kenji Ikeda2, Joji Toyota3, Yoshiyasu Karino3, Yoshiiku Kawakami1, Akio Ido4, Kazuhide
Yamamoto5, Koichi Takaguchi6, Namiki Izumi7, Kazuhiko Koike8, Tetsuo Takehara9, Norifumi Kawada10, Michio Sata11,
Hidetaka Miyagoshi12, Timothy Eley13, Fiona McPhee13, Wenhua Hu13, Hiroki Ishikawa12, Eric A. Hughes13, Hiromitsu Kumada2
1. Hiroshima University, Hiroshima, Japan.
2. Toranomon Hospital, Tokyo, Japan.
3. Sapporo-Kousei General Hospital, Sapporo, Japan.
4. Kagoshima University, Kagoshima, Japan.
5. Okayama University, Okayama, Japan.
6. Kagawa Prefectural Hospital, Kagawa, Japan.
7. Musashino Red Cross Hospital, Tokyo, Japan.
8. University of Tokyo, Tokyo, Japan.
9. Osaka University, Osaka, Japan.
10. Osaka City University, Osaka, Japan.
11. Kurume University, Fukuoka, Japan.
12. Bristol-Myers KK, Tokyo, Japan.
13. Bristol-Myers Squibb, Princeton, NJ, United States.
11
HCV RNA < LLOQ, n (%)
Ineligible naïve/Intolerant
(IN/I) Patients
n = 135a
Nonresponder (NR)
Patients
n = 87b
Total
N = 222
RVR, Week 4
114 (84.4)
53 (60.9)
167 (75.2)
cEVR, Week 12
125 (92.6)
77 (88.5)
202 (91.0)
SVR4
126 (93.3)
71 (81.6)
197 (88.7)
SVR12
120 (88.9)
70 (80.5)
190 (85.6)
SVR24
118 (87.4)
70 (80.5)
188 (84.7)
aIneligible
bNull
naïve: n=100; Intolerant: n=35
responders: n=48; Partial responders: n=36; Undetermined: n=3
12
Interferon- and Ribavirin-free Regimen of ABT-450/r + ABT-267
in HCV Genotype 1b-infected Treatment-naïve Patients and
Prior Null Responders
Eric Lawitz1, Christophe Hezode2, Peter Varunok3, Paul J. Thuluvath4, Tolga Baykal5, Mudra Kapoor5,
Sandra S. Lovell5, Tianli Wang5, Tami Pilot-Matias5, Regis A. Vilchez5, Barry Bernstein5
1. The Texas Liver Institute, University of Texas Health Science Center,
San Antonio, TX, United States.
2. Assistance Publique Hopitaux de Paris, Paris, France.
3. Premier Medical Group of the Hudson Valley, PC, Poughkeepsie, NY, United States.
4. The Institute for Digestive Health and Liver Disease at Mercy, Baltimore, MD, United States.
5. AbbVie Inc., North Chicago, IL, United States.
13
• ABT-450 is an HCV protease inhibitor
(dosed with ritonavir 100 mg, ABT-450/r)
• ABT-267 is an NS5A inhibitor
• Both compounds have shown potent antiviral
activity in vitro against HCV genotypes (GT)
1-4 and 6.
Lawitz E, et al. Abstract #75, AASLD 2013
14
Planned HCV Genotype/Regimen
N BL Treatment Experience Week 12
Group 1 40
Substudy 1:
Patients
Without
Cirrhosis
Group 2 40
Group 3 40
Group 4 40
Group 5 40
Group 6 40
Substudy 2: Group 7 40
Patients With
Compensated Group 8 40
Cirrhosis
Week 24
GT4 ABT-450/r + ABT-267
Treatment-naïve
GT1b ABT-450/r + ABT-267
Treatment-naïve
GT1b ABT-450/r + ABT-267
Null Responders
GT4 ABT-450/r + ABT-267 + rbv
Treatment-naïve
GT4 ABT-450/r + ABT-267
Partial/Null Responders & Relapsers
GT4 ABT-450/r + ABT-267 + rbv
Partial/Null Responders & Relapsers
GT1b ABT-450/r + ABT-267
Treatment-naïve
GT1b ABT-450/r + ABT-267
Partial/Null Responders & Relapsers
Lawitz E, et al. Abstract #75, AASLD 2013
15
Percentage of Patients (%)
100
97.6
97.6
95.2
42/42
41/42
41/42
40/42
Week 4
Week 12
(EOTR)
100
80
60
40
20
0
SVR4
SVR12
Lawitz E, et al. Abstract #75, AASLD 2013
16
Percentage of Patients (%)
100
97.5
97.5
39/40
39/40
92.5
90.0
37/40
36/40
80
60
40
20
0
Week 4
Week 12
(EOTR)
SVR4
SVR12
Lawitz E, et al. Abstract #75, AASLD 2013
17
GT1b-infected
Treatment-naïve Patients
(N=42)
GT1b-infected
Prior Null Responders
(N=40)
Headache
14 (33.3)
10 (25.0)
Nausea
8 (19.0)
0
Dry Skin
7 (16.7)
0
Fatigue
6 (14.3)
0
Pruritus
6 (14.3)
0
Diarrhea
6 (14.3)
0
Event, n (%)
Lawitz E, et al. Abstract #75, AASLD 2013
18
High Efficacy and Safety of the All-Oral Combination Regimen,
MK-5172/MK-8742 +/- RBV for 12 Weeks in HCV Genotype 1
Infected Patients: The C-WORTHY Study
Eric Lawitz1, John M. Vierling2, Abel Murillo3, Marcelo Kugelmas4, Jan Gerstoft5, Peter Winkle6, Luis A.
Balart7, Peer B. Christensen8, Reem H. Ghalib9, Ronald Nahass10, Melissa Shaughnessy11, Xiao Sun11,
Peggy Hwang11, Janice Wahl11, Michael Robertson11, Barbara Haber11
1. University of Texas Health Science Center, Texas Liver Institute, San Antonio, TX, United States.
2. Baylor College of Medicine, Houston, TX, United States.
3. Advanced Intervention & Pain Management Research Clinic, Miami, FL, United States.
4. South Denver Gastroenterology, PC, Englewood, CO, United States.
5. Epidemiklinikken, Rigshospitalet, Copenhagen, Denmark.
6. Anaheim Clinical Trials, Anaheim, CA, United States.
7. Tulane University Medical Center, New Orleans, LA, United States.
8. Infektionsmed. Afd Q 2 sal, Odense Universitets Hospital, Odense, Denmark.
19
Follow-up
n=25
MK-5172 (100 mg)
+ MK-8742 (20 mg)
+ RBV; G1a & G1b
Follow-up
n=27
MK-5172 (100 mg)
+ MK-8742 (50 mg)
+ RBV; G1a & G1b
Follow-up
n=13
MK-5172 (100 mg)
+ MK-8742 (50 mg);
G1b
D1
TW4
TW12
SVR4 SVR8 SVR12
SVR24
Lawitz E, et al. Abstract #76, AASLD 2013
20
% HCV-RNA <25 IU/mL
100
90
80
70
60
50
40
30
20
10
0
100
93
100
96 93 100
96
100
89
96
100
89
MK-5172 (100 mg) +
MK-8742 (20 mg) +
RBV (n=25)
MK-5172 (100 mg) +
MK-8742 (50 mg) +
RBV (n=27)
25 25 13
25 27 13
24 25 13
25 27 13
24 24 13
25 27 13
24 24 13
25 27 13
TW4
TW12
SVR4
SVR12
Treatment
MK-5172 (100 mg) +
MK-8742 (50 mg)
(n=13)
Follow-up
Lawitz E, et al. Abstract #76, AASLD 2013
21
Number of patients (%)
MK-5172 100 mg +
MK-8742 20 mg
+ RBV
n=25
MK-5172 100 mg
+ MK-8742 50 mg
+ RBV
n=28
MK-5172 100 mg
+ MK-8742 50 mg
n=12
All arms
N=65
Fatigue
8 (32)
5 (18)
4 (33)
17 (26)
Headache
4 (16)
5 (18)
5 (42)
14 (22)
Nausea
3 (12)
7 (25)
2 (17)
12 (18)
Diarrhea
3 (12)
4 (14)
1 (8)
8 (12)
Dizziness
4 (16)
2 (7)
1 (8)
7 (11)
Rash
1 (4)
5 (18)
1 (8)
7 (11)
Common Adverse
Event
* Incidence ≥10% in all arms
Lawitz E, et al. Abstract #76, AASLD 2013
22
Rapid and Consistent Virologic Responses in a Phase 2 Trial
of a New All-Oral Combination of Faldaprevir, Deleobuvir, and
PPI-668, with and without Ribavirin, in Patients with HCV
Genotype-1a Infection
Jacob P. Lalezari1, Laura Holland1, Eileen Glutzer1, Pamela Vig2, Mabrouk Elgadi3, Jerry O. Stern3, Richard
Colonno2, Sherin Halfon2, Eric Ruby2, Ningwu Huang2, Qi Huang2, Eileen Nash2, Nathaniel A. Brown2
1. Quest Clinical Research, San Francisco, CA, United States.
2. Presidio Pharmaceuticals, San Francisco, CA, United States.
3. Boehringer Ingelheim, Ridgefield, CT, United States.
23
Primary
• To assess the efficacy of 12 weeks of treatment with a new three
investigational drug, all-oral antiviral regimen of PPI-668 (NS5A
inhibitor) added to faldaprevir (protease inhibitor, FDV) and
deleobuvir (non-nucleoside NS5B inhibitor, DBV), with and without
ribavirin (RBV), in patients with HCV gt-1a infection
Secondary
• To assess the efficacy of two dose levels of DBV (600 mg BID vs.
400 mg BID), in the context of a three drug investigational regimen
• To assess the safety/tolerance of each of the treatment regimens
Lalezari JP, et al. Abstract #LB-20, AASLD 2013
24
Study Design and Methods
Treatment Period
PostTreatment Period
Cohort 1
(n=12)
600 mg BID DBV + 120 mg QD
FDV* + 200 mg QD 668 + RBV
Cohort 2
(n=12)
400 mg BID DBV + 120 mg QD
FDV* + 200 mg QD 668 + RBV
Cohort 3
(n=12)
600 mg BID DBV + 120 mg QD
FDV* + 200 mg QD 668 (no RBV)
Day
0
Week
12
Week 16
SVR4
Week 24
SVR12
Week 36
SVR24
*FDV loading dose (240 mg) on Day 1
Lalezari JP, et al. Abstract #LB-20, AASLD 2013
25
<LLOQ/<LLOD (%)1
•
Time
Cohort 1
n
Cohort 2
n
Cohort 3
(RBV-free)
n
All
Cohorts
n
Week 2
92/42
12
92/67
12
67/17
12
83/42
36
Week 4
92/75
12
100/100
12
100/67
12
97/81
36
Week 6
100/100
112
100/92
12
100/100
10
100/97
33
Week 8
100/100
112
100/100
11
100/100
4
100/100
26
Week 12
100/100
92
100/100
8
N/A3
0
100/100
17
SVR4
100/100
72
100/100
6
N/A3
0
100/100
13
Overall, 97% of patients across all three cohorts achieved HCV RNA <LLOQ (81% <LLOD) at week 4,
regardless of RBV use
1Percentage
based on number of patients achieving LLOQ and LLOD at the indicated time point for each cohort
1 patient who discontinued at Week 5 due to viral breakthrough
3RBV-free Cohort 3 was initiated later, after efficacy and safety criteria were met in Cohorts 1 and 2
Lalezari JP, et al. Abstract #LB-20, AASLD 2013
2Excludes
26
• Clinical adverse events (AEs) have been similar to those previously seen in
studies of FDV and DBV (skin rashes and GI side effects, mild to moderate
in intensity)
• Patients in the RBV-free cohort (Cohort 3) exhibited a clear predominance of
mild AEs (83% indicated as “mild”) compared with mixed mild-moderate
severity for RBV-containing regimens (Cohorts 1 and 2)
• Grade ≥1 bilirubin elevations were common
– 88% of Cohort 1 and 2 patients, less common in RBV-free Cohort 3 (46%)
Lalezari JP, et al. Abstract #LB-20, AASLD 2013
27
Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination
with or without Ribavirin Resulted in ≥95% Sustained Virologic
Response In Patients with HCV Genotype 1, Including Patients
with Cirrhosis: the LONESTAR trial
Eric Lawitz1, Fred Poordad1, Robert H. Hyland2, Xiao Ding2, Christy Hebner2, Phil S. Pang2,
William T. Symonds2, John G. McHutchison2, Fernando E. Membreno1
1. The Texas Liver Institute, University of Texas Health
Science Center, San Antonio, TX, United States.
2. Gilead Science, Inc, Foster City, CA, United States.
28
COHORT 2
(n=40)
PI Failures
(50%
cirrhosis)
Randomized
1:1
Treatment
COHORT 1 Naïve
(n=60)
(No
cirrhosis)
Randomized
1:1:1
Wk 0
Wk 8
Wk 12
Wk 20
Wk 24
SOF/LDV
SVR12
SOF/LDV + RBV
SVR12
SOF/LDV
SVR12
SOF/LDV
SVR12
SOF/LDV + RBV
SVR12
• Single center study of GT 1 patients
• Broad inclusion criteria
– No upper limit to age or BMI
– Platelets ≥50,000/mm3
Lawitz E, et al. Abstract #215, AASLD 2013
29
PI Failures
n=40
Prior treatment with boceprevir
22/40 (55)
Prior treatment with telaprevir
18/40 (45)
Cirrhosis, n (%)
22/40 (55)
Mean platelet count, x 103/µL
107
Mean albumin, g/dL
3.8
• All patients were required to have experienced virologic failure
– Patients who stopped prior therapy due to an AE were excluded
Lawitz E, et al. Abstract #215, AASLD 2013
30
100
95
100
95
95
100
Patients (%)
80
60
40
20
0
RBV
Duration (week)
19/20
21/21
18/19
18/19
21/21
─
8
+
─
12
─
12
+
8
Treatment Naïve
(No Cirrhosis)
12
PI Failures
(50% Cirrhosis)
Lawitz E, et al. Abstract #215, AASLD 2013
31
100
100
100
100
18/19
21/21
8/8
10/10
10/11
11/11
─
+
─
+
─
+
95
100
91
Patients (%)
80
60
40
20
0
RBV
Duration (week)
12
12
Overall
No Cirrhosis
12
Cirrhosis
Lawitz E, et al. Abstract #215, AASLD 2013
32
SOF/LDV
n=58
SOF/LDV+RBV
n=42
24 (41)
24 (57)
0
6 (14)
2* (3)
2† (5)
0
0
Grade 3-4
laboratory abnormality
4 (7)
6 (14)
Hemoglobin <10 g/dL
0
8 (19)
Hemoglobin <8.5 g/dL
0
2 (5)
Patients, n (%)
AEs
Overall
safety
Grade 3-4 AEs
Serious AEs
Treatment discontinuation
due to AEs
Laboratory
abnormalities
*Peptic ulcer, spinal compression fracture; †Delirium, suicidal ideation.
Lawitz E, et al. Abstract #215, AASLD 2013
33
34
Sofosbuvir + Ribavirin for 12 or 24 Weeks for Patients with
HCV Genotype 2 or 3: the VALENCE trial
Stefan Zeuzem1, Geoffrey M. Dusheiko2, Riina Salupere3, Alessandra Mangia4, Robert Flisiak5, Robert H.
Hyland6, Ari Illeperuma6, Evguenia S. Svarovskaia6, Diana M. Brainard6, William T. Symonds6, John G.
McHutchison6, Ola Weiland7, Hendrik W. Reesink8, Peter Ferenci9, Christophe Hezode10, Rafael Esteban11
1. Johann Wolfgang Goethe University, Frankfurt, Germany.
2. Royal Free and University College School of Medicine,
Royal Free Hospital, London, United Kingdom.
3. Tartu University Hospital, Tartu, Estonia.
4. "Casa Sollievo della Sofferenza" Hospital, San Giovanni
Rotondo, Italy.
5. Medical University of Bialystok, Bialystok, Poland.
6. Gilead Sciences, Inc., Foster City, CA, United States.
7. Karolinska Institutet, Karolinska University Hospital
Huddinge, Stockholm, Sweden.
8. Academic Medical Center, Amsterdam, Netherlands.
9. Medical University of Vienna, Vienna, Austria.
10. Hôpital Henri Mondor, Créteil, France.
11. Hospital Universitario Val d’Hebron, Barcelona, Spain.
35
Wk 0
Wk 12
Wk 24
SVR4, SVR12,
SVR24
Placebo*
(n = 85)
Sofosbuvir + Ribavirin
(n = 84)*
Sofosbuvir + Ribavirin
(n = 250)
*Protocol amended to eliminate placebo arm and to extend treatment duration to 24 weeks
for patients with genotype 3 HCV irrespective of prior treatment history.
Zeuzem S, et al. Abstract #1085, AASLD 2013
36
SVR12 in GT 2 Patients Treated
for 12 Weeks
SVR12 in GT 2 and
3 Patients*
100
100
93
97
100
91
88
85
80
SVR12 (%)
SVR12 (%)
80
60
40
60
40
20
20
68/73
212/
250
GT 2
SOF+RBV 12 wk
GT 3
SOF+RBV 24 wk
0
29/30
0
Naïve,
Noncirrhotic
2/
2
Naïve,
Cirrhotic
30/33
Experienced,
Noncirrhotic
7/
8
Experienced,
Cirrhotic
*3 of 11 patients (27%) with HCV GT 3 who received 12 weeks of SOF+RBV achieved SVR 12.
Zeuzem S, et al. Abstract #1085, AASLD 2013
37
100
94
92
87
SVR12 (%)
80
60
60
40
20
0
86/92
12/13
87/100
27/45
Naïve,
Noncirrhotic
Naïve,
Cirrhotic
Experienced,
Noncirrhotic
Experienced,
Cirrhotic
Zeuzem S, et al. Abstract #1085, AASLD 2013
38
Sofosbuvir in Combination With PegIFN and Ribavirin for 12 Weeks
Provides High SVR Rates in HCV-Infected Genotype 2 or 3 Treatment
Experienced Patients with and without Compensated Cirrhosis:
Results from the LONESTAR-2 Study
Eric Lawitz1, 2, Fred Poordad1, 2, Diana M. Brainard3, Robert H. Hyland3, Di An3,
William T. Symonds3, John G. McHutchison3, Fernando E. Membreno1, 2
1. Texas Liver Institute, San Antonio, TX, United States.
2. University of Texas Health Science Center, San Antonio, TX, United States.
3. Gilead Science, Inc, Foster City, CA, United States.
39
Wk 0
GT 2/3
(N=47)
•
Wk 12
SOF + PEG/RBV
Wk 24
Wk 36
SVR12
Study population
– HCV GT 2 or 3
– Failed treatment with pegylated interferon and ribavirin
– Approximately 50% with compensated cirrhosis
– HIV and HBV coinfected patients excluded
Lawitz E, et al. Abstract #LB-4, AASLD 2013
40
100
89
96
83
SVR12
(%)
80
60
40
20
0
42/47
22/23
20/24
Overall
GT 2
GT 3
Lawitz E, et al. Abstract #LB-4, AASLD 2013
41
No Cirrhosis
SVR12 (%)
100
Cirrhosis
100
93
83
83
9/9
13/14
10/12
10/12
80
60
40
20
0
GT 2
GT 3
Error bars represent 95% confidence intervals.
Lawitz E, et al. Abstract #LB-4, AASLD 2013
42
43
Sustained Virological Response After Protease Inhibitor-based
Therapy For Hepatitis C Recurrence After Liver
Transplantation: A Multicentric European Experience
Audrey Coilly1, 2, Jerome Dumortier4, Danielle Botta-Fridlund5, Marianne Latournerie6, Vincent Leroy7, Georges-Philippe
Pageaux8, Emiliano G. Giostra9, Christophe Moreno10, Bruno Roche1, 3, Pascal Lebray11, Sylvie Radenne12, Anne-Catherine
Saouli13, Yvon Calmus14, Laurent Alric15, Maryline Debette-Gratien16, Victor de Ledinghen17, Francois Durand18, Christophe
Duvoux19, Didier Samuel1, 2, Jean-Charles Duclos-Vallee1, 3
1. Centre Hepato-Biliaire, AP-HP, Hopital Paul Brousse, Villejuif, France.
2. Unit 785, Inserm, Villejuif, France.
3. UMR-S785, Univ Paris-Sud, Villejuif, France.
4. Dept Hepato-gastro-enterologie, Hopital Edouard Herriot, Lyon, France.
5. Hepato-gastro-enterologie, AP-HM Hopital de la Conception, Marseille, France.
6. Maladies du foie et de l'appareil digestif, Centre Hospitalier Universitaire Pontchaillou, Rennes,
France.
7. Hepato-gastro-enterologie, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.
8. Hepato-gastro-enterologie et Transplantation, CHU - Hopital Saint Eloi, Montpellier, France.
9. Gastro-enterologie et Hepatologie, Hopitaux Universitaire de Geneve, Geneve, Switzerland.
10. Hepato-Gastro-Enterologie, Hopital Erasme - Cliniques Universitaires de Bruxelles, Bruxelles, Belgium.
11. Hepato-gastro-enterologie, AP-HP, Hopital Pitié Salpétrière, Paris, France.
12. Hepato-gastro-enterologie, Hopital de la Croix Rousse, Lyon, France.
13. Hepato-gastro-enterologie, CHRU de Strasbourg, Strasbourg, France.
14. Chirurgie Digestive, AP-HP, Hopital Saint Antoine, Paris, France.
15. Médecine Interne, CHU Purpan, Toulouse, France.
16. Hepato-gastro-enterologie, Centre Hospitalier Régional Universitaire Dupuytren, Limoges, France.
17. Hepatogastroenterologie et Oncologie digestive, CHU de Bordeaux - Hopital Haut Leveque, Pessac,
France.
18. Hepato-Gastro-Enterologie, AP-HP, Hopital Beaujon, Clichy, France.
19. Hepato-gastro-enterologie, AP-HP, Hopital Henri Mondor, Creteil, France.
44
• Study cohort
• N=79 (who would have achieved SVR12)
• Enrolled between March 2011 and July 2012
• In 17 liver transplant centers in France, Belgium and Switzerland
• Inclusion criteria:
– Genotype 1 active and chronic hepatitis C
– Recurrence defined by a fibrosis stage >1 (METAVIR) or FCH
– Stable immunosuppressive regimen
– No HBV or HIV coinfection
Coilly A, et al. Abstract #216, AASLD 2013
45
n=35
PegIFN/RBV
PegIFN/RBV+BOC(800mg tid)
n=19
PegIFN/RBV
PegIFN/RBV+TVR (750mg tid)
n=25
PegIFN/RBV+TVR (750mg tid)
Week -4
Week 0
Week 4
Week 12
Planned therapy duration: 48 weeks
Coilly A, et al. Abstract #216, AASLD 2013
46
p=0.176
p=0.373
60%
p=0.132
TVR
Tela
BOC
Boce
51%
43%
47%
41%
27%
n=44
n=35
EOT
n=44
n=35
SVR
RVS12
12
n=38
n=32
SVR
RVS 24
24
Coilly A, et al. Abstract #216, AASLD 2013
47
SVR12 according to fibrosis stage
54%
p=ns
F0 F1 F2 (n=45)
35%
33%
33%
F3 F4 (n=34)
F4 (n=18)
FCH (n=9)
Coilly A, et al. Abstract #216, AASLD 2013
48
SVR12 according to genotype
SVR12 according to previous response
55%
44%
45%
46%
p=ns
29%
G1a (n=25)
G1b (n=53)
Naïve (n=35) Relapse (n=11) Nul NR (n=17)
Coilly A, et al. Abstract #216, AASLD 2013
49
Sofosbuvir and Ribavirin for the Treatment of Established Recurrent
Hepatitis C Infection After Liver Transplantation:
Preliminary Results of a Prospective, Multicenter Study
Michael R. Charlton1, Edward J. Gane2, Michael P. Manns3, Robert S. Brown4, Michael P. Curry5,
Paul Y. Kwo6, Robert J. Fontana7, Richard Gilroy8, Lewis W. Teperman9, Andrew J. Muir10,
John G. McHutchison11, William T. Symonds11, Jill M. Denning11, Lindsay McNair11, Sarah Arterburn11,
Norah Terrault12, Didier Samuel13, Xavier Forns14
1. Mayo Clinic, Rochester, MN, United States.
2. Auckland City Hospital, Auckland, New Zealand.
3. Hannover Medical School, Hannover, Germany.
4. Columbia University, New York, NY, United States.
5. Beth Israel Deaconess Medical Center, Boston, MA, United States.
6. Indiana School of Medicine, Indianapolis, IN, United States.
7. University of Michigan, Ann Arbor, MI, United States.
8. Kansas University Medical Center, Lawrence, KS, United States.
9. NYU Medical Center, New York , NY, United States.
10. Duke University Medical Center, Durham, NC, United States.
11. Gilead Sciences, Foster City, CA, United States.
12. University of California, San Francisco, CA, United States.
13. Université Paris-Sud, Villejuif, France.
14. The Liver Unit, Barcelona, Spain.
50
Week 0
12
24
36
SOF 400 mg + RBV 400‒1200 mg (N=40)
SVR12
• Patients with recurrent HCV post-liver transplant, all genotypes
• Low, ascending-dose RBV regimen starting at 400 mg/day, escalated
based on hemoglobin levels
• Study objectives
– Primary: sustained virologic response 12 weeks post treatment with
sofosbuvir + RBV in liver transplant recipients
– Secondary: safety, tolerability and viral kinetics
Charlton MR, et al. Abstract #LB-2, AASLD 2013
51
Virologic Response
Rate (%)
100
100
100
77
80
60
40
20
40/40
39/39
27/35†
Week 4
EOT*
SVR 4
0
*1 patient still on treatment; †4 patients have not reached SVR4 visit.
Charlton MR, et al. Abstract #LB-2, AASLD 2013
52
100
Patients (%)
80
70
60
35
40
28
25
20
0
5
28/40
14/40
11/40
10/40
2/40
Tacrolimus
Mycophenolate
mofetil
Prednisone
Cyclosporin
Azathioprine
• No interactions reported between SOF and any immunosuppressive agents during study
• 4 patients increased tacrolimus dosing during SOF therapy
Charlton MR, et al. Abstract #LB-2, AASLD 2013
53
Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence
of HCV Infection after Liver Transplantation
Michael P. Curry1, Xavier Forns2, Raymond T. Chung3, Norah Terrault4, Robert S. Brown5, Jonathan M.
Fenkel6, Fredric D. Gordon7, Jacqueline G. O'Leary8, Alexander Kuo9, Thomas D. Schiano10, Gregory T.
Everson11, Eugene R. Schiff12, Alex Befeler13, John G. McHutchison14, William T. Symonds14, Jill M.
Denning14, Lindsay McNair14, Sarah Arterburn14, Dilip Moonka15, Edward J. Gane16, Nezam H. Afdhal1
1. Beth Israel Deaconess Medical Center, Boston, MA, United States.
2. The Liver Unit, Barcelona, Spain.
3. Massachusetts General Hospital, Boston, MA, United States.
4. University of California San Francisco, San Francisco, CA, United States.
5. Columbia University, New York, NY, United States.
6. Thomas Jefferson University Hospital, Philadelphia, PA, United States.
7. Lahey Clinic, Burlington, MA, United States.
8. Baylor University Medical Center, Dallas, TX, United States.
9. University of California San Diego, La Jolla, CA, United States.
10. Mount Sinai School of Medicine, New York, NY, United States.
11. University of Colorado, Denver, CO, United States.
12. University of Miami, Miami, FL, United States.
13. St. Louis University, St. Louis, MO, United States.
14. Gilead Sciences, Foster City, CA, United States.
15. Henry Ford Health System, Detroit, MI, United States.
16. Auckland City Hospital, Auckland, New Zealand.
54
• Recurrent HCV infection of the allograft is universal in
patients with detectable HCV RNA at the time of liver
transplantation (LT) and may result in accelerated
progression to cirrhosis and graft loss.
• Interferon-based antiviral treatment before LT can
prevent HCV recurrence, but this treatment is poorly
tolerated and effective in only a minority of patients.
Curry MP, et al. Abstract #213, AASLD 2013
55
• In this phase 2 open-label study, patients with chronic HCV infection of
any genotype (GT) listed for LT for hepatocellular carcinoma (HCC)
received up to 48 weeks of SOF 400 mg/day and RBV 1000-1200
mg/day before LT.
• All patients had HCC within Milan criteria and well compensated
cirrhosis (Child-Pugh-Turcotte score of ≤7).
• The primary endpoint was virologic response (HCV RNA <25 IU/mL)
12 weeks after LT in patients who had HCV RNA <25 IU/mL at their last
measurement prior to LT (SVR12).
• Post-LT immunosuppressive regimen was tacrolimus plus prednisone
with or without mycophenolate mofetil.
Curry MP, et al. Abstract #213, AASLD 2013
56
• 36 patients included in efficacy analysis
• Received a mean of 17.1 (range 3.3 to 33.7) weeks of treatment prior
to LT
• At the time of writing, 26 patients have reached at least 12 weeks post-
transplant, of whom 18 (69%, 90% CI 51% to 84%) achieved SVR12.
• The most frequently reported adverse events were fatigue, anemia,
and rash.
• Two patients discontinued treatment due to AEs of acute renal failure
and pneumonitis, neither was attributed to study drug.
• One SAE, anemia, was considered related to study drug.
Curry MP, et al. Abstract #213, AASLD 2013
57