Transcript Option A

Geoffrey Dusheiko, MD
London, UK
This activity is supported by an independent medical
education grant from AbbVie, Bristol-Myers Squibb
and Gilead Sciences
1
All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With or
Without Ribavirin for 12 or 24 Weeks in TreatmentExperienced Genotype 1 HCV-Infected Patients:
The Phase 3 ION-2 Study
Nezam Afdhal1, Rajender K. Reddy2, Paul Pockros3, Adrian M. Di Bisceglie4, Sanjeev Arora5,
Jenny C. Yang6, Hadas Dvory-Sobol6, Yanni Zhu6, Phil S. Pang6, William T. Symonds6,
John G. McHutchison6, Mark Sukowski7, Paul Kwo8
1Beth
Israel Deaconess Medical Center, Boston, MA, USA; 2University of Pennsylvania, Philadelphia, PA,
USA; 3Scripps Clinic, La Jolla, CA; 4St Louis University, Saint Louis, MO, USA; 5University of New Mexico,
Albuquerque, NM; 6Gilead Sciences, Inc., Foster City, CA; 7Johns Hopkins Medical Center, Baltimore, MD,
USA; 8Indiana University School of Medicine, Indianapolis, IN, USA
2
Wk 0
Wk 12
Wk 24
LDV/SOF
SVR12
LDV/SOF + RBV
SVR12
Wk 36
LDV/SOF
SVR12
LDV/SOF + RBV
SVR12
• GT 1 HCV patients who had failed prior IFN-based therapy, including regimens
containing a NS3/4A protease inhibitor
• Broad inclusion criteria
– Targeted 20% enrollment of patients with cirrhosis
– No upper age or BMI limit
– Platelet count ≥50,000/mm3, no neutrophil minimum
• 440 patients randomized 1:1:1:1 across four arms
• Stratified by HCV subtype (1a or 1b), cirrhosis, prior treatment response
Afdhal, N. et al. EASL 2014, Abstract #O109
3
12 Weeks
24 Weeks
LDV/SOF
n=109
LDV/SOF+RBV
n=111
LDV/SOF
n=109
LDV/SOF+RBV
n=111
56 (24–67)
57 (27–75)
56 (25–68)
55 (28–70)
Male, n (%)
74 (68)
71 (64)
74 (68)
68 (61)
Black, n (%)
24 (22)
16 (14)
17 (16)
20 (18)
7 (6)
12 (11)
11 (10)
11 (10)
29 (19–47)
28 (19–45)
28 (19–41)
28 (19–50)
IL28B CC, n (%)
10 (9)
11 (10)
16 (15)
18 (16)
GT 1a, n (%)
86 (79)
88 (79)
85 (78)
88 (79)
6.5 (5.0–7.5)
6.4 (4.6–7.3)
6.4 (4.7–7.4)
6.5 (3.1–7.4)
HCV RNA ≥800,000 IU/mL
103 (95)
98 (88)
93 (85)
96 (87)
Prior non-responders, n (%)
49 (45)
46 (41)
49 (45)
51 (46)
Prior protease inhibitor
failures, n (%)
66 (61)
64 (58)
50 (46)
51 (46)
Cirrhosis, n (%)
22 (20)
22 (20)
22 (20)
22 (20)
Mean age, y (range)
Hispanic, n (%)
Mean BMI, kg/m2 (range)
Mean HCV RNA,
log10 IU/mL (range)
• Arms were balanced with respect to demographics and baseline characteristics
Afdhal, N. et al. EASL 2014, Abstract #O109
4
100
94
96
99
99
102/109
107/111
108/109
110/111
LDV/SOF
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
SVR12 (%)
80
60
40
20
0
12 Weeks
24 Weeks
Error bars represent 95% confidence intervals.
Afdhal, N. et al. EASL 2014, Abstract #O109
5
Failed PEG/RBV
100
93
94
40/43
62/66
Failed Protease Inhibitor
96
97
100
98
98
100
45/47
62/64
58/58
49/50
58/59
51/51
SVR12 (%)
80
60
40
20
0
LDV/SOF
LDV/SOF + RBV
12 Weeks
LDV/SOF
LDV/SOF + RBV
24 Weeks
Error bars represent 95% confidence intervals.
Afdhal, N. et al. EASL 2014, Abstract #O109
6
Absence of Cirrhosis
100
95
100
86
82
Cirrhosis
99
100
99
100
86/87
22/22
88/89
22/22
SVR12 (%)
80
60
40
20
83/87
19/22
89/89
18/22
0
LDV/SOF
LDV/SOF + RBV
12 Weeks
LDV/SOF
LDV/SOF + RBV
24 Weeks
Error bars represent 95% confidence intervals.
Afdhal, N. et al. EASL 2014, Abstract #O109
7
Ledipasvir/Sofosbuvir With and Without Ribavirin for 8
Weeks Compared to Ledipasvir/Sofosbuvir for 12 Weeks in
Treatment-Naïve Noncirrhotic Genotype-1
HCV-Infected Patients: The Phase 3 ION-3 Study
Kris V. Kowdley1, Stuart C. Gordon 2, K. Rajender Reddy3, Lorenzo Rossaro4, David E. Bernstein5,
Di An6, Evguenia S. Svarovskaia6, Robert H. Hyland6, Phillip S. Pang6,
William T. Symonds6, John G. McHutchison6, Andrew J. Muir7, Paul J. Pockros8,
David C. Pound9, Michael W. Fried10
1Virginia
Mason Medical Center, Seattle, WA, USA; 2Henry Ford Health System, Detroit, MI, USA;
3Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA; 4University of
California Davis Medical Center, Sacramento, CA, USA; 5North Shore University Hospital, Manhasset, NY,
USA; 6Gilead Sciences, Inc., Foster City, CA; 7Division of Gastroenterology and Duke Clinical Research
Institute, Duke University School of Medicine, Durham, NC, USA; 8Scripps Clinic, La Jolla, CA; 9Indianapolis
Gastroenterology Research Foundation, Indianapolis, IN, USA; 10University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA
8
• Short, safe, and effective interferon- and ribavirin-free
treatment options for patients with chronic HCV GT 1
infection are currently lacking
• LDV/SOF ± RBV for 8 weeks and LDV/SOF for 12 weeks
demonstrated high SVR rates in the Phase 2 LONESTAR
study in treatment-naïve HCV patients without cirrhosis1
• To evaluate whether LDV/SOF for 8 weeks is effective for
HCV treatment-naïve, non-cirrhotic, GT 1 patients or if RBV
or a longer treatment duration of 12 weeks is required to
achieve high SVR rate
1. Lawitz E, et al. Lancet. 2014;383:515-23.
Kowdley, K. et al. EASL 2014, Abstract #O56
9
Wk 8
Wk 0
Wk 12
Wk 20
LDV/SOF
SVR12
LDV/SOF + RBV
SVR12
LDV/SOF
Wk 24
SVR12
• GT 1 treatment-naïve patients without cirrhosis
• Broad inclusion criteria
– No upper age or BMI limit
– Opiate substitution therapy allowed
• 647 patients randomized 1:1:1 across three arms
• Stratified by HCV subtype (1a or 1b)
Kowdley, K. et al. EASL 2014, Abstract #O56
10
p=0.52
p=0.70
100
p=0.30
95
94
93
202/215
201/216
LDV/SOF
LDV/SOF + RBV
SVR12 (%)
80
60
40
20
0
8 Weeks
206/216
206/216
LDV/SOF
12 Weeks
Error bars represent 95% confidence intervals.
Kowdley, K. et al. EASL 2014, Abstract #O56
11
• LDV/SOF ± RBV for 8 or 12 weeks results in high
SVR12 rates
• No difference in efficacy among the groups was observed
• Host and viral factors traditionally associated with lower
SVR rates did not affect SVR12 rates
• LDV/SOF ± RBV was safe and well tolerated
– RBV contributed to a higher incidence of AEs and laboratory
abnormalities
• An 8 week LDV/SOF treatment regimen is a safe and
effective treatment for treatment-naïve non-cirrhotic
patients with HCV GT 1 infection
Kowdley K, et al. NEJM In Press
Kowdley, K. et al. EASL 2014, Abstract #O56
12
Sofosbuvir/Ledipasvir Fixed Dose Combination is Safe and
Effective in Difficult-to-treat Populations Including Genotype-3
Patients, Decompensated Genotype-1 Patients, and Genotype-1
Patients With Prior Sofosbuvir Treatment Experience
E.J. Gane1, R.H. Hyland2, D. An2, P.S. Pang2, W.T. Symonds2, J.G. McHutchison2, C.A. Stedman3
1Auckland
Clinical Studies, Auckland, New Zealand; 2Gilead Sciences, Inc., Foster City, CA, United States;
3Christchurch Clinical Studies Trust, Christchurch, New Zealand
13
Wk 12
Wk 0
SVR12
LDV/SOF + RBV, n=19
GT 1
CPT class B
LDV/SOF, n=20
Randomized
GT 1
Prior SOF exposure
GT 3
Treatment naïve
Wk 24
LDV/SOF, n=25
LDV/SOF + RBV, n=26
1. HCV GT 1, relapsed after previous treatment with
SOF-containing regimens in ELECTRON-1
2. HCV GT 1 decompensated cirrhosis (Child Pugh Turcotte B)
3. HCV GT 3, treatment naïve
Gane, E. et al. EASL 2014, Abstract #O6
14
Re-treatment
100
SOF+RBV 12 wk
Prior Null
Responders
100
SOF+RBV 12 wk
Treatment Naïve
n=4
80
SVR12 (%)
n=6
n=1
GS-9669 + SOF
+RBV 12 wk
Treatment Naïve
n=8
LDV/SOF +RBV
6 wk
Treatment Naïve
• All 19 previous SOF-regimen failures had relapsed
60
40
20
0
19/19
19/19
LDV/SOF +
RBV
12 Weeks
Gane, E. et al. EASL 2014, Abstract #O6
15
GT 1
CPT Class B
100
1.5 (0.7-3.7)
3.1 (2.3-3.8)
Median INR
(range)
1.2 (1.0-3.0)
Ascites, n (%)
4 (20)
Hepatic encephalopathy,
n (%)
6 (30)
Median platelet count,
103/µL (range)
65
80
Median serum albumin,
g/dL (range)
84 (44-162)
SVR12 (%)
Median total bilirubin,
mg/dL (range)
7 relapsers
60
40
20
0
13/20
LDV/SOF 12 Weeks
Error bar represents the 95% confidence interval.
Gane, E. et al. EASL 2014, Abstract #O6
16
100
100
64*
SVR12 (%)
80
60
40
20
0
16/25
26/26
LDV/SOF 12 Weeks
LDV/SOF + RBV 12 Weeks
*Failure due to relapse (n=8) or discontinuation due to AE (n=1)
Gane, E. et al. EASL 2014, Abstract #O6
17
LDV/SOF regimens for 12 weeks are safe and
effective IFN-free treatments for many diverse and
difficult-to-treat patient populations including:
• Patients infected with HCV GT 1 who have failed
previous SOF-containing regimens
• Patients infected with HCV GT 1 with
decompensated cirrhosis
• Patients infected with HCV GT 3
Gane, E. et al. EASL 2014, Abstract #O6
18
Safety and Efficacy of Treatment With the Interferon-free,
Ribavirin-free Combination of Sofosbuvir+GS-5816 For 12
Weeks in Treatment Naïve Patients With Genotype 1-6
HCV Infection
G.T. Everson1, T.T. Tran2, W.J. Towner3, M.N. Davis4, D. Wyles5, R. Nahass6, J. McNally7,
D.M. Brainard7, L. Han7, B. Doehle7, E. Mogalian7, W.T. Symonds7, J.G. McHutchison7, T. Morgan8,
R.T. Chung9
1University
of Colorado Denver, Aurora, CO, 2Cedars-Sinai Medical Center, 3Kaiser Permanente, Los
Angeles, CA, 4Digestive CARE, South Florida Center of Gastroenterology, LLC, Wellington, FL, 5University
of California, San Diego, CA, 6ID CARE, Hillsborough, NJ, 7Gilead Sciences, Inc., Foster City, 8VA Long
Beach, Long Beach, CA, 9Massachusetts General Hospital, Boston, MA, United States
19
Wk 0
GT 1
(N=55)
SOF + GS-5816 25 mg
GT 3
(N=54)
SOF + GS-5816 25 mg
GT 2-6
(N=45)
SOF + GS-5816 25 mg
Wk 12
Wk 24
SOF + GS-5816 100 mg
SVR12
SOF + GS-5816 100 mg
SOF + GS-5816 100 mg
• Open label
– SOF 400 mg + GS-5816 25 mg for 12 weeks
or
– SOF 400 mg + GS-5816 100 mg for 12 weeks
• Treatment-naïve patients with HCV GT 1-6 without cirrhosis
• No ribavirin administered
Everson, G. et al. EASL 2014, Abstract #O111
20
SOF + GS-5816 25 mg
GT 1
100
SOF + GS-5816 100 mg
GT 2
GT 3
96
100
91
100
93
93
26/27
28/28
10/11
10/10
25/27
25/27
SVR12 (%)
80
60
40
20
0
Everson, G. et al. EASL 2014, Abstract #O111
21
SOF + GS-5816 25 mg
GT 4
100
SOF + GS-5816 100 mg
GT 5
100
GT 6
100
100
100
4/4
5/5
86
SVR12 (%)
80
60
40
20
0
7/7
6/7
1/1
10/10
Everson, G. et al. EASL 2014, Abstract #O111
22
• SOF + GS-5816 for 12 weeks resulted in SVR12
rates >90% in all HCV genotypes (1-6)
– Relapse was observed more often in patients treated with
GS-5816 25 mg (N=3) compared to GS-5816 100 mg (N=1)
• The presence of pre-treatment NS5A variants was
not predictive of failure to achieve SVR 12
• SOF + GS-5816 was well tolerated with no
discontinuations due to AEs
• The combination of SOF 400 mg and GS-5816 100
mg is being evaluated in treatment-experienced
patients and patients with cirrhosis
Everson, G. et al. EASL 2014, Abstract #O111
23
SAPPHIRE-I: Phase 3 Placebo-Controlled Study of
Interferon-Free, 12-Week Regimen of ABT-450/r/ABT-267,
ABT-333, and Ribavirin in 631 Treatment-Naïve Adults
With Hepatitis C Virus Genotype 1
J.J. Feld1, K.V. Kowdley2, E. Coakley3, S. Sigal4, D. Nelson5, D. Crawford6,7, O. Weiland8, H. Aguilar9,
J. Xiong3, B. DaSilva-Tillmann3, L. Larsen3, T. Podsadecki3
1Toronto
Western Hospital Liver Centre, Toronto, ON, Canada, 2Digestive Disease Institute, Virginia Mason
Medical Center, Seattle, WA, 3AbbVie Inc., North Chicago, IL, 4NYU Langone Medical Center, New York, NY,
5University of Florida College of Medicine, Gainesville, FL, United States, 6Gallipoli Medical Research
Foundation, 7The University of Queensland, Brisbane, QLD, Australia, 8Karolinska University Hospital
Huddinge, Karolinska Institutet, Stockholm, Sweden, 9Louisiana Research Center, LLC, Shreveport, LA,
United States
24
Double-Blind
Treatment Period
Open-Label
Treatment Period
3D + RBV
(n=473)
Placebo
(n=158)
Week 0
48-Week
Follow-Up
48-Week
Follow-Up
3D + RBV
Week 12
Week 24
Week 60
Week 72
Primary Analysis:
SVR12
• 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD;
dasabuvir, 250 mg BID
• RBV: 1000-1200 mg daily according to body weight (<75 kg and >75kg,
respectively)
Feld, J. et al. EASL 2014, Abstract #O60
25
95.3%
98.0%
455/473
307/322
148/151
All
Patients
GT1a
GT1b
SVR12, % Patients
96.2%
Feld, J. et al. EASL 2014, Abstract #O60
26
Event, n/N (%)
SVR12
Non-SVR12
3D + RBV
(N=473)
455/473 (96.2)
18/473 (3.8)
Virologic failure
Breakthrough
1/473 (0.2)
Relapse
7/463 (1.5)
Prematurely discontinued study drug*
7/473 (1.5)
Lost to follow-up after completion of treatment
3/473 (0.6)
Breakthrough and relapse rates of 0.2% and 1.5%, respectively
*Patients (n=7) who prematurely discontinued without breakthrough; 2 due to adverse events, 5 withdrew consent/
lost to follow-up.
Feld, J. et al. EASL 2014, Abstract #O60
27
TURQUOISE-II: SVR12 Rates of 92%-96% in 380 Hepatitis C
Virus Genotype 1-Infected Adults With Compensated Cirrhosis
Treated With ABT-450/r/ABT-267 and ABT-333 Plus Ribavirin
(3D+RBV)
F. Poordad1, C. Hezode2, R. Trinh3, K.V. Kowdley4, S. Zeuzem5, K. Agarwal6, M.L. Shiffman7,
H. Wedemeyer8, T. Berg9, E.M. Yoshida10, X. Forns11, S.S. Lovell3, B. Da Silva-Tillmann3,
A.L. Campbell3, T. Podsadecki3
1The
Texas Liver Institute/University of Texas Health Science Center, San Antonio, TX, United States, 2Henri
Mondor Hospital, APHP, University Paris-Est, Inserm U955, Creteil, France, 3AbbVie Inc., North Chicago, IL,
4Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States, 5J.W. Goethe
University, Frankfurt, Germany, 6Institute of Liver Studies, Kings College Hospital, London, United Kingdom,
7Liver Institute of Virginia, Newport News, VA, United States, 8Medizinische Hochschule Hannover,
Hannover, 9Universit_tsklinikum Leipzig, Leipzig, Germany, 10University of British Columbia, Vancouver, BC,
Canada, 11Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain
28
SVR12
3D + RBV
(N=208)
SVR12
3D + RBV
(N=172)
All patients to be followed through 48 weeks post-treatment
Day 0
Week 12
Week 24
• 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25
mg QD; dasabuvir, 250 mg BID
• RBV: 1000-1200 mg daily according to body weight (<75 kg
and >75kg, respectively)
Poordad, F. et al. EASL 2014, Abstract #O163
29
100
91.8
P=0.089
95.9
SVR12, % Patients
80
60
40
20
0
191/208
165/172
12 Weeks
3D + RBV
24 Weeks
3D + RBV
Poordad, F. et al. EASL 2014, Abstract #O163
30
100
92.2 92.9
93.3 100
100 100
80.0 92.9
3D + RBV
12-week arm
24-week arm
SVR12, % Patients
80
60
40
20
0
59/64 52/56
14/15 13/13
11/11 10/10
Naïve
Prior Relapse
Response
Prior Partial
Response
40/50 39/42
Prior Null
Response
HCV Subtype 1a
Poordad, F. et al. EASL 2014, Abstract #O163
31
Results Of The Phase 2 Study M12-999:
Interferon-Free Regimen Of ABT-450/r/ABT-267+ABT333+Ribavirin In Liver Transplant Recipients With
Recurrent HCV Genotype 1 Infection
P. Kwo1, P. Mantry2, E. Coakley3, H. Te4, H. Vargas5, R. Brown Jr.6, F. Gordon7, J. Levitsky8, N.
Terrault9, J. Burton Jr10, W. Xie3, C. Setze3, P. Badri3, R.A. Vilchez3, X. Forns11
1Indiana
University, Indianapolis, IN, 2The Liver Institute at Methodist Dallas Medical Center, Dallas, TX,
3AbbVie Inc., North Chicago, 4University of Chicago Medicine, Chicago, IL, 5Mayo Clinic, Phoenix, AZ,
6Columbia University Medical Center Center for Liver Disease and Transplantation, New York, NY, 7Lahey
Hospital & Medical Center, Burlington, MA, 8Northwestern University Comprehensive Transplant Center,
Chicago, IL, 9University of California, San Francisco, San Francisco, CA, 10University of Colorado, Denver,
Aurora, CO, United States, 11Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain
32
SVR12
3D + RBV
(N=34)
Day 0
Week 24
To Week 72
• 3D: co-formulated ABT-450/r/ombitasvir, 150
mg/100 mg/25 mg QD; dasabuvir, 250 mg BID
• RBV: dosing was managed at the discretion of the
investigator and closely monitored per protocol
Kwo, P. et al. EASL 2014, Abstract #O114
33
• Based on previous drug-drug interaction findings,
recommended dosing during 3D treatment was:
– TAC
• 0.5 mg once weekly or
• 0.2 mg every 3 days
– CYA
• 1/5 of the daily pre-3D treatment dose given once daily
Kwo, P. et al. EASL 2014, Abstract #O114
34
100
100%
100%
34/34
97.0%
96.2%
34/34
32/33
25/26
RVR
EOTR
SVR4
SVR12
(Week 4)
(Week 24)
% Patients
80
60
40
20
0
• No patient had breakthrough
• One patient had a relapse (post-treatment day 3)
– At the time of relapse, this patient had R155K in NS3 protease, M28T+Q30R in NS5A, and
G554S+G557R in NS5B, none of which were present at baseline
Kwo, P. et al. EASL 2014, Abstract #O114
35
• An IFN-free, 24-week regimen of ABT-450/r/ombitasvir +
dasabuvir + RBV achieved high response rates in
immunosuppressed liver transplant recipients with recurrent
HCV GT1 infection
• In this on-going study:
– 100% achieved RVR (34/34) and EOTR (34/34)
– 97.0% (32/33) achieved SVR4 and 96.2% (25/26) achieved SVR12
• The regimen was generally well tolerated with 1 patient
discontinuing study drug due to AEs
– No deaths, graft losses, or episodes of rejection
• CNI dosing was manageable over the period of the study
Kwo, P. et al. EASL 2014, Abstract #O114
36
Results From the Phase 2 PEARL-I Study:
Interferon-Free Regimens of ABT-450/R + ABT-267 With or
Without Ribavirin in Patients With HCV Genotype 4 Infection
C. Hezode1, P. Marcellin2, S. Pol3, T. Hassanein4, K. Fleischer-Stepniewska5, T. Baykal6, T. Wang6,
S.S. Lovell6, T. Pilot-Matias6, R.A. Vilchez6
1Assistance
Publique Hopitaux de Paris, Paris, 2Hopital Beaujon Inserm Crb3 - U 773 - Service Hepatologie,
Clichy, 3Groupe Hospitalier Cochin-Saint Vincent de Paul, Paris, France, 4Southern California Liver Centers
and Southern California Research Center, Coronado, CA, United States, 5EMC Instytut Medyczny Spolka
Akcyjna, Wroclaw, Poland, 6AbbVie Inc., North Chicago, IL, United States
37
Substudy 1*
No Cirrhosis
Group 1 (GT4)
(n=44)
Group 2 (GT1b)
(n=42)
Group 3 (GT1b)
(n=40)
Group 4 (GT4)
(n=42)
Compensated
Cirrhosis
ABT-450/r + Ombitasvir
Treatment-Naïve
ABT-450/r + Ombitasvir
Null Responders
ABT-450/r + Ombitasvir + RBV
Treatment-Naïve
Group 5 (GT4)
ABT-450/r + Ombitasvir
Partial/Null Responders & Relapsers
Group 6 (GT4)
ABT-450/r + Ombitasvir + RBV
Partial/Null Responders & Relapsers
(n=49)
Substudy 2*
ABT-450/r + Ombitasvir
Treatment-Naïve
Group 7 (GT1b)
(n=47)
Group 8 (GT1b)
(n=52)
ABT-450/r + Ombitasvir
Treatment-Naïve
ABT-450/r + Ombitasvir
Partial/Null Responders & Relapsers
Baseline
Week 12
Week 24
*Planned number of patients: 40 per treatment arm
ABT-450/r (150/100 mg qd); ombitasvir (25 mg QD); RBV (weight-based 1000 or 1200 mg/day divided BID)
All patients followed through 48 weeks post-treatment
Hezode, C. et al. EASL 2014, Abstract #O58
38
100
97.7% 95.5%
97.6% 100%
100% 100%
RVR (Week 4)
93.2% 90.9%
EOTR (Week 12)
SVR4
80
Patients (%)
SVR12
60
40
20
43
44
0
42
44
41
44
40
44
ABT-450/r + Ombitasvir
(N=44)
41
42
42
42
42
42
42
42
ABT-450/r + Ombitasvir
+ RBV
(N=42)
Hezode, C. et al. EASL 2014, Abstract #O58
39
100%
100
100%
100%
RVR (Week 4)
EOTR (Week 12)
SVR4
Patients (%)
80
60
40
20
0
49/49
49/49
37/37
ABT-450/r + Ombitasvir + RBV
(N=49)
Hezode, C. et al. EASL 2014, Abstract #O58
40
• All-oral, IFN-free, 12-week regimens of
ABT-450/r + ombitasvir resulted in:
– High SVR12 rates in treatment-naïve HCV GT4infected patients
• 90.9% with ABT-450/r + ombitasvir
• 100% with ABT-450/r + ombitasvir + RBV
– An SVR4 rate of 100% in treatment-experienced
patients receiving ABT-450/r + ombitasvir + RBV
• 12-week regimens of ABT-450/r + ombitasvir +/-
RBV were generally well-tolerated, with no study
drug discontinuations or interruptions due to AEs,
and few decreases in hemoglobin <10 g/dL
Hezode, C. et al. EASL 2014, Abstract #O58
41
Safety and Efficacy of the All-oral Regimen of MK5172/MK-8742 + Ribavirin in Treatment-naïve, Noncirrhotic Patients With Hepatitis C Virus Genotype 1
Infection: The C-WORTHy Study
C. Hezode1, L. Serfaty2, J.M. Vierling3, M. Kugelmas4, B. Pearlman5, W. Sievert6, W. Ghesquiere7,
E. Zuckerman8, F. Sund9, M. Shaughnessy10, P. Hwang10, J. Wahl10, M.N. Robertson10, B. Haber10
1Department
of Hepatology-Gastroenterology, Henri Mondor Hospital, University of Paris-Est, Creteil,
and Hepatology, H_pital Saint Antoine, APHP and INSERM UMR_938, Universit_ Pierre
& Marie Curie, Paris, France, 3Hepatology, Baylor College of Medicine, Houston, TX, 4South Denver
Gastroenterology, PC, Englewood, CO, 5Center for Hepatitis C, Atlanta Medical Center, Atlanta, GA, United
States, 6Gastrointestinal and Liver Unit, Monash University, Clayton, VIC, Australia, 7Vancouver Island
Health Authority, Victoria, BC, Canada, 8Carmel Medical Center, Technion Faculty of Medicine, Haifa, Israel,
9Infectious Diseases, Uppsala University Hospital, Uppsala, Sweden, 10Merck, Whitehouse Station, NJ,
United States
2Gastroenterology
42
• To assess the efficacy/safety of an 8- to 12-week regimen of MK-5172 +
MK-8742 ± weight-based ribavirin in treatment-naïve, noncirrhotic
patients with HCV G1 infection
Treatment-naïve, noncirrhotic
12 weeks ± RBV
(n=65)
Treatment-naïve
Noncirrhotic
8-12 weeks ± RBV
(n=94)
Treatment-naïve
Cirrhotic
12-18 weeks ± RBV
(n=123)
Null responders
Cirrhotic/noncirrhotic
12-18 weeks ± RBV
(n=130)
HIV/HCV coinfected
Noncirrhotic
12 weeks ± RBV
(n=59)
• Key inclusion/exclusion criteria:
–
–
–
–
–
Treatment-naïve patients ≥ 18 years old with chronic HCV G1a or G1b infection
Liver biopsy or noninvasive test (METAVIR F0-F3)
Minimum baseline hemoglobin: 12 g/dL (females) or 13 g/dL (males)
HIV and hepatitis B virus negative
Alanine aminotransferase (ALT) as aspartate aminotransferase (AST) <350 IU/L
Hezode, C. et al. EASL 2014, Abstract #O10
43
Part B
Part A
RBV-Containing Regimen
G1a/b
N=25
MK-5172 (100 mg)
MK-8742 (20 mg)
+ RBV
G1a/b
n=27
MK-5172 (100 mg)
MK-8742 (50 mg)
+ RBV
G1b
n=13
MK-5172 (100 mg)
MK-8742 (50 mg)
G1a
n=30
MK-5172 (100 mg)
MK-8742 (50 mg)
+ RBV
G1a/b
n=33
MK-5172 (100 mg)
MK-8742 (50 mg)
+ RBV
RBV-Free Regimen
PART A
SVR24
(AASLD 2013)
at ≥SVR4
(28/30 SVR8)
PART B
Follow-up ongoing
SVR4/8
100% at SVR8
MK-5172 (100 mg)
MK-8742 (50 mg)
G1a
n=31
D1
TW4
TW8
TW12
SVR4
SVR8
SVR12
SVR24
Study Week
SVR, sustained virologic response; TW = treatment week.
Hezode, C. et al. EASL 2014, Abstract #O110
44
HCV RNA BLOQ (<25 IU/mL), % Patients
8 weeks with RBV
100
100
95
100
12 weeks with RBV
100
96
12 weeks (no RBV)
100
94
98
83
75
50
25
0
30/30
81/85
44/44
Treatment Week 4
30/30
82/85
44/44
End of Treatment
25/30
80/85
43/44
SVR 4-24
*Part A: 100% of patients have completed SVR24; Part B: 8-week arm, 93% of patients have completed SVR8;
12-week arms, 100% of patients have completed SVR8; 2 patients (Part A), 2 patients (Part B) discontinued early
(and are counted as failures).
Hezode, C. et al. EASL 2014, Abstract #O110
45
• Efficacy
– MK-5172/MK8742 once daily with or without RBV for 12 weeks is
highly efficacious with a SVR of 94%-98%
– MK-5172/MK-8742 + RBV for 8 weeks in patients with HCV G1a
infection had an SVR44/8 of 83%
– Most common type of virologic failure was relapse after a treatment
duration of 8 weeks
• Safety
– All treatment regimens were generally safe and well-tolerated
– There were no early discontinuations due to drug-related Aes
– No grade 3 or 4 laboratory abnormalities
Hezode, C. et al. EASL 2014, Abstract #O110
46
Efficacy and Safety of the All-Oral Regimen, MK-5172/MK8742 +/- RBV For 12 Weeks in GT1 HCV/HIV Co-Infected
Patients: The C-WORTHY Study
Mark Sulkowski1, Josep Mallolas2, Marc Bourliere3, Jan Gerstoft4, Oren Shibolet5, Ronald Nahass6,
Edwin DeJesus7, Melissa Shaughnessy8, Peggy Hwang8, Barbara Haber8
1Johns
Hopkins University School of Medicine, Baltimore, MD, USA; 2Hospital de Dia. Enfermedades
Infecciosas, Barcelona, Spain; 3Service d'hépato-gastroentérologie, Hôpital Saint-Joseph, Marseille, France;
4Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark; 5Liver Unit, Department of
Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel; 6ID Care, Hillsborough, NJ, USA; 7Orlando
Immunology Center, Orlando, Florida; 8Merck & Co., Inc., Whitehouse Station, NJ, USA.
47
• Globally, ~7 million patients are co-infected with HIV and HCV(1)
• HIV/HCV co-infected patients have a higher rate of progression to cirrhosis and hepatic
decompensation than HCV mono-infected patients(1-4)
• MK-5172 and MK-8742 can be dosed with raltegravir + dual NRTI (tenofovir or abacavir +
emtricitabine or lamivudine) without dosage adjustments
• MK-5172/MK-8742 has the potential to provide an all-oral, highly efficacious, simple, and
well-tolerated regimen
C-WORTHy: MK-5172/MK-8742 ± RBV in 471 HCV G1-infected patients
Treatment-naive, non-cirrhotic
12 weeks ± RBV
(n = 65)
Null responders
Treatment-naive
Treatment-naive
HIV/HCV co-infected
Cirrhotic / Non-cirrhotic
Non-cirrhotic
Cirrhotic
Non-cirrhotic
12-18 weeks ± RBV
8-12 weeks ± RBV 12-18 weeks ± RBV
12 weeks ± RBV
(n = 130)
(n = 94)
(n = 123)
(n = 59)
1. Sulkowski, et al., Clin Infect Dis. 30 (Suppl 1):S77, 2000; 2. Rockstroh JK, et al., Am J Gastroenterol. 91:2563, 1996;
3. DHHS Antiretroviral Guidelines; for Adults and Adolescents. February, 2013; 4. Naggie S, et al. Gastroenterology.
142:1324, 2012
Sulkowski, M. et al. EASL 2014, Abstract #O63
48
N = 29
MK-5172 +
MK-8742 + RBV
Follow-up
N = 30
MK-5172 +
MK-8742 (No RBV)
Follow-up
Primary
endpoint
D1
TW2
TW4
TW8
TW12 SVR4
SVR12
SVR24
MK-5172 (100 mg QD) + MK-8742 (50 mg QD); 12 weeks
Sulkowski, M. et al. EASL 2014, Abstract #O63
49
% HCV RNA <25 IU/mL
100
90
80
70
60
50
40
30
20
10
0
100 100
100
100
90
29
29
30
30
TW4
29
29
90
27
30
29
29
TW8
27
30
TW12
97
28
29
90
26
29*
MK-5172 +
MK-8742 +
RBV (n=29)
MK-5172 +
MK-8742
(No RBV;
n=30)
SVR4
Week
Virologic Failures: 1 relapse in +RBV arm;
2 breakthrough and 1 lost to follow up in No RBV arm
* One patient has not yet reached FU4
Sulkowski, M. et al. EASL 2014, Abstract #O63
50
Efficacy
• Treatment with MK-5172 + MK-8742 ± RBV for 12 weeks demonstrated high
efficacy (90-97% 4 weeks after end-of-treatment; SVR4)
• Three of 59 patients experienced virologic failure
– 1 relapse, 2 breakthrough
Safety
• MK-5172 + MK-8742 ± RBV was generally safe and well tolerated in coinfected patients
• The most common AEs in co-infected patients were headache and asthenia
• All co-infected patients had suppressed HIV and stable CD4 counts
• There were no early discontinuations due to drug-related adverse events
Overall
• Observed efficacy and safety in patients with HIV/HCV coinfection was similar
to other patient populations in C-WORTHy
Sulkowski, M. et al. EASL 2014, Abstract #O63
51