best of hcv from easl 2014
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Best of HCV from EASL 2014. Geoffrey Dusheiko , MD London, UK. This activity is supported by an independent medical education grant from AbbVie , Bristol-Myers Squibb and Gilead Sciences. Abstract #O109. - PowerPoint PPT PresentationTRANSCRIPT
1
Geoffrey Dusheiko, MDLondon, UK
Best of HCV from EASL 2014
This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead Sciences
2
Abstract #O109
All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With or Without Ribavirin for 12 or 24 Weeks in Treatment-Experienced 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
3
• 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
Wk 0 Wk 12 Wk 36Wk 24
LDV/SOF SVR12
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
SVR12
SVR12
SVR12
Afdhal, N. et al. EASL 2014, Abstract #O109
Study DesignGT 1 Treatment-Experienced (ION-2)
4
• Arms were balanced with respect to demographics and baseline characteristics
Results: DemographicsGT 1 Treatment-Experienced (ION-2)
Afdhal, N. et al. EASL 2014, Abstract #O109
12 Weeks 24 Weeks
LDV/SOFn=109
LDV/SOF+RBVn=111
LDV/SOFn=109
LDV/SOF+RBVn=111
Mean age, y (range) 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)
Hispanic, n (%) 7 (6) 12 (11) 11 (10) 11 (10)
Mean BMI, kg/m2 (range) 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)
Mean HCV RNA,log10 IU/mL (range) 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)
5
Results: SVR12GT 1 Treatment-Experienced (ION-2)
Error bars represent 95% confidence intervals.
Afdhal, N. et al. EASL 2014, Abstract #O109
0
20
40
60
80
10094 96 99 99
107/111
12 Weeks 24 Weeks
LDV/SOF + RBV
102/109 108/109
SV
R12
(%
)
110/111
LDV/SOF + RBVLDV/SOF LDV/SOF
6
Error bars represent 95% confidence intervals.Afdhal, N. et al. EASL 2014, Abstract #O109
SVR12: PEG/RBV vs PI + PEG/RBV Failures GT 1 Treatment-Experienced (ION-2)
0
20
40
60
80
100 93 96 100 9894 97 98 100
Failed PEG/RBV Failed Protease Inhibitor
SV
R12
(%
)
40/43 62/66 45/47 62/64 58/58 49/50 58/59 51/51
12 Weeks 24 Weeks
LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF
7
0
20
40
60
80
10095 100 99 9986 82
100 100
Absence of Cirrhosis Cirrhosis
SV
R12
(%
)
83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22
12 Weeks 24 Weeks
LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF
Error bars represent 95% confidence intervals.Afdhal, N. et al. EASL 2014, Abstract #O109
SVR12: Absence of Cirrhosis vs CirrhosisGT 1 Treatment-Experienced (ION-2)
8
Abstract #O56
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
9
1. Lawitz E, et al. Lancet. 2014;383:515-23.Kowdley, K. et al. EASL 2014, Abstract #O56
Background and AimsGT 1 Treatment-Naïve (ION-3)
• 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
10
• 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)
LDV/SOF
LDV/SOF
LDV/SOF + RBV
Wk 0 Wk 8 Wk 12 Wk 24Wk 20
SVR12
SVR12
SVR12
Kowdley, K. et al. EASL 2014, Abstract #O56
Study DesignGT 1 Treatment-Naïve (ION-3)
11
0
20
40
60
80
100
p=0.70 p=0.30
206/216
8 Weeks 12 Weeks
LDV/SOFLDV/SOF LDV/SOF + RBV
201/216202/215 206/216
SV
R12
(%
)p=0.52
Kowdley, K. et al. EASL 2014, Abstract #O56
Results: Non-Inferiority ComparisonGT 1 Treatment-Naïve (ION-3)
Error bars represent 95% confidence intervals.
12
Kowdley K, et al. NEJM In PressKowdley, K. et al. EASL 2014, Abstract #O56
ConclusionsGT 1 Treatment-Naïve (ION-3)
• LDV/SOF ± RBV for 8 or 12 weeks results in highSVR12 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
13
Abstract #O6
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
14
Wk 0 Wk 12 Wk 24
SVR12
LDV/SOF + RBV, n=26
LDV/SOF, n=25GT 3
Treatment naïve
Ra
nd
om
ize
d
ELECTRON-2: Study Design
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
LDV/SOF + RBV, n=19GT 1
Prior SOF exposure
GT 1CPT class B LDV/SOF, n=20
Gane, E. et al. EASL 2014, Abstract #O6
15
19/19
SV
R12
(%
)
Re-treatment
GS-9669 + SOF+RBV 12 wk
Treatment Naïve
SOF+RBV 12 wk Prior Null
Responders
n=6
n=4
n=8
n=1
LDV/SOF +RBV 6 wk
Treatment Naïve
SOF+RBV 12 wk Treatment Naïve
19/19
ELECTRON-2 Results:(1) Prior Sofosbuvir-Treated GT 1 Patients
• All 19 previous SOF-regimen failures had relapsed
Gane, E. et al. EASL 2014, Abstract #O6
16
SV
R12
(%
)13/20
GT 1CPT Class B
Median total bilirubin,mg/dL (range)
1.5 (0.7-3.7)
Median serum albumin,g/dL (range)
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)
84 (44-162)
7 relapsers
Gane, E. et al. EASL 2014, Abstract #O6
Error bar represents the 95% confidence interval.
ELECTRON-2 Results:(2) Patients With CPT B Cirrhosis
17
SV
R12
(%
)
16/25 26/26
100
64*
0
20
40
60
80
100
LDV/SOF + RBV 12 Weeks
26/2616/25
LDV/SOF 12 Weeks
*Failure due to relapse (n=8) or discontinuation due to AE (n=1)Gane, E. et al. EASL 2014, Abstract #O6
ELECTRON-2 Results:(3) Patients With HCV GT 3, Treatment Naïve
18Gane, E. et al. EASL 2014, Abstract #O6
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
ELECTRON-2 Conclusions
19
Abstract #O111
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
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Study Design
Everson, G. et al. EASL 2014, Abstract #O111
GT 1(N=55)
GT 3(N=54)
GT 2-6(N=45)
SOF + GS-5816 25 mg
SOF + GS-5816 100 mg
SOF + GS-5816 25 mg
SOF + GS-5816 100 mg
SOF + GS-5816 25 mg
SOF + GS-5816 100 mg
Wk 0 Wk 12 Wk 24
SVR12
• 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
21
Results: SVR12
Series10
20
40
60
80
100 96 91 93100 100 93
SOF + GS-5816 25 mg SOF + GS-5816 100 mg
SV
R12
(%
)
Everson, G. et al. EASL 2014, Abstract #O111
GT 1 GT 2 GT 3
26/27 28/28 10/11 10/10 25/27 25/27
22
Results: SVR12
Series10
20
40
60
80
100100 100 100
86
100
SOF + GS-5816 25 mg SOF + GS-5816 100 mg
SV
R12
(%
)
Everson, G. et al. EASL 2014, Abstract #O111
GT 4 GT 5 GT 6
7/7 6/7 10/10 4/4 5/51/1
23
Conclusions
• 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
24
Abstract #O60
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
25
• 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)
Week 0 Week 12 Week 24 Week 60 Week 72
3D + RBV(n=473)
Placebo(n=158) 3D + RBV
Double-BlindTreatment Period
Open-LabelTreatment Period
Primary Analysis: SVR12
48-WeekFollow-Up
48-WeekFollow-Up
Feld, J. et al. EASL 2014, Abstract #O60
SAPPHIRE-I: Placebo-Controlled Design (N=631)
26
SV
R12
, %
Pat
ien
ts
All Patients
96.2% 95.3% 98.0%
455/473 307/322 148/151
GT1a GT1b
Feld, J. et al. EASL 2014, Abstract #O60
SAPPHIRE-I Results: ITT SVR12 Rates (Superiority to Calculated Placebo Rate)
27
Event, n/N (%)3D + RBV(N=473)
SVR12 455/473 (96.2)
Non-SVR12 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
SAPPHIRE-I: Reasons for Non-SVR12
28
Abstract #O163
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
29
• 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)
Day 0 Week 24Week 12
SVR12
SVR12
3D + RBV(N=208)
3D + RBV(N=172)
All patients to be followed through 48 weeks post-treatment
Poordad, F. et al. EASL 2014, Abstract #O163
TURQUOISE-II Study Design: Phase 3 Trial Conducted Exclusively in GT1-Infected Cirrhotic Patients (N=380)
30
TURQUOISE-II Results: ITT SVR12 Rates of 92% to 96%
Poordad, F. et al. EASL 2014, Abstract #O163
0
20
40
60
80
100S
VR
12,
% P
atie
nts
12 Weeks3D + RBV
91.8
191/208
95.9
165/172
24 Weeks3D + RBV
P=0.089
31
0
20
40
60
80
10092.2
12-week arm
24-week arm
92.9
Naïve Prior RelapseResponse
3D + RBV
SV
R12
, %
Pat
ien
ts
59/64 14/1552/56 13/13
93.3 100 100 100 80.0 92.9
11/11 40/5010/10 39/42
Prior PartialResponse
Prior NullResponse
HCV Subtype 1aPoordad, F. et al. EASL 2014, Abstract #O163
TURQUOISE-II Results: ITT SVR12 Rates by Prior Treatment Response in HCV Subtype 1a
32
Abstract #O114
Results Of The Phase 2 Study M12-999:Interferon-Free Regimen Of ABT-450/r/ABT-267+ABT-
333+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
33
• 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
Day 0 Week 24
SVR12
To Week 72
3D + RBV(N=34)
Kwo, P. et al. EASL 2014, Abstract #O114
Study M12-999: Design
34Kwo, P. et al. EASL 2014, Abstract #O114
Calcineurin Inhibitor (CNI) Dosing With 3D Regimen • 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
35
Study M12-999: Preliminary Efficacy Results
• 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
0
20
40
60
80
100
% P
atie
nts
100%
34/34
97.0%
34/34
100% 96.2%
32/33 25/26
SVR4 SVR12RVR(Week 4)
EOTR(Week 24)
36
• 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
Study M12-999: Conclusions
Kwo, P. et al. EASL 2014, Abstract #O114
37
Abstract #O58
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
38
PEARL-I: Study DesignSubstudy 1*No Cirrhosis
Substudy 2*CompensatedCirrhosis
*Planned number of patients: 40 per treatment armABT-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
Group 1 (GT4)(n=44)
Group 2 (GT1b)(n=42)
Group 3 (GT1b)(n=40)
Group 4 (GT4)(n=42)
Group 5 (GT4)
Group 6 (GT4)(n=49)
Baseline Week 12 Week 24
ABT-450/r + OmbitasvirTreatment-Naïve
ABT-450/r + OmbitasvirNull Responders
ABT-450/r + Ombitasvir + RBVTreatment-Naïve
ABT-450/r + OmbitasvirPartial/Null Responders & Relapsers
ABT-450/r + Ombitasvir + RBVPartial/Null Responders & Relapsers
Group 7 (GT1b)(n=47)
Group 8 (GT1b)(n=52)
ABT-450/r + OmbitasvirTreatment-Naïve
ABT-450/r + OmbitasvirPartial/Null Responders & Relapsers
ABT-450/r + OmbitasvirTreatment-Naïve
Hezode, C. et al. EASL 2014, Abstract #O58
39
0
20
40
60
80
10097.7%
Pat
ien
ts (
%)
ABT-450/r + Ombitasvir(N=44)
ABT-450/r + Ombitasvir+ RBV(N=42)
SVR4
SVR12
RVR (Week 4)
EOTR (Week 12)
95.5%93.2% 90.9%
97.6% 100% 100% 100%
4344
4244
4144
4044
4142
4242
4242
4242
PEARL-I GT4-Infected Treatment-Naïve Patients: ITT Efficacy Analysis
Hezode, C. et al. EASL 2014, Abstract #O58
40
0
20
40
60
80
100
Pat
ien
ts (
%)
ABT-450/r + Ombitasvir + RBV(N=49)
100% 100% 100%
49/49 49/49 37/37
SVR4
RVR (Week 4)
EOTR (Week 12)
PEARL-I GT4-Infected Treatment-Experienced Patients: ITT Efficacy Analysis
Hezode, C. et al. EASL 2014, Abstract #O58
41
PEARL-I GT4-Infected Patients:Conclusions
• All-oral, IFN-free, 12-week regimens of ABT-450/r + ombitasvir resulted in:– High SVR12 rates in treatment-naïve HCV GT4-
infected 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
42
Abstract #O10
Safety and Efficacy of the All-oral Regimen of MK-5172/MK-8742 + Ribavirin in Treatment-naïve, Non-cirrhotic 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, 2Gastroenterology 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
43
Aim: C-WORTHy TN
Hezode, C. et al. EASL 2014, Abstract #O10
• 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
• 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
Treatment-naïve, noncirrhotic 12 weeks ± RBV
(n=65)
Treatment-naïve Noncirrhotic
8-12 weeks ± RBV(n=94)
Treatment-naïveCirrhotic
12-18 weeks ± RBV(n=123)
Null respondersCirrhotic/noncirrhotic
12-18 weeks ± RBV(n=130)
HIV/HCV coinfected Noncirrhotic
12 weeks ± RBV(n=59)
44
Study Design
SVR, sustained virologic response; TW = treatment week.Hezode, C. et al. EASL 2014, Abstract #O110
RBV-Containing Regimen RBV-Free Regimen
MK-5172 (100 mg)MK-8742 (20 mg)+ RBV
MK-5172 (100 mg)MK-8742 (50 mg)+ RBV
MK-5172 (100 mg)MK-8742 (50 mg)+ RBV
MK-5172 (100 mg)MK-8742 (50 mg)
MK-5172 (100 mg)MK-8742 (50 mg)
MK-5172 (100 mg)MK-8742 (50 mg)+ RBV
PART ASVR24
(AASLD 2013)
PART BFollow-up ongoing
SVR4/8
at ≥SVR4(28/30 SVR8)
100% at SVR8
Study Week
Pa
rt A
Pa
rt B
G1a/bN=25
G1a/bn=27
G1bn=13
G1an=30
G1a/bn=33
G1an=31
D1 TW4 TW8 TW12 SVR4 SVR8 SVR12 SVR24
45
C-WORTHy (A+B) – Overall Efficacy (SVR4-24)*Intention-to-Treat (Nonvirologic Discontinuation = Failure)
Treatment Week 4 End of Treatment SVR0
25
50
75
100100 100
83
95 96 94100 100 98
8 weeks with RBV 12 weeks with RBV 12 weeks (no RBV)
HC
V R
NA
BL
OQ
(<
25
IU
/mL
), %
Pa
tie
nts
*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
4-24
30/30 81/85 44/44 30/30 82/85 44/44 25/30 80/85 43/44
46
Summary
• 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
47
Abstract #O63
Efficacy and Safety of the All-Oral Regimen, MK-5172/MK-8742 +/- 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.
48
• 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-cirrhotic12 weeks ± RBV
(n = 65)
Treatment-naive Non-cirrhotic
8-12 weeks ± RBV(n = 94)
Treatment-naive Cirrhotic
12-18 weeks ± RBV(n = 123)
HIV/HCV co-infectedNon-cirrhotic
12 weeks ± RBV(n = 59)
Null responders Cirrhotic / Non-cirrhotic
12-18 weeks ± RBV(n = 130)
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, 2012Sulkowski, M. et al. EASL 2014, Abstract #O63
Background
49
MK-5172 + MK-8742 + RBV
MK-5172 + MK-8742 (No RBV)
N = 29
N = 30
Follow-up
Follow-up
D1 TW12 SVR12TW4TW2 TW8 SVR24SVR4
Primary endpoint
MK-5172 (100 mg QD) + MK-8742 (50 mg QD); 12 weeks
Sulkowski, M. et al. EASL 2014, Abstract #O63
Study DesignHIV/HCV Co-infected Non-cirrhotic Patients
50
TW4 TW8 TW12 SVR40
102030405060708090
100100 100 100 97100
90 90 90
MK-5172 + MK-8742 + RBV (n=29)
MK-5172 + MK-8742 (No RBV; n=30)
Week
% H
CV
RN
A <
25 I
U/m
L
2929
28 29
2929
2929
3030
2629*
2730
2730
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
Virologic Responses ITT Population
51
Summary
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 co-
infected 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